Recent Advances in Otolaryngology

Recent Advances in OTOLARYNGOLOGY Head and Neck Surgery

Recent Advances in OTOLARYNGOLOGY Head and Neck Surgery Vol. 3 Editors

Anil K Lalwani MD Professor and Vice-Chair for Research Director, Division of Otology, Neurotology and Skull Base Surgery Director, Columbia Cochlear Implant Center Columbia University College of Physicians and Surgeons New York, NY, USA

Markus HF Pfister MD MBA Associate Professor of Otolaryngology & Head and Neck Surgery Affiliated with Klinik St Anna, Lucerne, Hirslanden Group HNO Sarnen, Switzerland Kantonsspital Obwalden Swissana Clinic, Meggen, Switzerland

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Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2014, Jaypee Brothers Medical Publishers The views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. This book is designed to provide accurate, authoritative information about the subject matter in question. However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contraindications. It is the responsibility of the practitioner to take all appropriate safety precautions. Neither the publisher nor the author(s)/ editor(s) assume any liability for any injury and/or damage to persons or property arising from or related to use of material in this book. This book is sold on the understanding that the publisher is not engaged in providing professional medical services. If such advice or services are required, the services of a competent medical professional should be sought. Every effort has been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material. If any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the first opportunity. Inquiries for bulk sales may be solicited at: [email protected] Recent Advances in Otolaryngology—Head and Neck Surgery First Edition: 2014 ISBN 978-93-5152-145-7 Printed at:

Dedicated to My parents, Madan and Gulab Lalwani; my in-laws, Rikhab and Ratan Bhansali; my children; Nikita and Sahil; and, most specially to my wife, Renu Bhansali Lalwani, a wonderful partner, friend, mother, community activist, and the smartest internist I know! This book is also dedicated to Bruce A Rosenfield and the Zausmer Foundation for their commitment to supporting research in Otolaryngology that make advances possible – the focus of this book. Anil K Lalwani My parents—Ingeborg and Hermann Pfister; my uncle and aunt—Alfred and Isolde Demmler and most specially to my beloved Doris, a wonderful partner and my center of inspiration. Markus HF Pfister

International Editorial Board

Head and Neck William I Wei MD Hong Kong, China Patrick J Gullane MD Toronto, Canada Anil K D’Cruz MD Mumbai, India Ashok Shaha MD New York, USA

Facial Plastics and Reconstructive Surgery Fazil Apadyin MD Izmir, Turkey Pietro Palma MD Milan, Italy Peter Lohuis MD Amsterdam, Netherlands Holger G Gassner MD Regensburg, Germany Abel-Jan Tasman MD St Gallen, Switzerland

Pediatric Otolaryngology Marci Lesperance MD Ann Arbor, USA Anne Pitkaranta MD Helsinki, Finland Thomas P Nikolopoulos MD Athens, Greece Sanjay Parikh MD Seattle, USA

Masafumi Sakagami MD Nishinomiya, Hyogo, Japan Chong Sun Kim MD Seoul, South Korea Ramesh C Deka MD New Delhi, India Maurizio Barbara MD Rome, Italy Jussi Jero MD Helsinki, Finland Abdulrahman Hagr MD Riyadh, Saudi Arabia

Rhinology Manuel Bernal-Sprekelsen MD Barcelona, Spain Paolo Castelnuovo MD Varese, Italy Antje Welge-Luessen MD Basel, Switzerland Tim Smith MD Portland, USA T Metin Onerci MD Ankara, Turkey

Laryngology Albert L Merati MD Seattle, USA Mark Courey MD San Francisco, USA

Otology & Neurotology

Robert H Ossoff MD Nashville, USA

Robert Vincent Béziers, France

Sibylle Brosch MD Ulm, Germany

Contributors

Francine Blei MD MBA

Robin T Cotton MD

Medical Director Vascular Birthmark Institute of New York Roosevelt Hospital New York, NY, USA Department of Otolaryngology at UKB Hospital of the University of Berlin Berlin, Germany

Professor Department of Otolaryngology— Head and Neck Surgery University of Cincinnati College of Medicine Division of Pediatric Otolaryngology— Head and Neck Surgery Cincinnati Children’s Hospital Medical Center, Burnet Avenue Cincinnati, Ohio, USA

Ingo Baumann MD

Hardik K Doshi MD

Dietmar Basta PhD

Medical Doctor Professor of Otorhinolaryngology Department of Otolaryngology University of Heidelberg Heidelberg, Germany

Divya Chari BS Columbia University College of Physicians and Surgeons Fort Washington Avenue Harkness Pavilion New York, NY, USA

Edgar Mauricio López-Chacón MD Department of Otolaryngology— Head and Neck Surgery Hospital Clinic Villarroel, Barcelona, Spain

Maura K Cosetti MD

Department of Otorhinolaryngology New York -Presbyterian Hospital/ Columbia & Weill Cornell Otolaryngology/Head and Neck Surgery Washington Avenue, USA

Arnaud Devèze MD PhD Associate Professor University Hospital Nord, Marseille, France

Timothy R DeKlotz MD Clinical Instructor Department of Otolaryngology University of Pittsburgh School of Medicine Fellow, Center for Cranial Base Surgery University of Pittsburgh Medical Center The Eye & Ear Institute, Suite Pittsburgh, Pennsylvania, USA

Marchioni Daniele MD

Assistant Professor Louisiana State University Health Sciences Center Shreveport, Louisiana, USA

Policlinico di Modena ENT Department University of Modena Modena, Italy

Aliza P Cohen MA

Arne Ernst MD PhD

Medical Writer Department of Otolaryngology— Head and Neck Surgery University of Cincinnati College of Medicine Division of Pediatric Otolaryngology— Head and Neck Surgery Cincinnati Children’s Hospital Medical Center Burnet Avenue Cincinnati, Ohio, USA

Associate Professor Department of Otolaryngology at UKB Hospital of the University of Berlin Berlin, Germany

Albrecht Eiber PhD Institute of Engineering and Computational Mechanics University of Stuttgart Pfaffenwaldring, Stuttgart, Germany

viii Recent Advances in Otolaryngology—Head and Neck Surgery David E Eibling MD FACS

Karen M Kost MD FRCS(C)

Professor of Otolaryngology–HNS University of Pittsburgh School of Medicine Surgical Service, VA Pittsburgh University Drive Pittsburgh, Pennsylvania, USA

Associate Professor of Otolaryngology— Head and Neck Surgery McGill University, Montreal Director of the Voice and Dysphagia Center McGill University Montreal, Quebec, Canada

John C Flickinger MD Professor, Radiation Oncology University of Pittsburg Pennsylvania, USA

Ascanio Guarini Swarthmore College College Avenue Swarthmore Pennsylvania, USA

Nicolas Gürtler MD Department of Otorhinolaryngology University Hospital Basel Petersgraben, Basel, Switzerland

Jennifer R Grandis MD Vice-Chair for Research UPMC Endowed Chair in Head and Neck Cancer Surgical Research Department of Otolaryngology Assistant Vice Chancellor for Research Program Integation in the Health Sciences Distinguished Professor of Otolaryngology & Pharmacology University of Pittsburgh School of Medicine Program Leader, Head & Neck Cancer Program University of Pittsburgh Cancer Institute American Cancer Society Clinical Research Professor University of Pittsburgh Eye and Ear Institute, Suite Pittsburgh, Pennsylvania, USA

Catherine K Hart MD Assistant Professor Department of Otolaryngology— Head and Neck Surgery University of Cincinnati College of Medicine Division of Pediatric Otolaryngology— Head and Neck Surgery Cincinnati Children’s Hospital Medical Center, Burnet Avenue Cincinnati, Ohio, USA

Hideyuki Kano Research Assistant Professor of Neurological Surgery, University of Pittsburgh UPMC-Presbyterian, Lothrop Street UPMC Presbyterian Pittsburgh Pennsylvania, USA

Anil K Lalwani MD Professor and Vice-Chair for Research Director, Division of Otology, Neurotology and Skull Base Surgery Director, Columbia Cochlear Implant Center Columbia University College of Physicians and Surgeons New York, NY, USA

Rainer Laskawi MD Professor of Otorhinolaryngology ENT Department, Medical School University of Göttingen Niedersachsen, Germany

L Dade Lunsford MD FACS Professor of Neurological Surgery Distinguished Professor University of Pittsburgh Pennsylvania, USA

Stefan Mlot MD Columbia University Medical Center/ New York-Presbyterian Hospital New York, NY, USA

Edward Monaco III MD PhD Assistant Professor of Neurological Surgery University of Pittsburgh UPMC-Presbyterian, Lothrop Street UPMC Presbyterian Pittsburgh Pennsylvania, USA

Ajay Niranjan MD MBA Associate Professor of Neurosurgery University of Pittsburgh Director, UPMC Brain Mapping Center Director of Radiosurgery Research Center of Image-Guided Neurosurgery Pennsylvania, USA

Laura Oleaga PhD MD Medical Director Radiologist, Department of Radiology Hospital Clinic Villarroel, Barcelona, Spain

Contributors ix Markus HF Pfister MD MBA

Peter A Tass MD PhD

Associate Professor of Otolaryngology & Head and Neck Surgery Affiliated with Klinik St Anna, Lucerne Hirslanden Group HNO Sarnen, Switzerland Kantonsspital Obwalden Swissana Clinic, Meggen, Switzerland

Director, Institute of Neuroscience and Medicine (INM-7) Neuromodulation Research Center Jülich, Germany Department of Neuromodulation University of Cologne, Cologne, Germany Clinic for Stereotactic and Functional Neurosurgery University of Cologne, Cologne, Germany

Livio Presutti MD Director of ENT Department Policlinico di Modena University Hospital, Modena, Italy

Saskia Rohrbach MD Registrar, Doctor for ENT and Phoniatrics and Pedaudiology Department of Phoniatrics and Pedaudiology, Augustenburger Platz 1 Berlin, Germany

Benno Röthlisberger Cantonal Hospital Aarau Center of Laboratory Medicine Aarau, Switzerland

Rahmatullah Rahmati MD Assistant Professor of Otolaryngology— Head and Neck Surgery Columbia University Medical Center Washington Avenue, New York, NY, USA

Manuel Bernal-Sprekelsen PhD MD Department of Otolaryngology— Head and Neck Surgery Hospital Clinic, Barcelona, Spain

Carl H Snyderman MD MBA Professor, Departments of Otolaryngology and Neurological Surgery University of Pittsburgh School of Medicine Co-Director, Center for Cranial Base Surgery University of Pittsburgh Medical Center The Eye & Ear Institute, Suite Pittsburgh, Pennsylvania, USA

Timea Tóth MD PhD Institute of Neuroscience and Medicine Neuromodulation Research Center Jülich, Germany

Muaaz Tarabichi MD American Hospital Dubai Dubai, UAE

Jan Hendrik Wagner MD Department Otolaryngology at UKB Hospital of the University of Berlin Berlin, Germany

Eric W Wang MD Assistant Professor Department of Otolaryngology University of Pittsburgh School of Medicine Center for Cranial Base Surgery University of Pittsburgh Medical Center The Eye & Ear Institute, Suite Pittsburgh, Pennsylvania, USA

Xiao Xiao MD New York Medical College School of Medicine Old Farm Road Valhalla, New York, USA

Contributors xi

Preface

Otolaryngology—Head and Neck Surgery is a dynamic medical and surgical specialty characterized by rapid advances in its scientific foundation and of its therapeutic armamentarium. Simultaneously, there are novel technical and technological innovations that positively impact on patient care. Consequently, Otolaryngology is constantly evolving as new knowledge comes forth and new technologies become available. Recent examples of advances in Otolaryngology include the use of robotics in treatment of sleep apnea, image guidance in sinus surgery, endoscopic repair of CSF leaks, personalized therapy for head and neck cancer, and endoscopic ear surgery, among others. The challenge for the busy clinician in the 21st century is to remain abreast of these ever-expanding body of knowledge, surgical techniques, diagnostic test, imaging technology, and prosthetics, while deeply immersed in their clinical practice. Ironically, this has become even more difficult with the explosion of technologies designed to put information at one’s fingertips. This annual periodical, Recent Advances in Otolaryngology—Head and Neck Surgery, covering all the subspecialties of Otolaryngology, is designed to make it easy for the clinician to keep current with what is new. Due to its rapid publication cycle, the material is current, topical, and immediately relevant to the clinician. Reviews emphasize clear artwork rendered in color to convey new concepts and surgical approaches. We have assembled an outstanding international editorial board to assist us in this exciting project. Similarly, invited authors are leaders in the field and have made seminal contributions in their topics. We hope that you will enjoy reading this 3rd Volume as much as we have enjoyed assembling it. Anil K Lalwani Markus HF Pfister

Contributors xiii

Acknowledgments

We would like to thank Ms Chetna Malhotra Vohra (Senior Manager–Business Development) and Sheetal Arora (Development Editor) of M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India, for their assistance with the 3rd volume of Recent Advances in Otolaryngology—Head and Neck Surgery.

Contents 1. Transoral Robotic Surgery for Obstructive Sleep Apnea

1

Hardik K Doshi, Rahmatullah Rahmati

Transoral Robotic Surgery Background and Technique 1 Transoral Robotic Sleep Surgery Literature Review 2

2. Image Guidance in Sinus Surgery

9

Laura Oleaga, Manuel Bernal-Sprekelsen

Computed Tomography 9 Magnetic Resonance Imaging 19

3. Endoscopic Repair of Cerebrospinal Fluid Leaks

23

Timothy R DeKlotz, Eric W Wang, Carl H Snyderman

Types of CSF Leaks 23 Epidemiology 25 Preoperative Assessment and Considerations 26 Adjunctive Measures 29 Methods of Repair 32 Outcomes 39 Complications 39

4. Measuring Quality of Life in Nasal Surgery

44

Ingo Baumann

Quality of Life—Basics and Definitions 44 Quality of Life in Patients with Chronic Rhinosinusitis 45 Quality of Life after Septoplasty 50 Quality of Life after Rhinoplasty 52

5. Personalized Therapy in Head and Neck Cancer

61

Xiao Xiao, Jennifer R Grandis

EGFR Pathway 62 JAK-STAT Pathway 68 PI3K Pathway 69

6. Vascular Anomalies—Advances and Updates for the Otolaryngologist Francine Blei, Ascanio Guarini

How to Distinguish a Hemangioma from a Vascular Malformation? 75 Treatment of Hemangiomas 85 Vascular Malformations 85 Clinical Pearls to Distinguish Vascular Malformations 88 Genetics and Vascular Malformations 88

74

xvi Recent Advances in Otolaryngology—Head and Neck Surgery 7. Open Procedures for Airway Obstruction

102

Catherine K Hart, Aliza P Cohen, Robin T Cotton

Historical Overview 102 Preoperative Assessment 102 Preoperative Decision Making 103 Expansion Surgery 105 Resection Surgery 108

8. Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea 114 Stefan Mlot, Rahmatullah Rahmati

Physiology of the Upper Airway in OSA 114 Measures of Respiratory Status Used in the Analysis of Patients with Obstructive Sleep Apnea 116 The Current State of Hypoglossal Nerve Stimulation 117 Future Directions 123

9. Cochlear Implants: An Update

125

Divya Chari, Maura K Cosetti, Anil K Lalwani

Updates in Cochlear Implant Technology: Hardware and Software 126 Developments in Device Design 128 Updates in CI Candidacy and Assessment of Efficacy 134

10. Implantable Hearing Aids

149

Arnaud Devèze

What are the Drawbacks of Conventional Hearing Aids that AMEI should Overcome? 151 Active Middle Ear Implants 153 Bone Conduction Implants 154 The Different Types of Currently Available Implants and their Characteristics 156 The Middle Ear Transducer (MET; Previously Otologics LLC, Boulder, CO, USA, and Now Cochlear, Australia) 159 The Ideal AMEI: Discussion on Limitations and Challenge to Improve the Output and Use of Implantable Auditory Prostheses 170 What are the Main Indications of AMEI Nowadays? 177 What is the Preoperative Selection Workup? 177

11. Endoscopic Ear Surgery Muaaz Tarabichi, Marchioni Daniele, Livio Presutti

History 187 Instrumentation 188 Discussion 188 Basic Techniques and Management Algorithm 199 Transcanal Transpromontorial Exclusive Endoscopic Approach 215 Transvestibular Approach 222 Transcochlear Approach 225

187

Contents xvii

12. Some Mechanical Aspects of Implant Coupling

234

Albrecht Eiber, Markus HF Pfister

Mechanics of Middle Ear 234 Implants 236 Mechanical Coupling of Implants to Natural Structures 240 Clinical Aspects 249 Preload 249

13. Stereotactic Radiosurgery for Acoustic Neuroma

257

Ajay Niranjan, Edward Monaco III, Hideyuki Kano, John C Flickinger, L Dade Lunsford

Gamma Knife Radiosurgery Technique for Acoustic Neuromas 258 Radiosurgery: Clinical Results 260

14. Vestibular Rehabilitation

271

Jan Hendrik Wagner, Dietmar Basta, Arne Ernst

Mechanisms of Compensation of a Vestibular Loss 271 Mobile Posturography 274 Vestibular Rehab (Training) Programs 274 Surgical Treatment of Vestibular Disorders 276 Disorders of the Semicircular Canals 277 Further Otological Disorders with Vertigo 278

15. Tinnitus T herapy

281

Timea Tóth, Markus HF Pfister, Peter A Tass

History of Tinnitus Medicine 281 Treatments of Tinnitus 283 Pharmacological Treatment 283 Treatment of Chronic Tinnitus 286 Hyperbaric Oxygen Therapy 288 Sound Therapy (Hearing Devices) 289 Tinnitus Retraining Therapy 291 Cognitive Behavior Therapy 293 Biofeedback and Neurofeedback 294 Magnetic and Electrical Brain Stimulation 297 Acoustic Coordinated Reset (CR) Neuromodulation 301 Music Therapy 304

16. Geriatric Otolaryngology—An Emerging Subspecialty Karen M Kost, David E Eibling

General Concepts in Geriatrics 314 Geriatric Otolaryngology 317 Dysphonia in the Elderly 318 Dysphagia in the Elderly 320 Presbycusis 324 Balance in the Elderly 326

313

xviii Recent Advances in Otolaryngology—Head and Neck Surgery 17. Genetics in Otolaryngology

332

Nicolas Gürtler, Benno Röthlisberger

Hereditary Hearing Impairment 333 Oncology 341 Miscellaneous 345

18. Botulinum Toxin in Otorhinolaryngology

350

Saskia Rohrbach, Rainer Laskawi

How Botulinum Toxin Acts 350 Well-Established BTX Indications 351 More Recent and Rare Indications 354 More Recent Salivary Gland Applications 358

19. Computer-assisted Surgery of the Paranasal Sinuses and Skull Base

371

Edgar Mauricio López-Chacón, Manuel Bernal-Sprekelsen

Technical Characteristics 371 Accuracy of CAS 376 Indications for CAS 377 Advantages and Disadvantages 378 Special Features 379

Index 383

Chapter Transoral Robotic Surgery for Obstructive Sleep Apnea

1

Hardik K Doshi, Rahmatullah Rahmati

Introduction Obstructive sleep apnea (OSA) is characterized by repetitive airway collapse resulting in oxygen desaturation and sleep interruption. OSA is associated with cardiopulmonary morbidity and mortality, neurocognitive impairment, and reduced quality of life. Positive airway pressure (PAP) remains the gold standard treatment for moderate-to-severe OSA.1 In patients who are not compliant or tolerant of PAP, a variety of surgical interventions exist. Surgical options for OSA aim to increase or stabilize the size of the airway via repositioning or removing the bony and/or soft tissue architecture at various subsites most prone to collapse during respiration.2 Evidence supports the role for multilevel surgery to address these areas of collapse along the upper aerodigestive tract.1 With the innovation of various medical devices, an increasing number of interventions have become available in the field of sleep surgery. Most notably, the da Vinci surgical robot by Intuitive Surgical, which was FDA approved for use in the extirpation of head and neck neoplasms, has been investigated for its potential application in treating OSA. This chapter will review the literature describing the feasibility and outcomes of transoral robotic surgery (TORS) for OSA.

Transoral robotic surgery— background and technique First established as an efficacious method of resecting oropharyngeal cancers, the application of the surgical robot in the management of OSA has been investigated more recently.2–4 With the tongue base recognized as a major site of obstruction in OSA, various procedures such as genioglossus advancement, partial midline glossectomy, hyoid myotomy, and Repose stay sutures currently exist to address the region.5 However, these surgeries are potentially limited by the need for external incisions, inadequate exposure, nonarticulated instrumentation, and overall technical difficulty. In an effort

2 Recent Advances in Otolaryngology—Head and Neck Surgery to add to the surgical armamentarium for managing OSA, Vicini et al. in 2010 investigated the tolerability and effectiveness of transoral robotic tongue base resection.4 Through the use of the EndoWrist articulated instruments and threedimensional high-definition cameras (0o and 30o), TORS offers an additional level of precision to excise the soft tissue of the upper aerodigestive tract that would otherwise require a complex open approach. As with any surgery, patients should be carefully selected for transoral robotic surgical intervention. For access purposes, any anatomical limitations such as retrognathia, micrognathia, trismus, or the inability to hyperextend the neck should be examined. Candidates for TORS ideally have primary obstruction at the tongue base, though interventions at the supraglottis and soft palate via the robot have also been described.6–9 Though it is safest to limit the tissue resection to the superficial layer of lingual lymphoid tissue, most tongue base cases require dissection into the tongue base musculature. Deeper dissection and the absence of dependable landmarks can lead to exposure of the lingual artery and its dorsal branches and injury to the hypoglossal and lingual nerves.7 Thus, familiarity with the anatomy of the underlying neurovascular bundle is paramount. Based on cadaveric and angiographic studies, the distance between the foramen cecum and hypoglossal/lingual neurovascular bundle is approximately 1.7 cm. Therefore, tongue base resection performed within approximately 1.5 cm of the foramen cecum is reported to be safe.10 Any additional tissue removal would require vigilance under sufficiently high magnification. Alternatively, some surgeons have used Doppler ultrasound to directly trace the path of bilateral lingual arteries to provide anatomical boundaries for resection.9 Various techniques for tongue base resection have been described in the literature. Resection is generally performed in a piecemeal or en bloc fashion. Preoperative sleep endoscopy may be used to delineate the lateral extent of resection.2,5 Vicini et al. utilize a piecemeal resection starting in the midline and then carefully extending the resection laterally.4 Friedman et al. describe removing a triangular wedge of the tongue base musculature after parallel cuts are made in the circumvallate papillae/foramen cecum region of the tongue base.9 Lee et al. performed a piecemeal lingual tonsillectomy and only a small amount of the underlying musculature.5 Figure 1.1 illustrates before and after changes to base of tongue region after robotic resection for hypertrophic lingual tonsils.

Transoral robotic sleep surgery literature review The first article to report on the use of transoral robotic tongue base resection in OSA was published by Vicini et al. in 2010. This retrospective study followed 10 patients for a minimum of 3 months who demonstrated an

Transoral Robotic Surgery for Obstructive Sleep Apnea 3

Fig. 1.1: Schematic of narrowed retrolingual space due to lingual tonsil hypertrophy before and after robotic resection.

Epworth sleepiness scale (ESS) score > 11, apnea–hypopnea index (AHI) > 20, nonacceptance or dropout from continuous PAP use, and clinical tongue base hypertrophy with adequate tongue base exposure. All patients prior to intervention underwent a tracheostomy procedure; however, no serious airway or bleeding complications were reported. Furthermore, no cases required an open conversion or need for revision surgery to address the tongue base. The blood loss and operating time were equal to or less than an open or endoscopic laser resection, while the TORS procedure allowed for multiplanar visualization of the tissue. All patients were decannulated between the 5th or 13th day and all patients had satisfactory swallowing after 2 weeks resulting in no significant reduction in postoperative BMI scores. Measuring preoperative and postoperative indices, AHI and ESS scores reached statistically significant changes (Table 1.1). Vicini et al. followed the preliminary paper with a follow-up the subsequent year with 10 additional (20 total) patients along with anatomic analysis of the tongue base in 3 cadaveric heads. A similar inclusion criterion was utilized; however, patients were followed out for a minimum time of

4 Recent Advances in Otolaryngology—Head and Neck Surgery 10 months. In order to better differentiate between subjective improvement in OSA symptoms and objective improvement, patients were deemed surgically cured if posttreatment AHI and ESS scores were < 10. In turn, 70% of the cohort was found to be cured based on their AHI, and 90% based on their ESS. Overall, 60% (12/20) were found to be cured of both. Additionally, it was found that setting up and operating time improved with experience. Once again, measuring preoperative and postoperative indices including AHI, ESS, and additionally lowest oxygen saturation, these levels reached statistically significant improvement (Table 1.1). In an effort to address other subsites problematic in OSA, Vicini et al. used a cadaver model to develop a technique of geniohyoidpexy to complete the basic TOR tongue base with supraglottoplasty surgery to improve outcomes to match those described by Chabolle et al. where a hyoid epiglottoplasty is

Table 1.1: Literature comparison AHI

ESS

Lowest O2 saturation

Complications Minor requiring OR complications intervention

Vicini et al (2010) Preoperative

38.3 ± 23.5 12.4 ± 3.5

Postoperative 20.6 ± 17.3 6.9 ± 2.8

0/10

Minor bleeding (30%), severe pharyngeal edema (10%)

0/20

Minor bleeding (15%), severe pharyngeal edema (5%), subcutaneous emphysema (10%)

0/27

Dysphagia (# of patients not reported)

Vicini et al (2010) Preoperative

36.3 ± 21.1 12.6 ± 4.4 77.7 ± 9.7

Postoperative 16.4 ± 15.2 7.7 ± 3.3

81.9 ± 7.3

Friedman et al. Preoperative (Robot)

54.6 ± 21.8 14.4 ± 4.5 78.5 ± 7.4

Postoperative 18.6 ± 9.1 (Robot) Preoperative (Smile)

53.7± 29.3

5.4 ± 3.1

86.5 ± 6.3

14.8 ± 4.0 79.7 ± 11.9 Contd...

Transoral Robotic Surgery for Obstructive Sleep Apnea 5 Contd... AHI

ESS

Postoperative 26.6 ± 23.9 6.7 ± 4.7 (Smile) Preoperative (RFBOT)

Lowest O2 Complications Minor saturation requiring OR complications intervention 84.8 ± 9.0

0/22


0/24


1*/24 (4.2%)

Transient dysphagia (20.85%), transient dysgeusia (12.5%), transient globus (8.3%)

54.7 ± 26.6 16.6 ± 2.8 80.8 ± 7.8

Postoperative 34.6 ± 22.5 10.8 ± 3.5 84.3 ± 7.5 (RFBOT) Lee et al. Preoperative

55.6 ± 26.0 13.4 ± 6.1 75.8 ± 9.6

Postoperative 24.1 ± 19.6 5.9 ± 4.7

81.7 ± 8.2

Lin et al. Preoperative

43.9 ± 41.1 13.7 ± 5.2 83.3 ± 5.5

Postoperative 17.6 ± 16.2 6.4 ± 4.5

84.0 ± 6.4

1**/12 (8.3%) Transient dysgeusia (25%)

Note: Bold and italicized are statistically significant. 1* Bleeding POD7; 1** Oropharyngeal scarring requiring lysis. (AHI: Apnea–hypopnea index; ESS: Epworth sleepiness scale).

utilized with an open tongue base approach.6,11 A dissection method within the sagittal avascular plane inside an ideal triangle between the mandible, hyoid bone body, and the lingual frenulum is outlined. Ultimately, the hyoid is tied under slight tension to the mandible with the procedure taking roughly < 20 minutes in total. Additionally, to elucidate the improvement in treatment of OSA when used in conjunction with TORS, Vicini et al. also investigated the modified Pang expansion sphincter pharyngoplasty (nonrobotic) to the uvulopharyngoplasty (nonrobotic) procedure.12 Though the Pang expansion sphincter pharyngoplasty required more time to perform (average of 39 minutes), it was found to be superior in post-procedure AHI and ESS to the classic uvulopharyngoplasty when used in conjunction with TORS. It is thought that that the expansion sphincter pharyngoplasty creates a greater angle between the lateral wall and palate.8

6 Recent Advances in Otolaryngology—Head and Neck Surgery Friedman et al. investigated the feasibility of performing a Z-palatoplasty with a robotically assisted partial glossectomy without tracheotomy to those who underwent a Z-palatoplasty with tongue base reduction via radio frequency (radio frequency base-of-tongue reduction [RFBOT] or coblation (submucosal minimally invasive lingual excision [SMILE].) Twenty seven TORS patients were compared with 24 RFBOT patients and 22 SMILE patients. As with Vicini et al. rate of cure was defined as AHI < 20 and reduction in AHI ≥ 50%. Like the reports by Vicini et al. no incidence of significant bleeding or airway complications were reported (Table 1.1). It was found that only the robot group had a statistically significant improvement in minimum oxygen saturation, while all groups had a statistical significant decrease in AHI and ESS (though a greater percentage in absolute decrease was seen within the robot group for both AHI and ESS) (Table 1.1). Interestingly, no direct correlation was found between the weight of lingual tissue removed and the degree of improvement in minimum oxygen saturation, or ESS. TORS required longer length of stay in the hospital (1.6 ± 0.7) and return to normal diet (19.3 ± 8.4 days). The percentage of surgical cure was higher in the robot group (66.7%) versus the coblation (45.5%) and radio frequency (20.8%), though statistically significant compared with only the radio frequency group. In similar fashion of investigating TORS with a concomitant palate surgery, Lee et al. investigate transoral robotic lingual tonsillectomy with the classic uvulopharyngoplasty. Traditional surgery involving uvulopalatopharyngoplasty alone has not reliably led to normalization of the AHI for patients with moderate-to-severe OSA. Lee et al. offered those patients who underwent drug-induced sleep endoscopy and were found to have significant obstruction at the level of the retroglossal region the option of an uvulopharyngoplasty and transoral robot lingual tonsillectomy. These patients, selected prospectively, were matched against historical controls. In alignment with reports by Vicini and Friedman, surgical success was defined as a 50% reduction of preop AHI and postop AHI of < 20, while surgical response was defined as a reduction from the preoperative AHI of at least 50%. AHI, ESS, and lowest oxygen saturation levels were all found to be statistically significant postoperatively with 13 patients meeting the criteria for surgical response and 9 meeting the criteria for surgical cure (Table 1.1). Unlike data published by Vicini and Friedman, one patient did experience a postoperative bleed (postoperative day 7) that required a visit to the operating room for cauterization (Table 1.1). Minor complications included dysphagia, dysgeusia, and transient globus—all of which resolved by 3 months. With OSA generally resulting from obstruction at various subsites throughout the upper airway, much of the literature compares various outcomes (i.e. AHI, ESS, and minimum oxygen saturations) after performing multilevel surgery. Therefore, reports describing base of tongue resection

Transoral Robotic Surgery for Obstructive Sleep Apnea 7

concomitantly with other upper airway procedures make interpretation of the efficacy of base of tongue reduction alone difficult to assess. Lin et al. in a retrospective analysis examined 27 patients who underwent TORS for base of tongue reduction only, though the majority has previously undergone a combination of other airway procedures including a uvulopalatopharyngoplasty/Zpalatoplasty, coblation-assisted lingual tonsillectomy, hyoid advancement, and tracheostomy. Similar to the criteria outlined by Vicini, Friedman, and Lee, surgical response was defined as a 50% reduction in AHI and final AHI < 20 postoperatively. Both AHI and ESS demonstrated statistical significance with 50% of the patients achieving surgical cure comparable with the results produced by others who underwent concomitant multilevel airway surgery to treat OSA (Table 1.1). However, unlike other reported papers, one patient (8%) demonstrated oropharyngeal scarring causing dysphagia that required scar tissue lysis (Table 1.1). With the possibility of oropharyngeal scarring from tongue base resection and concomitant palatal surgery, the authors recommended considering a two-stage approach with the TORS-assisted base of tongue resection occurring prior to a second-stage palate surgery.

Conclusion The application of the robot, in order to provide improved access, enhanced visualization and precision has been demonstrated to be feasible and tolerable in patients with OSA. The studies thus far reveal improved AHI, ESS, and O2 saturations with robotic sleep surgery. With additional studies and appropriate patient selection, TORS may become a powerful tool in the armamentarium of the otolaryngologist to effectively treat airway obstruction at the base of tongue and possible adjacent sites of airway collapse.

References 1. Caples SM, Rowley JA, Prinsell JR, et al. Surgical modifications of the upper airway for obstructive sleep apnea in adults: a systematic review and metaanalysis. Sleep. 2010;33(10):1369–407. 2. Lin HS, Rowley JA, Badr MS, et al. Transoral robotic surgery for treatment of obstructive sleep apnea-hypopnea syndrome. Laryngoscope. 2013;123:1811–6. 3. O’Malley BW Jr, Weinstein GS, Synder W, et al. Transoral robotic surgery (TORS) for base of tongue neoplasms. Laryngoscope. 2006;116:1465–1472. 4. Vicini C, Dallan I, Canzi P, et al. Transoral robotic tongue base resection in obstructive sleep apnoea-hypopnoea syndrome: a preliminary report. ORL J Otorhinolaryngol Relat Spec. 2010;72:22–7. 5. Lee Jm, Weinstein GS, O’Malley Jr. BW, et al. Transoral robot-assisted lingual tonsillectomy and uvulopalatopharyngoplasty for obstructive sleep apnea. Ann Otol Rhinol Laryngol. 2012;121(10):635–9.

8 Recent Advances in Otolaryngology—Head and Neck Surgery 6. Vicini C, Montevecchi F, Dallan I, et al. Transoral robotic geniohyoidpexy as an additional step of transoral robotic tongue base reduction and supraglottoplasty: feasibility in a Cadaver model. Otorhinolaryngol Relat Spec. 2011;73(3):147–50. 7. Vicini C, Dallan I, Canzi P, et al. Transoral robotic surgery of the tongue base in obstructive sleep apnea-hypopnea syndrome: anatomic considerations and clinical experience. Head Neck. 2012;34(1):15–22. 8. Vicini C, Montevecchi F, Pang K, et al. Combined transoral robotic tongue base surgery and palate surgery in obstructive sleep apnea-hypopnea syndrome: expansion sphincter pharyngoplasty versus uvulopalatopharyngoplasty. Head Neck. 2013;00:1–7. 9. Friedman M, Hamilton C, Samuelson CG, et al. Transoral robotic glossectomy for the treatment of obstructive sleep apnea-hypopnea syndrome. Otolaryngol Head Neck Surg. 2012;146:854–62. 10. Lauretano AM, Li KK, Caradonna DS, Khosta RK, Fried MP. Anatomic location of the tongue base neurovascular bundle. Laryngoscope. 1997;107:1057–9. 11. Chabolle F, Wagner I, Blumen MB, et al. Tongue base reduction with hyoepi gottoplasty a treatment for severe obstructive sleep apnea. Laryngoscope. 1999;109:1273–80. 12. Pang KP, Woodson BT. Expansion sphincter pharyngoplasty: a new technique for the treatment of obstructive sleep apnea. Otolaryngol Head Neck Surg. 2007;30:110–4.

Chapter Image Guidance in Sinus Surgery

2

Laura Oleaga, Manuel Bernal-Sprekelsen

Introduction Sinonasal cavities are part of the upper respiratory tract. The most frequent pathological processes involving the paranasal sinuses are inflammatory or allergic conditions. Tumors in this region represent 3–4% of head and neck neoplasms.1 Imaging studies are crucial in the assessment of the anatomy and to further characterize lesions or stage tumors. The main indications for imaging the nasal cavity and paranasal sinuses are trauma, subacute, chronic or recurrent rhinosinusitis, preoperative planning for functional endoscopic sinus surgery (FEES), postoperative complications, and in the study and staging of benign or malignant tumors. The two most important imaging procedures used to evaluate the nasal cavity and paranasal sinuses are computed tomography (CT) and magnetic resonance imaging (MRI). Plain radiographs nowadays are rarely used in patients with sinonasal disease, due to the overlapping of the anatomic structures that prevents the adequate display of important structures such as the ostiomeatal complex. High-resolution CT has replaced plain films in the initial workup of sinonasal inflammatory diseases. For the assessment of sinonasal tumors, both CT and MRI provide good complementary information.

Computed tomography CT imaging is important to depict the anatomy of the most important structures in the sinonasal region and skull base. CT is more sensitive and accurate in assessing the osseous margins of the sinonasal cavity. It provides an accurate evaluation of the craniofacial bones and pneumatization of the paranasal sinuses.1–3 High-resolution CT provides high-quality images allowing good delineation of the local inflammatory process, detection of disease-related complications, and description of the anatomical variations that may be important

10 Recent Advances in Otolaryngology—Head and Neck Surgery during FESS, to avoid relevant complications. Major complications include blindness due to damage of the optic nerve, cerebrospinal fluid (CSF) leak, meningitis, life-threatening hemorrhage due to internal carotid injury, orbital injury with blurred or double vision, severe bleeding from any of the ethmoidal arteries or branches of the sphenopalatine artery, and nasolacrimal duct stenosis producing epiphora. FESS is limited to a box located between the middle turbinate, the anterior skull base, and the lamina papyracea of the orbit. The more anatomical landmarks are identified, the better the orientation and, subsequently, the risk of any complication is considerably reduced. Critical structures to identify on CT images to guide FESS include the following: • Cribriform plate and the depth of the olfactory fossa, as classified by Keros4 • Lamina papyracea to delineate the orbit • Internal carotid artery bulging into the sphenoid sinus and its potential dehiscence • Optic nerve: identify the exact location in relation to the sphenoid sinus or the posterior ethmoid cell (Onodi cell) • Sphenoid sinus with all the variations in pneumatization • Anterior ethmoidal artery These landmarks are better demonstrated at in the coronal plane, as it offers the same direction of the surgical procedure, with the exception of the internal carotid and optic nerve bulging, that are better visualized in axial planes.

CT Technique High-resolution axial images, parallel to the hard palate or orbitomeatal unit of the sinuses, are acquired with a spiral CT technique with a rotation time of 1s or less, using a display matrix of 512 × 512 or 1024 × 1024 pixels. Axial, coronal and sagittal 2 mm images are reformatted from the volume raw data set for soft tissue and bone algorithms. No intravenous contrast is necessary for sinus CT unless complications of sinusitis or tumors are suspected. For contrast examination studies, 80–100 mL of iodinated contrast media, with a concentration of 300 mgr, is applied with an injection rate of 2 mL/s followed by 20 mL of saline at the same injection rate. The start delay of the scan varies between 60 and 80s in order to achieve an optimal interstitial contrast.5 The main concern when using CT imaging of the head and neck region is the radiation dose delivered to the lens and to the thyroid gland. Cone-beam CT systems (CBCT) have been proposed for sinus applications; however, low tissue contrast and inferior visualization of thin anatomical structures discourage its use for detection of sinonasal pathology.

Image Guidance in Sinus Surgery 11

Standard CT protocols for paranasal sinuses use 140 kV and effective mAs of 100. With the new multidetector CT systems, images of diagnostic quality can be obtained using a low-dose technique at 120 kV and 40 mAs in the axial plane.6 The new-generation multidetector helical CT scanners provide a better spatial and contrast resolution and more dose-efficient detectors, maintaining image quality at lower mAs. Modern CT scanners have different dose reduction systems that enable modulation of the radiation dose using different reconstruction-algorithm such as filtered back-projection or iterative reconstruction.7 Three-dimensional spiral CT data sets may be transferred directly into computer systems and thus be used in computer-assisted surgery.8,9 The coronal plane is the best to depict the anterior ostiomeatal complex and the level of the anterior skull base, together with the anterior ethmoidal arteries. This is the preferred plane by surgeons, as it shows the anatomy in the same direction of the surgical procedure; it provides an excellent road map of the sinus anatomy and extent of disease.1,2,10 The axial plane is useful for identifying the basal lamella, which divides the anterior and posterior ethmoidal sinuses,1–3 and posteriorly the bulging of the optic nerve and the internal carotid artery. Both, coronal and axial planes, delineate the relationship of the paranasal sinuses with the orbit. The sagittal plane is useful for the evaluation of the posterior ostiomeatal complex. It provides excellent evaluation of the posterior ethmoidal air cells and the sphenoethmoidal recess.1–3 It can be helpful to study the frontal recess. Posteriorly, also the relationship with the pituitary gland is nicely depicted in a sagittal view.

CT Anatomy Detailed radiological study of the anatomy of the nasal cavity and paranasal sinuses is crucial before FESS. The anterior ostiomeatal complex/unit is the crossroad for the maxillary sinus, the frontal, and the anterior ethmoidal cells. It is here where the inflammatory disease initially starts, and thus it deserves special attention. The following key anatomic structures of the anterior ostiomeatal complex and its vicinity are the ethmoid infundibulum, uncinate process, perpendicular plate and basal lamella of the middle turbinate, ethmoid bulla, nasofrontal recess, the lamina papyracea, and the fovea ethmoidalis.10,11 The anterior ostiomeatal complex/unit includes the superomedial maxillary sinus ostium, maxillary infundibulum, uncinate process, hiatus semilunaris, ethmoid bulla, middle turbinate, and middle meatus (Fig. 2.1). Coronal and axial planes are the most useful planes to evaluate the anterior ostiomeatal complex. The maxillary ostium is located in the superior segment of the medial maxillary wall and drains into the posterior aspect of

12 Recent Advances in Otolaryngology—Head and Neck Surgery

Fig. 2.1: Coronal noncontrast computed tomography (bone window). Anterior ostiomeatal unit, uncinate process (arrow), infundibulum (asterisk), hiatus semilunaris (small arrow), middle turbinate (mt), and middle meatus (white line).

the ethmoid infundibulum. The infundibulum is the tunnel that connects the maxillary sinus to the middle meatus. The limits of the infundibulum are the uncinate process medially and the inferomedial wall of the orbit laterally. The uncinate process is a wing-shaped piece of bone. It attaches ante riorly to the posterior edge of the lacrimal bone, and inferiorly to the superior edge of the inferior turbinate. Superior attachment of the uncinate process is highly variable, may be attached to the lamina papyracea, or the roof of the ethmoidal sinus, or sometimes to the middle turbinate.1,2,10 The hiatus semilunaris is a semilunar region between the uncinate process and ethmoid bulla; it receives drainage from anterior ethmoid air cells and maxillary sinus via infundibulum. The ethmoid bulla is a large ethmoid air cell located at the superior aspect of the ostiomeatal complex, receives drainage from anterior ethmoid air cells. The sinus lateralis or suprabullar recess is the space between the posterior wall of the ethmoid bulla and the basal lamella. The middle turbinate attaches superiorly to the cribriform plate via vertical lamella and posteriorly and laterally to the lamina papyracea via basal lamella. The middle meatus receives drainage from the maxillary sinus via the hiatus semilunaris, ethmoid bullae, and frontal sinus. The frontal recess is a narrow space with a complex anatomy surrounded by various anterior ethmoidal cells (Fig. 2.2). The frontal recess is the outflow tract for frontal sinus drainage into the middle meatus.11 It is important to have a comprehensive understanding of the anatomy of the anterior ethmoid cells: agger nasi, frontal cell, supraorbital ethmoid cell, frontal bullar cell, suprabullar cell, and interfrontal sinus septal cell to identify the frontal recess


Fig. 2.2: Sagittal noncontrast computed tomography (bone window). Frontal sinus (fs), frontal recess (arrow), anterior ethmoid cell (asterisk), and sphenoid sinus (ss).

Fig. 2.3: Sagittal noncontrast computed tomography (bone window). Sphenoid sinus ostia (arrow) and sphenoethmoidal recess (asterisk).

and its pneumatization pattern.12 Incomplete removal of cells in the frontal recess is the most common cause of failed FEES. The best imaging plane to analyze the frontal recess is the sagittal reconstruction plane. The posterior ostiomeatal complex/unit includes the sphenoid sinus ostium, sphenoethmoidal recess, and posterior ethmoid cells. It is the region of drainage of the sphenoid sinus and posterior ethmoid cells into the sphenoethmoidal recess that drains into the superior meatus of the nose (Fig. 2.3). The sphenoid sinus ostium is found at the anterosuperior portion of the sphenoid sinus and it is better seen in the axial and sagittal planes.1,2,10


Fig. 2.4: Axial noncontrast computed tomography (bone window). Image demonstrates both pterygopalatine fossae (arrows) back to the posterior wall of maxillary sinuses.

The pterygopalatine fossa (PPF) is an important, strategic, anatomic space, which communicates the middle cranial fossa, orbital, nasal and oral cavities, pharynx, foramen lacerum, and the infratemporal fossa (Fig. 2.4). There are a large number of fissures and canals communicating with the PPF: the inferior orbital fissure, the foramen rotundum (Fig. 2.5), the vidian canal (Fig. 2.6), the sphenopalatine foramen, the pterygomaxillary fissure, the greater pterygopalatine canal, the lesser pterygopalatine canal, and the palatinovaginal or pharyngeal canal.4,13 It represents a major pathway of spread of malignancy and infection in the deep face.

Normal Anatomic Variants A large number of anatomical variants can narrow the sinus drainage pathways and limit surgical access. It is important to recognize those anatomical variants when reading CT images.1,2,11,14 Nasal septum variants, deviations, or spurs may involve the middle meatus. Concha bullosa: Aeration of middle turbinate is seen in 4–15% of the population. Large concha bullosa can narrow the middle meatus (Fig. 2.7). Uncinate process: Pneumatization of the uncinate process may result in anatomic narrowing of the infundibulum. The uncinate process might be deviated medially obstructing the middle meatus or laterally obstructing the infundibulum. Lateral deviation of the uncinate process can increase the risk of medial orbital wall injury during uncinectomy. Anterior ethmoidal bulla: When enlarged can narrow or obstruct the middle meatus and infundibulum (Fig. 2.8).


Fig. 2.5: Axial noncontrast computed tomography (bone window). Pterygopalatine fossa (asterisk) communicates with foramen rotundum (arrow).

Fig. 2.6: Axial noncontrast computed tomography (bone window). Pterygopalatine fossa (asterisks) communicates with vidian canal (arrows).

Agger nasi air cell: The most anterior ethmoid cell, lateral to lamina papyracea, adjacent to frontal recess. The frontal recess can be narrowed by enlargement of the agger nasi cell (Fig. 2.9). Frontal cell: Anterior ethmoid cell above the agger nasi cell. Its enlar gement can produce narrowing of the frontal recess. Haller cells: Ethmoidal cells extending along the medial floor of the orbit. When they enlarge may cause narrowing of the infundibulum (Fig. 2.10).


Fig. 2.7: Coronal noncontrast computed tomography (bone window). Pneumatized left middle turbinate (asterisk) ‘concha bullosa’.

Fig. 2.8: Coronal noncontrast computed tomography (bone window) through the ethmoid sinuses. Anterior ethmoid bulla (asterisk) and anterior ethmoid air cells (arrow).

Onodi cells: The most posterior ethmoidal cells that extend postero laterally and surround, at least partially, the optic canal. The lateral lamella represents the segment of bone lateral to the attachment of middle turbinate and medial to the roof of the ethmoid or fovea ethmoidalis. It is the thinnest part of the cribriform plate and at risk of fracture during FES (Fig. 2.11). The appearance of the cribriform plate has been classified into Keros types 1–3 according to the depth that it extends into the nasal cavity.4 The risk of


Fig. 2.9: Sagittal noncontrast computed tomography (bone window). Agger nasi cell (an), most anterior ethmoid cell, and frontal recess (arrow).

Fig. 2.10: Coronal noncontrast computed tomography (bone window). Haller cell located lateral to maxillary infundibulum inferolateral to the orbit (asterisk).

perforating the cribriform plate during FESS increases when the olfactory fossae are deep or asymmetric. Medial deviation or dehiscence of the lamina papyracea: The anterior ethmoidal artery runs through a bone canal in the superior lamina papyracea and serves as a surgical landmark. It can be identified on coronal CT images. It emerges between the medial rectus muscle and the superior oblique muscle in a kind of pyramid. It is usually located at the insertion of the anterior wall of the ethmoidal bulla or behind. When it courses through the ethmoidal


Fig. 2.11: Coronal noncontrast computed tomography (bone window). Fovea ethmoidalis (arrow), lateral lamella (arrowhead).

air cells, can be inadvertently injured. Penetration of the lamina papyracea during FESS can also cause orbital injury. Extensive pneumatization of the sphenoid sinus: Bone dehiscence of the sphenoidal walls can produce a bulging of the optic or carotid canals and places them at risk of injury during surgery.

CT Indications CT is the imaging modality of choice for evaluation of inflammatory rhinosinusitis and preoperative planning of FEES. CT is used mainly to assess the extent of the disease, characterize bone lesions, identify bone involvement, and serve as a surgical road map to check for normal anatomy and potential anatomic variants that can affect surgery. CT is useful in the evaluation of FESS complications. Complications after FESS include orbital hematoma, emphysema, and abscess. Other complications associated with FESS include interruption of the lamina papyracea usually at the site of attachment of the basal lamella; orbital fat can be herniated into the ethmoid sinus. Diplopia is one of the major orbital complications usually caused by extraocular muscle damage due to direct muscle injury. The most commonly injured extraocular muscle is the medial rectus muscle, followed by the inferior rectus muscle and superior oblique muscle. Intracranial complications include CSFs leak, intracranial bleed, and cerebritis. CT can provide helpful information to assess the integrity of the cribriform plate, lateral lamella, fovea ethmoidalis, and anterior cranial fossa.


Magnetic resonance imaging MRI provides better soft tissue contrast and the possibility of acquiring the images in multiple different planes. An important advantage of MRI over CT is the absence of artifacts due to dental filling. The most important disadvantage is the long imaging time required when comparing with CT. It is the study of choice in cases of intracranial extension of infection or tumors and for perineural infiltration assessment.15–18

MRI Technique MRI studies are obtained using the head coil or a head and neck coil as a receiver, with a slice thickness of 2–4 mm and acquisition matrix of 256 × 256. Contrast-enhanced images are acquired with a paramagnetic contrast media gadolinium diethylenetriaminepenta-acetic acid (Gd-DTPA), dosage of 0.2 mmol/kg body weight. The recommended MRI protocol includes axial, coronal, and sagittal noncontrast T1-weighted images, axial diffusion-weighted images, axial and coronal noncontrast T2-weighted images, and postcontrast gadolinium-enhanced axial, coronal, and sagittal T1-weighted images with fat suppression.19,20 Coronal and sagittal planes allow assessment of craniocaudal tumor extension. Imaging should include the paranasal sinuses, the orbits, skull base, and adjacent intracranial structures.

MRI Indications MRI is better than CT for separating tumor from inflammatory mucosal disease and retained secretions increasing the staging accuracy.16,17,19 Sinonasal secretions demonstrate low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. In chronic secretions, the signal intensity may vary depending on the protein concentration and the extent of free water resorption.16,17 As the protein content increases up to 25% in an obstructed sinus, the signal intensity on T1-weighted images becomes high and remains high on T2-weighted images. Above 25% protein concentration, both T1- and T2-weighted signal intensities decrease (Fig. 2.12). MRI is indicated for sinonasal tumors staging before surgery to determine resectability and define optimal surgical approach.20 Tumors display low signal intensity on T1-weighted images and higher signal intensity than muscle on T2-weighted images and enhance after gadolinium injection.21 MRI provides good delineation of the tumor, assessment of the extension, and involvement of adjacent structures, such as the skull base, the anterior and middle cranial fossa, orbits, paranasal soft tissues, palate, infratemporal fossa, and PPF (Fig. 2.13). It is more sensitive to evaluate skull base invasion and to depict perineural spread.21


Fig. 2.12: Coronal T2-weighted magnetic resonance imaging allows separating the high signal intensity secretions in the right maxillary sinus (S) from tumor (T).

Fig. 2.13: Coronal T1-weighted gadolinium-enhanced fat suppression magnetic resonance imaging. Sinonasal undifferentiated carcinoma, orbital (arrows), and cribriform plate (asterisk) invasion.

MRI is more sensitive than CT to depict perineural spread. Postcontrast images with fat suppression are crucial to demonstrate perineural infiltration.22 Certain tumors can be characterized by its MRI appearance. Heman giomas of the nasal cavity are well-defined masses with high signal intensity on T2-weighted images, and hemorrhage. Inverted papillomas have a characteristic convoluted cerebriform pattern on MRI (Fig. 2.14). MRI is the imaging of choice in aggressive sinonasal inflammatory diseases (aggressive bacterial sinusitis, fungal sinusitis, Wegener’s granulomatosis) that spread to the skull base, brain, orbit, or cavernous sinus (Fig. 2.15).


Fig. 2.14: Axial T2-weighted magnetic resonance imaging inverted papilloma demonstrating a characteristic convoluted cerebriform pattern (arrows).

Fig. 2.15: Axial T1W gadolinium-enhanced fat suppression magnetic resonance imaging fungal sinusitis involving the left maxillary sinus with invasion of the pterygopalatine fossa (arrows).

References 1. Hoang JH, Eastwood JD, Tebbit CL, et al. Multiplanar sinus CT: a systematic approach to imaging before functional endoscopic sinus surgery. AJR. 2010; 194:527–36. 2. Lame1 FJ, Smoker WR. The ostiomeatal unit and endoscopic surgery: anatomy, variations, and imaging findings in inflammatory diseases. AJR. 1992;159: 849–57.

22 Recent Advances in Otolaryngology—Head and Neck Surgery 3. Anzai J, Yueh B. Imaging evaluation of sinusitis: diagnostic performance and impact on health outcome. Neuroimag Clin N Am. 2003;13:251–63. 4. Rudmik L, Smith TL. Evaluation of the ethmoid skull base height prior to endoscopic sinus surgery: a preoperative CT evaluation technique. Int Forum Allergy Rhinol. 2012;2:151–4. 5. Sievers KW, Greess H, Baum U, et al. Paranasal sinuses and nasopharynx CT and MRI. Eur J Radiol. 2000;33:185–202. 6. Zammit-Maempel I, Chadwick CL, DCR(R), et al. Radiation dose to the lens of eye and thyroid gland in paranasal sinus multislice CT. Br J Radiol. 2003;76: 418–20. 7. Willemink MJ, de Jong PA, Leiner T, et al. Iterative reconstruction techniques for computed tomography Part 1: technical principles. Eur Radiol. 2013;23: 1623–31. 8. De Nicola M, Salvolini L, Salvolini U. Virtual endoscopy of nasal cavity and paranasal sinuses. Eur J Radiol. 1997;24:175–80. 9. Dearking AC, Pallanch JF. Mapping the frontal sinus ostium using virtual endoscopy. Laryngoscope. 2012;122:2143–7. 10. Rao VM, El-Noueam KI. Sinonasal imaging. Radiol Clin N Am. 1998;36:921–39. 11. Daniels DL, Mafee MF, Smith MM, et al. The frontal sinus drainage pathway and related structures. AJNR. 2003;24:1618–27. 12. Park SS, Yoon BN, Cho KS, et al. Pneumatization pattern of the frontal recess: relationship of the anterior-to-posterior length of frontal isthmus and/or frontal recess with the volume of Agger nasi cell. Clin Exp Otorhinolaryngol. 2010;3: 76–83. 13. Daniels DL, Mark LP, Ulmer JL, et al. Osseous anatomy of the pterygopalatine fossa. AJNR. 1998;19:1423–32. 14. Martinez Del Pero M, Philpott C. A useful tool – systematic checklist for evaluating sinus scans. Clin Otolaryngol. 2012;37:82–4. 15. Loevner LA, Sonners AI. Imaging of neoplasms of the paranasal sinuses. Magn Reson Imaging Clin N Am. 2002;10:467–93. 16. Hartman MJ, Gentry LR. Aggressive inflammatory and neoplastic processes of the paranasal sinuses. Magn Reson Imaging Clin N Am. 2012;20:447–71. 17. Mossa-Basha M, Blitz AM. Imaging of the paranasal sinuses. Semin Roentgenol. 2013;48:14–34. 18. Walden MJ, Aygun N. Head and neck cancer. Semin Roentgenol. 2013;48:75–86. 19. Tomura N, Hirano H, Kato K, et al. Comparison of MR imaging with CT in depiction of tumour extension into the pterygopalatine fossa. Clin Radiol. 1999;54:361–6. 20. Shah GV, Nancy J, Fischbein NJ, et al. Newer MR imaging techniques for head and neck. Magn Reson Imaging Clin N Am. 2003;11:449–69. 21. Jégouxa F, Métreaua A, Louvelb G, et al. Paranasal sinus cancer. In press. European Annals of Otorhinolaryngology Head and Neck diseases (2013), http:// dx.doi.org/10.1016/j.anorl.2012.07.007 22. Lawrence E, Ginsberg LE. MR imaging of perineural tumor spread. Neuroimag Clin N Am. 2004;14:663–77.

Chapter Endoscopic Repair of Cerebrospinal Fluid Leaks

3

Timothy R DeKlotz, Eric W Wang, Carl H Snyderman

Introduction The management of cerebrospinal fluid (CSF) leaks of the anterior skull base has evolved dramatically over the past several decades. Craniotomy was once considered the preferred approach for definitive repair. Open techniques, however, faced several obstacles to more long-lasting acceptance. Traditionally, reported success rates range from only 70% to 80% with high recurrence rates.1,2 Additionally, these more invasive techniques have the potential for significant morbidity including but not limited to seizures, intracranial hemorrhage, anosmia, memory issues, and mortality.1 While open techniques still have a role in the overall management algorithm, this role is shrinking as even very large, high flow defects can be reliably repaired with less invasive techniques.3 Wigand4 is attributed with the first published description of an endoscopic CSF leak repair. Since this time, further advances in endoscopic techniques, technological advancement, and a greater understanding of endoscopic anatomy have allowed endoscopic approaches to become a first-line approach at most major medical centers for the treatment of sinonasal CSF leaks.5 These advances have enabled less invasive surgery without sacrificing the overall outcome of successful repair.5–8 By taking advantage of natural corridors to the anterior skull base via the nasal cavity, the surgeon is able to limit the morbidity from traversing/retracting important neurovascular structures.9

Types of CSF leaks There is no universally agreed upon classification scheme of sinonasal CSF leaks and there is often a lack of uniformity in reporting of results with regard to subtypes (congenital, traumatic, iatrogenic, neoplasia-related, and idiopathic/spontaneous). A broader categorization simply divides these into traumatic versus spontaneous leaks.


Traumatic CSF Leaks The subgroup of traumatic CSF leaks can be thought to include environmental accidents as well as iatrogenic trauma caused by both inadvertent skull base injury and those expected leaks caused by surgical resection of benign and malignant pathologies. This is a fairly eclectic group whose management strategy varies significantly. Environmental accidental trauma was historically considered to be the most common source of sinonasal CSF leaks;10 however, more recent studies call this into question with a recent systematic review of endoscopic repairs reporting nearly equal proportions of traumatic versus nontraumatic etiologies.5,10 Regardless of the incidence, this subgroup is often initially managed with conservative measures (Table 3.1) due to high rates of spontaneous closure.10 The use of lumbar drains (LD) is not universal, but is commonly employed.11 The length of time that is advocated for conservative management is an area of controversy, though most recommend allowing at least 3–7 days for spontaneous closure. Further delay has been shown to significantly increase the risk of meningitis10,11 and definitive repair is advised. Surgically induced CSF leaks are generally not managed with any period of conservative measures and immediate definitive repair is indicated at the time of injury, regardless of whether the leak is expected or incidental. A possible exception to this rule is with the delayed presentation of a postoperative leak or one that was present but not recognized at the time of surgery. While some advocate a period of conservative measures, there is evidence to support more immediate closure.12 Functional endoscopic sinus surgery is a frequent source of iatrogenic leaks. While skull base injury is an exceedingly rare complication of these surgeries, there are > 12,500 cases performed annually in the United States alone.13,14 Typically, these injures are quite small and easily repaired at the time of surgery (see “Methods of repair” section). Another subset of inadvertent injury to the skull base are those secondary to open neurosurgical procedures. These also are typically repaired at the time of surgery. However, delayed recognition of these postoperative CSF leaks renders them amenable to endoscopic repair, thereby avoiding a second craniotomy and its attendant complications. The final group of patients includes those with expected leaks after endoscopic skull

Table 3.1: Conservative/nonsurgical measures Bed rest Head of bed elevation > 30° Laxatives Antitussives Avoidance of straining Lumbar drainage

Endoscopic Repair of Cerebrospinal Fluid Leaks 25

base resection of benign and malignant pathologies. Large and complex defects created by tumor resection underscore the necessity for reliable reconstruction and have been a driving force for innovative reconstructive techniques, most notably the development of numerous intranasal pedicled flaps.15–17

Spontaneous CSF Leaks Spontaneous CSF leaks have gained more attention in recent years as their management and outcomes have improved. Some authors stress that this is a group that should only be considered with those leaks in which there is not an identifiable and inciting event,18 although there is frequent co-reporting with other etiologies (neoplasia related, congenital). An important advancement in this area is the greater recognition of increased intracranial pressure (ICP) as a key factor in the pathophysiology of a significant number of these leaks.18–20 In this particular subset, their development is thought to be secondary to the continual dural pulsations at sites of inherent weakness of the anterior skull base leading to erosion, subsequent dehiscence, and possible herniation.18 Spontaneous leakage is theorized to act as a pressure release valve in the face of elevated ICP20,21 with other associated symptoms of this potentially presenting only after a leak has been repaired.

Epidemiology Sites of CSF leakage within the sinonasal cavity include the posterior wall of the frontal sinus, cribriform recess, fovea ethmoidalis, and lateral recess of the sphenoid sinus. The incidence of occurrence at each of these sites is highly variable in the literature. A recent systematic review of endoscopic CSF leak repair identified the ethmoid roof and cribriform plate as the most common sites (Fig. 3.1). The gender difference when all leaks are considered as a whole is negligible.5 Environmental traumatic CSF leaks are more frequent

Fig. 3.1: Incidence of sinonasal cerebrospinal fluid leaks by site. Data adapted from Psaltis et al.5

26 Recent Advances in Otolaryngology—Head and Neck Surgery in males,11 whereas spontaneous CSF leaks (notably, those associated with increased ICP) are much more prevalent in females.1,22 Additional risk factors for spontaneous CSF leak include middle age (forties) and obesity.

Preoperative assessment and considerations Clinical Assessment A high degree of clinical suspicion is necessary to accurately diagnose CSF rhinorrhea, given that it mimics other more common ailments such as allergic and nonallergic rhinitis. While identification is potentially easier with traumatic cases, the physician must be cognizant that CSF rhinorrhea is not always from a defect in the nose or paranasal sinuses and may in fact be from a temporal bone fracture or defect with egress through the eustachian tube. Rhinorrhea is the most common presenting symptom, but others include headache and a history of meningitis.1,5 A history of unilateral drainage, increased rhinorrhea upon straining, reservoir sign (sudden drainage of CSF with changes in head position), prior surgery, or head trauma all raise suspicion of the diagnosis. Symptoms of headache, pulsatile tinnitus, balance issues, and visual disturbance can alert the physician to the possibility of an underlying condition of benign intracranial hypertension. Nasal endoscopy is important to further localize the pathologic site from evidence of robust clear drainage or the presence of an encephalocele. Historically, the demonstration of a halo sign on filter paper was helpful in the diagnosis, but the lack of specificity has led to the identification of other more accurate methods.10

Biochemical Testing The use of biochemical testing has become standard in the workup of CSF rhinorrhea. Testing of drainage for glucose concentration was once more commonly employed, but low specificity and sensitivity have led to the replacement by more reliable diagnostic tests.20,23,24 Beta-2-transferrin is a protein solely found in CSF, perilymph, and vitreous humor. The diagnostic accuracy of this test with its high sensitivity (97%) and specificity (93%)23,25–27 has made this a preferred diagnostic test within the United States. Beta-trace protein has also been reported to be a reliable marker of CSF rhinorrhea with sensitivity and specificity reported as high as 100%.27 While this protein is also found in nasal secretions and serum, the concentration within CSF is an order of magnitude higher. Relative advantages of the beta-trace protein test include rapidity of diagnosis and simplicity of method.

Imaging Assessment The use of both noninvasive and invasive imaging techniques in a stepwise approach (Fig. 3.2) can aid in localizing the defect as well assist in


Fig. 3.2: Diagnostic algorithm for sinonasal cerebrospinal fluid leaks. Assessment begins with noninvasive techniques. More invasive methods are only considered with failure to accurately detect and localize the pathology.

identifying potential concurrent pathology (i.e. encephalocele, possible intra-cranial hypertension). High-resolution computed tomography (CT) can greatly aid in identifying a skull base defect, given its superb definition of bony anatomy and is typically the initial imaging study of choice. Fine cuts (≤ 1 mm) in a bone algorithm with reconstructions in the coronal plane are recommended. When evaluating various aspects of the skull base for a defect, the plane of imaging that is perpendicular to that aspect of the skull base is the most helpful (e.g. the axial plane for the posterior wall of the frontal sinus and the coronal plane for the anterior cranial base). Magnetic resonance imaging (MRI) is often complementary to CT findings in identifying additional pathology.28 With spontaneous leaks, it is able to define cerebral herniations and distinguish between a meningocele and meningoencephalocele, an important consideration for surgical planning. Additionally, there are a number of radiological signs that are associated with increased ICP26,29,30 (Table 3.2). The most predictive sign is flattening of the posterior aspect of the globes (specificity = 100%, sensitivity = 43%).29,31 MR cisternography is a noninvasive extension of standard MRI that utilizes fine-cut MR slices with

28 Recent Advances in Otolaryngology—Head and Neck Surgery Table 3.2: MRI findings associated with ↑ ICP29–31 Flattening of the posterior globe Empty sella Slit-like ventricles Tight CSF spaces Optic nerve protrusion Vertical tortuosity of the optic nerve Arachnoid pits (ICP: Intracranial pressure; CSF: Cerebrospinal fluid; MRI: Magnetic resonance imaging).

T2-weighted fast-spin-echo images. In successful cases, it is able to delineate a column of CSF communicating with the nasal cavity, both confirming and localizing the leak. While there is some variation in its reported success, studies have demonstrated an overall accuracy of up to 96% with a sensitivity and specificity of 94% and 100%, respectively.32,33 Two important caveats to remember with use of the above imaging is recognition that areas of congenital thinning or dehiscence are not necessarily the site of the leak as well as the fact that multiple leak sites may be present. Invasive imaging techniques are available to supplement noninvasive imaging should localization remain elusive. CT cisternography and nuclear cisternography entail injection of either water soluble contrast or a radionucleotide (often technetium-99m) into the intrathecal space. For the former, a CT scan is then performed to look for egress of contrast material into the sinonasal cavity. A major restriction is that it requires an active fistula for diagnosis that leads to variable accuracy with reports of 40–90% success in identifying a leak.34 With regard to the nuclear study, cottonoids are placed in various locations within the nasal cavity (i.e. the middle meatus and olfactory cleft) and later removed to examine for radioactivity. This methodology also requires an active leak to be present. It is hindered by poor spatial resolution of the actual leak site. A further limitation of this study is the high rate of false positive results in up to 33%.25 While the above techniques have the potential to be helpful in diagnosis and localization, their mixed accuracy as well as their invasive nature have prevented these modalities from becoming firstline choices in the diagnostic armamentarium (Fig. 3.2).

Indications for Repair While chronic rhinorrhea or postnasal drip can be an annoyance for the patient, the underlying drive for repair is the prevention of more serious and potentially life-threatening infectious complications. In considering the concept of CSF fistula in its most basic form, it is a direct communication between the sterile intracranial cavity and the contaminated nasal and sinus cavities.


A number of reports have attempted to quantify the risk of intracranial infection. In a prospective analysis, Daudia et al.35 identified an overall risk of meningitis to be 19% in those with persistent leaks with most episodes occurring within the first year from onset. Others have reported the risk of meningitis to be up to 29% in post-traumatic leaks with a delay in presentation ranging from 2 days to over 6 years.36 Endoscopic closure has been found to prevent ascending meningitis in these patients.37 While meningitis can often be adequately treated with systemic antibiotic therapy, the morbidity is significant and fatal results are not uncommon.25

Adjunctive measures CSF Diversion and ICP Management The use of CSF diversion or drainage, on a temporary or permanent basis, is an area of controversy. The use of LD in open lateral and posterior skull base procedures has been shown to decrease the rate of postoperative leaks from 35% to 12%,38 while the role in anterior skull base surgery and in particular endoscopic procedures is still being defined. This controversy in large part stems from the risk:benefit ratio of temporary LD or permanent diversion systems, commonly ventriculoperitoneal shunts (VPS). There currently is a lack of level-one data to support their routine use at this time despite the fact that their use makes physiologic sense. While the overall utility is still undefined, the morbidity from them is well known.7,39 LD complications including lumbar leakage, overdrainage, retained catheter tip, and pneumocephalus have been reported at up to12%39 and the long-term complication rate (including mechanical dysfunction, infection, and mortality) of permanent shunting is up to 24%.40 Perioperative LD has also been shown to be a significant predictor of intracranial complications.41 The use of LD varies greatly and excellent success rates have been reported by both extremes. Those patients most likely to benefit are those with underlying elevated ICP, given their higher rates of failure if ICP is not addressed.21 A number of groups have taken a more aggressive approach to identify those who will need long-term drainage prior to failure. Patients who are potentially at higher risk of elevated ICP can be identified preoperatively (Table 3.3),23 and imaging characteristics noted on preoperative assessment (Table 3.2) may also raise suspicion.

Table 3.3: Risk factors for ↑ ICP23 Idiopathic/spontaneous leaks Recurrent leaks History of subarachnoid hemorrhage History of intracranial infection (ICP: Intracranial pressure).


Fig. 3.3: Algorithm for management of intracranial pressure in spontaneous and high-risk* cerebrospinal leaks; (CSF: Cerebrospinal fluid; LD: Lumbar drainage; ICP: Intracranial pressure; VPS: Ventriculoperitoneal shunt). *See Table 3.3. † Optimum length of LD has not been defined and is controversial.

Lumbar puncture and measurement of opening pressure in the preoperative period has been shown to be inaccurate, especially in the face of an active leak that may act as a ‘pressure-release’ valve.18,21 In high-risk patients, many physicians will routinely utilize perioperative LD. Following surgical repair, Schlosser et al.42 and Woodworth et al.19 advocate clamping the LD after 24 hours with subsequent measurement of ICP 3–4 hours later. Those found to have moderately elevated ICP were treated with acetazolamide, while those with severely elevated ICP (> 35 mm H2O) were referred for VPS. Carrau et al.23 report utilizing a LD for a longer period of 3–5 days prior to clamping with subsequent removal if there is no leak after 24 hours. A separate lumbar puncture is performed 24 hours later and if opening pressure is elevated, a VPS is placed. Both of these reports demonstrate that more aggressive management of elevated ICP can achieve success rates comparable to those in patients without elevated ICP (see Figure 3.3 for suggested treatment algorithm).


Intrathecal Fluorescein Low-flow leaks can be difficult to identify, especially in the absence of an obvious skull base defect on preoperative imaging. When other methods fail, the use of intrathecal fluorescein can aid in localizing occult leaks and can be especially helpful when multiple sites of leakage are present.19 The greenish color imparted to CSF is typically easily recognizable with standard white light alone, but can be augmented by its fluorescent capability when a bluelight filter is applied.43 The use of intrathecal fluorescein for improved identification of leaks is also an area of controversy. It is more commonly utilized outside of the United States; lack of FDA approval for intrathecal injection has prevented widespread and routine use.23 Hesitancy also stems from early reports of major complications including cardiac arrhythmias, peripheral neuropathies, opisthotonos, seizures, and death. The majority of these were secondary to the use of much higher concentrations as well as the rapid injection of the agent. A total dose of < 50 mg is generally thought to be safe although rare complications are still reported.5 Numerous studies have demonstrated that slow intrathecal injection over 10 minutes with very low doses of 0.1–0.25 mL of 10% injectable fluorescein mixed with 10 mL of CSF is associated with excellent safety profiles without loss of diagnostic advantage.22,43 Some have recommended premedicating patients with steroids and antihistamines to further diminish the risk.43

Antibiotics The use of prophylactic antibiotics has been an area of dispute. Proponents argue that they decrease the incidence of meningitis, while detractors voice concerns over the selection of potentially more resistant organisms.6 A recent Cochrane review evaluated the use of prophylactic antibiotics in skull base fractures and found no difference between the two groups with respect to incidence of meningitis, mortality, and the need for surgical correction,44 and thus concluded that current evidence does not support their routine use. While this study was specifically looking at traumatic leaks, the recommendation has been extrapolated to spontaneous leaks. Although prophylactic use is controversial, perioperative use is fairly well accepted. Given the repeated passage of instruments and grafts through the contaminated nasal cavity, there is a real risk of direct contamination of the intracranial contents.45 Additionally, routine postoperative use is common with intranasal packing or LD being the most commonly cited reasons.5 At present, there is no universally agreed upon protocol for their use that likely stems from a lack of high-level evidence.5 Many authors advocate broad-spectrum antibiotic coverage (i.e. ceftriaxone or cefepime),6,12,46 while

32 Recent Advances in Otolaryngology—Head and Neck Surgery others focus more on the need for gram-positive coverage (i.e. vancomycin or cefazolin).45 Ultimately, further work is needed to define the optimal perioperative antibiotic management strategy, though their use in some form appears practical and is recommended.

Methods of repair Basic Steps While there are many variations used by different physicians (see section ‘Variations in techniques’), there are a number of universally agreed upon steps that are critical to a successful repair. These steps are irrespective of etiology of the defect. Perhaps most important is localization of the defect based on preoperative imaging (see section ‘Preoperative assessment and considerations’) or intraoperative inspection with or without intrathecal fluorescein. Although the use of image guidance systems has not been found to improve rates of closure, it lends itself to increased levels of surgeon confidence47 and is helpful in localizing the site of a defect visualized on preoperative imaging. The patient is prepared in the same manner as for endoscopic sinus surgery. LD can be placed immediately preceding or following the operation. The navigation system is registered and accuracy is verified. The nasal cavity is decongested with topical oxymetazoline, neosynephrine, or cocaine per the surgeon’s preference and the surgery proceeds according to the steps listed below.

Wide Exposure Adequate exposure is a critical first step and varies significantly by site. Although small CSF leaks of the cribriform plate can be visualized by lateral displacement of the middle turbinate, these defects typically involve the lateral lamella and are best addressed with resection of the middle turbinate and partial ethmoidectomy. Similarly, CSF leaks of the ethmoid roof require an ethmoidectomy and resection of the middle turbinate. Leaks in the region of the frontal outflow tract or posterior wall of the frontal sinus can be difficult to expose and require greater dissection for adequate exposure. Anterior ethmoidectomy with exenteration of all frontal outflow tract air cells is key. This step alone may be adequate for select leaks; however, more superiorly or laterally located defects require increased opening of the frontal sinus. Further exposure can be obtained via an endoscopic modified Lothrop procedure,48 thereby creating a wide combined outflow among the frontal sinuses. Binarial access, in particular, provides greater lateral access and improved angles for instrumentation. Far lateral leaks within the frontal sinuses, especially in well-pneumatized sinuses, may not be accessible by endoscopic techniques alone and can be supplemented with a small brow


Fig. 3.4: Wide exposure of a right lateral recess sphenoid meningoencephalocele (ME) via a transpterygoid approach. Note the contralateral sphenoid has been opened (asterisks – margins of meningoencephalocele).

or Lynch (external ethmoidectomy) incision. Access to the sphenoid sinus is provided by sequential approaches with increasing amounts of exposure. The nasal corridor alone may be adequate for small centrally located leaks with direct wide sphenoidotomy performed by enlarging the natural sphenoid ostium. A bilateral approach with resection of the sphenoid rostrum can be performed if additional exposure is required. Similar to a frontal sinus exposure, this provides more lateral access and greater room for instrumentation. Partial resection of the middle turbinate and posterior ethmoidectomy can provide improved visualization of the sphenoid roof. The above techniques are inadequate for defects of the lateral recess in a well-pneumatized sphenoid sinus; a transpterygoid approach is required. This is accomplished by a total ethmoidectomy and wide sphenoidotomy as described above. A wide maxillary antrostomy is then performed. The posterior wall of the maxillary sinus is removed after cauterization of the sphenopalatine artery and its branches. The contents of the pterygopalatine fossa are displaced laterally and the vidian nerve is identified where it exits the vidian (pterygoid) canal and is preserved. The foramen rotundum and second division of the trigeminal nerve are identified superolateral to the vidian canal, and the intervening bone is removed with rongeurs or drill to fully expose the lateral recess of the sphenoid sinus (Fig. 3.4).

Resection of Meningocele or Encephalocele If present, the identified meningocele or encephalocele is resected. Herniated cerebral tissue is considered to be nonfunctional, and reduction of


Fig. 3.5: The encephalocele (E) is fulgurated using bipolar cautery until flush with the bony defect.

this tissue back into the intracranial vault is generally not recommended. Preoperative imaging should be carefully studied, however, to visualize cerebral vasculature that may have herniated into the defect. Resection is typically accomplished with gentle fulguration using bipolar cautery until flush with the underlying skull base defect (Fig. 3.5). Care is taken to avoid injury to any vessels and achieve complete hemostasis. The use of radiofrequency coblation has also been reported to be an effective, rapid, and safe means to accomplish this goal as well.49

Definition of the Defect After exposure and resection of any associated herniated cerebral tissue, defining the bony edges of the defect is critical for success. It is important to note that the skull base can be quite thin in select areas and even gentle manipulation can lead to enlargement of the defect. All surrounding mucosa and loose bone fragments should be removed circumferentially. This step exposes the underlying bone and dura and provides a surface for healing of grafted tissues (Fig. 3.6). Failure to completely expose the margins of the defect inevitably leads to failure of the reconstruction.

Repair of the Defect There is great variability of reconstructive technique among surgeons. Some of these common variations will be discussed in the following sections. Reconstruction typically involves a multilayered closure and may utilize a multitude of materials and tissues. The superiority of a particular material or method has not been demonstrated.50


Fig. 3.6: Edges of the defect are circumferential cleared to enable a graft to heal to the exposed bony edges (asterisks) (E: Encephalocele).

Variations in Techniques Three basic techniques have emerged for the definitive endoscopic repair of CSF leaks. An overlay method entails the extracranial placement of a graft overlying the nasal side of the defect alone. It is important for the graft to be in contact with dura and bone and provide complete coverage of the entire defect with sufficient overlap of the edges. This method can be used in isolation for very small defects or hairline fractures with excellent outcomes. The underlay or inlay technique involves intracranial placement of a graft either between the dura and arachnoid layer or between the dura and bone of the skull base. This may not be possible where the defect abuts another structure such as the crista galli or there is risk associated with additional dural dissection. This technique is rarely used in isolation and rather a combination of both overlay and underlay techniques is the frequent method of choice. A supplemental technique, most frequently utilized for sphenoid defects, involves obliteration with a fat graft. This involves the meticulous removal of all surrounding mucosa so as to prevent both reconstructive failure and the development of a mucocele. A meta-analysis evaluating the efficacy of these techniques demonstrated no statistical difference between them.50

Graft Choice Countless studies have been published on the use and efficacy of various graft materials (autologous, homologous, and allogeneic). There appears to be no significant difference in terms of overall success between the various grafts for smaller defects (generally considered < 1 cm).50 Free grafts include

36 Recent Advances in Otolaryngology—Head and Neck Surgery fat, fascia lata, bone, cartilage, temporalis fascia, fat, cadaveric acellular dermis, collagen and dural matrix substitutes, and mucosa (for overlay only) among others. One area of debate is in the necessity of rigid reconstruction with either bone or cartilage. This can be cumbersome to place, especially in an underlay fashion. Many proponents argue for it use, especially in larger defects or in those with suspected or confirmed elevated ICP.7,19,51 No study has demonstrated improved success rates with it routine use, however, and numerous reports describe excellent results without its use.6,25 Despite some debate over its use, most would agree that it should not be utilized following oncologic resections in which adjuvant radiation is planned, given concerns over the development of osteomyelitis in the free graft. The use of bone cement or metal (titanium plates or mesh) is discouraged due to risk of chronic infection and migration. Advancements in endoscopic skull base surgery and its application to large tumors have led to impressive advances in reliable skull base reconstruction, primarily with the use of pedicled flaps. In contrast to smaller defects, a distinct advantage has been shown in the use of vascularized flaps for larger defects (typically considered >3 cm) with less than half the failure rate being reported in a recent meta-analysis.3 The pedicled nasoseptal flap (NSF), first described by Hadad and Bassagasteguy et al.,52 has become a workhorse for skull base reconstruction, especially for large defects of the anterior cranial base.15 This flap, based on the posterior septal branch of the sphenopalatine artery, has a large surface area and wide arc of rotation that can be tailored to the size of the defect (Fig. 3.7). While typical NSFs extend inferiorly to the maxillary crest, extended flaps can be designed to include

Fig. 3.7: A graft is placed to close the defect. In this patient, a nasoseptal flap has been chosen as the reconstructive method.


the entire ipsilateral nasal floor. Large defects extending from the posterior wall of the frontal sinus to the sella turcica and incorporating the entire interorbital width can be adequately repaired with a large flap.52 Others have demonstrated successful repair of clival defects53,54 as well as middle fossa defects using the NSF.55,56 Further utility comes from the ability to elevate and reuse the NSF (in the same location) should revision surgery become necessary. While the NSF is the preferred method for endonasal reconstruction of skull base defects, alternative pedicled flaps must be considered in situations when either the NSF is unavailable (i.e. due to tumor involvement, prior septal or endonasal surgery) or if the size of the defect is significantly larger than the harvested flap. Local flap options, also based on branches of the sphenopalatine artery, include the middle turbinate flap (MTF) and the inferior turbinate flap (ITF).16,17,57,58 MTFs are generally less favored since they are thinner, have a smaller surface area, and are technically more demanding to elevate, although they can be considered for small defects of the fovea ethmoidalis, planum, and sella.58 The ITF is a more robust flap and easier to harvest than the MTF. It is a reasonable choice for reconstruction of small clival or select sellar defects,3,17 though it lacks sufficient length to reach the anterior cranial fossa. Repair of larger clival defects can potentially be accomplished with a combination of flaps or a regional pedicled flap. Regional pedicled flaps are utilized when intranasal flap options have been exhausted or fail to meet the reconstructive need. The pericranial flap (PCF) is a time-tested reconstructive method of open skull base surgery, though its use has been adapted to endonasal use. Endoscopic harvesting has been described,59 though it is generally harvested via a bicoronal incision. The flap can be unilaterally or bilaterally pedicled and is transposed endonasally through an adequately sized bony window created at the level of the nasion. Defects of the entire anterior cranial base extending to the sella and beyond can reliably be reconstructed (see Fig. 3.8). Of note, this flap requires a Draf III frontal sinusotomy in order to maintain an adequate drainage pathway for the frontal sinuses. The temporoparietal fascial flap (TPFF) is another welldescribed flap that has been adapted to endonasal use. Similar to the PCF, it requires an external hemicoronal incision. Endonasal transposition is accomplished via a serially dilated infratemporal tunnel combined with an endonasal transpterygoid approach.60 The TPFF has been reported to provide coverage of anterior, middle, clival, and parasellar defects,60 though others have questioned its utility for anterior defects due to the significant pedicle rotation that is required.3 Many surgeons will use a dural sealant or fibrin glue to further immobilize the graft, although the need for this practice as it relates to improvement in outcomes has recently been called into question.6,61 Following the


A

B Figs 3.8A and B: A large anterior skull base defect extending from the posterior wall of the frontal sinus to the sphenoid planum and from orbit to orbit. (A) Collagen matrix fascial graft placed in an underlay fashion. (B) Pericranial flap covering entire defect after transposition through a nasal window (top of photo) (asterisks – margin of flap).

above listed steps, the graft site is reinforced with absorbable gelatin foam that acts to both immobilize the graft and prevent disruption of the graft upon removal of any additional packing materials. Below the absorbable packing, expandable nasal tampons, antibiotic impregnated petroleum gauze, or a Foley catheter balloon are placed to provide additional support. These are left for variable amounts of time, but typically 2–7 days depending on the size of the defect, reconstructive technique, risk factors for elevated ICP, and surgeon preference.


Outcomes The high degree of successful repair has made the endoscopic approach the method of choice for repair of CSF fistulae. A recent meta-analysis identified a successful primary repair rate of 90.6% with a revision success rate of 97%.5 Even spontaneous leaks associated with elevated ICP, which historically demonstrated higher failure rates, can achieve comparable success when ICP is accounted for in a proactive manner.19,23 As mentioned previously, there have been no significant differences in outcomes between the various techniques applied and even the grafting materials utilized.50 An exception to this, however, likely exists in the realm of advanced endoscopic skull base procedures that lead to large defects. In these situations, vascularized flaps have been shown to improve outcomes over free grafting techniques, dropping the postoperative leak rate from 15.6% to 6.7%.3

Complications Endoscopic repair of CSF leaks has a low incidence of complications. Compared with open repair, the endoscopic approach is associated with significantly lower rates of meningitis, abscess, sepsis, and mortality. The overall major complication rate is low50 with a recent meta-analysis reporting a rate of 0.03% with the most frequent of these being meningitis. This is much likely lower than the true rate as the majority of reports fail to comment on either the presence or absence of complications.5 In addition to meningitis, other reported major complications include brain abscess, subdural hemorrhage, anosmia, pneumocephalus, mucocele formation, and vasospasm.5,50,62 Olfactory loss is a necessary sequela of repair of CSF leaks of the cribriform area and may be noticed even if olfaction is preserved on the contralateral side. Perioperative antibiotic prophylaxis is essential for the duration of nasal packing to prevent nasal cellulitis, meningitis, and toxic shock syndrome.

Summary The treatment paradigm of CSF leaks has changed dramatically over the past several decades. While open techniques still have their role, the endoscopic approach has become the method of choice for repair of fistulae of the sinonasal cavity, regardless of etiology. This shift in treatment has come in large part due to the long-term success rates equaling if not exceeding those of open approaches. Additionally, major complications are infrequent. Enhancements in optics, the development of instruments suited to skull base surgery, improved technique, and better localization of leaks have enabled this progress. The development of pedicled flaps has further expanded the role of endoscopic skull base reconstruction and enabled reliable repair of even large defects. Continued innovation of surgical techniques with development of new biomaterials is expected to further improve outcomes.


References

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Endoscopic Repair of Cerebrospinal Fluid Leaks 41 17. Fortes FSG, Carrau RL, Snyderman CH, et al. The posterior pedicle inferior turbinate flap: a new vascularized flap for skull base reconstruction. Laryngoscope 2007; 117:1329–32. 18. Soler ZM, Schlosser RJ. Spontaneous cerebrospinal fluid leak and management of intracranial pressure. Adv Otorhinolaryngol 2013; 74:92–103. 19. Woodworth BA, Prince A, Chiu AG, et al. Spontaneous CSF leaks: a paradigm for definitive repair and management of intracranial hypertension. Otolaryngol Head Neck Surg 2008; 138:715–20. 20. Wang EW, Vandergrift WA 3rd, Schlosser RJ. Spontaneous CSF leaks. Otolaryngol Clin North Am 2011; 44:845–56, vii. 21. Ramakrishnan VR, Suh JD, Chiu AG, et al. Reliability of preoperative assessment of cerebrospinal fluid pressure in the management of spontaneous cerebrospinal fluid leaks and encephaloceles. Int Forum Allergy Rhinol 2011; 1:201–5. 22. Seth R, Rajasekaran K 3rd, Luong A, et al. Spontaneous CSF leaks: factors predictive of additional interventions. Laryngoscope 2010; 120:2141–6. 23. Carrau RL, Snyderman CH, Kassam AB. The management of cerebrospinal fluid leaks in patients at risk for high-pressure hydrocephalus. Laryngoscope 2005; 115:205–2. 24. Maguire RC, Gull J, Weaver M, et al. Otolaryngologic uses for spinal drains. Ear Nose Throat J 2010; 89:E17–22. 25. Daele JJM, Goffart Y, Machiels S. Traumatic, iatrogenic, and spontaneous cerebrospinal fluid (CSF) leak: endoscopic repair. B-ENT 2011; 7:47–60. 26. Meurman OH, Irjala K, Suonpää J, et al. A new method for the identification of cerebrospinal fluid leakage. Acta Otolaryngol (Stockh) 1979; 87:366–9. 27. Arrer E, Meco C, Oberascher G, et al. beta-Trace protein as a marker for cerebrospinal fluid rhinorrhea. Clin Chem 2002; 48:939–41. 28. Mostafa BE, Khafagi A. Combined HRCT and MRI in the detection of CSF rhinorrhea. Skull Base Off J North Am Skull Base Soc Al 2004; 14:157–62; discussion 162. 29. Agid R, Farb RI. Neuroimaging in the diagnosis of idiopathic intracranial hypertension. Minerva Med 2006; 97:365–70. 30. Silver RI, Moonis G, Schlosser RJ, et al. Radiographic signs of elevated intracranial pressure in idiopathic cerebrospinal fluid leaks: a possible presentation of idiopathic intracranial hypertension. Am J Rhinol 2007; 21:257–61. 31. Agid R, Farb RI, Willinsky RA, et al. Idiopathic intracranial hypertension: the validity of cross-sectional neuroimaging signs. Neuroradiology 2006; 48: 521–7. 32. Rajeswaran R, Chandrasekharan A, Mohanty S, et al. Role of MR cisternography in the diagnosis of cerebrospinal fluid rhinorrhoea with diagnostic nasal endoscopy and surgical correlation. Indian J Radiol Imaging 2006; 16:315. 33. El Gammal T, Sobol W, Wadlington VR, et al. Cerebrospinal fluid fistula: detection with MR cisternography. AJNR Am J Neuroradiol 1998; 19:627–31. 34. Zuckerman JD, DelGaudio JM. Utility of preoperative high-resolution CT and intraoperative image guidance in identification of cerebrospinal fluid leaks for endoscopic repair. Am J Rhinol 2008; 22:151–4.

42 Recent Advances in Otolaryngology—Head and Neck Surgery 35. Daudia A, Biswas D, Jones NS. Risk of meningitis with cerebrospinal fluid rhinorrhea. Ann Otol Rhinol Laryngol 2007; 116:902–5. 36. Bernal-Sprekelsen M, Bleda-Vázquez C, Carrau RL. Ascending meningitis secondary to traumatic cerebrospinal fluid leaks. Am J Rhinol 2000; 14:257–9. 37. Bernal-Sprekelsen M, Alobid I, Mullol J, et al. Closure of cerebrospinal fluid leaks prevents ascending bacterial meningitis. Rhinology 2005; 43:277–81. 38. Bien AG, Bowdino B, Moore G, Leibrock L. Utilization of preoperative cerebrospinal fluid drain in skull base surgery. Skull Base 2007; 17:133–9. 39. Ransom ER, Palmer JN, Kennedy DW, et al. Assessing risk/benefit of lumbar drain use for endoscopic skull-base surgery. Int Forum Allergy Rhinol 2011; 1:173–7. 40. Korinek A-M, Fulla-Oller L, Boch A-L, et al. Morbidity of ventricular cerebrospinal fluid shunt surgery in adults: an 8-year study. Neurosurgery 2011; 68:985–94; discussion 994–5. 41. Pepper J-P, Lin EM, Sullivan SE, Marentette LJ. Perioperative lumbar drain placement: an independent predictor of tension pneumocephalus and intracranial complications following anterior skull base surgery. Laryngoscope 2011; 121:468–73. 42. Schlosser RJ, Wilensky EM, Grady MS, et al. Cerebrospinal fluid pressure monitoring after repair of cerebrospinal fluid leaks. Otolaryngol Head Neck Surg 2004; 130:443–8. 43. Placantonakis DG, Tabaee A, Anand VK, et al. Safety of low-dose intrathecal fluorescein in endoscopic cranial base surgery. Neurosurgery 2007:161–5; discussion 165–6. 44. Ratilal BO, Costa J, Sampaio C, et al. Antibiotic prophylaxis for preventing meningitis in patients with basilar skull fractures. Cochrane Database Syst Rev Online 2011; (8):CD004884. 45. Brown SM, Anand VK, Tabaee A, et al. Role of perioperative antibiotics in endoscopic skull base surgery. Laryngoscope 2007; 117:1528–32. 46. Eloy JA, Kuperan AB, Choudhry OJ, et al. Efficacy of the pedicled nasoseptal flap without cerebrospinal fluid (CSF) diversion for repair of skull base defects: incidence of postoperative CSF leaks. Int Forum Allergy Rhinol 2012; 2:397–401. 47. Tabaee A, Kassenoff TL, Kacker A, et al. The efficacy of computer assisted surgery in the endoscopic management of cerebrospinal fluid rhinorrhea. Otolaryngol Head Neck Surg 2005; 133:936–43. 48. Becker SS, Duncavage JA, Russell PT. Endoscopic endonasal repair of difficultto-access cerebrospinal fluid leaks of the frontal sinus. Am J Rhinol Allergy 2009; 23:181–4. 49. Smith N, Riley KO, Woodworth BA. Endoscopic CoblatorTM-assisted management of encephaloceles. Laryngoscope 2010; 120:2535–9. 50. Hegazy HM, Carrau RL, Snyderman CH, et al. Transnasal endoscopic repair of cerebrospinal fluid rhinorrhea: a meta-analysis. Laryngoscope 2000; 110: 1166–72. 51. Tabaee A, Anand VK, Brown SM, et al. Algorithm for reconstruction after endoscopic pituitary and skull base surgery. Laryngoscope 2007; 117:1133–7.

Endoscopic Repair of Cerebrospinal Fluid Leaks 43 52. Hadad G, Bassagasteguy L, Carrau RL, et al. A novel reconstructive technique after endoscopic expanded endonasal approaches: vascular pedicle nasoseptal flap. Laryngoscope 2006; 116:1882–6. 53. Saito K, Toda M, Tomita T, et al. Surgical results of an endoscopic endonasal approach for clival chordomas. Acta Neurochir (Wien) 2012; 154:879–86. 54. Koutourousiou M, Gardner PA, Tormenti MJ, et al. Endoscopic endonasal approach for resection of cranial base chordomas: outcomes and learning curve. Neurosurgery 2012; 71:614–24; discussion 624–5. 55. Alexander NS, Chaaban MR, Riley KO, et al. Treatment strategies for lateral sphenoid sinus recess cerebrospinal fluid leaks. Arch Otolaryngol Head Neck Surg 2012; 138:471–8. 56. Chaaban MR, Illing E, Riley KO, et al. Spontaneous cerebrospinal fluid leak repair: a five-year prospective evaluation. Laryngoscope 2013; 57. Simal Julián JA, Miranda Lloret P, Cárdenas Ruiz-Valdepeñas E, et al. Middle turbinate vascularized flap for skull base reconstruction after an expanded endonasal approach. Acta Neurochir (Wien) 2011; 153:1827–32. 58. Prevedello DM, Barges-Coll J, Fernandez-Miranda JC, et al. Middle turbinate flap for skull base reconstruction: cadaveric feasibility study. Laryngoscope 2009; 119:2094–8. 59. Zanation AM, Snyderman CH, Carrau RL, et al. Minimally invasive endoscopic pericranial flap: a new method for endonasal skull base reconstruction. Laryngoscope 2009; 119:13–8. 60. Fortes FSG, Carrau RL, Snyderman CH, et al. Transpterygoid transposition of a temporoparietal fascia flap: a new method for skull base reconstruction after endoscopic expanded endonasal approaches. Laryngoscope 2007; 117:970–6. 61. Eloy JA, Choudhry OJ, Friedel ME, et al. Endoscopic nasoseptal flap repair of skull base defects: is addition of a dural sealant necessary? Otolaryngol Head Neck Surg 2012; 147:161–6. 62. Hunt JP, Richards T. Cerebrovasospasm following endoscopic cerebrospinal fluid leak repair. Skull Base 2010; 20:363–6.


Chapter

Measuring Quality of Life in Nasal Surgery

4

Ingo Baumann

Quality of life—basics and definitions The goal of any medical treatment should be the cure of the patient. If it is not possible to cure the patient, all efforts must be made to reduce the symptoms. In this context, the communication between doctor and patient is of particular importance, since the physician must first clearly understand the symptoms and discomfort of his patients in order to initiate then appropriate treatment. From this necessity, the first questionnaires were developed in the context of clinical trials. Validation procedures for checking the questionnaires were designed to obtain reliable and reproducible information. The use of validated standardized questionnaires measuring subjective patient assessments has been established over the past decades and evolved to be the basis of quality-of-life (QOL) research in clinical medicine. It has been shown that validated QOL instruments may reflect the clinical presentation of patients very comprehensively and reproducible. However, in clinical rhinology objective measurement methods like the rhinomanometry or computed tomography (CT) of the paranasal sinuses are often not able to establish significant correlations between the collected data and the symptoms reported by the patients. Therefore, the importance of validated QOL instruments has increased steadily in recent years. The outcome of a medical treatment is determined by two main influences. It can be stated that the assessment of health-related QOL of the patients is one important factor in the assessment of outcome. Furthermore, the outcome of a patient is also determined by the objective measurements in the investigations and by clinical findings raised by the doctor. In recent decades, a consensus has emerged that both the subjective QOL ratings of patients and the medical evaluation and measurements define the patient’s outcome. Against this background, it is of great importance that the concept of health-related QOL is clearly defined. The World Health Organization (WHO) distinguishes general QOL and health-related QOL. Subjective assessments are carried out in a specific cultural, social, and environment-related context.

Measuring Quality of Life in Nasal Surgery 45

QOL is seen as a multidimensional construct.1 Schipper2 defines QOL as follows: ‘Quality of life represents the functional effect of an illness and its consequent therapy upon the patient, as perceived by the patient’. The importance of QOL measurements in clinical research has increased steadily in recent years. Nowadays, clinical studies are usually conducted using validated QOL measurement tools to evaluate the outcome. It is expected that for the reimbursement of medical treatments by payers such as insurances the evidence of intervention-related QOL improvement will increasingly be demanded. In addition, QOL instruments are extremely helpful in daily practical work with the patient, as they indicate directly how the patient is doing. They ensure that important symptoms are not overlooked and the doctor can use them as a working basis on which he can purposefully communicate with the patients.3

Quality of life in patients with chronic rhinosinusitis Chronic rhinosinusitis (CRS) is one of the most common diseases in industrialized countries. In Germany, it affects around 10–15% of the population.4 In the United States, CRS was the most frequently reported chronic disease in a representative cohort of the ‘National Health Interview Survey 1998’ comprising data of 100,000 adults.5 Consequently, QOL of patients with CRS shifted early into the focus of research interest. Until the 1990s, clinical studies on paranasal sinus surgery usually reported clinical-endoscopic findings, complications, reoperation rates, etc. It was assumed that postoperative clinical-endoscopic findings showing no evidence of disease indicated successful treatment. However, these findings were often substantially different to the subjective assessments by the patients.6 For the past 20 years, validated QOL instruments were used to improve the assessment of patient outcome. The number of publications with QOL ratings in CRS patients has steadily increased. A recent PubMed search for the most commonly used disease-specific QOL instruments in CRS, the SNOT-20, SNOT-22, and CSS revealed 127, 53, and 55 hits, respectively.7

General Quality of Life in CRS The application of generic QOL instruments in patients with CRS demonstrated a significant impact of this disease on the overall QOL. The Short Form 36 Health Survey (SF-36) is the most widely used instrument to measure general health-related QOL.8 It has demonstrated positive effects of endonasal sinus surgery on health-related QOL in patients with CRS in several studies.9,10 We detected these effects in our own patients, too.11 In a

46 Recent Advances in Otolaryngology—Head and Neck Surgery Table 4.1: Benefit assessment by CRS patients using the Glasgow Benefit Inventory

n

Overall benefit

General health

Social support

Physical functioning

Salhab et al.16

77

11.1

12.5

0

0

Baumann et al.17

82

22.6

26.8

2.9

23.7

Newton et al.18

50

25.0

29.2

0

16.7

(CRS: Chronic rhinosinusitis).

prospective long-term study, Khalid et al. found even 3 years postoperatively significantly improved scores in 6 out of 8 scales (except physical functioning and emotional role function).12 The SF-36 was frequently used in combination with disease-specific instruments. For example, in a prospective controlled study significant improvements after medical or surgical treatment of CRS could be detected in both the SF-36 and the SNOT-20 with no differences in treatment success between the two patient groups.13 For children with recurrent CRS, the Child Health Questionnaire (CHQ) demonstrated a significantly reduced QOL compared with the general population and other chronic pediatric diseases.14 The Glasgow Benefit Inventory (GBI) has been validated and introduced in 1996 as a post-interventional instrument for ENT procedures.15 The benefit of CRS patients after functional endoscopic sinus surgery (FESS) procedures measured with the GBI in various studies is listed in Table 4.1. Additionally, the study of Salhab et al. demonstrated a greater benefit of FESS in patients with polyposis compared with patients without polyposis.16

Disease-specific Quality of Life in Chronic Rhinosinusitis To measure the disease-specific QOL in CRS a series of measuring instruments was developed and validated. Of these, particularly the Sino-Nasal Outcome Test 20 (SNOT-20), the SNOT-22, and the Chronic Sinusitis Survey (CSS) have prevailed. An overview of the published instruments and their psychometric properties is given in Table 4.2.

Sino-Nasal Outcome Test 20 (SNOT-20) Piccirillo et al. presented a 31-item questionnaire in 1995 which they called the Rhinosinusitis Outcome Measure (RSOM-31).29 It contained rhinosinusitisspecific and general questions. An abridged version of this questionnaire is the SNOT-20, which like its predecessor has been validated.25,30 The work with the shorter questionnaire showed a higher compliance by patients because of the lower time consumption.

X X

English

English

English, Chinese, Norwegian

General Nasal Patient Inventory (GNPI)2

X

English, Czech, Danish, Portuguese (Brazil), Lithuanian

German

Sino-Nasal Outcome Test 22 (SNOT-22)27

Sino-Nasal Outcome Test 20 German Adapted Version (SNOT-20 GAV)28

(CRS: Chronic rhinosinusitis; QOL: Quality of life; NR: Not reported).

-

English, French


X

-

English, Japanese, Chinese Spanish (Chile) Portuguese


X

English

Rhinosinusitis quality-of-life survey (RhinoQoL)24

Chronic Sinusitis Survey (CSS)

9

Sinunasal-5 quality of life survey (SN-5)

X

English

Sino-Nasal Assessment Questionnaire (SNAQ-11)21

23

X

English, Turkish

Rhinosinusitis Disability Index (RSDI)20 X

X

English

Nasal Symptom Questionnaire19

Nasal obstruction

Language

Measuring instrument

X

X

X

X

X

X

X

X

X

X

X

Nasal discharge

X

X

X

X

X

X

X

X

X

X

X

X

X

-

-

-

-

X

X

X

X

X

Facial Loss of fullness/ smell pressure

Main symptoms of CRS

X

X

X

X

X

X

X

NR

X

X

X

Relia bility

X

X

X

X

X

X

X

(X)

X

NR

X

Validity

X

X

X

X

X

X

X

NR

X

NR

X

Sensitivity to change (Responsiveness)

Psychometric characteristics

Table 4.2: Major symptoms of CRS and psychometric characteristics in different disease-specific QOL instruments


48 Recent Advances in Otolaryngology—Head and Neck Surgery The SNOT-20 polls 20 CRS symptoms that are associated with the five subgroups: nasal, paranasal, sleep, social, and emotional symptoms. Patients rate their discomfort on a 6-point scale with increasing symptomatology from 0 (‘no problem’) to 5 (‘problem as bad as it can be’). The SNOT-20 score is calculated by summing all symptom scores. Thus, the score values range from 0 to 100. In addition, patients may indicate the five most stressful symptoms. The SNOT-20 was widely used as a QOL instruments in patients with CRS. In conservative treatment of CRS with nasal steroids, a reduction in the pretreatment total score of 19 to a post-therapeutic score of 13 was reached.31 In a prospective, randomized study to evaluate the medication versus surgical treatment of CRS by QOL measurements with the SNOT-20 and SF-36, no differences between the two forms of therapy were found.13 The influence of the presence of polyps in patients with CRS on the subjective evaluation of the result of surgery was also investigated. Here, conflicting results have been reported. While Ragab et al.13 did not regard nasal polyps as a prognostic factor for the outcome of therapy, Deal and Kountakis32 found based on their results that polyposis patients frequently showed more pronounced symptoms, smaller improvements after surgical therapy, higher CT scores, and a significantly increased rate of revision surgery.

Sino-Nasal Outcome Test 22 (SNOT-22) The SNOT-22 resulted from the SNOT-20 by the addition of items ‘nasal obstruction’ and ‘olfactory impairment’. These important items are two of the main symptoms of the definition of CRS.33 The absence of these items in the SNOT-20 represented a lack of quality in this measuring instrument that was now addressed. However, the validation of the SNOT-22 was performed only in 2009 by Hopkins.27 In the meantime, in 2007 a German group validated and published a corrected and modified version of the SNOT-20, the so-called SNOT-20 GAV (German Adapted Version) (see section ‘Sino-Nasal Outcome Test 20 German Adapted Version (SNOT-20 GAV)’).28 The largest published study using the SNOT-22 was carried out in the UK in 2003.34 The National Comparative Audit of Surgery for Nasal Polyposis and CRS was supported by the Clinical Effectiveness Unit of the Royal College of Surgeons of England. In 2000, this survey was conducted in 87 hospitals in the National Health Service in England and Wales. The SNOT-22 was used prospectively in 3128 patients (preoperatively and 3 and 12 months post operatively). It has to be mentioned that the SNOT-22 at that time had not been validated yet. However, it covered completely the definition of CRS by adding the items ‘nasal obstruction’ and ‘olfactory impairment’ as opposed to the SNOT-20. Overall, a high level of satisfaction with the results of sinus surgery could be determined. After 3 months, 12 clinically significant improvements


in SNOT-22 scores were found for the entire patient cohort. However, between the 3rd and 12th month a deterioration of ratings was observed with persisting significant improvements only in polyposis patients. Of the CRS patients without polyposis only 43.4% reported a persisting significant improvement in their symptoms after 12 months, while 31.9% rated their symptoms equal or worse compared with the preoperative state. Therefore, CRS patients with nasal polyposis benefited more from surgery than CRS patients without polyposis.

Sino-Nasal Outcome Test 20 German Adapted Version (SNOT-20 GAV) To assess the impact of CRS on QOL in German-speaking patients, a German questionnaire called the Sino-Nasal Outcome Test 20 German Adapted Version (SNOT-20 GAV)28 was developed on the basis of the SNOT-20.25 Due to the criticism of Fahmy et al.35 and to cover all aspects of the current definition of CRS,33 some changes were introduced in the questionnaire. On the basis of statistical evaluations of the SNOT-20 the issues ‘Wake up tired’ and ‘Lack of good night’s sleep’ were replaced by the not yet existing but important issues ‘nasal obstruction’ and ‘olfactory impairment.’ As the original SNOT-20 summarizes disease-specific and general QOL issues in one overall score options for specific analysis are reduced. To allow a more specific evaluation, three subscores were introduced in the SNOT-20 GAV: Primary Nasal Symptoms (PNS), Secondary Rhinogenous Symptoms (SRS), and General Quality of Life (GQOL). The changes in the SNOT-20 and the transmission into the German language required a validation of the SNOT-20 GAV that was successfully performed.28 In addition, normative values were calculated on the basis of data from a comparative cohort (n = 778). A rating scale, which was calculated on the basis of these data, allows assessing the severity of disease for every individual patient.36

Chronic Sinusitis Survey (CSS) The CSS was developed by Gliklich and Metson.9 Since then this instrument was besides the SNOT-20 the most frequently used questionnaire to measure health-related QOL in CRS patients. The CSS consists of six individual questions and was able to demonstrate its statistical validity and reliability.36–38 It consists of a symptom-based and medication-based part. Of the cardinal symptoms of CRS, the olfactory impairment is not requested. In contrast to other QOL measurement instruments, not only the severity of the impairment but also the time duration of the symptoms was surveyed due to the higher retest reliability coefficients revealed in the development of the questionnaire.9

50 Recent Advances in Otolaryngology—Head and Neck Surgery The CSS demonstrated to have a high sensitivity to clinical changes over time in CRS patients. Measurements with the CSS showed that endonasal sinus surgery reduced the duration of symptoms in patients with CRS.9,37–39 A cost-benefit analysis of endonasal sinus surgery for CRS patients using the CSS showed that the treatment of mild forms of CRS compared with pan sinusitis is more cost-effective.38 A linear proportionality between the severity of disease and cost-benefit ratio did not exist. The preoperative CSS score and the severity of disease on CT of the paranasal sinuses were identified as predictive factors for postoperative CSS score.37

Quality of life after septoplasty Surgery of the nasal septum (septoplasty) is a very common procedure. In 2007, over 95,000 septoplasties were carried out in Germany. This corres ponds to 0.7% of all surgical procedures. Furthermore, this operation occupies rank 37 of surgical procedures performed in Germany in the evaluations of the Federal Health Monitoring, while tonsillectomy occupies rank 38.40 Disease-specific QOL measurement instruments have always been superior to the general QOL measurement instruments when the disease burden is lower than the threshold detected with the general measurement instrument9. Specific complaints that can clearly affect the life are not always adequately covered by the general measuring instruments. Nevertheless, general measuring instruments are essential to capture the impact of specific diseases on general health. In addition, general measuring instruments allow comparisons of the influence of various diseases on QOL. Some studies have postulated that patients with septal deviation have limited ‘nose-specific’ QOL, but normal levels of overall QOL. While nasal symptoms improved after septoplasty, general scales of the Nottingham Health Profile (NHP) and the General Health Questionnaire (GHQ) remained unchanged.41 Another study with elderly patients > 65 years revealed an improvement from 52 points to 77 points on a 0-100-scale, while improvements were not significant in the generic SF-12 questionnaire.42 However, a study by Buckland et al. with the SNOT-22 showed a significant improvement in nasal and general items after septoplasty.43 It has to be suspected that effects of septoplasty on general QOL are smaller compared with the effects of FESS on patients with CRS. However, patients with CRS are more affected by the disease in different QOL domains compared with patients who receive septoplasty for nasal obstruction alone. Therefore, the potential for improvement might be higher in CRS patients.44 In many studies, surgical treatment of CRS lead to significant QOL improvements in generic measures.45,46 Measurements with the GBI detected higher improvements for CRS patients than for septoplasty patients.17,47,48


Only few studies dealing with the disease-specific health-related QOL after septoplasty were published. Most of the papers used retrospective data, which were collected with inappropriate or nonvalidated measures. However, some interesting conclusions can be deduced from these data. During the last decades, the subjective outcome after septoplasty was assessed increasingly systematic and with more and more improved measures. One could observe a development from the simple questioning of satisfaction, via the use of visual analogue scales (VAS) and the use of nonspecific QOL measures to the use of the specific NOSE scale.

Assessment of Satisfaction A reinvestigation 10 years after septoplasty revealed 84% satisfaction (31 out of 37 patients).49 Further studies detected a range from 70.5% to 86% satisfied patients.50–54 Jessen reported that 9 months after septoplasty 74% of the patients were satisfied with the result of surgery. After 9 years, 69% of the patients were still satisfied after septoplasty, while the proportion of patients reporting to be free of obstruction halved from 51% to 26%.55 In a rhinomanometry study, patients with postoperatively reduced nasal resistance were more often satisfied compared with patients with increased nasal resistance (67 out of 83 vs. 7 out of 17).56 However, the quality of the data regarding validity and reliability of the used questionnaire is arguable. A bias during questioning cannot be precluded, while the conclusions are blurred and data collection was retrospective in all studies.

Measurements with Visual Analogue Scales Visual Analogue Scales have been used repeatedly for the assessment of septoplasty results, as disease-specific QOL instruments were not avai lable. Compared with assessment of satisfaction, they stand for methodical progress. A retrospective long-term evaluation 2–10 years after septoplasty yielded a mean satisfaction of 6 on a 1–10-scale.57 Furthermore, the authors stated a significant correlation between anterior septal deviation and satisfaction with the result of surgery. In a comparison of conventional versus endoscopic septoplasty, subjective assessment of obstruction by VAS did not detect a difference between the two techniques.58

Measurements with Rhinosinusitis-specific Instruments A prospective study with 93 septoplasty patients using the Nasal Health Survey (NHS, analogical to the CSS) demonstrated a significant reduction in symptoms and use of medication after surgery.45 A clinical significant improvement, which was indicated by a 50% reduction in nasal symptoms, was found in 71% of the patients. Revision surgery and female gender were identified to be predictors for a worse outcome.59 Similar results were found

52 Recent Advances in Otolaryngology—Head and Neck Surgery in another study with 40 patients above 65 years showing a significant increase in the NHS score from 52 to 77.42 A further study with 121 patients using the Fairley Nasal Symptom Score revealed a postoperative improvement of nasal obstruction in 74%, facial pain in 72%, and nasal discharge in 64% of the patients.41

Measurements with an Obstruction-specific Instrument (NOSE Scale) The application of validated disease-specific measures in prospective studies is required to achieve a high level of evidence-based medicine (EBM). Stewart et al. addressed themselves to this task and developed the Nasal Obstruction Symptom Evaluation (NOSE) scale within the scope of a multicentre study.60 A team of experts developed an alpha-version of the instrument with 10 obstruction-specific items that were scored using a 5-point Likert scale. This measure was validated by the assessment and calculation of reliability (test-retest reliability, internal consistency), validity (content validity, construct validity, discrimination validity, concurrent validity), and response sensitivity (standardized response mean, effect size). During this process, the measure was reduced to five items that are the following: nasal congestion or stuffiness, nasal blockage or obstruction, trouble breathing through the nose, trouble sleeping, unable to get enough air through the nose during exercise or exertion. The NOSE scale was then subsequently used in a prospective study with 59 patients addressing outcome evaluation after septoplasty, the multicenter so-called Nasal Obstruction Septoplasty Effectiveness (NOSE) study.61 Data revealed a significant improvement in the mean NOSE score from 67 points to 23 points (p < 0.001) on a 0–100 scale after 3 months that was also detectable after 6 months. Patient satisfaction was high with 63% of the patients being very or extremely satisfied. Furthermore, reduced use of medication was observed. Another study with 12 patients treated with extracorporeal septoplasty detected an improvement in the NOSE score from 77 points to 13 points.62 However, even if the above-mentioned studies have a high quality, the data represent short-term results. Prospective long-term studies have not been published until today.

Quality of life after rhinoplasty For the last years QOL research in facial plastic surgery has boomed, while validated QOL measures for many other fields of otolaryngology have been developed much earlier. The late onset of QOL research in this field might astonish, as subjective evaluation of results with special regard to the patient’s satisfaction is a daily challenge.63 It was potentially objected to misinterpret psychological specifics of the patients.64


Three substantial aspects of the outcome of rhinoplasty have been highlighted in the literature: 1. Quantitative measurement of nasal appearance changes 2. Quantitative and qualitative changes of nasal function 3. Subjective assessment of patient satisfaction and health-related QOL.65 The assessment of satisfaction with the result of rhinoplasty was used as a subjective outcome parameter for many years. More than 90% of the patients were satisfied with nasal appearance and breathing in retrospective studies.66,67 The measures were developed ad hoc and were used without validation. QOL measurements with validated instruments have been performed in few studies. However, it has been highlighted that such instruments should be used in studies.68

General Quality of Life and Rhinoplasty In a SF-36 study, rhinoplasty patients without nasal obstruction who wanted surgery for esthetic reasons scored general health status significantly worse compared with the normal population. This difference was not detectable 6 months after surgery.69 Another study with the Health Measurement Questionnaire (HMQ) showed improvements in general QOL after rhinoplasty. However, the degree of improvement was significantly smaller compared with other plastic procedures (mammoplasty, abdominoplasty).70 The GBI was developed in 1996 as a general measure for retro spective assessment of benefit after otolaryngologic procedures.15 With this instrument, rhinoplasty patients who were operated for nasal trauma were investigated. Factor analysis showed that subjective benefit of rhinoplasty was strongly associated with surgical success of the operation but less associated with psychological factors.71 This is consistent with the results of another study that detected more psychic alterations in rhinoplasty patients without nasal trauma compared with trauma patients.72

Disease-specific Quality of Life and Rhinoplasty The NOSE scale was applied in 41 rhinoplasty patients.73 It must be pointed out here that the NOSE scale is a disease-specific instrument dealing only with the functional outcome of nasal breathing but does not query any psychosocial aspects. The nasal obstruction in the prospectively studied patients was significantly positively influenced by the rhinoplasty. Neither the use of spreader grafts nor the reduction in the inferior turbinates was able to demonstrate a significant advantage. A disease-specific measure named Rhinoplasty Outcome Evaluation (ROE) was validated in 2001 reporting the data of 26 patients.63 Long-term results of revision rhinoplasty were retrospectively investigated with 88% of

54 Recent Advances in Otolaryngology—Head and Neck Surgery the patients being satisfied with the result. Satisfaction was reduced with increasing number of revision surgeries.74 Retrospective assessment of preoperative conditions and ex post comparison with present conditions is intended to compensate the disadvantages of prospective evaluations. The phenomenon of response shift has to be regarded in such questionings. Postoperatively a shift of responses regarding the preoperative conditions occurs as a result of success or failure of the intervention and the preoperatively misinterpreted impact of the disease on health status.75 Furthermore, the ROE was administered in a prospective study with 58 patients.76 Independently from the initial indication for surgery (traumatic, esthetic, functional), improvements in the scores were reported. The authors did not detect any impact of age, gender, or primary versus revision surgery. The ROE primarily deals with the esthetic aspects of septorhinoplasty. Only one out of six items asks for functional limitations. However, in many patients, functional aspects play an important role in determining the indication for surgery. Our group is therefore the process of developing a diseasespecific measurement instrument that addresses the functional as well as the esthetic aspects of septorhinoplasty.

The Impact of Psyche and Body Dysmorphic Disorder The psychosocial effects of rhinoplasty must not be underestimated. Some studies in psychiatric literature report a high incidence of psychopathologies in patients desiring rhinoplasty.64,77,78 Furthermore, it has to be pointed out that rhinoplasty significantly changes the appearance of the patient (‘type change’) which requires more psychological support compared with restoring interventions like facelift.79 However, most of the patients benefit from rhinoplasty regardless of the motivation for surgery.80 These effects continue to exist even 5 years after the operation.81 Another study confirmed these results and highlighted that the patients felt to be better accepted in social relationships.82 However, a small group of patients will not be satisfied even if the surgery was objectively successful. These patients who are suffering from body dysmorphic disorder (BDD) or dysmorphophobia count around 5% of all patients desiring for esthetic surgery. Those patients are typically young, depressive and anxious. They observe little or imaginary deformities of the nose. They feel unattractive and frequently have multiple bodily complaints.83 In many cases, these patients live in social isolation and have enormous but not warranted expectations regarding postoperative change of life.84 It is desirable to identify such patients before the operation. However, until now no reliable test exists, which fulfills this requirement. Beside these hardly detectable personality disorders also psychoses and neuroses might complicate the patient management. The potential surgeon


should refer the patient to a psychological and/or psychiatric examination to reassess applicability of surgery. In the worst case, surgery might lead to exacerbation of a psychiatric disorder.

conclusion Over the past years, several validated QOL measures for rhinology have been developed. Therewith, important preconditions for intensified efforts in this research field have been established. However, this should only be regarded as a beginning. The number and quality of studies in rhinologic QOL research related to the evidence criteria of the Oxford Centre for Evidence-based Medicine are not sufficient. Publications in this field rarely reach high levels of evidence. One important challenge for the future is the implementation of rhinologic QOL research using validated measures into randomized, controlled trials. Well-established English QOL instruments should be validated in other languages. Alternatively, new instruments should be developed and validated.

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58 Recent Advances in Otolaryngology—Head and Neck Surgery 45. Baumann I, Blumenstock G, Praetorius M, et al. Krankheitsspezifische und allgemeine gesundheitsbezogene Lebensqualität bei Patienten mit chronischer Rhinosinusitis. HNO 2006;54:544–9. 46. Metson RB, Gliklich RE. Clinical outcomes in patients with chronic sinusitis. Laryngoscope 2000; 110:24–8. 47. Konstantinidis I, Triaridis S, Triaridis A, et al. Long term results following nasal septal surgery. Focus on patients’ satisfaction. Auris Nasus Larynx 2005;32: 369–74. 48. Newton JR, Shakeel M, Ram B. Evaluation of endoscopic sinus surgery by Glasgow benefit inventory. J Laryngol Otol 2008;122:357–60. 49. Bohlin L, Dahlqvist A. Nasal airway resistance and complications following functional septoplasty: a ten-year follow-up study. Rhinology 1994;32:195–7. 50. Samad I, Stevens HE, Maloney A. The efficacy of nasal septal surgery. J Otolaryngol 1992;21:88–91. 51. Denholm SW, Sim DW, Sanderson RJ, et al. Otolaryngological indicator operations: one year’s experience. J R Coll Surg Edinb 1993;38:1–3. 53. Sherman AH. A study of nasal airway function in the postoperative period of nasal surgery. Laryngoscope 1977;87:299–303. 54. Stocksted P. Long-term results, following plastic septum surgery. Rhinology 1969;7:53–61. 55. Jessen M, Ivarsson A, Malm L. Nasal airway resistance and symptoms after functional septoplasty: comparison of findings at 9 months and 9 years. Clin Otolaryngol Allied Sci 1989;14:231–4. 56. Broms P, Jonson B, Malm L. Rhinomanometry. IV. A pre- and postoperative evaluation of functional septoplasty. Acta Otolaryngol 1982;94:523–9. 57. Dinis PB, Haider H. Septoplasty: long-term evaluation of results. Am J Otolaryngol 2002;23:85–90. 58. Bothra R, Mathur NN. Comparative evaluation of conventional versus endoscopic septoplasty for limited septal deviation and spur. J Laryngol Otol 2009; 123:737–41. 59. Siegel NS, Gliklich RE, Taghizadeh F, et al. Outcomes of septoplasty. Otolaryngol Head Neck Surg 2000;112:228–32. 60. Stewart MG, Witsell DL, Smith TL, et al. Development and validation of the Nasal Obstruction Symptom Evaluation (NOSE) Scale. Otolaryngol Head Neck Surg 2004;130:157–63. 61. Stewart MG, Smith TL, Weaver EM, et al. Outcomes after nasal septoplasty: results from the Nasal Obstruction Septoplasty Effectiveness (NOSE) study. Otolaryngol Head Neck Surg 2004;130:283–90. 62. Most SP. Anterior septal reconstruction. Outcomes after a modified extracorporeal septoplasty technique. Arch Facial Plast Surg 2006;8:202–7. 63. Alsarraf R, Larrabee WF Jr, Anderson S, et al. Measuring cosmetic facial plastic outcomes. A pilot study. Arch Facial Plast Surg 2001;3:198–201. 64. Hern J, Hamann J, Tostevin P, et al. Assessing psychological morbidity in patients with nasal deformity using the CORE questionnaire. Clin Otolaryngol 2002;27:359–64.

Measuring Quality of Life in Nasal Surgery 59 65. Most SP, Alsarraf R, Larrabee WF. Outcomes of facial cosmetic procedures. Facial Plast Surg 2002;18:119–24. 66. Guyuron B, Bokhari F. Patient satisfaction following rhinoplasty. Aest Plast Surg 1996;20:153–57. 67. Dziewulski P, Dujon D, Spyriounis P, et al. A retrospective analysis of the results of 218 consecutive rhinoplasties. Br J Plast Surg 1995;48:451–4. 68. Alsarraf R. Outcomes instruments in facial plastic surgery. Facial Plast Surg 2002;18:77–86. 69. Klassen A, Jenkinson C, Fitzpatrick R, Goddacre T. Patients’ health related quality of life before and after aesthetic surgery. Br J Plast Surg 1996;49: 433–8. 70. Cole RP, Shakespeare V, Shakespeare P, et al. Measuring outcome in low-priority plastic surgery patients using quality of life indices. Br J Plast Surg 1994;47:117–21. 71. Stewart EJ, Robinson K, Wilson JA. Assessing of patient’s benefit from rhinoplasty. Rhinology 1996;34:57–9. 72. Slator R. Rhinoplasty patients revisited. Br J Plast Surg 1993;46:327–31. 73. Most SP. Analysis of outcomes after functional rhinoplasty using a diseasespecific quality-of-life instrument. Arch Facial Plast Surg 2006;8:306–9. 74. Hellings PW, Nolst Trenite GJ. Long-term patient satisfaction after revision rhinoplasty. Laryngoscope 2007;117:985–9. 75. Timmerman AA, Anteunis LJ, Meesters CM. Response-shift bias and parentreported quality of life in children with otitis media. Arch Otolaryngol Head Neck Surg 2003;129:987–91. 76. Meningaud JP, Lantieri L, Bertrand JC. Rhinoplasty: an outcome research. Plast Reconstr Surg 2008;121:251–7. 77. Jerome L. Body dysmorphic disorder: a controlled study of patients requesting cosmetic rhinoplasty. Am J Psychiatry 1992;149:577–8. 78. Thomas CS, Goldberg DP. Appearance, body image and distress in facial dysmorphophobia. Acta Psychiatr Scand 1995;92:231–6. 79. Castle DJ, Honigman RJ, Phillips KA. Does cosmetic surgery improve psycho social wellbeing? Med J Aust 2002;176:601–4. 80. Ercolani M, Baldoro B, Rossi N, et al. Short-term outcome of rhinoplasty for medical or cosmetic indication. J Psychosom Res 1999;47:277–81. 81. Ercolani M, Baldoro B, Rossi N, et al. Five-year follow-up of cosmetic rhinoplasty. J Psychosom Res 1999;47:283–6. 82. Dinis PB, Dinis M, Gomes A. Psychosocial consequences of nasal aesthetic and functional surgery: a controlled prospective study in an ENT setting. Rhinology 1998;36:32–6. 83. Phillips KA, Dufresne RG. Body Dysmorphic Disorder. A guide for dermato logists and cosmetic surgeons. Am J Clin Dermatol 2000;1:235–43. 84. Veale D, De Haro L, Lambrou C. Cosmetic rhinoplasty in body dysmorphic disorder. Br J Plast Surg 2003;56:546–51.


Appendix How to get access to the QOL questionnaires mentioned in this article?

Generic Questionnaires 1. The Short Form 36 Health Survey (SF-36), www.sf-36.org 2. The Health Measurement Questionnaire (HMQ), Publication No. 69 3. The Child Health Questionnaire (CHQ) Landgraf JM, Abetz L, Ware JE. Child Health Questionnaire (CHQ): A user’s manual. Boston, MA: Health Institute, New England Medical Center, 1996. 4. The Glasgow Benefit Inventory (GBI), http://www.ihr.mrc.ac.uk/products/display/questionnaires

Disease-specific Questionnaires 1. Sino-Nasal Outcome Test 20 (SNOT-20), http://oto2.wustl.edu/clinepi/ downloads.html 2. Sino-Nasal Outcome Test 16 (SNOT-16), http://oto2.wustl.edu/clinepi/ downloads.html 3. Sino-Nasal Outcome Test 22 (SNOT-22), https://entuk.org/professionals/clinical_outcomes 4. Sino-Nasal Outcome Test 20 German Adapted Version (SNOT-20 GAV) Publication No. 28 5. Chronic Sinusitis Survey (CSS), Publication No. 9 6. Nasal Symptom Questionnaire, Publication No. 19 7. Rhinosinusitis Disability Index (RSDI), Publication No. 20 8. Sino-Nasal Assessment Questionnaire (SNAQ-11), Publication No. 21 9. General Nasal Patient Inventory (GNPI), Publication No. 22 10. Sinunasal-5 quality of life survey (SN-5), Publication No. 23 11. Rhinosinusitis quality-of-life survey (RhinoQoL), Publication No. 24 12. NOSE Scale, Publication No. 59 13. Rhinoplasty Outcome Evaluation (ROE), Publication No. 62

Chapter Personalized Therapy in Head and Neck Cancer

5

Xiao Xiao, Jennifer R Grandis

Overview Head and neck cancer is the fifth most common cancer in the world, with approximately 40,000 new cases a year in the United States. The majority of malignancies that arise in the mucosal surfaces of the head and neck are squamous cell carcinomas (HNSCCs). This review will focus on HNSCC including cancers of the oral cavity, pharynx, and larynx. HNSCC has long been associated with tobacco and alcohol exposure, generally occurring in older individuals. However, there is an increasing incidence of HNSCC that arises in younger individuals who have no history of smoking and are linked to exposure to human papillomavirus (HPV). Head and neck cancer is challenging to treat because surgery and radiation to the region often impacts swallowing and speech. HNSCCs are characterized by a high incidence of recurrence and second primary tumor formation that reduces overall survival. Standard HNSCC treatment approaches include surgery (primarily for oral cavity tumors), and/or radiation (RT) in combination with chemotherapy (CRT). As sequencing technologies and platforms for sharing such data advance in recent years, however, many disease-specific genomic alterations were discovered and translated into clinical practice. Selected groups of HNSCC patients are starting to benefit from personalized medicine that would identify effective therapies according to the genetic profile of the patient’s tumor. Cancer genomics are complex and can be investigated using a variety of parameters including alterations in DNA sequence, transcription, and protein expression.1 The first challenge is to identify unique groups of driver genetic alterations in the context of tumor heterogeneity. Targeted subgroups can be small but clinically meaningful. The second challenge is to elucidate genes and pathways that mediate tumor formation and/or progression. Some oncogene mutations are more readily targeted with existing or developing therapeutic reagents. Personalized or precision medicine may be understood as the ability to identify reliable predictive biomarkers. For example, HER2 (ErbB2)

62 Recent Advances in Otolaryngology—Head and Neck Surgery amplification represents a biomarker in breast cancer, which identifies patients for HER2 targeting strategies including lapatinib, a tyrosine kinase inhibitor (TKI) against HER2.2 Non-small-cell lung cancer (NSCLC) that harbors activating mutations of the epidermal growth factor receptor (EGFR) is amenable to treatment with EGFR TKI such as gefitinib and erlotinib.3 Nevertheless, drug resistance may impede promising clinical responses due to secondary mutations and complimentary mechanisms, such as EGFRT790M in gefitinib- and erlotinib-resistant lung cancer.4 Predictive markers of HNSCC are still unknown and treatment resistance mechanisms are poorly defined. Current treatment of HNSCC still depends largely on the TNM staging of the tumor. More advanced tumors receive more aggressive multimodality treatment, and early stage lesions may be treated with surgery or radiation alone. HPV-positive oropharyngeal cancer (HPV/OPSCC) generally has improved survival compared with HPV-negative OPSCC, although HPV-selective therapies are lacking. Although prophylactic HPV vaccines are FDA-approved and there is increasing evidence that vaccination reduces oral HPV infection, it will take decades for vaccination regimens to impact the incidence of HPV-associated HNSCC. Although HNSCC lacks reliable predictive biomarkers, advances in genomic information through such efforts as The Cancer Genome Atlas (TCGA, cancergenome.nih.gov) are revealing new targets and pathways that can be explored in this cancer. In this review, we will outline some of the most promising molecular targets/pathways and their associated inhibitors in HNSCC.

EGFR pathway The epidermal growth factor receptor (EGFR) (HER1; Erb-B1) is the most extensively studied biomarker in HNSCC due to its widespread overexpression in more than 90% HNSCC tumors.5 EGFR is a type I member of the ErbB/ HER family of transmembrane tyrosine kinase receptors that bind to ligands such as EGF, transforming growth factor-α (TGF-α), and amphiregulin (AR).6 The receptor, after binding with a soluble ligand, changes its conformation to allow homo- and heterodimerization with its family members, which in turn causes autophosphorylation and activates downstream signaling pathways including the signal transducer and activator of transcription (STAT) and the phosphoinositide 3-kinase (PI3K)-AKT pathways (Fig. 5.1).7,8 Abnormalities in EGFR signaling have been implicated as oncogenic drivers in multiple cancers. In particular, EGFR overexpression, not mutation, leads to upregulation of the EGFR pathway in HNSCC. EGFR expression is generally recognized as a prognostic marker for disease progression and decreased overall survival.9 Increased gene copy number or gene

Personalized Therapy in Head and Neck Cancer 63

Fig. 5.1: Epidermal growth factor receptor (EGFR) pathway. EGFR is a type I member of the ErbB/HER family of transmembrane tyrosine kinase receptors that bind to ligands such as EGF, transforming growth factor-α (TGF-α), and AR. The receptor, after binding with a soluble ligand, changes its conformation to allow homo- and heterodimerization with its family members, which in turn causes autophosphorylation and activates downstream signaling pathways including the signal transducer and activator of transcription (STAT) and the phosphoinositide 3-kinase (PI3K)-AKT pathways. Increased EGFR activity leads to uncontrolled cell growth, proliferation, and survival. Anticancer strategies, such as EGFR monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), have been developed to target the EGFR pathway. The mAbs work by binding to the extracellular domain to interfere with the ligand–receptor interaction, while the TKIs block the intracellular domain, inhibiting subsequent downstream signaling and autophosphorylation.

amplification and activation of transcription and over-representation of protein expression are potential mechanisms for elevated EGFR expre ssion.10,11 Aberrant stimulation of the EGFR signaling pathway may also be due to direct activation by over-produced autocrine ligands, such as TGF- α and AR, in addition to transactivation by other signaling pathways involving G-protein-coupled receptors (GPCR).12,13 Increased EGFR activity plays a central role in HNSCC tumorigenesis leading to uncontrolled cell proliferation, apoptosis inhibition, angiogenesis, and increased invasion and migration. Thus, many anticancer strategies have been developed to target the EGFR pathway, most notably, EGFR monoclonal antibodies (mAbs) and TKIs. The mAbs work by binding to the extracellular domain to interfere with the ligand–receptor interaction, resulting in

64 Recent Advances in Otolaryngology—Head and Neck Surgery autophosphorylation but interrupting downstream signaling, while the TKIs block the intracellular domain, inhibiting autophosphorylation and subsequent downstream signaling.14 Cetuximab (Erbitux or C225) is an EGFR-targeted chimeric mAb and is the only molecular targeting agent approved by FDA for use in HNSCC. The landmark clinical study that demonstrated the efficacy of cetuximab was reported by Bonner et al. in 2006 (ClinicalTrials.gov number, NCT00004227).15 This phase III study compared radiotherapy (RT) alone with combined RT plus cetuximab in treating locoregionally advanced HNSCC (LA-HNSCC), and found that combined therapy improved overall survival by 19.3 months and progression-free survival (PFS) by 4.7 months, without significantly increasing the toxic effects commonly associated with RT. Treating LA-HNSCC with combined cetuximab plus chemoradiotherapy (CRT), however, did not result in better PFS (64.3% CRT vs. 63/4% CRT + cetuximab).16 The addition of cetuximab to platinum-based CT improved overall survival by 2.7 months and PFS by 2.3 months in patients with recurrent or metastatic HNSCC (R/M-HNSCC) in the ‘Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer’ (EXTREME) trial (NCT00122460).17 Despite the feasibility of using cetuximab in HNSCC, predictive biomarkers are lacking to guide its use for either newly diagnosed or recurrent/metastatic HNSCC. Neither EGFR expression levels nor gene amplification have been correlated with clinical responses to cetuximab.18 Some of the current clinical trials are testing the efficacy of variants of EGFR mAbs, such as zalutumumab and nimotuzumab, with concurrent RT or CRT (Table 5.1). Although EGFR TKIs such as erlotinib and gefitinib have shown to reduce tumor growth similar to cetuximab, TKIs lack positive phase III data in HNSCC. Combined TKIs and RT or CRT treatment continue to be evaluated in phase I/II clinical trials (Table 5.2). TKIs achieved modest response rate as a monotherapy in R/M-HNSCC: erlotinib and gefitinib had 4.3% and 10.6% response rates, respectively.19,20 The incremental and often inconsistent clinical outcomes of EGFR targeting therapies in HNSCC support the contribution of primary or acquired resistance pathways in treatment-refractory tumors. In order to overcome resistance and improve treatment responses, several potential mechanisms have been proposed. Elevated EGFR expression levels, including nuclear EGFR expression, is a prominent feature of HNSCC and a strong prognostic marker, but its association with the clinical response to EGFR inhibition remains inconclusive. Signaling through alternative growth factor pathways, such as vascular endothelial growth factor (VEGFR) and mesenchymal epithelial transition factor (c-Met), can overcome the inhibition of EGFR by activating common signal transducers and coactivating downstream signal pathways.21 Thus, simultaneously targeting multiple ErbB receptors and growth factor receptors might reduce treatment resistance (Table 5.3).


Table 5.1: Clinical studies of EGFR monoclonal antibodies in HNSCC Identifier Phase Official title NCT00496652 Phase III DAHANCA 19: A randomized study of the importance of the EGFR-Inhibitor zalutumumab for the outcome after primary curative radiotherapy for aquamous cell carcinoma of the head and neck NCT00736619 Phase I Phase I study of weekly nanoparticle Albumin-Bound Paclitaxel (Abraxane) + weekly cetuximab + radiation therapy (IMRT: Intensity-modulated radiation therapy) in patients with stage III-IVB head and neck squamous cell carcinoma (HNSCC) NCT01566435 Phase II Phase II Trial of Nab-Paclitaxel, cisplatin, and 5-FU (ACF) as induction therapy followed by definitive concurrent chemoradiation for locally advanced squamous cell carcinoma of the head and neck (HNSCC) NCT00265941 Phase III A randomized phase III trial of concurrent accelerated radiation and cisplatin versus concurrent accelerated radiation, cisplatin, and cetuximab (C225) [Followed by surgery for selected patients] for stage III and IV head and neck carcinomas NCT01232374 Phase II A clinical study of nimotuzumab in combination with concurrent chemotherapy and radiation for patients with local advanced esophageal squamous cell carcinoma NCT00382031 Phase III An open-labeled randomized parallel group yrial of zalutumumab, a human monoclonal anti-EGFR antibody, in combination with best supportive care (BSC) versus BSC, in Pts with non-curable SCCHN Who have failed standard platinum-based chemotherapy NCT01216020 Phase II Multi-institutional open label randomized phase II study somparing cetuximab and radiotherapy versus cisplatin and radiotherapy as first-line treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-NHSCC)

Agent(s) RT, zalutumumab

Cetuximab, IMRT (Intensity-modulated radiation therapy), Albumin-bound paclitaxel (Abraxane)

Paclitaxel albumin-stabilized nanoparticle formulation, cisplatin, fluorouracil, IMRT, cetuximab Cetuximab, cisplatin

Nimotuzumab, cisplatin, CRT

Zalutumumab, best supportive care

Cetuximab, cisplatin, RT

(EGFR: Epidermal growth factor receptor; RT: Radiotherapy; IMRT: Intensity modulated radia tion therapy; CRT: Chemoradiotherapy; HNSCC: Head and neck squamous cell carcinoma).

66 Recent Advances in Otolaryngology—Head and Neck Surgery Table 5.2: Clinical studies of EGFR tyrosine kinase inhibitors in HNSCC Identifier

Phase

Official title

Agent(s)

NCT01737008

Phase I

Phase I trial of dacomitinib concomitant with radiotherapy with and without cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck

Dacomitinib, RT, cisplatin

NCT01515137

Phase II

Phase II study of TARCEVA (Erlotinib) as adjuvant treatment for locally advanced head and neck squamous cell carcinoma with evaluation of neoadjuvant biomarker modulation with TARCEVA versus TARCEVA plus sulindac

Erlotinib, sulindac, placebo

NCT00083057

Phase I

A Pilot phase I dose escalation study of the EGFR tyrosine kinase inhibitor gefitinib (Iressa) combined with paclitaxel (Taxol) and external beam radiation therapy in patients with advanced squamous cell carcinoma of the head and neck (SCCHN)

Gefitinib, paclitaxel, RT

NCT00720304

Phase II

A phase II study of the epidermal growth factor receptor tyrosine kinase inhibitor, Erlotinib, in combination with docetaxel and radiation in locally advanced squamous cell cancer of the head and neck

Erlotinib, docetaxel, RT

NCT01824823

Phase II

A randomized, placebo controlled phase II trial of afatinib (BIBW2992) as adjuvant therapy following chemoradiation in patients with head and neck squamous cell carcinoma at high risk of recurrence

Afatinib

NCT00098631

Phase II

A Phase II study of GW572016 in squamous cell carcinoma of the head and neck (SCCHN)

Lapatinib

(RT: Radiotherapy; EGFR: Epidermal growth factor receptor; HNSCC: Head and neck squamous cell carcinoma).


Table 5.3: Clinical studies of EGFR inhibitors in combination in HNSCC Identifier

Phase

Official title

Agent(s)

NCT00392665

Phase II

Randomized study of bevacizumab/ Bevacizumab Tarceva and Tarceva/Sulindac in (mAbs: VEGF-A), squamous cell carcinoma of the erlotinib, sulindac head and neck

NCT01316757

Phase II

Phase II trial of carboplatin/ paclitaxel and cetuximab, followed by carboplatin/paclitaxel/cetuximab and erlotinib, with correlative studies in patients with metastatic or recurrent squamous cell carcinoma of the head and neck.

NCT00514943

Phase II

BIBW 2992 A randomized, open-label phase II (afatinib), study of BIBW 2992 versus cetuximab cetuximab (Erbitux) in patients with netastatic or recurrent head and neck squamous cell carcinoma (HNSCC) after failure of platinumcontaining therapy with a crossover period for progressing patients

mAbs + TKIs

Cetuximab, paclitaxel, carboplatin, erlotinib hydrochloride

Novel: Antisense DNA NCT01592721

Phase I/II

Safety and efficacy of radiation and cetuximab plus intratumoral EGFR antisense DNA in patients with locally advanced head and neck squamous cell carcinoma

EGFR antisense DNA, cetuximab, RT

(mAbs: Monoclonal antibody; VEGF-A: Vascular endothelial growth factor A; EGFR: Epidermal growth factor receptor; HNSCC: Head and neck squamous cell carcinoma).

Heterodimerization of EGFR with other ErbB receptors, such as Her2, 3, 4 and c-Met, binds to EGF-like ligand and bypasses the inhibition. Since HER2 (ErB2) is the preferred partner of heterodimerization for EGFR and other receptors, several studies have investigated dual inhibition of EGFR/HER2 by TKIs with some evidence of reducing treatment resistance.22–24 Mutant forms of EGFR may also contribute to resistance to EGFRtargeting therapy, notably the type III EGFR deletion mutation (EGFRvIII) that is expressed in a wide range of human tumors but not in any normal tissue. EGFRvIII, lacking most of the external ligand-binding domain, cannot bind EGF-like ligands, but it dimerizes and constitutively phosphorylates downstream pathways.25 EGFRvIII expression is a potential prognostic marker, and the addition of EGFRvIII-specific mAbs and inhibitors may increase the efficacy of EGFR targeting therapy.26,27 Novel and multipathway approach would hopefully shed light on overcoming resistance to EGFR inhibition (Table 5.3).


JAK-STAT pathway EGFR autophosphorylation activates intracellular signal cascades including the signal transducer and activator of transcription (STAT). In addition to EGFR, interleukin-6 receptor (IL-6R) also can constitutively activate STAT though Janus-activated kinase (JAK), independent of EGFR expression.28 IL-6R-activated JAKs phosphorylate STAT proteins, which then translocate into the nucleus and activate target gene expression. Expression of STAT proteins has been associated with many cancers. STAT1 is generally thought to demonstrate a tumor suppressor function that initiates cell cycle arrest and apoptosis, while STAT3 and STAT5 are oncogenic, increasing cell proliferation, angiogenesis, and cell survival.29 STAT3 represents a plausible therapeutic target in HNSCC, but it is challenging to develop selective inhibitors for a transcription factor, generally considered ‘undruggable.’ One solution is to nonselectively block STAT3 by inhibiting upstream JAKs. Ruxolitinib (INCB018424) is a potent inhibitor of JAK1 and JAK2 that was approved by the FDA after showing notable clinical benefits in patients with myelofibrosis (NCT00509899).30 Another novel JAK2 treatment (AZD1480) is being evaluated in patients with myeloproliferative diseases (NCT00910728). OPB-31121 is a small molecule STAT3 inhibitor that inhibits JAK2, and it induces apoptosis and antitumor activities in gastric cancer cells.31 It is currently undergoing phase I testing in advanced solid cancers (NCT00955812). Other JAK inhibitors in clinical trials include baricitinib, CYT387, lestaurtinib, pacritinib, and TG101348. JAK inhibitors have been studied in myeloproliferative disorders and leukemia, but their efficacy has not been investigated to date in HNSCC. STAT3 activity can be blocked by regulating RNA with a dominantnegative form of STAT3 (DN-STAT3), antisense-RNA, small interfering RNA (siRNA), and microRNA (miRNA). STAT3β, a DN-STAT3, blocked STAT3 transcriptional activation and significantly inhibited cell proliferation and invasion in lung cancer cells.32 ISIS-STAT3Rx (ISIS 481464 or AZD9150) is an antisense oligonucleotide inhibitor of STAT3 in phase I/II clinical investigation for advanced cancers (NCT01563302). Gao et al. designed siRNA that targets specific sites on STAT3 messenger RNA (mRNA) and found that expression of STAT3 was suppressed and apoptosis was induced in prostate cancer cells and in nude mice tumor models.33 STAT3 inhibitory effects were also observed in laryngeal tumors.34 MicroRNAs control gene expression through mRNA degradation or mRNA translation at the post-transcriptional level, and STAT3 is associated with miR-17-92 cluster family members (OncomiR-1) to promote tumorigenesis, particularly with miR-21.35 Thus, targeting miRs might downregulate STAT3 activity in tumors. An innovative approach to target STAT3 was recently reported by Sen et al., who conducted the first-in-human Phase 0 Trial of a STAT3 decoy oligonucleotide in head and neck tumors (NCT00696176).36 The


double-stranded STAT3 oligonucleotide decoy is a highly specific STAT3 inhibitor that binds with STAT3, prevents STAT3 binding to the genomic DNA, and thus inhibits expression of target genes in HNSCC. The original STAT3 decoy underwent modifications to improve systemic delivery by enhancing thermal and enzymatic stability. The modified cyclic STAT3 decoy reduced the expression of STAT3 target genes in vitro and in vivo, and also inhibited cell proliferation and xenograft tumor growth. Most significantly, the success of STAT3 decoy opened up the horizon of treatment for those ‘undruggable’ transcription factors.

PI3K pathway The phosphoinositide 3-kinase (PI3K) pathway is a major mitogenic pathway downstream of EGFR. Aberrant PI3K/AKT/mTOR activity also closely associates with cell proliferation, inhibited apoptosis, differentiation, and motility. We recently reported results on 151 HNSCC primary tumors and found that the PI3K pathway has a high mutational frequency of about 30%, in contrast to only about 9% of tumors with mutations or amplification of the JAK/STAT pathway.37 Mutations in the PI3K pathway are associated with mutations in other cancer-related genes, and only stage IV tumors harbored multiple PI3K pathway mutations.38 This finding suggests that PI3K mutation is involved in HNSCC progression, and advanced-stage HNSCC patients represent a subgroup that might benefit from treatment with PI3K pathway inhibitors. Among mutations in the PI3K pathway, PIK3CA is mutated at the greatest frequency with both canonical and novel mutations identified. PIK3CA mutations, when expressed in cell lines, enhanced cell growth compared with controls. Further investigation demonstrated that treatment of HNSCC patient-derived tumorgrafts with PIK3CA mutations with the mTOR/PI3K inhibitor BEZ-235 plus cetuximab was more effective than treatment with cetuximab alone. A phase I/II is underway to test the efficacy of combined therapy using the pan-PI3K inhibitor BKM120 and cetuximab for R/M-HNSCC (NCT01816984). Another phase I/II trial is comparing thepanPI3K inhibitor PX-866 plus docetaxel versus docetaxel alone in HNSCC and NSCLC (NCT01204099). Although clinical results are pending, PI3K represents a promising predictive marker for HNSCC. Table 5.4 summarizes the PI3K inhibitors that are being investigated in clinical trials.

Conclusion Personalized HNSCC cancer medicine offers the promise of delivering the right drug to the right patient at the right time. As we continue to unravel the complex and heterogeneous genomic landscape of HNSCC, we are poised to identify those mutations and pathways that can be effectively targeted to

70 Recent Advances in Otolaryngology—Head and Neck Surgery Table 5.4: PI3K inhibitors in clinical development Names

Target(s)

Status and comments

BEZ-235

PI3K, mTOR

Phase I/II trials underway for advanced solid tumors, breast cancer, pNET, CRPC

BKM120

PI3K

Phase I/II trials underway for NSCLC, melanoma, glioblastoma, HNSCC, colorectal cancer Phase III trials for breast cancer Phase IV trials for cervical cancer

PX-866

PI3K (alpha, gamma, delta isoforms)

Phase I/II trials underway for colorectal carcinoma, HNSCC, NSCLC, advanced solid tumor, prostate cancer, glioblastoma

BGT226

PI3K

Phase I/II trials completed for advanced solid tumor

GDC-0941 bismesylate

PI3K (P100alpha, p100delta isoforms)

Phase I/II trials underway for solid tumors, breast cancer, NSCLC

BAY 80-6946

PI3K

Phase I/II trials underway for advanced cancer

GSK2126458

PI3K

Phase I trials underway for pulmonary fibrosis, advanced solid tumors

BYL719

PI3K (all four isoforms)

Phase I/II trials underway for HNSCC, breast cancer, advanced solid tumor, ESCC, gastric cancer, colorectal cancer

ZSTK474

PI3K

Phase I/II trials underway for advanced solid tumor

WX-037

PI3K

Phase I trial underway for advanced solid tumor

(PI3K: Phosphoinositide 3-kinase; mTOR: Mammalian target of rapamycin; pNET: Pancreatic neuroendocrine tumor; CRPC: Castration-resistant prostate cancer; NSCLC: Non-small cell lung cancer; ESCC: Esophageal squamous cell carcinoma).

improve clinical outcome. Cumulative results to date suggest that despite being a prognostic marker, EGFR remains an unsatisfactory predictive biomarker marker for EGFR-targeted therapies in HNSCC. The coupling of our increased understanding of HNSCC biology with the rapid development of targeted agents should facilitate rational trial design and more rapid translation of key observations in relevant preclinical models.

References

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Personalized Therapy in Head and Neck Cancer 71 3. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39. 4. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73. 5. Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res. 1993;53(15):3579–84. 6. Harris RC, Chung E, Coffey RJ. EGF receptor ligands. Exp Cell Res. 2003 Mar 10;284(1):2–13. 7. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–37. 8. Quesnelle KM, Boehm AL, Grandis JR. STAT-mediated EGFR signaling in cancer. J Cell Biochem. 2007;102(2):311–9. 9. Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62(24):7350–6. 10. Chung CH, Ely K, McGavran L, et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol. 2006;24(25):4170–6. 11. Sunpaweravong P, Sunpaweravong S, Puttawilbul P, et al. Epidermal growth factor receptor and cyclin D1 are independently amplified and overexpressed in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol. 2005;131:111–9. 12. Salomon DS, Brandt R, Ciardiello F, et al. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995; 19(3):183–232 13. Prenzel N, Zwick E, Daub H, et al. EGF receptor transactivation by G-proteincoupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature. 1999;402(6764):884–8. 14. Yoshida T, Okamoto I, Okabe T, et al. Matuzumab and cetuximab activate the epidermal growth factor receptor but fail to trigger downstream signaling by Akt or Erk. Int J Cancer. 2008;122(7):1530–8. 15. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–78. 16. Ang KK, Zhang Q, Rosenthal DI, et al. A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC). J Clin Oncol. 2011;29:5500. 17. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116–27. 18. Licitra L, Mesia R, Rivera F, et al. Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study. Ann Oncol. 2011;22(5): 1078–87.

72 Recent Advances in Otolaryngology—Head and Neck Surgery 19. Soulieres D, Senzer NN, Vokes EE, et al. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol. 2004;22:77–85. 20. Cohen EE, Rosen F, Stadler WM, et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol. 2003;21:1980–7. 21. Montagut C, Settleman J. Targeting the RAF-MEK-ERK pathway in cancer therapy. Cancer Lett. 2009;283(2):125–34. 22. Motoyama AB, Hynes NE, Lane HA. The efficacy of ErbB receptor-targeted anticancer therapeutics is influenced by the availability of epidermal growth factorrelated peptides. Cancer Res. 2002;62:3151–8. 23. Wong TW, Lee FY, Yu C, et al. Preclinical antitumor activity of BMS-599626, a pan-HER kinase inhibitor that inhibits HER1/HER2 homodimer and heterodimer signaling. Clin Cancer Res. 2006;12(20 Pt 1):6186–93. 24. Erjala K, Sundvall M, Junttila TT, et al. Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells. Clin Cancer Res 2006;12(13):4103–11. 25. Fernandes H, Cohen S, Bishayee S. Glycosylation-induced conformational modification positively regulates receptor-receptor association: a study with an aberrant epidermal growth factor receptor (EGFRvIII/DeltaEGFR) expressed in cancer cells. J Biol Chem. 2001;276:5375–83. 26. Sok JC, Coppelli FM, Thomas SM, et al. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res. 2006;12(17):5064–73. 27. Modjtahedi H, Moscatello DK, Box G, et al. Targeting of cells expressing wildtype EGFR and type-III mutant EGFR (EGFRvIII) by anti-EGFR MAb ICR62: a two-pronged attack for tumour therapy. Int J Cancer. 2003;105(2):273–80. 28. Sriuranpong V, Park JI, Amornphimoltham P, et al. Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system. Cancer Res.2003;63:2948–56. 29. Watanabe G, Kaganoi J, Imamura M, et al. Progression of esophageal carcinoma by loss of EGF-STAT1 pathway. Cancer J. 2001;7(2): 132–9. 30. Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117–27. 31. Kim MJ, Nam HJ, Kim HP, et al. OPB-31121, a novel small molecular inhibitor, disrupts the JAK2/STAT3 pathway and exhibits an antitumor activity in gastric cancer cells. Cancer Lett. 2013;335(1):145–52. 32. Xu G, Zhang C, Zhang J. Dominant negative STAT3 suppresses the growth and invasion capability of human lung cancer cells. Mol Med Rep. 2009;2(5):819–24. 33. Gao L, Zhang L, Hu J, et al. Down-regulation of signal transducer and activator of transcription 3 expression using vector-based small interfering RNAs suppresses growth of human prostate tumor in vivo. Clin Cancer Res. 2005;11(17):6333–41.

Personalized Therapy in Head and Neck Cancer 73 34. Gao LF, Wen LJ, Yu H, et al. Knockdown of Stat3 expression using RNAi inhibits growth of laryngeal tumors in vivo. Acta Pharmacol Sin. 2006;27(3):347–52. 35. Hong L, Lai M, Chen M, et al. The miR-17-92 cluster of microRNAs confers tumorigenicity by inhibiting oncogene-induced senescence. Cancer Res. 2010;70(21):8547–57. 36. Sen M, Thomas SM, Kim S, et al. First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy. Cancer Discov. 2012;2(8):694–705. 37. Stransky N, Egloff AM, Tward AD, et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011;333:1157–60. 38. Vivian WY, Hedberg ML, Li H, et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov. 2013;3(7)761–9.


Chapter

Vascular Anomalies— Advances and Updates for the Otolaryngologist

6

Francine Blei, Ascanio Guarini

Introduction This review will summarize vascular anomalies with emphasis on issues relevant to cervicofacial lesions that may require input of the otolaryngologist, focusing on typical concerns, which arise when seeing these patients. To begin, a basic problem is inconsistent terminology amongst involved specialists—pathologists, radiologists, clinicians, and researchers. It is essential to appreciate that not every vascular lesion is a hemangioma. A thorough history (including family history), physical examination, and assessment for patterns of anatomic distribution of vascular lesions will greatly aid the practitioner in establishing the correct diagnosis, and plan ning the most appropriate evaluation and management plan. Table 6.1 summarizes the fundamental separation of vascular anomalies into those lesions with a proliferative component (vascular tumors) versus relatively static vascular malformations. This distinction serves a platform from which to provide optimal evaluation and potential treatment for patients. Absent from this classification are more obscure diagnoses, syndromes, genetic information, and histologic data, which will be incorporated into an updated classification system (underway by the ISSVA Scientific Committee). Hassanein and colleagues analyzed publications listed in PubMed during 1 year (2009) and estimated that the term ‘hemangioma’ was misused in 71.3% of publications, independent of medical subspecialty, concluding ‘Hemangioma continues to be commonly misused to describe any type of vascular anomaly, and terminological imprecision is prevalent among both medical and surgical fields. Inaccurate designation of the vascular anomaly is associated with an increased risk of erroneous management’.2 Similarly, Greene et al. reported an incorrect referral diagnosis in 47% of patients referred to a Vascular Anomalies Multidisciplinary Referral Center.3 It is also important to recognize that early referral to subspecialists is essential, and that many patients require the input of multiple specialists who are aligned in terminology and awareness of vascular anomalies. Primary management of the patient varies by institution, availability of other specia lists, and patient needs.

Vascular Anomalies—Advances and Updates for the Otolaryngologist 75

Table 6.1: Updated ISSVA* classification of vascular anomalies Vascular tumors

Vascular malformations

Infantile hemangiomas

Slow-flow vascular malformations: Capillary malformation (port wine stain, telangiectasia, angiokeratoma) Venous malformation (VM) VM (common sporadic VM, Bean syndrome, familial cutaneous and mucosal VM, glomuvenous malformation, Maffucci syndrome Lymphatic malformation

Congenital hemangiomas Fast-flow vascular malformations RICH (rapidly involuting congenital hemangioma) Arterial malformation, NICH (noninvoluting congenital hemangioma) arteriovenous fistula, arteriovenous malformation Tufted angioma (with or without Kasabach– Merritt syndrome)

Complex-combined vascular malformations: CVM, CLM, LVM, CLVM, AVM-LM, CM-AVM

Kaposiform hemangioendothelioma (with or without Kasabach–Merritt syndrome) Spindle cell hemangioendothelioma Other rare hemangioendotheliomas (epithelioid, composite, retiform, polymorphous, Dabska tumor, lymphangioendothelioma, etc.) Dermatologic acquired vascular tumors (pyogenic granuloma, targetoid hemangioma, glomeruloid hemangioma, microvenular hemangioma, etc.) (C: Capillary; V: Venous; L: Lymphatic; AV: Arteriovenous; M: Malformation). *International Society for the Study of Vascular Anomalies Adapted from.1 Cambridge University Press grants permission freely for the reproduction in another work of a short prose extract (less than 400 words), a single figure or a single table in which it holds rights. In such cases a request for permission need not be submitted, but the reproduced material must be accompanied by a full citation of the original source.

How to distinguish a hemangioma from a vascular malformation? Clinical Pearls •

Hemangioma –– Rapidly involuting congenital hemangioma (RICH)—grows prena tally, resolves postnatally, may have high flow, transient thrombocy topenia


Fig. 6.1: Growth curves of different types of hemangiomas (RICH: Rapidly involuting congenital hemangioma; NICH: Noninvoluting congenital hemangioma and typical infantile hemangioma). Mulliken and Enjolras. J Am Acad Dermatol 2004; 50:876.

–– Noninvoluting congenital hemangioma (NICH)—grows prenatally and does not change –– Infantile hemangioma—minimal if any marking at birth, rapid growth, stabilization then gradual involution, GLUT-1-positive, cervicofacial propensity, female > male • Capillary malformation—macular, blanches with pressure • Arteriovenous malformation—bruit, thrill, cardiac murmur • Venous malformation—fills with valsalva, dependent position • Lymphatic malformation—transilluminates, ± small clear or white round blebs, infection prone After establishing the diagnosis class (hemangioma vs. vascular malfor mation), specific questions can aid in determining if further evaluation is necessary. For a hemangioma, the following key points must be taken into consideration: • When did the hemangioma appear—prenatally, shortly after birth? Figure 6.1 depicts the growth cycles of RICH, NICH, and typical infantile hemangiomas (the most common). RICH lesions may warrant in utero or immediately postnatal treatment if high flow. Large RICH lesions, although they will involute, may require surgery to remove redundant skin or areas of alopecia (if located on scalp). • Where is the hemangioma located? The ‘real estate’ of the hemangioma is key in determining the risk poten tial and helps guide treatment timing and choice. Associated or impending


A

B

Figs 6.2A and B: Image of typical hemangioma—barely visible perinatally (left panel), with rapid proliferation postnatally (right panel).

symptoms—e.g. stridor, ptosis, ulceration, bleeding, high flow state, and functional imitation—will necessitate prompt intervention. Early detec tion and effective treatment of airway hemangioma may prevent the need for laser and/or tracheotomy. Infants with superficial hemangiomas in the ‘beard’ or ‘partial beard’ distribution are at increased risk of symptomatic airway hemangiomas.4 Hemangiomas on the scalp, if large, may result in alopecia, therefore earlier surgical intervention may be warranted, exploiting the infant scalp flexibility and obviating the need for tissue expanders in the future.5 • What is the age of the patient? –– Prenatal, newborn, neonate, older infant, older child Patient age will help determine the diagnosis as well as the mode of therapy. With regard to hemangiomas, a young infant may warrant therapy to prevent proliferation, while an older child may require intervention to remove or correct redundant skin and/or contour abnormalities. A common misconception is that hemangiomas ‘go away.’ In actual fact, they improve. Depending on the location and ultimate size of the hemangioma, a laissez faire approach may not be appropriate. Figures 6.2A and B illustrate the typical initial appearance of a cutaneous hemangioma, with subsequent rapid proliferation, whereas Figures 6.3A to D demonstrate a hemangioma that is fully grown at birth, often with high flow, and which will spontaneously involute postnatally. Figures 6.4A and B demonstrate a parotid hemangioma with arterial flow (thrill and bruit, cardiac murmur on physical examination), which responded gradually but completely to medical therapy.


A

C

B

D

Figs 6.3A to D: Magnetic resonance angiography (MRA), immediately postnatal, and preoperatively (3 ½ months of age) and 2 ½ weeks postoperatively. Note highflow extracranial mass non-MR study, with spontaneous shrinkage of lesion with preoperative wrinkly skin and alopecia.

Figures 6.5A and B compare the sequelae of late referral. Two patients with similar cutaneous distribution of hemangiomas were referred early (a) and late (b). The patient in (b) has multiple medical issues including proptosis, ptosis, hypertrophy of the earlobe and lower lip, and bulky hemangioma of the neck with cardiac hypertrophy due to a high output state. Medical inter vention has helped prevent further growth and expedite involution; however, multiple surgical interventions will be necessary. Patient (a) has fully recov ered from early progressive stridor due to a subglottic hemangioma, and is responding to medical therapy without developing anatomic distortion. Figures 6.6A and B show the result of an untreated hemangioma, clearly demonstrating the hemangiomas ‘improve’ if left untreated; however, do not fully ‘go away.’ The resultant excess thin skin is unsightly. The patient is selfconscious and the lesion will require surgical excision.


A

B Figs 6.4A and B: High-flow parotid hemangioma.

A Fig. 6.5A


B Figs 6.5A and B : (A) Early (6 weeks of age) referral of a patient with faint vascular lesion on lip, chin, and preauricular and scalp areas – presented with progressive stridor and treated immediately with systemic medication. (B) Late referral (5 months) of a patient with untreated hemangioma that will require surgical intervention of right ear and lips after medical intervention.

A

B

Figs 6.6A and B: Previously untreated hemangioma in 5½ year olds patient. Noticed excess stretchy skin, necessitating surgical intervention.

Figures 6.7A to C depict the dramatic result of an untreated hemangioma. Early medical intervention would have likely spared the patient the need for surgical intervention, and would have spared the family the emotional stress. • Is the hemangioma focal or segmental? Segmental facial hemangiomas should alert the physician to the possi bility of PHACES syndrome (Posterior Fossa or other CNS structural anoma lies, Hemangioma–facial segmental), Arterial anomalies, Cardiac anomalies,


A

B

C Figs 6.7A to C: (A, B) Untreated lip hemangioma in 7 months old child; (C) Postoperative photograph. Surgery by M. Waner, MD.


Fig. 6.8: Segmental distribution of cutaneous hemangiomas. From Haggstrom et al.6

Eye anomalies ± sternal or other midline anomalies).6 A multicenter study revealed that 31% of infants with large facial segmental hemangiomas had PHACE—larger hemangiomas encompassing > 1 segment more highly corre lated to an extracutaneous manifestation of the syndrome.7 Frontotemporal and frontonasal hemangiomas were likely to be associated with PHACE. In one study, upper segment hemangiomas were associated with CNS struc tural and cerebrovascular anomalies, S1 with ocular anomalies, and S3 with airway, ventral, and cardiac anomalies.8,9 Conductive or sensorineural hearing loss has also been described.10 These observations have played an important role in stratifying patients at risk and driven research efforts to further characterize the etiology of hemangiomas. Figure 6.8 illustrates the cutaneous segmental distribution of hemangiomas, which has provided a visual guideline for practitioners. Several adult patients have been diagnosed with PHACE incidentally (e.g. after trauma-related concussion) or during evaluation for specific symp toms (e.g. stroke, transient ischemic attack, and chronic hearing loss).11,12 In these cases, the diagnosis is made by astute radiologists and who identify radiologic evidence compatible with PHACE, and a clinical history of facial hemangioma in infancy (which is typically acquired in retrospect). Time helps define the diagnosis. Vascular lesions that are diagnosed prenatally will be vascular malformations (which will not significantly change postnatally or RICH. The latter may be associated with high blood flow and also transient self-resolved thrombocytopenia postnatally.13 Some vascular anomalies are treated in utero. The otolaryngologist may be consulted


A

B

C Figs 6.9A to C: (A) Prenatally diagnosed large lymphatic malformation diagnosed at 5 months gestational age. Photograph courtesy of Robert Ward, MD; (B and C) Same patient after initial surgical resection and after sclerotherapy procedures.

prenatally if the lesions may cause potential airway compromise and an EXIT procedure or postnatal airway management may be necessary. Figures 6.9A to C show such a patient with large lymphatic malformation. RICH lesions are discussed above (see Fig. 6.3). Although hemangiomas do improve with time, early intervention in early treatment will often minimize the potential for functional deficits and facilitate an optimal esthetic outcome. Often the role of the specialist is to distinguish which hemangiomas pose a risk of disfigurement or disability from those lesions that will resolve with an acceptable result.

84 Recent Advances in Otolaryngology—Head and Neck Surgery Table 6.2: Propranolol potential mechanisms of action Proposed mechanism of action

Reference

Early vasoconstriction (decreased nitrous oxide) Angiogenesis inhibition (interference with VEGF- and bFGF-induced endothelial cell proliferation) Apoptosis induction

Storch et al. 21

G/G phase cell cycle arrest, Inhibition of (VEGF)-induced tyrosine phosphorylation of VEGF-R-2

Lamy et al.17

Inhibition of endothelial progenitor cell homing

Zou et al.19

Hastens adipogenesis in hemangioma stem cells Triggers apoptosis of hemangioma endothelial cells

Wong et al.18

Endothelial cell type-independent Blockade of endothelial cell proliferation, migration, and multiple functions

Stiles et al.23

Inhibition of inhibit hemangioma endothelial cell proliferation and induction of apoptosis, dose-dependent VEGF expression downregulation

Ji et al.16

Inhibition of angiotensin converting enzyme and angiotensin II receptor 2, resulting in decreased ATII and VEGF

Itinteang et al.15

Inhibition of hemangioma β2-adrenoceptor

Hadaschik et al.24, Ji et al.16

Inhibition of hemangioma endothelial nitric oxide synthase

Dai et al.25

HIF-1 alpha-related inhibition of VEGF-A

Chim et al.26

Targeting hemangioma endothelial cell pericytes

Boscolo et al.27

(VEGF: Vascular endothelial growth factor; BFGF: Basic fibroblast growth factor; HIF-1 alpha: Hypoxia inducible factor 1 alpha).

Early treatment of hemangiomas can include pulsed dye laser and/ or topical therapy. Systemic medical therapy with corticosteroids has been essentially replaced by the use of beta blockers after the original serendi pitous discovery that propranolol was effective in preventing hemangioma proliferation and inducing and earlier and more complete involution.14 In vitro studies demonstrate an antiproliferative apoptotic effects, stimulation of adipogenesis, as well as direct effects on endothelial beta adrenic receptors and other cellular pathways, as summarized in Table 6.2.15–21 Since the use of beta blockers, it is rare to require other medical therapies for hemangiomas. Combined pulsed dye laser treatments and oral Propranolol is reportedly effective in some patients.22 Early surgical management for bleeding or problematic ulcerating hemangiomas may be large scalp hemangiomas. Later surgery is often to remove excess tissue after involution as noted in Figure 6.6, to reconstruct hypertrophied lips (Figs 6.5B and 6.7), nasal carti lage, or distorted anatomic structures.


Treatment of hemangiomas • •

•

• • • •

Observation Local therapy –– Flashlamp pulsed dye laser –– Intralesional treatments –– Topical treatments –– Surgery Systemic therapy –– Oral propranolol – predominant systemic therapy –– Oral corticosteroids –– Intravenous vincristine –– Interferon Combined therapies Topical beta blocker Combination oral beta blocker and pulsed dye laser Surgical management

Vascular malformations Vascular malformations are present prenatally; however, may not be recog nized until birth. They can involve one or more vascular component—arterial, venous, lymphatic, or capillary may have associated hypertrophy/atrophy, limb length discrepancy, pain, and/or excess bleeding or thrombosis. Lesions of the orofacial areas may be associated with dysphagia, breathing difficulties, macroglossia, dental/orthodonture issues, sleep apnea, hearing abnormalities (otitis, hearing loss), sinus infections, epistaxis, and bony overgrowth/asymmetries. The management of vascular malformations is dependent on the type of lesion, location, and age of the patient. While arteriovenous malformations may be symptomatic prenatally or shortly after birth due to a high output state, and cervicofacial lymphatic malformations can threaten the airway, many vascular lesions are asymptomatic until peripubertal hormones trigger symptoms. Careful monitoring of potential symptoms relevant to the airway, nasal cartilage, feeding, dentition, bone growth, sleep patterns, infections, and hearing are all important for the otolaryngologist. Specific otolaryngolo gist guidelines relevant for lymphatic malformations are reviewed by Perkins and colleagues.28,29

Syndromes with Vascular Malformations A number of syndromes exist with a vascular anomaly as a predominant feature. Patients with hereditary hemorrhagic telangiectasia depend on an otolaryngologist experienced in controlling epistaxis due to hypervascu larity (Fig. 6.10). There have been several clinical trials and isolated reports


Fig. 6.10: Patient with hereditary hemorrhagic telangiectasia—multiple small red vascular lesions of the tongue, lips face, and elsewhere, with clinical symptoms of intraoral bleeding. Strong family history of similarly affected individuals.

Fig. 6.11: Patient with blue rubber bleb nevus syndrome—typically present with upper and/or lower gastrointestinal bleeding due to numerous small venous malformations of the gastrointestinal tract.

and small studies describing pharmacologic (including local bevacizumab) management of this disorder.30–33 Multiple small blue soft vascular lesions on the skin and mouth with gastrointestinal bleeding should alert the practitioner to possible blue rubber bleb nevus syndrome (Fig. 6.11). This multifocal venous malformation syndrome may also be associated with larger venous malformations (e.g. cervical). Coordination of management with an interventional radiolo gist and gastroenterologist/surgeon is often necessary.


Fig. 6.12: Patient with Sturge–Weber syndrome—large cutaneous facial capillary malformation, glaucoma, and seizure disorder.

Patients with Sturge–Weber syndrome (trigeminal distribution facial capillary malformation, ± glaucoma ± seizure disorder/developmental delays may be seen by the otolaryngologist due to intraoral manifestations (buccal mucosa, lips, gingiva, palate, floor of mouth) or nasal/lip/phrenulum hyper trophy (Fig. 6.12). One study identified sinusitis, recurrent otitis, sleep distur bances, and other ear nose and throat issues in patients with Sturge–Weber syndrome.34 Skeletal (especially maxillary) and soft tissue (lip, cheek, nares) overgrowth is common, and can be corrected surgically.35 Therapy for malformations depends on the type of lesion, associated symptoms, and age of the patient. Medical, laser, surgical and endovascular treatments are available and often used sequentially or together.

Management of Vascular Malformations • • • • • •

Medical Analgesics Antibiotics Anticoagulants Rapamycin—clinical trials Sildenafil—clinical trial

88 Recent Advances in Otolaryngology—Head and Neck Surgery Table 6.3: Genetic mutations in vascular anomalies Syndrome

Genetic mutation

Reference

Cutaneous and/or cutaneomucosal venous malformations

Tie-2 activating mutation

Wouters et al.38

Hereditary hemorrhagic telangiectasia (HHT) Multifocal arteriovenous malformations

HHT1 – endoglin HHT2 – ALK-1 (ACVRL-1) HHT + juvenile polyposis MADH4

McDonald et al.39

Arteriovenous PTEN hamartoma syndrome malformation/thyroid disorders/trichilemmomas/ cancer predisposition

Tan et al.40, Blumenthal et al.41

Arteriovenous malformation/capillary malformation

RASA-1 mutation

Eerola et al.36

Glomuvenous malformation

Glomulin gene

Brouillard et al.42

CLOVES syndrome

PIK3CA somatic mutation

Kurek et al.43

Capillary malformation

GNAQ somatic mutation

Shirley et al.44

Proteus syndrome

AKT1 somatic mutation

Lindhurst et al.45,46

Capillary malformation microcephaly

STAMBP

McDonell et al.47

Lymphedema

Many genes

Connell et al.48

• • • • •

Bevacizumab, thalidomide, interferon Laser therapy Sclerotherapy/embolization Surgery Often require combined approach

Clinical pearls to distinguish vascular malformations • • •

Arteriovenous malformation: bruit, thrill, cardiac murmur Venous malformation: fills with valsalva, dependent position Lymphatic malformation: transilluminates, infection prone

Genetics and vascular malformations In the past decade, many germ line and somatic mutations have been identified in patients with vascular anomalies and are listed in Table 6.3.


Table 6.4: Mimickers of vascular anomalies Rhabdomyosarcoma Neuroblastoma Myofibroma Fibrosarcoma Glioma Hemangiopericytoma Leukemia Other

Table 6.5: What not to miss Beard distribution hemangioma Facial segmental hemangioma PTEN hamartoma syndromes PHACE syndrome present in an adult Other potential symptoms

This genetic information gives us insight into potential pathologic mecha nisms and provides opportunity for family planning (if germ line mutations). The recognition of the clinical criteria for syndromes with vascular anomalies (e.g. patients with arteriovenous malformations and capillary malformations) should alert the physician to confirm the genetic diagnosis (RASA-1 mutation).36 Entities with genotype–phenotype correlations (such as HHT) are also important to define genetically. Research of the causative genes in vascular anomalies and how this may impact potential therapies are reviewed by Uebelhoer et al.37 Not every vascular lesion is a vascular anomaly. An atypical history, clin ical course, and physical examination (e.g. very firm mass) should prompt the physician to seek a histologic diagnosis. Table 6.4 lists the most frequent mimickers of hemangiomas and other vascular lesions, and Table 6.5 summa rizes some important features for the otolaryngologist to keep in mind. Tables 6.6–6.8 summarize the current open clinical trials and registries for patients with vascular anomalies. Studies for patients with hereditary hemorrhagic telangiectasia are listed in a separate table.8 Updates are avail able at http://clinicaltrials.gov/. Table 6.9 lists extremely helpful websites for physicians and patients.

NCT01598116

Ohio State University

A prospective longitudinal study to identify biomarkers in children with hemangiomas

NCT01873131

Massachusetts General Hospital

A clinical trial of pulsed-dye laser versus timolol topical solution versus observation on the growth of hemangioma in newborn Randomized Single blind NCT01072045

NCT00967226

Children’s Research Institute (Children’s National Medical Center)

Propranolol vs. prednisolone for symptomatic hemangiomas Phase 2 Randomized Single blind

Comparative study of the use of beta blocker University of Sao Paulo and oral corticosteroid in the treatment of infantile hemangioma

NCT01743885

University Hospital, Montpellier, France

Efficacy and safety of Propranolol versus acebutolol on the proliferative phase of infantile hemangioma Single blind Phase 3

ClinicalTrials. gov identifier

Primary site

Title of study Hemangiomas

Table 6.6: Clinical trials

Contd...

Up to 5 months Urine collection and ultrasonography

Up to 2 years

Up to 3 months old

Primary outcome measure: reduction in hemangioma size

Up to 5 months old

Up to 6 months old Primary outcome measure: hemangioma size (visual analogue scale) over 3 months

Details


Columbia University

Mahidol University, Bangkok, Thailand

Optical tomographic imaging of infantile hemangiomas

Topical timolol for superficial infantile hemangioma Phase 3 Randomized

University of Texas Health Science Center at San Antonio

Children’s Hospital of Philadelphia

Timolol for the prevention of proliferation of infantile hemangioma (TiPPIH trial) Phase 1 Randomized Double blind

Timolol option for ulcerated hemangiomas (TOUCH trial) Phase 2 Randomized

Comparative study of the use of beta blocker University of Sao Paulo, Brazil and oral corticosteroid in the treatment of infantile hemangioma Phase 2

Primary site


Contd...

NCT01408056

NCT01434849

NCT01072045

NCT01685398

NCT01673971


Contd...

1–8 Months Timolol vs. Mupirocin Primary outcome measure: time to wound reepithelization at 3 months

< 6 months premature infants birth weight < 1500 g

up to 2 Years of age Primary outcome measure: Reduction on tumor volume

Up to 2 years old Efficacy of the topical 0.5% timolol maleate solution vs. placebo Hemangioma size (visual analogue scale)

Infants up to 2 months of age with hemangiomas > 2 cm in diameter in area accessible to probe, not necessitating medial or surgical intervention Handheld wireless device using diffuse optical imaging (DOI), measuring hemangioma blood flow; correlate with clinical findings

Details


NCT01598116

NCT00833599

The Ohio State University Nationwide Children’s Hospital

University of Texas Health Science Center, Houston

Primary Site

University Hospital, Bordeaux

A prospective longitudinal study to identify biomarkers in children with hemangiomas Observational

Imaging Lymphatic Function in Normal Subjects and in Persons With Lymphatic Disorders

Title of Study Vascular Malformations

Cryoablation of Venous Vascular Malformations (CRYOMAV) Phase 1,2

NCT01845935

ClinicalTrials. gov Identifier:

NCT01533376

Wills Eye

Treatment of port-wine mark in Sturge– Weber syndrome (SWS) using topical timolol Phase 1 Randomized


Primary site


Contd...

Contd...

> 18 years old inoperable venous vascular malformations in soft tissues with indication of cryoablation. Percutaneous Image-guided Cryoablation (FPRPR3508 IceRod® PLUS Needles)

Details

6 years of age and older imaging and blood tests Grade I-II Lymphedema vs Healthy Controls feasibility of near-infrared fluorescence imaging of subjects with acquired and hereditary lymphedema and lymphovascular disorders and to attempt to correlate imaging phenotype with genotype

Up to 5 month old Urine collection and ultrasonography (of hemangioma)

Timolol vs. placebo

2–10 years of age with Parkes Weber syndrome (PWS) or SWS

Details


NCT01811667

Cliniques universitaires Saint-LucUniversité Catholique de Louvain

University of Kentucky

Stanford University

Children’s Hospital Medical Center, Cincinnati

Efficacy and Safety of the Mammalian Target of Rapamycin (mTor Rapamycin) Inhibitor in Vascular Malformations (vasca-LM) Phase III

The Effects of Aldara as an Adjunct to Laser Treatment Phase II Randomized Double Blind

An Investigational Pilot Study to Evaluate Sildenafil for the Treatment of Lymphatic Malformations Non-Randomized Phase 1, 2 Active, not recruiting

Safety and Efficacy Study of the mTOR Inhibitor Sirolimus in Complicated Vascular Anomalies Active, not recruiting Phase 2

NCT00975819

NCT01290484

NCT00979550

NCT01105676

Medical College of Wisconsin

Vascular Malformations and Abnormalities of Growth

ClinicalTrials. gov Identifier

Primary Site

Title of Study Vascular Malformations

Contd...

Up to 31 years old Complex vascular anomalies requiring systemic medical therapy

6 months – 10 years old at lease 3 cm LM or mixed venous lymphatic malformation involving the skin and subcutaneous tissue

2–60 years of age with port wine stain

Up to 70 years

12 months of age plus skin biopsy to assess specific gene and protein expression levels that can distinguish affected from unaffected tissue in patients.

Details


NCT00576888

NCT01018082



Stanford University

Registry for vascular anomalies associated with coagulopathy (VAC)

Longitudinal study of neurologic, cognitive, and radiologic outcomes of PHACE syndrome

National lymphatic disease and lymphedema registry

NCT01336790

NCT01016756


Genetic analysis of PHACE syndrome (hemangioma with other congenital anomalies)

ClinicalTrials.gov identifier

Primary site

Title of study

Lymphatic disease Lymphangiectasia Lymphedema Protein-losing enteropathy Lymphangiomatosis Vascular anomalies http://www.lymphaticresearch.org/patients/patient-registry Contd...

4–6 years old with PHACE syndrome Pilot study to assess and track neurodevelopmental sequelae in PHACE patients Collect neuroimaging studies and patient tissue and DNA samples to enhance an existing tissue repository to facilitate future studies, such as validation of biomarkers Determine the prevalence and describe the spectrum of neurodevelopmental impairment in a cohort of patients 4–6 years of age with PHACE syndrome

Subjects with a vascular anomaly with coagulopathy

Establish a DNA and tissue bank Determine candidate genes for PHACE syndrome using a genomewide approach

Details

Table 6.7: Registries and observational studies


Sturge–Weber syndrome (SWS) patients with CNS involvement 1 month and older National Consortium Database to acquire clinical data/registry information for future clinical trials Assess urine vascular biomarkers; assess somatic mutation possibly causing SWS

NCT01425944

NCT01364857

NCT01803685

Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

University Hospital, Tours

Beijing Tiantan Hospital

Innovative approaches to gauge progression of Sturge–Weber syndrome (SWS)

French National Cohort of Children With Port Wine Stain (CONAPE)

Nationwide Treatment Survey of Intracranial Arteriovenous Malformation in China (NTSIAVMC)

Treatment survey/database

2–12 years of age Port-wine stain on one or both lower limbs Klippel–Trenaunay syndrome Parkes Weber syndrome polymorphisms of RASA1 gene

Blood sample patients vs. volunteers ‘exploration of the microparticles, endothelial cells and progenitor cells and investigate the relationship between endothelial markers and genetic and clinical characteristics of the disease’

NCT01774916

Assistance Publique Hopitaux de Marseille

Details

Identification of genetic and cellular markers associated with vascular endothelial modifications in cutaneous arteriovenous malformations


Primary site

Title of study

Contd...


University of Minnesota

Office-sclerotherapy for epistaxis due to hereditary hemorrhagic telangiectasia

NCT01856842

St. Michael’s Hospital, Toronto

Georgia Regents University

Reperfusion of pulmonary arteriovenous malformations after embolotherapy Randomized trial of Interlock Fibered IDC occlusion system vs. Nester coils

North American Study of Epistaxis in HHT (NOSE)

Cerebral hemorrhage risk in hereditary hemorrhagic telangiectasia (BVMN6203)

St. Michael’s Hospital, Toronto multicenter

NCT01761981

Hospital Italiano de Buenos Aires

Institutional registry of hemorrhagic hereditary telangiectasia

Double blind Phase 2

NCT01485224

IRCCS Policlinico S. Matteo

Efficacy of thalidomide in the treatment of hereditary hemorrhagic telangiectasia (THALIHHT) Phase 2

NCT01158807

NCT0140803

NCT01908543

Imperial College, London

NCT01408732


Iron deficiency and hereditary hemorrhagic telangiectasia

Randomized, crossover

Primary site

Title of study

Table 6.8: HHT studies

Identify factors for CNS AVM rupture, CNS AVM genetics and imaging characteristics

Compare 3 nasal sprays (bevacizumab, estriol, tranexamic acid), vs. to placebo, for HHT-related nosebleeds

Angiography and embolotherapy

18 years old and older thalidomide HHT patients with severe recurrent epistaxis

Ferrous sulfate 200 mg oral tablet

Sclerotherapy with sodium tetradecyl sulfate, for HHT-related recurrent epistaxis

Details



Table 6.9: Internet resources for patients and physicians Program

Website

About Face

http://www.aboutfaceinternational.org

Arkansas Children’s Hospital Vascular Anomalies Program

http://www.birthmarks.org

Boston Children’s Hospital Vascular Anomalies Program

http://www.childrenshospital.org/ clinicalservices/Site1964/mainpageS1964P0.html

Children’s Hospital of Wisconsin Vascular Anomalies Program

http://www.chw.org/display /PPF/DocID/36150/router.asp

Cincinnati Children’s Hospital Vascular Anomalies Program

http://www.cincinnatichildrens.org/ service/h/hemangioma/default/

Genetics Home Reference

http://ghr.nlm.nih.gov/

HHT Foundation

http://hht.org/

HHT Mutation Database

http://www.arup.utah.edu/database/hht/

International Society for the Study of Vascular Anomalies

http://www.issva.org/

Lymphatic Research Foundation

http://www.lymphaticresearch.org/

Medline Plus

www.medlineplus.gov

National Organization for Rare Diseases

http://www. rarediseases.org

National Organization of Vascular Anomalies

http://www.novanews.org

Seattle Children’s’ Hospital Vascular Anomalies Program

http://www.seattlechildrens.org/clinics-programs/ vascular-anomalies/

Sturge-Weber Foundation

http://www.sturge-weber.org/

UCSF Vascular Anomalies Program

http://www.bvac.ucsf.edu/

Vascular Birthmark Institute of NY

http://www.vbiny.org/

Vascular Birthmark Foundation

http://birthmark.org/

Vascular Anomaly and Lymphedema Mutation Database

http://www.icp.ucl.ac.be/vikkula/VAdb/home.php

References 1. Enjolras O, Wassef M, Chapot R. Color atlas of vascular tumors and vascular malformations. 1 edn. Cambridge University Press, 2006. 2. Hassanein AH, Fishman SJ, Mulliken JB, et al. Metastatic neuroblastoma mimicking infantile hemangioma. J Pediatr Surg 2010; 45:2045–9. PubMed PMID: 20920727.

98 Recent Advances in Otolaryngology—Head and Neck Surgery 3. Greene AK, Liu AS, Mulliken JB, et al. Vascular anomalies in 5,621 patients: guidelines for referral. J Pediatr Surg 2011;46:1784–9. PubMed PMID: 21929990. Epub 2011/09/21. eng. 4. Orlow SJ, Isakoff MS, Blei F. Increased risk of symptomatic hemangiomas of the airway in association with cutaneous hemangiomas in a “beard” distribution. J Pediatr. 1997;131:643–6. PubMed PMID: 9386676. 5. Spector JA, Blei F, Zide BM. Early surgical intervention for proliferating heman giomas of the scalp: indications and outcomes. Plast Reconstr Surg 2008; 122:457–62. PubMed PMID: 18626361. 6. Haggstrom AN, Lammer EJ, Schneider RA, et al. Patterns of infantile heman giomas: new clues to hemangioma pathogenesis and embryonic facial deve lopment. Pediatrics 2006;117:698–703. PubMed PMID: 16510649. 7. Haggstrom AN, Garzon MC, Baselga E, et al. Risk for PHACE syndrome in infants with large facial hemangiomas. Pediatrics 2010;126:e418–426. PubMed PMID: 20643720. Epub 2010/07/21. eng. 8. Oza VS, Wang E, Berenstein A, et al. PHACES association: a neuroradiologic review of 17 patients. AJNR American Iournal of Neuroradiology 2008;29: 807–13. PubMed PMID: 18223093. 9. Tangtiphaiboontana J, Hess CP, Bayer M, et al. Neurodevelopmental abnormal ities in children with PHACE syndrome. J Child Neurol 2012. PubMed PMID: 22805249. 10. Duffy KJ, Runge-Samuelson C, Bayer ML, et al. Association of hearing loss with PHACE syndrome. Arch Dermatol 2010; 146:1391–6. PubMed PMID: 20713775. 11. Arora SS, Plato BM, Sattenberg RJ, et al. Adult presentation of PHACES syndrome. Interv Neuroradiol: journal of peritherapeutic neuroradiology, surgical proce dures and related neurosciences. 2011; 17:137–46. PubMed PMID: 21696650. Pubmed Central PMCID: 3287263. Epub 2011/06/24. eng. 12. Chou PS, Guo YC. Limb-shaking transient ischemic attacks in an adult PHACE syndrome: a case report and review of the literature. Neurol Sci: official journal of the Italian Neurological Society and of the Italian Society of Clinical Neuro physiology. 2012; 33:305–7. PubMed PMID: 21710124. 13. Baselga E, Cordisco MR, Garzon M, et al. Rapidly involuting congenital haemangioma associated with transient thrombocytopenia and coagulopathy: a case series. Br J Dermatol 2008; 158:1363–70. PubMed PMID: 18410425. 14. Leaute-Labreze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008; 358:2649–51. PubMed PMID: 18550886. Epub 2008/06/14. eng. 15. Itinteang T, Brasch HD, Tan ST, et al. Expression of components of the reninangiotensin system in proliferating infantile haemangioma may account for the propranolol-induced accelerated involution. J Plast Reconstr Aesthet Surg 2011; 64:759–65. PubMed PMID: 20870476. Epub 2010/09/28. eng. 16. Ji Y, Li K, Xiao X, et al. Effects of propranolol on the proliferation and apop tosis of hemangioma-derived endothelial cells. J Pediatr Surg 2012; 47:2216–23. PubMed PMID: 23217879.

Vascular Anomalies—Advances and Updates for the Otolaryngologist 99 17. Lamy S, Lachambre MP, Lord-Dufour S, et al. Propranolol suppresses angio genesis in vitro: inhibition of proliferation, migration, and differentiation of endothelial cells. Vascul Pharmacol 2010; 53:200–8. PubMed PMID: 20732454. Epub 2010/08/25. eng. 18. Wong A, Hardy KL, Kitajewski AM, et al. Propranolol accelerates adipogenesis in hemangioma stem cells and causes apoptosis of hemangioma endothelial cells. Plast Reconstr Surg 2012; 130:1012–21. PubMed PMID: 23096601. 19. Zou HX, Jia J, Zhang WF, et al. Propranolol inhibits endothelial progenitor cell homing: a possible treatment mechanism of infantile hemangioma. Cardiovasc Pathol: the official journal of the Society for Cardiovascular Pathology. 2012. PubMed PMID: 23151525. 20. Stiles J, Amaya C, Pham R, et al. Propranolol treatment of infantile hemangioma endothelial cells: a molecular analysis. Exp Ther Med 2012; 4:594–604. PubMed PMID: 23170111. Pubmed Central PMCID: 3501380. 21. Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action. Br J Dermatol 2010; 163:269–74. PubMed PMID: 20456345. Epub 2010/05/12. eng. 22. Reddy KK, Blei F, Brauer JA, et al. Retrospective study of the treatment of infan tile hemangiomas using a combination of propranolol and pulsed dye laser. Dermatol Surg: official publication for American Society for Dermatologic Surgery [et al]. 2013; 39:923–33. PubMed PMID: 23458381. 23. Stiles JM, Amaya C, Rains S, et al. Targeting of beta adrenergic receptors results in therapeutic efficacy against models of hemangioendothelioma and angio sarcoma. PloS one 2013; 8:e60021. PubMed PMID: 23555867. 24. Hadaschik E, Scheiba N, Engstner M, et al. High levels of beta2-adrenoceptors are expressed in infantile capillary hemangiomas and may mediate the thera peutic effect of propranolol. J Cutan Pathol 2012; 39:881–3. PubMed PMID: 22764832. 25. Dai Y, Hou F, Buckmiller L, et al. Decreased eNOS protein expression in invo luting and propranolol-treated hemangiomas. Arch Otolaryngol Head Neck Surg 2012; 138:177–82. PubMed PMID: 22351865. 26. Chim H, Armijo BS, Miller E, et al. Propranolol induces regression of heman gioma cells through HIF-1alpha-mediated inhibition of VEGF-A. Ann Surg 2012; 256:146–56. PubMed PMID: 22580939. 27. Boscolo E, Mulliken JB, Bischoff J. Pericytes from infantile hemangioma display proangiogenic properties and dysregulated angiopoietin-1. Arterioscler Thromb Vasc Biol 2013; 33:501–9. PubMed PMID: 23288163. Pubmed Central PMCID: 3573237. 28. Adams MT, Saltzman B, Perkins JA. Head and neck lymphatic malformation treatment: a systematic review. Otolaryngol Head Neck Surg 2012; 147:627–39. PubMed PMID: 22785242. 29. Balakrishnan K, Edwards TC, Perkins JA. Functional and symptom impacts of pediatric head and neck lymphatic malformations: developing a patientderived instrument. Otolaryngol Head Neck Surg 2012; 147:925–31. PubMed PMID: 22675002.

100 Recent Advances in Otolaryngology—Head and Neck Surgery 30. Amanzada A, Toppler GJ, Cameron S, et al. A case report of a patient with hereditary hemorrhagic telangiectasia treated successively with thalidomide and bevacizumab. Case Rep Oncol 2010; 3:463–70. PubMed PMID: 21611144. Pubmed Central PMCID: 3100268. Epub 2011/05/26. eng. 31. Dheyauldeen S, Ostertun Geirdal A, Osnes T, et al. Bevacizumab in hereditary hemorrhagic telangiectasia-associated epistaxis: effectiveness of an injection protocol based on the vascular anatomy of the nose. The Laryngoscope. 2012; 122:1210–14. PubMed PMID: 22565282. 32. Kanellopoulou T, Alexopoulou A. Bevacizumab in the treatment of heredi tary hemorrhagic telangiectasia. Expert Opin Biol Ther 2013. PubMed PMID: 23815519. 33. Reh DD, Hur K, Merlo CA. Efficacy of a topical sesame/rose geranium oil compound in patients with hereditary hemorrhagic telangiectasia associated epistaxis. The Laryngoscope 2013; 123:820–2. PubMed PMID: 23401038. 34. Irving ND, Lim JH, Cohen B, et al. Sturge-Weber syndrome: ear, nose, and throat issues and neurologic status. Pediatr Neurol 2010; 43:241–4. PubMed PMID: 20837301. 35. Greene AK, Taber SF, Ball KL, et al. Sturge-Weber syndrome: soft-tissue and skel etal overgrowth. J Craniofac Surg 2009; 20:617–21. PubMed PMID: 19182685. 36. Eerola I, Boon LM, Mulliken JB, et al. Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet 2003; 73:1240–49. PubMed PMID: 14639529. Pubmed Central PMCID: 1180390. Epub 2003/11/26. eng. 37. Uebelhoer M, Boon LM, Vikkula M. Vascular anomalies: from genetics toward models for therapeutic trials. Cold Spring Harb Perspect Med 2012;2(8). PubMed PMID: 22908197. Epub 2012/08/22. eng. 38. Wouters V, Limaye N, Uebelhoer M, et al. Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyperphosphorylating effects. Eur J Hum Genet: EJHG. 2010; 18:414–20. PubMed PMID: 19888299. Pubmed Central PMCID: 2841708. 39. McDonald J, Bayrak-Toydemir P, Pyeritz RE. Hereditary hemorrhagic telan giectasia: an overview of diagnosis, management, and pathogenesis. Genet Med: official journal of the American College of Medical Genetics. 2011 Jul;13(7): 607-16. PubMed PMID: 21546842. 40. Tan WH, Baris HN, Burrows PE, et al. The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management. J Med Genet 2007; 44:594–602. PubMed PMID: 17526801. Pubmed Central PMCID: 2597949. Epub 2007/05/29. eng. 41. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet: EJHG 2008; 16:1289–300. PubMed PMID: 18781191. Epub 2008/09/11. eng. 42. Brouillard P, Boon LM, Revencu N, et al. Genotypes and phenotypes of 162 families with a glomulin mutation. Mol Syndromol 2013; 4:157–64. PubMed PMID: 23801931. Pubmed Central PMCID: 3666456. 43. Kurek KC, Luks VL, Ayturk UM, et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet 2012; 90:1108–15. PubMed PMID: 22658544. Pubmed Central PMCID: 3370283. Epub 2012/06/05. eng.

Vascular Anomalies—Advances and Updates for the Otolaryngologist 101 44. Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 2013; 368:1971–9. PubMed PMID: 23656586. 45. Lindhurst MJ, Sapp JC, Teer JK, et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 2011; 365:611–19. PubMed PMID: 21793738. Pubmed Central PMCID: 3170413. 46. Lindhurst MJ, Wang JA, Bloomhardt HM, et al. AKT1 gene mutation levels are correlated with the type of dermatologic lesions in patients with Proteus syndrome. J Invest Dermatol 2013. PubMed PMID: 23884311. 47. McDonell LM, Mirzaa GM, Alcantara D, et al. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome. Nat Genet 2013; 45:556–62. PubMed PMID: 23542699. 48. Connell F, Gordon K, Brice G, et al. The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. Clin Genet 2013. PubMed PMID: 23621851.


Chapter

Open Procedures for Airway Obstruction

7

Catherine K Hart, Aliza P Cohen, Robin T Cotton

Historical overview Over the past several decades, great strides have been made in the surgical management of children with airway obstruction. Laryngotracheoplasty (LTP) as a treatment for acquired subglottic stenosis (SGS) was first introduced by Cotton and Evans in the 1970s. During the 1980s, the posterior cricoid split was first performed by Grahne, and both the first posterior graft LTP and the first single-stage LTP were introduced by Cotton. These innovations were followed by Monnier’s description of pediatric cricotracheal resection (CTR) in the 1990s, an evolution of work that had previously been done in adults. By the early 2000s, expansion and resection techniques had become the mainstays of open surgical management of pediatric laryngotracheal stenosis. The slide tracheoplasty is also fast becoming an integral component of the surgical armamentarium. First described by Tsang,1 later popularized by Grillo,2 and subsequently modified by Rutter,3 this has become the operation of choice for congenital complete tracheal rings and is increasingly being performed to address acquired tracheal stenosis. Despite the utility of these collective advancements, the role of endoscopic intervention as a complementary approach has had a resurgence in recent years.

Preoperative assessment Regardless of the procedure performed, the importance of conducting a meticulous assessment and ensuring patient optimization cannot be overemphasized, as both are crucial steps in achieving successful surgical outcomes. Optimally, the overall assessment is made through the collaborative efforts of an interdisciplinary team composed of experts in pulmonology, gastroenterology, otolaryngology, and speech pathology (Table 7.1). It is particularly useful to evaluate vocal fold function and assess the risk of aspiration. Given that gastroesophageal reflux disease, eosinophilic esophagitis, an ‘active’ larynx, and airway colonization with pseudomonas or methicillin-resistant

Open Procedures for Airway Obstruction 103

Table 7.1: Components of preoperative evaluation prior to open airway procedure

Diagnostic test/procedure

Goal of test

Microlaryngoscopy, bronchoscopy

Assess airway and characterize stenosis

Flexible bronchoscopy

Assess airway dynamics and pulmonary comorbidities

EGD* with biopsies

Assess gastrointestinal tract, rule out eosinophilic esophagitis

pH-multichannel impedance testing

Assess for gastroesophageal reflux

VSS ± FEES*

Determine safety of swallow, assess for aspiration

Flexible laryngoscopy

Evaluate vocal fold function

Tracheal and nasal cultures

Rule out tracheal MRSA colonization

(*EGD: Esophagogastroduodenoscopy; VSS: Videofluoroscopic swallow study; FEES: Fiberoptic endoscopic evaluation of swallowing; MRSA: Methicillin-resistant Staphylococcus aureus).

Staphylococcus aureus (MRSA) are all conditions known to decrease the likelihood of surgical success, they must also be diagnosed and addressed prior to surgery.4–7 Careful endoscopic evaluation of the airway to assess the grade, extent and location of the stenosis is essential, as it enables the surgeon to characterize the stenosis. Endoscopy also allows for identification of underlying conditions and/or secondary airway lesions such as laryngomalacia, tracheomalacia, or stomal issues, which may impact the operation selected. Endoscopy is repeated immediately prior to a planned open procedure to ensure that the selected procedure is appropriate.

Preoperative decision making Single-versus Double-stage Procedures Airway reconstruction can be performed either as a single- or double-stage procedure. In a single-stage procedure, the patient’s airway is reconstructed either without tracheotomy placement or with removal of the tracheotomy at the time of the reconstruction. In contrast, in a double-stage procedure, patients either maintain their prior tracheotomy or undergo a tracheotomy at the outset of the procedure. Decannulation is attempted once the airway is deemed adequate. Decision making involves multiple factors, including the surgeon’s comfort level with the procedure, the capability of the intensive care unit to manage the patient postoperatively, and the severity of the patient’s medical comorbidities. Complex patients with poor pulmonary

104 Recent Advances in Otolaryngology—Head and Neck Surgery function, multilevel airway obstruction, a known history of difficult intubation, a history of sedation issues, or previous reconstructive failure are considered poor candidates for single-stage reconstruction.

Advantages and Risks In a single-stage procedure, the patient is usually nasally intubated for a period as brief as a few hours to as long as 2 weeks, with the duration of intubation depending on the operation performed (Table 7.2). Although a singlestage procedure offers advantages such as the avoidance of a tracheotomy or immediate decannulation and the ability to address stomal issues, there are also associated risks. One of the most significant risks is unplanned extubation. To minimize this occurrence, many patients, particularly those younger than 3 years of age, receive heavy sedation. This in turn increases the risk of pulmonary complications and hypotension requiring inotropic support.8 Older patients often tolerate intubation with little or no sedation and are able to ambulate; some are even able to eat while intubated. In most double-stage procedures, a suprastomal stent is placed to support the reconstructed area and removed 2–8 weeks postoperatively. Typically, this stent is positioned with the distal end just above the tracheotomy and with the proximal end sitting at the level of the false vocal folds. Although a suprastomal silicone stent (Fig. 7.1A) is generally preferred, a cut T-tube (Fig. 7.1B) or Teflon stent can also be used.9 To minimize the risk of aspiration, the proximal end of the stent is either capped or sewn shut. It is essential to be cognizant of the fact that children with a suprastomal stent in place are essentially entirely tracheotomy tube dependent. Accidental decannulation can therefore be catastrophic. A large, relatively recent (2010) study reported by Smith et al.10 indicates that operation-specific and overall decannulation rates for singlestage versus double-stage LTP are 91% and 100% versus 68% and 93%, respectively.

Table 7.2: Intubation guidelines for single-stage procedures Procedure

Duration of intubation (days)

Anterior costal cartilage graft

0–5

Posterior costal cartilage graft

5–10

Anterior and posterior costal cartilage grafts

7–14

Cricotracheal resection

0–5

Tracheal resection

0–5

Slide tracheoplasty

0–3


A

B Figs 7.1A and B: Suprastomal stents. (A) Silicone stent; (B) Cut T-tube stent.

Expansion surgery Anterior Graft Although double-stage LTP with anterior cartilage grafting has historically been the cornerstone of SGS management, anterior graft LTP is now used primarily to manage patients with mild SGS or suprastomal collapse (Figs 7.2A and B). Anterior grafting is typically performed as a single-stage procedure, and a single-stage anterior graft has been shown to be successful in > 90% of patients.11 Costal cartilage and thyroid ala cartilage are the most commonly used expansion materials.


A

B Figs 7.2A and B: Anterior costal cartilage graft laryngotracheoplasty. (A) Graft being sutured in place; (B) Graft secured.

In infants younger than 9 months of age with symptomatic SGS, a singlestage anterior graft can be performed concomitantly with a posterior cricoid split. Our experience shows that the posterior cricoid split heals quickly enough to avoid the need for placing a posterior graft. A 7- to 10-day period of intubation is required. In older children, a posterior graft is necessary to allow for adequate distraction of the posterior plates of the divided cricoid lamina.

Posterior Graft A posterior cricoid cartilage graft LTP is indicated in patients with posterior glottic stenosis, high-grade SGS, or bilateral vocal fold dysfunction. Costal cartilage is the most frequently used graft material. Ideally, when splitting


A

B Figs 7.3A and B: Posterior costal cartilage laryngotracheoplasty.

the posterior cricoid, the anterior commissure should be preserved. Keeping the thyroid cartilage intact anteriorly allows for a more stable larynx. If a complete laryngofissure is required, endoscopic visualization of the anterior commissure during the division of the thyroid cartilage minimizes the risk of damage to the anterior commissure. Pockets are created on the esophageal side of the posterior cricoid plate using a round knife. It is best to avoid overdistraction of the posterior cricoid. A 5 mm wide graft is adequate in a 2-yearold and an 8–10 mm graft is sufficient in a teenager. Once the graft is carved, it is then snapped into position; in most cases, sutures are not required (Figs 7.3A and B). An age-appropriate endotracheal tube or stent is then placed to provide additional stabilization for the graft. The endotracheal tube is removed in 5–10 days, and the stent is left in place for 2–8 weeks. If required,

108 Recent Advances in Otolaryngology—Head and Neck Surgery an anterior graft can then be placed. A study conducted by Rutter and Cotton indicates that patients with posterior glottic stenosis who undergo posterior graft placement have an overall decannulation rate of 97%.12

Anterior and Posterior Cartilage Grafts LTP with anterior and posterior cartilage grafts is indicated in patients with high-grade stenosis, especially when a resection is contraindicated, and in patients in whom a previous resection has been performed. Success rates reportedly range from 83% to 96%.10,11,13

Resection surgery Cricotracheal Resection The goal of CTR is (1) to remove the stenotic segment of the trachea, including the anterior cricoid and the anterior two-thirds of the lateral cricoid, and (2) to then reconnect the healthy superior and inferior segments. Care should be taken not to disrupt the cricothyroid joints, thereby minimizing risk to the recurrent laryngeal nerves (Figs 7.4A and B). As with expansion surgery, CTR can be performed as a single-or double-stage procedure. Older children may be extubated on the day of the operation, whereas younger children usually remain intubated for several days, allowing time for glottic edema to resolve. CTR is indicated in patients with severe SGS (grade 3 or 4) or a structurally inadequate subglottis and in those who have undergone previous airway reconstruction. Relative contraindications to CTR include low-grade SGS, stenosis involving the vocal folds, or conditions that impair mobilization of the trachea, such as previous distal tracheal surgery or previous injury to the tracheoesophageal septum. Successful decannulation following CTR is achieved in > 90% of patients.4,14–16 Patients with glottic or supraglottic pathology are at higher risk of decannulation failure after a single procedure. Patients with eosinophilic esophagitis and postoperative MRSA also have significantly lower operationspecific success rates.4

Tracheal Resection Tracheal resection with primary anastomosis is performed far less frequently in children than in adults, for it has long been felt that it is less likely to be successful in children owing to their smaller airway diameter and poor tolerance of tension on the anastomosis. Although careful patient selection improves pediatric outcomes, the cervical slide tracheoplasty (CST) is now the favored approach for managing children with tracheal stenosis (see section below).


A

B Figs 7.4A and B: Cricotracheal resection. (A) Removal of stenotic segment; (B) Beginning of anastomosis.

Intrathoracic Slide Tracheoplasty The slide tracheoplasty was originally developed as an operation to repair congenital tracheal stenosis caused by complete tracheal rings.1 Presently, however, indications for this procedure include repair of stenosis due to absent tracheal rings, sleeve trachea, and distal tracheoesophageal fistula. Although slide tracheoplasty can be performed using extracorporeal membrane oxygenation (ECMO) or jet ventilation, the use of cardiopulmonary bypass facilitates the repair by eliminating the need for ventilation during the procedure and allowing for better exposure and repair of coexisting cardiovascular anomalies. Once the patient is placed on cardiopulmonary bypass, the proximal and distal extents of the airway lesion are identified

110 Recent Advances in Otolaryngology—Head and Neck Surgery under direct endoscopic visualization using a 30-gauge needle. A beveled incision from proximal anterior to distal posterior is carried out to transect the airway. A posterior split of the distal segment and an anterior split of the proximal segment are then made. The anastomosis is performed in a posterodistal to anteroproximal fashion, using a running continuous double-armed 4.0 polydioxanone suture (Figs 7.5A to D). In the largest cohort of patients to date (n = 80) who have undergone slide tracheoplasty on cardiopulmonary bypass, Manning et al.17 found that 63% were extubated within 48 hours of surgery and 30% required significant airway intervention, including multiple endoscopic procedures, temporary stent placement, and revision surgery. Importantly, the mortality rate in this cohort was only 5%—far lower than the reported mortality rate of 10–30% for patients with tracheal stenosis.

A

B Figs 7.5A and B


C

D Figs 7.5A to D: Slide tracheoplasty. (A) Stenosis; (B) Stenosis after transection of trachea; (C) Split lower trachea; (D) Completed anastomosis.

Cervical Slide Tracheoplasty Expansion and resection techniques have been the mainstays of management for patients with tracheal stenosis until recently, when de Alarcón and Rutter18 introduced the CST for the surgical management of a broad spectrum of anomalies, including long-segment stenosis, ‘A-frame’ deformities, multilevel laryngotracheal stenosis, and tracheoesophageal fistula. CST is performed by starting with a standard mid-neck incision, exposing and skeletonizing the airway. As done in the intrathoracic slide tracheoplasty, the proximal and distal extents of the stenosis are identified under endoscopic visualization. The trachea is divided and split as described above.

112 Recent Advances in Otolaryngology—Head and Neck Surgery In patients with severe stenosis, partial resection may be performed. The anastomosis is performed in a posterodistal to anteroproximal fashion, using a running continuous double-armed 4.0 polydioxanone suture. In the largest study to date (n = 29) of patients who have undergone CST, de Alarcón and Rutter report operation-specific and overall success rates of 79% and 90%, respectively.18

References 1. Tsang V, Murday A, Gillbe C, et al. Slide tracheoplasty for congenital funnelshaped tracheal stenosis. Ann Thorac Surg. 1989;48:632–5. 2. Grillo HC, Wright CD, Vlahakes GJ, et al. Management of congenital tracheal stenosis by means of slide tracheoplasty or resection and reconstruction, with long-term follow-up of growth after slide tracheoplasty. J Thorac Cardiovasc Surg. 2002;123:145–52. 3. Rutter MJ, Cotton RT, Azizkhan RG, et al. Slide tracheoplasty for the management of complete tracheal rings. J Pediatr Surg. 2003;38:928–34. 4. White DR, Cotton RT, Bean JA, et al. Pediatric cricotracheal resection: surgical outcomes and risk factor analysis. Arch Otolaryngol Head Neck Surg. 2005;131:896–9. 5. de Alarcon A, Rutter MJ. Revision pediatric laryngotracheal reconstruction. Otolaryngol Clin North Am. 2008;41:959–80. 6. Meier JD, White DR. Multisystem disease and pediatric laryngotracheal reconstruction. Otolaryngol Clin North Am. 2012;45:643–51. 7. Statham MM, de.Alarcon A, Germann JN, et al. Screening and treatment of methicillin-resistant Staphylococcus aureus in children undergoing open airway surgery. Arch Otolaryngol Head Neck Surg. 2012;138:153–7. 8. McCormick ME, Johnson YJ, Pena M, et al. Dexmedetomidine as a primary sedative agent after single-stage airway reconstruction. Otolaryngol Head Neck Surg. 2013;148:503–8. 9. Preciado, D. Stenting in pediatric airway reconstruction. Laryngoscope. 2012; 122:S97–8. 10. Smith LP, Zur KB, Jacobs IN. Single- vs double-stage laryngotracheal reconstruction. Arch Otolaryngol Head Neck Surg. 2010;136:60–5. 11. Gustafson LM, Hartley BE, Liu JH, et al. Single-stage laryngotracheal reconstruction in children: a review of 200 cases. Otolaryngol Head Neck Surg. 2000;123:430–4. 12. Rutter MJ, Cotton RT. The use of posterior cricoid grafting in managing isolated posterior glottic stenosis in children. Arch Otolaryngol Head Neck Surg. 2004;130:737–9. 13. Younis RT, Lazar RH, Astor F. Posterior cartilage graft in single-stage laryngotracheal reconstruction. Otolaryngol Head Neck Surg. 2003;129:168–75. 14. Sandu K, Monnier P. Cricotracheal resection. Otolaryngol Clin North Am. 2008;41:981–98.

Open Procedures for Airway Obstruction 113 15. Rutter MJ, Hartley BE, Cotton RT. Cricotracheal resection in children. Arch Otolaryngol Head Neck Surg. 2001;127:289–92. 16. Monnier P, Lang F, Savary M. Partial cricotracheal resection for pediatric subglottic stenosis: a single institution’s experience in 60 cases. Eur Arch Otorhinolaryngol. 2003;260:295–7. 17. Manning PB, Rutter MJ, Lisec A, et al. One slide fits all: the versatility of slide tracheoplasty with cardiopulmonary bypass support for airway reconstruction in children. J Thorac Cardiovasc Surg. 2011;141:155–61. 18. de Alarcon A, Rutter MJ. Cervical slide tracheoplasty. Arch Otolaryngol Head Neck Surg. 2012;138:812–6.


Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea

Chapter

8

Stefan Mlot, Rahmatullah Rahmati

Introduction Obstructive sleep apnea (OSA) is characterized by repetitive upper airway collapse resulting in oxygen desaturation and sleep interruption. OSA is associated with cardiopulmonary morbidity and mortality, neurocognitive impairment, and reduced quality of life (QoL). Polysomnography (PSG) allows the diagnosis of OSA and its severity. Although continuous positive airway pressure (CPAP) and tracheostomy remain the gold standards for the medical and surgical management of OSA, there is a wide range of additional procedures available to address collapse of the upper airway. Unfortunately, many of these procedures have been shown to be either ineffective in reducing the apnea–hypopnea index (AHI) by themselves or are associated with significant locoregional morbidity when performed in combination.1 As the field of sleep surgery continues to evolve, newer procedures and medical devices are being investigated for their role in the management of OSA. One such area of interest is hypoglossal nerve (HGN) stimulation. This chapter provides an overview of the science and recent clinical trial outcomes of HGN stimulation in OSA management.

Physiology of the upper airway in OSA OSA is a common disorder involving collapse of the upper airway during sleep. It has been shown to be associated with an increased risk of hypertension, stroke, heart disease, type 2 diabetes, sudden death, depression, and decreased QoL, among other comorbidities.2–8 The primary locations of obstruction in OSA are the retropalatal and retrolingual regions of the pharynx, though usually a combination of multiple regions within the upper aerodigestive tract contributes to OSA.9 In these cases, addressing just one component of the upper airway typically does not result in improvement of the AHI. This is perhaps why procedures such as uvulopalatopharyngoplasty (UPPP), laser-assisted uvulopalatoplasty (LAUP), and soft palate implant insertion have not been demonstrated to be effective when used alone,

Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea 115

whereas multilevel upper airway surgery (especially when maxillomandi bular advancement [MMA] is performed) has been demonstrated to be effective in treating moderate–to-severe OSA and has been recommended as an option for OSA management by the American Academy of Sleep Medicine.1 Several anatomic and physiologic factors contribute to upper airway collapse and patency. Some of these act in a phasic pattern during the respiratory cycle, namely the intraluminal negative pressure generated on inspiration (contributing to airway collapse) and the longitudinal pressure exerted on the pharyngeal airway with lung inflation (contributing to airway stiffening and thus reducing collapse). The primary factors that play a role in airway collapse with OSA, however, are (1) the extraluminal positive pressure generated upon the pharynx by the surrounding soft tissue (increased with greater amounts of fat deposition, and thus related to obesity) and (2) anatomically constricting factors such as retrognathia, macroglossia, and adenotonsillar hypertrophy. In order to maintain airway patency, these collapsing forces must be counterbalanced by the dilating forces of the pharyngeal muscu lature.10 The primary muscles involved in maintaining airway patency are the intrinsic and extrinsic muscles of the tongue, which are innervated by the HGN. These muscles have a preponderance of fast-twitch muscle fibers anteriorly and slow-twitch muscle fibers posteriorly.11 Slow-twitch muscle fibers, located at the base of the tongue, are fatigue-resistant and provide the muscle tone important in maintenance of airway patency as well as the rhythmic contractions involved in deglutition, while fast-twitch fibers are more important in fine motor functions such as speech and mastication. During sleep, decreased tonic stimulation of the hypoglossal motor nucleus contributes to a loss of tonicity in slow-twitch muscle fibers, which in turn contributes to upper airway collapse in those patients who are predisposed to OSA due to constrictive anatomy and/or increased extraluminal pressure.10 Multiple studies have demonstrated that the pharyngeal musculature’s dilatory effects are due to a complex interaction between tongue protrusors such as the genioglossus and tongue retrusors such as the styloglossus and hyoglossus. Among the first to demonstrate this was Eisele et al.,12 who showed that stimulation of the entire HGN resulted in an increase in inspiratory flow in human subjects, both while awake and while asleep. The reasons for this have been elucidated by several animal and human studies. First, it was shown that any protruding or retruding movements of tongue musculature contribute to stiffness of the posterior lingual surface of the tongue, which in turn imparts stiffness to the superior pharyngeal constrictors of the oropharynx and the palatoglossal fold of the soft palate. These combined stiffening and protruding effects have the net effect of conferring patency to the upper airway.13,14 Second, direct stimulation of the genioglossus

116 Recent Advances in Otolaryngology—Head and Neck Surgery (the most intensely studied of the HGN-associated muscles) has been shown to increase airway dilation markedly, though stimulation of the genioglossus alone does not have as large an effect on airway patency during low-pressure events.15 Despite this finding, however, most researchers believe that selective stimulation of protrusor muscles such the genioglossus will confer better results in terms of airway patency and less muscle fatigue than whole nerve HGN stimulation. Such specificity would require selective stimulation of the nerve fiber bundles that innervate the protrusor muscles, located within the medial aspect of the HGN;16 indeed, this model is employed in the new systems currently undergoing clinical trials (see below). Finally, studies have shown that direct stimulation of the HGN can be effective in treating OSA without discomfort, as the motor recruitment threshold is lower than the arousal threshold.12

Measures of respiratory status used in the analysis of patients with obstructive sleep apnea Measuring the efficacy of HGN stimulation and other methods of OSA management involves the analysis of a number of different physiologic and QoL end points. Changes in AHI are typically the primary measurement of surgical success in upper airway surgery. Surgical success has been defined as an AHI reduction of at least 50% combined with a postoperative AHI of < 20/h at the 6-month follow-up visit.17 However, this second requirement is often difficult to meet in patient populations with moderate-to-severe OSA even if large improvements in AHI are observed postoperatively, so many studies also consider statistically significant raw improvement in AHI as a measure of surgical success. Additional physiologic end points include various data collected during PSG. These include total arousals, respiratory event-related arousals, total sleep time, sleep efficiency (defined as total sleep time as a percentage of time in bed), the oxygen desaturation index (ODI – defined as the number of oxygen desaturations of 4% or greater below the baseline level per hour of sleep), and the percentage of time spent in rapid eye movement (REM) sleep versus non-REM sleep. Several methods of anatomic analysis, both objective and subjective, are commonly employed in analyzing patients with OSA. Cephalometrics have long been used by oromaxillofacial surgeons to analyze the bony framework of the upper airway. Of particular utility are the anterior–posterior lengths of pharyngeal lucency at the levels of the inferior border of the mandibular body and the superior border of the mandibular body, both anterior and posterior to the soft palate. These measurements may also be made under fluoroscopy to assess the efficacy of a HGN stimulator system after implantation.18 Drug-induced sleep endoscopy (DISE) may also be used


to determine the site of upper airway collapse.19,20 Although DISE is qualitative and somewhat subjective, it is a useful method for determining the pattern and location of airway collapse. This is particularly meaningful for those patients who suffer from complete concentric collapse at the level of the velum and/or tongue base, as these collapse patterns are associated with increased body mass index (BMI) and are predictors of failure in upper airway surgery. The primary QoL measure used to analyze patients with OSA is the Epworth sleepiness scale (ESS),21 in which higher scores indicate the presence of more significant sequelae of OSA. There are a number of additional QoL assays that are often used as secondary end points, including the functional outcomes of sleep questionnaire (FOSQ), the calgary sleep apnea quality of life index (SAQLI), the fatigue severity scale (FSS), and the Pittsburgh sleep quality index (PSQI), among others. As OSA is often correlated with symptoms of major depressive disorder, many studies also employ the beck depression inventory (BDI) as a secondary end point in data analysis.

The current state of hypoglossal nerve stimulation The Inspire System HGN stimulation was first attempted in a clinical model at Johns Hopkins University using the Inspire I system, culminating in a phase I trial that was completed in 2001.22,23 This system used a half-cuff tripolar stimulation electrode, placed on the proximal portion of the HGN between the submandibular gland and the digastric tendon; a respiratory pressure transducer, inserted through a small hole drilled through the manubrium and thus allowing the measurement of intrathoracic pressure; and a pulse generator placed subcutaneously in the chest, which synchronized HGN stimulation with inspiration to prevent the muscle fatigue that would accompany tonic low-level stimulation. Additionally, the system employed a programming device capable of altering stimulation amplitude, pulse width, and stimulation frequency; and a patient programmer, which allowed the patient to turn the device on prior to the initiation of sleep and off upon waking. The programming was performed beginning 4 weeks postimplantation, at which point the patients began using their devices in a monitored setting, followed by use at home. Of the eight patients implanted, seven had a significant reduction in AHI, which was maintained through a follow-up period of 6 months. Despite these promising results, this initial trial ended prematurely due to technical faults such as lead rupture and respiratory sensor malfunction secondary to cardiac artifacts, though the three patients who did not experience adverse effects continued to use the device successfully throughout the battery life of the device.

118 Recent Advances in Otolaryngology—Head and Neck Surgery By 2009–2010, new technology spawned the development of three new systems, all of which are currently undergoing clinical trials. The Inspire II system24 is an updated version of the initial Inspire system, except that the previously described intrathoracic pressure sensor has been replaced by a respiratory motion sensor implanted within the intercostal muscles at the level of the fourth intercostal space. This alteration is intended to prevent cardiac artifacts from interfering with device function (see Fig. 8.1 and Table 8.1 for a comparison of the different HGN stimulator systems). In the first part of the trial, patient selection criteria limited participants to those with a BMI < 35 kg/m2 and an AHI ≥ 25/h, while the half-cuff electrode was placed around the HGN prior to its branching into medial and lateral segments. A selected portion of these patients also underwent DISE to determine the site, degree, and pattern of upper airway collapse. In the second part of the trial, patient selection criteria were altered based on data collected from DISE in part 1, with subjects selected for BMI ≤ 32 kg/m2 and an AHI between 20 and 50/h as well as a collapse pattern that did not involve complete concentric obstruction at the level of the soft palate. Additionally, in part 2 the

Fig. 8.1: Components of a hypoglossal nerve stimulation system. (Adapted from Eastwood et al., 2011).


Table 8.1: Comparison of the Inspire, Apnex, and ImThera hypoglossal nerve stimulator systems

Inspire II

Apnex

ImThera

Stimulator

Circumferential single electrode lead Placed around medial division of distal CN XII

Circumferential single electrode lead Placed around medial division of distal CN XII Final cuff placement adjusted based on intraoperative fluoroscopy

Circumferential 6-electrode lead Placed around proximal CN XII, near the middle tendon of the digastric

Respiratory sensor

Impedance sensor placed in ipsilateral fourth intercostal space

Impedance sensors placed in bilateral intercostal spaces

None

Other components Pulse generator, implanted in ipsilateral infraclavicular pocket

Pulse generator, implanted in ipsilateral infraclavicular pocket

Pulse generator, implanted in ipsilateral infraclavicular pocket

Programming

Activated 4 weeks postimplantation Electrode stimulated during inspiration only Titrations performed at 1, 3 and 6 months postimplantation

Activated 3–4 weeks postimplantation Electrodes stimulated cyclically in a pattern independent of the respiratory cycle Titrations performed at 1 and 12 months postimplantation

Activated 4 weeks postimplantation Electrode stimulated during inspiration only Titrations performed at 1, 2 and 4 months postimplantation

electrode was placed only around the medial segment of the nerve (Fig. 8.2). In total, 61 patients were enrolled in the study, with 31 receiving an implant: 22 patients during part 1 (with 2 lost to follow-up) and 9 patients during part 2 (with 1 lost to follow-up). The remainder of enrolled subjects did not meet inclusion criteria. Primary end points included AHI, ESS, and FOSQ. Results of the phase II trial were encouraging. During part 1, the study group found that subjects who responded to therapy (predefined as an AHI reduction of ≥ 50% from baseline and an AHI < 20/h at 6-month follow-up) had a significantly lower baseline AHI (26.1 ± 5.0 vs. 51.1 ± 16.8) and BMI (27.8 ± 1.8 vs. 30.7 ± 2.6) compared with nonresponders. A Fischer exact test was used to determine that cutoffs of AHI ≤ 50/h and BMI ≤ 32 kg/m2 were


Fig. 8.2: Hypoglossal nerve stimulator electrode location on the hypoglossal nerve.

appropriate for determination of likelihood of patient response, whereas there was no correlation with either ESS or FOSQ. For the responders in part 1, AHI was significantly reduced during both REM and non-REM sleep (total AHI reduced from 26.1 ± 4.5 to 7.7 ± 4.1, p < 0.01). Similarly, in part 2 of the study (Table 8.2), subjects also experienced a significant reduction in AHI (38.9 ± 9.8 vs. 10.0 ± 11.0, p < 0.01). Of note, despite the lack of significant AHI reduction among nonresponders in part 1 of the study, all 28 patients who received an implant during the study experienced improvements in ESS (11.0 ± 5.0 baseline vs. 7.6 ± 4.3 postimplant, p < 0.01) and FOSQ (89.1 ± 23.5 baseline vs. 100.8 ± 16.9 postimplant, p = 0.02). With regard to arousability, only responders experienced a significant decrease in arousals (170 ± 55 baseline and 55 ± 16 postimplant for responders, compared with 200 ± 51 baseline and 201 ± 81 postimplant for nonresponders). Only two patients experienced an adverse event: one patient presented with pain and swelling at the neck incision site, which responded to antibiotics, and one patient presented with a delayed infection that required device explantation. There were no cases of HGN palsy or pneumothorax.

The Apnex System Similarly, the Apnex system has shown encouraging results from phase II clinical trials.25 This system consists of a cuff electrode placed on the medial branch of the HGN (Fig. 8.2), a pulse generator inserted subcutaneously in the chest, and two respiratory sensing leads that measure changes in thoracic bioimpedance inserted into the intracostal space. Device programming was initiated under PSG guidance after a healing period of 30 days, with the patient able to use the device at home thereafter. Inclusion criteria for

–

–

–

PSQI

BDI

FSS

–

–

–

–

100.8

–

–

–

–

0.02

< 0.01

0.66

0.53

< 0.01

< 0.01

p

-

15.8

10.1

3.2

14.4

12.1

76.6

340.5

16.8

43.1

Baseline

–

9.7

8.7

4.9

16.7

8.1

81.7

349.5

9.1

19.5

6 months

Apnex**

-

< 0.001

0.19

< 0.001

< 0.001

< 0.001

0.03

0.88

< 0.001

< 0.001

p

4.5

–

–

–

–

10.8

69.8

413.5

29.2

45.2

Baseline

3.6

–

–

–

–

7.9

72.4

406.3

15.3

21

12 months

ImThera***

0.085

–

–

–

–

0.094

0.446

0.784

0.001

< 0.001

P

*Phase II trial. Part 2 of study (BMI ≤ 32 kg/m2, AHI 20–50/h). **Phase II trial. BMI ≤ 35 kg/m2. ***Phase I trial. BMI 25–40 kg/m2, AHI ≥ 20/h. (AHI: Apnea–hypopnea index; ODI: Oxygen desaturation index; ESS: Epworth sleepiness scale; FOSQ: Functional outcomes of sleep questionnaire; FSS: Fatigue severity scale; SAQLI: Calgary sleep apnea quality-of-life index; PSQI: Pittsburgh sleep quality index; BDI: Beck depression inventory).

–

SAQLI

7.6

11

89.1

ESS

FOSQ

77.2

74.9

Sleep efficiency (%)

9.5

305.8

32.1

319.0

ODI (events/h)

10.0

38.9

6 months

Inspire II*

Sleep time (min)

AHI (events/h)

Baseline

stimulator systems

Table 8.2: Outcomes from phase I/II trials of the Inspire, Apnex, and ImThera hypoglossal nerve


122 Recent Advances in Otolaryngology—Head and Neck Surgery the study included BMI ≤ 40 kg/m2 and an AHI between 20 and 100/h with a predominance of hypopneas (≥ 80%), among others. Primary end points were AHI and FOSQ, with secondary end points including ESS, SAQLI, PSQI, and BDI. Thirty-seven subjects were initially enrolled, with 21 of these subsequently implanted. Results at 6-month follow-up showed significant improvements in AHI, sleep quality, and QoL (Table 8.2). Patients experienced significant improvement in sleep latency (p = 0.03), sleep efficiency (p = 0.03), and time in REM versus non-REM sleep (p < 0.001). Improvement in AHI was limited to those subjects who were not morbidly obese: for those with a BMI < 35 kg/m2, AHI improved from 43.0 ± 19.5 to 14.0 ± 7.7, while for those with a BMI > 35 kg/m2, AHI only improved from 44.5 ± 13.6 to 31.5 ± 24.6 (p = 0.03 for comparison of 6-month AHI when stratified for BMI). For all patients, QoL scores showed significant improvement, with gains noted in FOSQ (p < 0.001), ESS (p < 0.001), SAQLI (p < 0.001), PSQI (p < 0.04), and BDI (p < 0.001). Adverse events were limited to two patients who had the device explanted (one electively due to the decision for alternative upper airway surgery and one due to a procedure-related hematoma and infection) and a third who required a replacement of the electrode cuff due to dislodgement. Other adverse effects were minor, with the primary device-related problem being the development of abrasions on the ventral surface of the tongue due to tongue movement over the lower incisors during sleep (addressed successfully by using a plastic dental guard over the mandibular teeth).

The ImThera System The third system, manufactured by ImThera,26 is a modification of the previously described design in that it eliminates the requirement for respiratory sensing leads. This device consists of a pulse generator, battery and stimulation system implanted subcutaneously in the chest, as well as a silicone cuff housing six electrodes that can independently stimulate segments of the HGN. This electrode is placed around the HGN near the digastric tendon, proximal to its division into medial and lateral branches (Fig. 8.2). After PSG-guided titration of the device, stimulation is cycled between the six electrodes, ensuring that no nerve fibers are continuously stimulated. This method of cyclical stimulation obviates the need for synchronization with the respiratory cycle, thus removing a component of the HGN stimulator system that previously had been the most frequent cause of device failure. The device has not yet completed phase II clinical trials, but results from the phase I trials are informative. Patient inclusion criteria included the requirements that AHI was ≥ 20/h, BMI was between 25 and 40 kg/m2, and modified Mallampati score was between 1 and 3. Primary end points were adverse events and mean change in AHI, while secondary end


points included ESS, FSS and various parameters of sleep quality. Adverse events included two patients with ipsilateral tongue hemiparesis lasting 2–3 months, two patients with cuff failures, and one patient who required device repositioning due to twiddler’s phenomenon, along with other minor events related to device titration. At 12-month follow-up, significant improvements were seen in AHI (45.2 ± 17.8 baseline vs. 21.0 ± 16.5 postimplant, p < 0.001) and arousals (36.8 ± 12.5 baseline vs. 24.9 ± 13.7 postimplant, p < 0.001), with trends for improvement noted in ESS (10.8 ± 6.2 baseline vs. 7.9 ± 4.2 postimplant, p = 0.094) and FSS (4.5 ± 1.6 baseline vs. 3.6 ± 1.5 postimplant, p = 0.085) (Table 8.2).

Future directions HGN stimulators hold promise as an additional tool in treating moderate-tosevere OSA. At the time of this publication, none of the three systems under investigation has been FDA approved for the treatment of OSA, though two are in phase III clinical trials. Data collection is scheduled to be completed for the Inspire system in March 2014 and for the Apnex system in October 2017. The ImThera system is currently in phase II trials in the United States, scheduled to be finished with data collection in April 2014. Preliminary data for all three devices demonstrate that HGN stimulation may be a useful procedure for patients with moderate-to-severe OSA in the absence of morbid obesity.

References 1. Aurora RN, Casey KR, Kristo D, et al. Practice parameters for the surgical modifications of the upper airway for obstructive sleep apnea in adults. Sleep. 2010;33(10):1408–13. 2. Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med. 2000;342:1378–84. 3. Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005;353:2034–41. 4. Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med. 2001;163:19–25. 5. Reichmuth KJ, Austin D, Skatrud JB, et al. Association of sleep apnea and type II diabetes: population-based study. Am J Respir Crit Care Med. 2005;172: 1590–5. 6. Young T, Finn L, Peppard PE, et al. Sleep-disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep. 2008;31:1071–8. 7. Peppard PE, Szklo-Coxe M, Hla KM, et al. Longitudinal association of sleeprelated breathing disorder and depression. Arch Intern Med. 2006;166:1709–15. 8. Baldwin CM, Griffith KA, Nieto FJ, et al. The association of sleep-disordered breathing and sleep symptoms with quality of life in the Sleep Heart Health Study. Sleep. 2001;24:96–105.

124 Recent Advances in Otolaryngology—Head and Neck Surgery 9. Sher AE. Upper airway surgery for obstructive sleep apnea. Sleep Med Rev. 2002;6(3):195–212. 10. White DP. Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med. 2005;172(11):1363–70. 11. Zaidi FN, Meadows P, Jacobowitz O, et al. Tongue anatomy and physiology, the scientific basis for a novel targeted neurostimulation system designed for the treatment of obstructive sleep apnea. Neuromodulation. 2013;16(4):376–86. 12. Eisele DW, Smith PL, Alam DS, et al. Direct hypoglossal nerve stimulation in obstructive sleep apnea. Arch Otolaryngol Head Neck Surg. 1997;123:57–61. 13. Fregosi RF. Influence of tongue muscle contraction and dynamic airway pressure on velopharyngeal volume in the rat. J Appl Physiol. 2008;104:682–93. 14. Oliven A, Odeh M, Geitini L, et al. Effect of coactivation of tongue protrusor and retractor muscles on pharyngeal lumen and airflow in sleep apnea patients. J Appl Physiol. 2007;103:1662–8. 15. Fuller DD, Williams JS, Janssen PL, et al. Effect of co-activation of tongue protrudor and retractor muscles on tongue movements and pharyngeal airflow mechanics in the rat. J Physiol. 1999;519(2):601–13. 16. Yoo PB, Durand DM. Effects of selective hypoglossal nerve stimulation on canine upper airway mechanics. J Appl Physiol. 2005;99:937–43. 17. Sher AE, Schechtman KB, Piccirillo JF. The efficacy of surgical modifications of the upper airway in adults with obstructive sleep apnea syndrome. Sleep. 1996;19:156–77. 18. Goding GS, Tesfayesus W, Kezirian EJ. Hypoglossal nerve stimulation and airway changes under fluoroscopy. Otolaryngol Head Neck Surg. 2012;146(6):1017–22. 19. Borek RC, Thaler ER, Kim C, et al. Quantitative airway analysis during druginduced sleep endoscopy for evaluation of sleep apnea. Laryngoscope. 2012;122(11):2592–9. 20. Gillespie MB, Reddy RP, White DR, et al. A trial of drug-induced sleep endoscopy in the surgical management of sleep-disordered breathing. Laryngoscope. 2013;123(1):277–82. 21. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540–5. 22. Schwartz AR, Bennet ML, Smith PL, et al. Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea. Arch Otolaryngol Head Neck Surg. 2001;127:1216–23. 23. Kezirian EJ, Boudewyns A, Eisele DW, et al. Electrical stimulation of the hypoglossal nerve in the treatment of obstructive sleep apnea. Sleep Med Rev. 2010;14:299–305. 24. Van de Heyning PH, Badr MS, Baskin JZ, et al. Implanted upper airway stimulation device for obstructive sleep apnea. Laryngoscope. 2012;122:1626–33. 25. Eastwood PR, Barnes M, Walsh JH, et al. Treating obstructive sleep apnea with hypoglossal nerve stimulation. Sleep. 2011;34(11):1479–86. 26. Mwenge GB, Rombaux P, Dury M, et al. Targeted hypoglossal neurostimulation for obstructive sleep apnoea. A 1 year pilot study. Eur Respir J 2013;41(2): 360–7.

Chapter Cochlear Implants: An Update

9

Divya Chari, Maura K Cosetti, Anil K Lalwani

Introduction Originally approved by the US Food and Drug Administration in 1985 for postlingually deafened adults with profound sensorineural hearing loss (SNHL), multichannel cochlear implants (CIs) have become the most successful neural prostheses to date. While SNHL can result from malfunction or injury to any portion of the auditory pathway, damage to the inner hair cells accounts for the majority of severe-to-profound deafness. In these patients, a CI restores varying amounts of auditory function by bypassing the inner hair cells and transmitting electrical impulses directly to the auditory nerve through a surgically implanted, intracochlear electrode. In the last 25 years, nearly all aspects of cochlear implantation have undergone significant evolution. Technological advancements include improvements in the internal device, speech processing strategies, and programming software. Advances in electrode design, atraumatic round window and cochleostomy techniques, and unified external hardware combining CI and traditional hearing aid (HA) technology have allowed some preservation of low-frequency residual hearing, with initial promising results in postoperative hearing outcomes. Recent research in electroacoustic stimulation demonstrates increased auditory perception, which may aid with speech perception in noise and music perception and appreciation. The initially narrow candidacy criteria has broadened to include a myriad of patients affected by sensorineural hearing loss (SNHL), including those at the extremes of age, patients with auditory neuropathy spectrum disorder (ANSD), and individuals with residual low-frequency hearing. Outcomes data in speech perception and, where appropriate, speech and language development, suggest benefit from increased access to sound in both traditional CI recipients as well as those in newly expanding candidate groups. The following review will highlight and discuss recent updates in hardware and software technology, electroacoustic stimulation, areas of CI candidacy, speech perception, and speech and language outcomes.


Updates in cochlear implant technology: hardware and software Developments in Speech Processing Software Three main devices are used in the United States: the Advanced Bionics HiRes 90K with a 16-electrode array (Valencia, CA, USA), the Cochlear Ltd. Nucleus Freedom with a 22-electrode array (Sydney, Australia) and the MED-EL GmbH (Innsbruck, Austria) Concert containing a 24-electrode array.1 Each of the manufacturers offers multiple processing strategies. In general, the default strategies are, respectively, high resolution (HiRes) for the Advanced Bionics device, the advanced combination encoder (ACE) for the Cochlear device, and fine structure processing (FSP) for the MED-EL device.2 In general, all coding strategies attempt to mimic the tonotopic organization of the organ of Corti. Higher-frequency bands are associated with electrodes in the basal cochlea, resulting in the perception of higher pitches; lower-frequency bands to electrodes are positioned more deeply in the direction of the apex, creating the perception of successively lower pitches. The standard continuous interleaved sampling (CIS) strategy filters input sound signals into bands of frequencies with a set of bandpass filters. Envelope variations in the different bands are nonlinearly compressed and are represented at corresponding electrodes in the cochlea by modulating trains of biphasic electrical pulses. The output of each bandpass channel is directed to a single intracochlear electrode, with low-to-high channels assigned to apical-to-basal electrodes in order to approximate the location of frequency mapping in the normal cochlea. Most signal processing strategies focus on how to encode spectral and temporal fine structure cues, elements that are crucial to speech perception in noise, music appreciation, and speech perception of tonal languages in CI users.3-4 Nie et al. (2006) developed a strategy that transforms the fastvarying temporal fine structure into a slow-varying frequency modulation signal by limiting the range and rate of frequency modulation.5 In another study, Throckmorton et al. (2006) evaluated fine frequency structure using a multiple carrier frequency algorithm and found substantive improvement with as few as two frequencies per channel.6 Despite this promising evidence, information on temporal fine structure is scant and the fundamental frequency of speech and other low-frequency cues might not be well transmitted with envelope-based strategies.7 MED-EL recently developed “fine structure processing” (FSP), a processing strategy intended to improve both temporal and tonotopic coding of sounds in CIs by using filters with a bell-shaped frequency response. In addition, the FSP strategy is thought to provide temporal fine structure by

Cochlear Implants: An Update 127

using stimulations at the 1–3 most apical electrodes that are elicited at a variable rate that corresponds to the fine structure of the signal in the specific filter band. The purpose of the FSP strategy is to provide CI users with improved pitch perception, which in theory enhances speech perception in noise, melody recognition, music appreciation, and sound localization.8 Multiple studies comparing the FSP and CIS strategies in the MED-EL system have demonstrated variable clinical effects on speech intelligibility and music sound quality and appreciation. One study, in which 14 CI users received new speech processors with FSP in exchange for their old CIS processors, showed significant improvements on speech and music perception tests as well as higher satisfaction with the FSP strategy.9 Notably, however, a oneyear follow-up of eight of the 14 subjects from the previous study, demonstrated nonsignificant differences between the baseline CIS results and the FSP results.10 A blinded paired comparison between FSP and CIS performed for subjective speech intelligibility demonstrated that although most individuals showed no significant preference, more individuals rated CIS as significantly better at the first two annual visits, but after two years, more individuals rated FSP as significantly better.11 Zierhofer and Schatzer (2008) outlined the method of simultaneous electrode stimulation available with the MED-EL processor termed “channel interaction compensation” (CIC).12 A fundamental characteristic of CIS is that stimulation pulses on individual electrodes are applied without any temporal overlap. In contrast, CIC stimulates simultaneously, in theory allowing for a better representation of a sound’s temporal fine structure. Preliminary testing of CIC did not lead to improved clinical performance in speech or music perception; however, its simultaneous approach that could be the basis for future stimulation strategies. To encode spectral fine structure, more independent electrodes are needed. Given the lack of space for more electrodes in the cochlea, research has investigated using focused stimulation to increase spectral resolution and using virtual channels (VCs) to increase the number of functional channels. Advanced Bionics Corporation uses VCs in speech processing software for the HiRes 120 and HiRes 90K cochlear implants. VCs increase the number of spectral channels beyond the number of physical electrodes provided by the CI array by varying the proportion of current delivered to each electrode of an electrode pair. Prior research suggests that while only four frequency bands are necessary for speech understanding in a quiet environment, eight bands are required for speech perception in a noisy environment, and an even greater number of bands is required for effective music perception.13 Modern CIs typically have 12 to 22 intracochlear electrodes, but most CI users do not demonstrate significant improvement beyond the use of 4–8 channels, perhaps because of the broad current spread from stimulated electrodes and the resulting

128 Recent Advances in Otolaryngology—Head and Neck Surgery channel interaction from overlapping neural populations.14 Multiple metho dologies attempting to minimize current interactions between electrodes have been investigated, including the use of monopolar, tripolar and even quadrupolar techniques for VC creation. Landsberger and Srinivasan (2009) found better VC discrimination with quadrupolar VCs than with monopolar VCs. Srinivasan et. al (2010) found that there was a sharper peak in the spread of excitation (measured with psychophysical forward masked excitation curves) with quadrupolar VCs than with monopolar VCs, which may explain better VC discrimination with quadrupolar VC stimulation.15 While some studies report clinical benefit in speech perception and music appreciation with HiRes 120, others suggest that benefits may be limited to a small number of HiRes 120 users. A study conducted by Firszt et al. (2009) of 8 postlingually deafened adults demonstrated a small but significant clinical benefit in both speech perception and music appreciation with the HiRes 120 current steering technology.16 However, another study by Donaldson et al. (2010) showed no clear evidence that HiRes 120 supports improved sentence recognition in noise. In 10 postlingually deafened adults implanted with the HiRes 90K CI, within-subject comparisons between traditional processing and current steering HiRes 120 strategy were performed. Speech perception was assessed for sentence recognition in noise and the spectral cues related to vowel F1 frequency, vowel F2 frequency, and consonant place of articulation. HiRes 120 showed no improvement over HiRes 90K on the speech measures tested.17 Current steering via monopolar VCs has not been shown to significantly improve speech perception, despite the increased number of single-channel pitch percepts.18,19 Multi-channel metrics, such as spectral modulation detection and spectral ripple resolution, tend to be more strongly correlated with speech perception, likely because multichannel metrics more accurately account for channel interactions across electrodes than do single-channel measures.20,21 Given these discrepancies, ongoing research is necessary to assess effectively the clinical implications of current steering technology.

Developments in device design Electrode Array The electrode array interfaces directly between the electrical output of the speech processor and the auditory neural tissue. Over the past few decades, these electrode arrays have undergone improvements; originally singlechannel and positioned near the lateral wall of the scala tympani, they are now multiple channels with 12–22 active contacts and typically placed closer to the modiolus.22 Depth of insertion of a multichannel CI has been suggested as a clinical variable that may correlate with word recognition,


perhaps because deeper insertion may allow stimulation of spiral ganglion cells serving lower frequencies.23 Current literature regarding the optimal depth of insertion is divided, with some studies arguing for longer MED-EL electrodes to obtain complete cochlear coverage, others suggesting that deep insertion yields poorer performance.24 In a study conducted by Lee et al. (2010), examination of cadaveric temporal bones with CIs found no correlation between histologically documented depth of insertion and last recorded measures of speech perception.25 With the use of real-time radiologic assessment, two studies reported a consensus regarding electrode insertion depth, scalar location, and distance from the modiolus.26,27 While these guidelines may allow future clarification of electrode position on postoperative performance, there have been no randomized controlled trials comparing electrode lengths to date. One of the major advances in electrode array design has been the introduction of low-cost thin-film electrodes. Initially proposed in the early 1980s, thin-film array technology allows for a greater density of stimulating sites within the limited diameter of the scala tympani.28 Guinea pig and cat models have shown promise with successful cochlear stimulation using a highdensity thin-film array.29 Recently, Iverson et al. (2011) conducted a study in which ten thin-film array electrodes were successfully inserted into ten individual cadaveric temporal bones via round window (5) and cochleostomy (5) approaches with minimal trauma.30 Continued development and testing of the thin-film array may improve speech perception achieved through cochlear implantation. In addition to advancements made in electrode design, electric acoustic stimulation (EAS) was developed to rehabilitate individuals with severe-toprofound hearing loss by electrical stimulation of the higher frequencies and acoustic stimulation of the functioning lower frequencies. Preservation of low-frequency residual hearing is critical for EAS and is achieved with “soft” surgical techniques and short atraumatic electrodes.31 Shorter insertion depth is less likely to result in loss of residual hearing. Gstoettner et al. (2004) was able to preserve residual hearing in 85% of patients with an insertion depth angle of 360° or less, while James et al. (2005) reported that insertion depth angle in the cochlea of >400° began to have a negative effect on hearing preservation.32,33 Approved for hearing preservation CI surgery in Europe, the Flex24 (formerly known as FlexEAS) electrode by Med-EL Corporation is 24 mm straight array with 19 electrode contacts spaced over 20.9 mm stimulation range (condensed spacing compared with the standard array). Seven basal contacts are paired, while the 5 apical electrode contacts are single to maximize flexibility and preservation of low-frequency residual hearing (Figs 9.1A to C). Lee et al. (2010) found significant improvement in speech perception outcomes after EAS in patients with profound high-frequency hearing loss and acoustically salvageable low-frequency hearing using FlexEAS electrodes.34


A

B

C Figs 9.1A to C: Cochlear Implant Electrode Array. The photomicrographs show the electrodes available for the three manufacturers currently approved by the US Food and Drug Administration: (A) Advanced Bionics Corporation’s HiFocus MidScala Electrode (A1), HiFocus 1J Electrode (A2), HiFocus Helix Electrode (A3); (B) MED-EL Corporation’s FLEX Electrode; (C) Cochlear Corporation’s Contour Advance Electrode (C1), and Slim Straight Array Electrode (C2). Currently, each of the manufacturers has multiple different electrodes available for cochlear implantation. Generally, they have become slimmer/thinner with some specially designed for round window insertion.


The Nucleus Hybrid-L24 electrode (Cochlear Corporation) is 15 mm by 0.4 mm by 0.2 mm and contains 22 electrode contacts. The hybrid model allows for electrical stimulation of the basal high-frequency tonotopic region of the cochlea with preservation of the apical low-frequency regions. Lenarz et al. (2009) found that among 32 recipients, the median hearing loss was 10 dB and patients were able to use residual postimplantation hearing to a similar extent as they could preoperatively.35 Driscoll et al. (2011) analyzed micro-CT images of the Nucleus Hybrid-L24 electrode following traditional cochleostomy and round window insertions in 10 cadaveric temporal bones; with this model, round window insertions appeared to provide greater hearing preservation over the traditional cochleostomy approach.36 Patients with preserved residual hearing demonstrated improvement in speech perception following implantation with the Nucleus Hybrid-L24 device.37

External Hardware Directional microphones have been heavily used in hearing aids to decrease the signal-to-noise ratio, but they have been only recently incorporated into external CI components, in particular with SmartSound Beam (Cochlear Corporation) and UltraZoon in the recently released Naida CIQ70 (Advanced Bionics). Directional microphones allow increased sensitivity to sounds emanating from a specific location, such as in front of the listener, and have been demonstrated to reduce background noise, improve sound quality, and enhance listening comfort in hearing aid users. While the outcomes of applying directional microphones to hearing aids and cochlear implants generally seem encouraging, minimal data is available thus far. In 2009, Chung et al. found improved speech recognition in 18 postlingually deafened cochlear implant users when an adaptive directional microphone was used over fixed directional and omnidirectional microphones.38 ClearVoice, developed by Advanced Bionics Corporation, is a preprocessing strategy that uses a digital signal analysis algorithm to distribute the incoming signal among frequency channels and to estimate each channel’s signal-to-noise level. Channels with lower signal-to-noise levels are reduced, emphasizing those more likely to contain speech signals. Results obtained in Europe show improvement in speech perception in noise in a group of 13 experienced HiRes 120 users immediately following ClearVoice activation.39 Med-EL recently introduced a single-unit processor (Figs 9.2A to C), the RONDO. This is the first and only currently available external device that combines the coil, control unit, battery pack and sound processor into a single component. Advanced Bionics Corporation’s Neptune is the first immiscible cochlear implant sound processor (Figs 9.3A and B). Currently in wide clinical use in Europe, the DUET external processor is a CI speech processor/hearing aid combination unit that also features a


A

B

C Figs 9.2A to C: Cochlear Implant Speech Processor. The photomicrographs show the speech processor for the three manufacturers currently approved by the US Food and Drug Administration: (A) Advanced Bionics Corporation’s Naida CI Q70; (B) MED-EL Corporation’s RONDO Single Unit Processor and OPUS 2X Audio Processor; (C) Cochlear Corporation’s Cochlear Nucleus 5 Sound Processor CP810. They all come with rechargeable batteries, pleasing color choices and remote controls.


A

B Figs 9.3A and B: Speech Processor and Water Compatibility. (A) Advanced Bionics Corporation’s Neptune is the first fully immiscible cochlear implant sound processor; (B) Cochlear Corporation’s Cochlear Nucleus Aqua Accessory. The accessory increases the Cochlear Nucleus 5 Sound Processor’s water resistance to IP68 of the International Standard IEC60529 (submersion into depth of 4 meters for up to 2 hours). The patient is required to purchase the single-use plastic accessory.

common audio input that allows patients to connect directly to other external devices such as MP3 players and FM radio systems. In 2008, Helbig et al. compared speech perception in EAS patients before and following transition to the DUET combined device; no change or only slight improvement in word score with the new device was demonstrated.40 In 2010, Helbig and Bauman found that patients who lost residual hearing following implantation did not use the hearing-aid portion of the DUET.41


Internal Hardware Introduced in 2010, the Nucleus CI512 (Cochlear Corporation) is a 3.9-mm-thick titanium device with lateral configuration of the electrode array and ground electrode and a 165° angle between magnet/coil and receiver/ stimulator. This implant device has since been removed from the market due to device failure and has been replaced by the previous generation Nucleus Freedom implant. The Concert titanium internal processor is the currently widely available nonceramic implant from the MED-EL Corporation (Figs 9.4A to C). Overall internal configuration diverges from the ceramic design and measures 45.7 mm in length, 24.8 mm in width, and 5.9 mm in maximal thickness.

Updates in CI candidacy and assessment of efficacy CI candidacy criteria have expanded to include myriad patients with sensorineural hearing loss (SNHL), including those at the extremes of age, patients with auditory neuropathy spectrum disorder, and individuals with residual low-frequency hearing.

Candidacy in Children Under 1 Year of Age Since the advent of pediatric cochlear implantation, formal candidacy criteria have included increasingly younger patients, a trend influenced by the correlation of earlier implantation with improved communication outcomes.42–44 In Miyamoto et al. (2008), a comparison of receptive and expressive language skills of children who received a CI before 1 year of age to those who received an implant between 1 and 3 years of age showed higher language scores for children implanted at a younger age.45 In 2010, Houston et al. found that children implanted during the first year of life had larger vocabularies than children implanted between 16 and 23 months after birth; however, there was no significant difference in speech perception.46 These results suggest that there may be a sensitive period for speech and language development. Ideally, cochlear implantation should occur before this window is closed to prevent impaired development. Currently, cochlear implantation is FDAapproved for children 1 year of age and older, but some centers implant younger children. Studies support the safety and efficacy of the procedure, and preliminary data seem to indicate language growth rates comparable to those of normal-hearing children.47,48 Information related to the etiology of deafness can assist with CI candidacy assessment, particularly in infants. Genetic mutations account for approximately 50% of cases of hereditary congenital hearing loss; 30% of these are associated with clinical features from a known syndrome, while


A

B

C Figs 9.4A to C: Cochlear Implant Internal Receiver. The photomicrographs show the internal receiver for three manufacturers currently approved by the US Food and Drug Administration: (A) Advanced Bionics Corporation’s HiRes 90K Advantage; (B) MED-EL Corporation’s CONCERT Cochlear Implant; (C) Cochlear Corporation’s Nucleus CI24RE Implant. Note the similarity in size, shape and the material used for the receiver. The internal receivers are small, thin, and covered with silastic. Currently, none of the devices uses ceramic.

136 Recent Advances in Otolaryngology—Head and Neck Surgery 70% are considered “nonsyndromic”.49 Among children with nonsyndromic profound SNHL, approximately half have mutations in the gene GJB2, which codes for a gap junction protein involved in cell-to-cell diffusion and recycling of ions such as potassium in the inner ear.50 In 2005, Preciado et al. suggested early GJB2 testing for infants with indications of severe to profound deafness in order to assist with early intervention, including cochlear implantation.51 An increase in early diagnosis afforded by the advent of universal newborn hearing screening has allowed greater opportunities for early intervention. Long-term data suggest that auditory rehabilitation commenced prior to 6 months of age, including hearing aid amplification, leads to significant gains in vocabulary, speech intelligibility, general language abilities, social-emotional development, parental bonding, and parental grief resolution when compared to late-identified peers.52,53 According to Korver et al. (2010), compared with distraction hearing screening, a newborn hearing screening program was associated with better developmental outcomes at age 3–5 among children with permanent childhood hearing impairment.54 Furthermore, with widespread newborn hearing screening, infants with bilateral severe-to-profound SNHL who do not benefit from a trial of conventional amplification (and who meet anatomic and medical criteria) are considered for cochlear implantation prior to 1 year of age. Universal hearing screening for newborns begins with behavioral evaluation. The gold standard for behavioral evaluation of hearing in infants is visual reinforcement audiometry (VRA).55 VRA can reliably be applied to children who have reached 6 months’ developmental age, but its efficacy decreases in cases of prematurity or neurocognitive delay.56 In addition to the somewhat subjective method of VRA, various objective audiometric assessments are available, including measurement of otoacoustic emissions, auditory brainstem response and auditory steady-state response (ASSR). Otoacoustic emissions are generated from the outer hair cells of the cochlea in response to an auditory stimulus; auditory brainstem response and ASSR assess the afferent neural connections between the inner hair cells, the vestibulocochlear nerve, and the brainstem. Objective testing may be used in combination with VRA or when VRA conditioning proves ineffective. Speech perception testing of infants remains challenging, as most tests are based around speech production. In this age-group, the Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS), a parental survey of early speech development, has been employed reliably to measure speech perception and linguistic development. This 10-question structured interview assesses the frequency of specific auditory behaviors, including vocalization, alerting to sound, and deriving meaning from sound.57 The Auditory Speech Sound Evaluation (A§E) test (The Eargroup, Antwerp, Belgium) is a language-independent test specifically suited to evaluate preverbal children; data suggest that this software package is reliable in infants.58,59


Perioperative safety, particularly anesthetic risk, is an important consideration in young children. Epidemiological studies of anesthesia-related complications found the incidence of morbidity, mortality, and life-threatening adverse events in children younger than 12 months to be significantly higher than in older children.60,61 Closer evaluation of these population-based studies, however, reveals that the greatest risk factors of anesthetic-related complications include emergency surgery and inadequate fasting period, neither of which applies to a scheduled CI surgery. Growing data supports safety in children implanted under 1 year of age, with complication rates comparable to those of older children and adults.62,63

Outcomes in Children Under 1 Year of Age Over the past decade, there has been a growing body of literature supporting improved auditory and linguistic outcomes in children implanted before 12 months of age.34,46,48,63-66 In a study conducted by Lesinski-Schiedat (2004), children implanted prior to 12 months of age demonstrated superior speech understanding compared to children implanted between 1 and 2 years of age.64 Using IT-MAIS, Waltzman and Roland (2005) and Roland et al. (2009) found speech perception scores of children implanted prior to 12 months of age were comparable to those of their normal-hearing peers.48,64 In 2005, Colletti et al. showed that 10 children implanted under 12 months of age had significantly better outcomes than children implanted at an older age, as measured by the Category of Auditory Performance, a global measure of auditory receptive abilities.65 Dettman et al. (2007) used the Rosetti Infant-Toddler Language Scale (RI-TLS) to examine communication abilities of 19 children implanted before 12 months of age; these children achieved receptive and expressive language growth rates comparable to their normal-hearing peers and significantly greater than rates achieved by children implanted between 12 and 24 months of age.49 Notably, Holt and Svirsky (2008) found improved receptive language skills in children implanted under 1 year of age, but negligible differences in expressive ability between those implanted before 12 months and between 12–24 months.66 Given that multiple studies suggest benefit in areas of receptive and expressive language development and speech perception, and current data support minimal anesthetic and long-term complications to young children, early implantation may maximize a child’s ability to achieve full linguistic potential with minimal risk.

Candidacy in Elderly Patients Hearing loss is one of the most common disabilities in the aging and can negatively impact quality of life and overall health status. Studies suggest that limited or minimal access to acoustic information can lead to social isolation, loss of self-esteem, depression, personality changes, cognitive impairment

138 Recent Advances in Otolaryngology—Head and Neck Surgery and reduced functional status.67,68 Unfortunately, elderly patients remain underserved by cochlear implantation due to concerns about perioperative safety and rehabilitative outcomes. Cochlear implantation in geriatric patients has long faced concerns about anesthetic risk and surgical complications, in particular flap necrosis, infection, facial nerve injury and cerebrospinal fluid leak. However, recent research on anesthetic risk supports safety and efficacy of CI in the elderly and contradicts the pervasive myth that advanced age is an important risk factor for anesthesia-related perioperative complications. In a retrospective review of 70 CI recipients over 70 years of age, Coelho et al. (2009) found that general anesthesia was well tolerated by elderly patients, with only 4 patients requiring intra-operative pressor support for hypotension and only 3 patients suffering from postoperative anesthesia-related complications. These complications included urinary retention, delayed extubation and congestive heart failure. No long-term morbidity or perioperative mortality was noted.69 Eshraghi et al. (2009) found no long-term medical or surgical complications or mortality in 21 patients of ages 79–89 following CI.70 Other concerns about candidacy include the age-related degeneration of the peripheral and central auditory systems and the overall cognitive deterioration and decreased neural plasticity associated with aging.71 Successful cochlear implantation requires an intact and functional auditory processing pathway, from spiral ganglion cells to auditory cortex. Dickstein et al. (2007) demonstrated an overall decrease in the number of dendrites and dendritic spines in the elderly brain, suggesting a decrease in synaptic activity and neural plasticity.72

Outcomes in Elderly CI Recipients Despite concerns related to age-related degeneration, multiple studies have documented improved speech perception outcomes in older adults after cochlear implantation.73–75 Budenz et al. (2011) compared speech perception outcomes in postlingually deafened adults implanted at age 70 and older with those from postlingually deafened adults implanted between ages 18 and 70. Although younger patients outperformed elderly subjects, differences correlated with duration of deafness rather than age.76 Vermeire et al. (2005) and Eshraghi et al. (2009) reported improved social life, confidence, and overall quality of life after implantation in the elderly population.71,77 Furthermore, increased communicative ability of elderly CI recipients allows many individuals to continue or return to full-time employment, a measure of the global societal impact of CI in this expanding population.78

Candidacy and Outcomes in Auditory Neuropathy Spectrum Disorder The diagnosis and management of auditory neuropathy spectrum disorder (ANSD) remains controversial. CI candidacy in individuals with ANSD


continues to be hotly debated. ANSD describes a heterogenous group of auditory processing abnormalities typically characterized by presence of otoacoustic emissions and/or cochlear micophonic potentials with a greatly abnormal or absent auditory brainstem response.79–81 In ANSD, the outer hair cells function normally, but sound is not properly transmitted from the outer hair cells to the auditory cortex due to desynchronized action potentials in the auditory nerve. For children and adults with ANSD and minimal auditory capacity, multiple studies have confirmed CI outcomes commensurate with those of peers with other forms of SNHL.80,81 Rance & Barker (2008) reported significant improvement in speech ability (consonant-nucleus-consonant phoneme scores) of children diagnosed with ANSD after cochlear implantation.82 A recent longitudinal study by Teagle et al. (2010) followed the largest cohort of participants receiving CI interventions to date. Of the 52 participants studied, 11 did not have sufficient pre- and postdata for analyses; the remaining 41 demonstrated improved speech perception abilities.82 Rance and Barker (2008) suggested that outcomes for a selected group of children with ANSD treated with hearing aid amplification may equal or exceed outcomes for those managed with CI.82 Current literature is inconclusive regarding audiologic treatment of ANSD in children. While some studies indicate that children with ANSD benefit from acoustic amplification, other studies focus on the effect of cochlear implantation on individuals with ANSD.83 Studies thus far have focused on the ability to perceive and recognize sounds or words, but further work is needed to address other functional aspects, including speech, language, learning, and social/emotional development in patients with ANSD.

Candidacy and Outcomes in Patients with Single-Sided Deafness Historically, patients with unilateral severe to profound deafness were not surgical candidates for cochlear implantation. In patients with single-sided deafness (SSD), rehabilitation of hearing on the deaf side traditionally was accomplished with specialized hearing aids allowing contralateral routing of sound (CROS) and bone-anchored hearing systems (BAHS), allowing contralateral routing of signal through the skull base bone. However, recent literature has investigated the outcomes of cochlear implantation in patients with unilateral profound sensorineural hearing loss. A review of these studies shows a modest, but significant improvement in sound localization and speech perception after cochlear implantation in patients with single-sided deafness, as compared to CROS and BAHS strategies. Arndt et al. (2011) assessed speech perception in unilateral hearing loss patients utilizing CROS, BAHS, and cochlear implantation. The patients were tested in three listening conditions: 1) sound and noise presented directly in front of the patient; 2) sound on the normal hearing side and noise on the

140 Recent Advances in Otolaryngology—Head and Neck Surgery deaf side; 3) sound on the deaf side and noise on the normal hearing side. The study demonstrated significant improvement in sound localization ability and in speech comprehension in CI patients over those with CROS, BAHS and unaided strategies.84 Stelzig et al. (2011) evaluated four patients with unilateral deafness months following cochlear implantation. Monaural (unilateral normal hearing) and binaural (normal and CI) hearing were tested. The study demonstrated a modest, but significant improvements in speech intelligibility on the Hochmair-Schulz-Moser sentence test (4.6 and 6.3% at speech reception thresholds (SRT) of 0 and -5 dB, respectively).85 In addition, patients with SSD have reported improvement in quality of life after cochlear implantation. Vermeire and Van de Heyning (2009) used the Speech Spatial and Qualities of Hearing Scale, a scale comprised of questions addressing speech understanding, spatial hearing, and hearing quality, to evaluate quality of life in patients after implantation. The authors reported a significant improvement in both the contralateral normal hearing and contralateral hearing aid groups in the speech understanding and hearing quality components of the scale following cochlear implantation.86

Candidacy and Outcomes in Patients with Residual Low-Frequency Hearing Expanding CI candidacy criteria now include individuals with low-frequency residual hearing. EAS (described previously) attempts to preserve the native acoustic function of the apical region, the site of low-frequency signal transduction.32 Maintenance of residual low-frequency hearing improves speech understanding in noise and music appreciation. The FlexEAS electrode, the Nucleus Hybrid-L24 electrode, and the Cochlear Corporation Hybrid S12 electrode are promising new devices that may aid the preservation of residual low-frequency hearing. Approved in Europe, the FlexEAS electrode (described previously) preserves residual hearing by atraumatic partial insertion into the cochlea, often through the round window. Multiple studies demonstrate hearing preservation with this method, sometimes referred to as partial deafness cochlear implantation (PDCI).87,88 Using round window insertion and partial implantation of a standard length electrode, Kiefer et al. (2005) accomplished some degree of low-frequency hearing preservation in 11 of 13 patients; the remaining 2 patients experienced total hearing loss.89 A study conducted by Lorens et al. (2008) includes data on 11 of 17 total PDCI subjects; two subjects were excluded for total hearing loss occurring between 1 month and 2 years postoperatively and an additional four could not utilize combined EAS. More recently, Skarzynski and Lorens (2010) reported improved rates of speech perception in quiet and noisy environments following PDCI in 15 children.90


The Nucleus Hybrid-L24 electrode (described previously) has been studied by Lenarz et al. (2009) and Driscoll et al. (2011).36,37 In the latter study, the authors found that the electrode could be inserted into the scala tympani without significant intracochlear trauma. The mean depth of insertion for this model was approximately 252 degrees or 70% of one full turn. They found that round window insertions followed a more predictable course and resulted in less intracochlear peripheral soft tissue trauma than cochleostomy insertions.37 The Cochlear Corporation Hybrid S12 or Iowa/Nucleus Hybrid CI with a 10 mm electrode has yielded preliminary results demonstrating preservation of residual low-frequency hearing in a recent Food and Drug Administration (FDA) clinical trial in the United States.91 Of the 87 subjects enrolled, 85 patients demonstrated residual hearing preservation 1 month postoperatively. Two patients had complete loss of hearing initially and an additional six lost all hearing between 3 and 60 months following surgery. In 61 patients with 9–12 months of device usage, 45 patients demonstrated improvement in either consonant-nucleus-consonant word score or speech reception threshold, with 29 individuals showing improvement in both metrics. Multivariate analysis of poor performers suggested that duration of high frequency deafness and preoperative word score were strong predictors of postoperative speech performance in the hybrid and combined conditions.89 In a study conducted by Reiss et al. (2007), the acoustic-alone score of 25 Iowa/Hybrid S12 patients was 44% at 12 months after implantation; the addition of electric stimulation increased this score to 58% at 12 months and 62% at 24 months.92 This high level of performance combined with ongoing improvement over 24 months led Reiss et al. (2007) to hypothesize that these subjects developed a highly compressed, shifted frequency map over time which ultimately corresponded to a perceptual change over time in the pitch associated with individual electrodes in the short array.90 Hybrid subjects demonstrate significantly improved speech perception compared with traditional long electrode CI recipients. Recognition of speech in background noise is related to improved frequency resolution, even if improvement is restricted to the low-frequency speech range.93,94 Normal hearing individuals utilize various cues, including pitch, timing and localization, to separate background speech from the speech of a target individual in a competing talkers condition.95 Systematic variation in these cues in normal hearing individuals suggested that pitch resolution may be the most important skill in eliminating the distracting effects of multi-talker background speech.96,97 Thus, when low-frequency residual hearing is preserved following implantation, fine pitch discrimination, and thus speech perception in noise, is significantly improved.


Conclusion Since the introduction of cochlear implantation, changes in CI candidacy, hardware, software and speech processing technology have allowed greater numbers of adults and children with various degrees of hearing impairment access to sound. Electrode design and atraumatic insertion techniques now allow some preservation of low-frequency residual hearing. Advances in speech processing strategies, including the use of temporal fine structure processing and virtual channels may allow patients to improve their hearing in noise and afford some music appreciation. Expanding candidacy criteria now allows an increasing number of hearing-impaired individuals, including infants, the elderly, patients with ANSD, and individuals with residual low-frequency hearing, access to cochlear implantation. Ongoing research in preservation of low-frequency residual hearing and more specifically, patients using EAS suggest that speech understanding in noise and music appreciation may be an attainable goal. Improvements in technology and surgical techniques to reduce electrode insertion trauma and improve surgical accuracy is on the horizon and future research in these areas will ultimately affect clinical practice.

Acknowledgments Images courtesy of Advanced Bionics Corporation, MED-EL Corporation, and Cochlear Corporation.

References

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Cochlear Implants: An Update 143 7. Magnusson L. Comparison of the fine structure processing (FSP) strategy and the CIS strategy used in the MED-EL cochlear implant system: speech intelli gibility and music sound quality. Int. J. Audiol. 2011;50(4):279-87. 8. Hochmair I, Nopp P, Jolly C, et al. MED-EL Cochlear implants: state of the art and a glimpse into the future. Trends Amplif. 2006;10:201–19. 9. Arnoldner C., Riss D., Brunner M., et al. Speech and music perception with the new fi ne structure speech coding strategy: Preliminary results. Acta Otolaryngol. 2007;127:1298 –1303. 10. Riss D., Arnoldner C., Reiss S., et al. One-year results using the Opus speech processor with the fine structure speech coding strategy. Acta Otolaryngol. 2009;129:988–91. 11. Magnusson L. Comparison of the fine structure processing (FSP) strategy and the CIS strategy used in the MED-EL cochlear implant system: speech intelligibility and music sound quality. Int. J. Audiol. 2011;50(4):279-87. 12. Zierhofer CM, Schatzer R. Simultaneous intracochlear stimulation based on channel interaction compensation: analysis and first results. IEEE Trans. Biomed. Eng. 2008;55(7):1907-16. 13. Fu QJ, Nogaki G. Noise susceptibility of cochlear implant users: the role of spectral resolution and smearing. J. Assoc. Res. Otolaryngol. 2005;6(1):19-27. 14. Landsberger DM, Srinivasan AG. Virtual channel discrimination is improved by current focusing in cochlear implant recipients. Hear Res. 2009;254(1-2):34-41. 15. Srinivasan AG, Landsberger DM, Shannon RV. Current focusing sharpens local peaks of excitation in cochlear implant stimulation. Hear Res. 2010;270:89–100. 16. Firszt JB, Holden LK, Reeder RM, et al. Speech recognition in cochlear implant recipients: comparison of standard HiRes and HiRes 120 sound processing. Otol Neurotol. 2009;30:146-52. 17. Donaldson GS, Dawson PK, Borden LZ. Within-subjects comparison of the HiRes and Fidelity120 speech processing strategies: speech perception and its relation to place-pitch sensitivity. Ear Hear. 2010;32(2):238-50. 18. Berenstein CK, Mens LHM, Mulder JJS, et al. Current Steering and Current Focusing in Cochlear Implants: Comparison of Monopolar, Tripolar, and Virtual Channel Electrode Configurations. Ear Hear. 2008;29:250–60. 19. Donaldson GS, Dawson PK, Borden LZ. Within-subjects comparison of the HiRes and Fidelity120 speech processing strategies: speech perception and its relation to place-pitch sensitivity. Ear Hear. 2011;32(2):238–50. 20. Won JH, Drennan WR, Rubinstein JT. Spectral-ripple resolution correlates with speech reception in noise in cochlear implant users. J Assoc Res Otolaryngol. 2007;8:384–92. 21. Litvak LM, Spahr AJ, Emadi G. Loudness growth observed under partially tripolar stimulation: model and data from cochlear implant listeners. J Acoust Soc Am. 2007;122:967–81. 22. Zeng FG, Rebscher S, Harrison WV, et al. Cochlear Implants: system design, integration and evaluation. IEE Rev Biomed Eng. 2008;1:115-42. 23. Geier LL, Norton SJ: The effects of limiting the number of Nucleus 22 cochlear implant electrodes programmed on speech perception. Ear Hear. 1992;13: 340–48.

144 Recent Advances in Otolaryngology—Head and Neck Surgery 24. Finley CC, Holden TA, Holden LK, et al. Role of electrode placement as a contri butor to variability in cochlear implant outcomes. Otol. Neurotol. 2008;29(7): 920-28. 25. Lee J, Nadol JB Jr, Eddington DK. Depth of electrode insertion and postoperative performance in humans with cochlear implants: a histopathologic study. Audiol. Neurootol. 2010;15(5):323-31. 26. Verbist BM, Skinner MW, Cohen LT, et al. Consensus panel on a cochlear coordinate system applicable in histologic, physiologic, and radiologic studies of the human cochlea. Otol. Neurotol. 2010;31(5):722-30. 27. Verbist BM, Joemai RM, Briaire JJ, et al. Cochlear coordinates in regard to cochlear implantation: a clinically individually applicable 3 dimensional CT-based method. Otol. Neurotol. 2010;31(5):738-44. 28. Wise KD, Phatti PT, Wang J, et al. High-density cochlear implants with position sensing and control. Hear Res. 2008;242:22-30. 29. Bhatti PT, Arcand BY, Wang J, et al. A high-density electrode array for a cochlear prosthesis. In: Proceedings of the IEEE International Conference on Solid-State Sensors and Actuators. Boston, MA:Institute of Electrical and Electronics Engineers: 2003;1750-3. 30. Iverson KC, Bhatti PT, Falcone J, et al. Cochlear Implantation using thin-film electrodes. Otolaryngol Head Neck Surg. 2011;144(6):934-9. 31. Gantz B., Turner C., Gfeller K. et al. Preservation of hearing in cochlear implant surgery: advantages of combined electrical and acoustical speech processing. Laryngoscope. 2005;115:796–802. 32. Gstoettner W., Kiefer J., Baumgartner W., et al. Hearing preservation in cochlear implantation for electric acoustic stimulation. Acta Otolaryngol. 2004;124: 348–352. 33. James C., Albegger C., Battmer R. et al. Preservation of residual hearing with cochlear implantation: how and why. Acta Otolaryngol. 2005;125:481–91. 34. Lee A, Jiang D, McLaren S, et al. Electric acoustic stimulation of the auditory system: experience and results of ten patients using MED-EL’s M and FlexEAS electrodes. Clin. Otolaryngol. 2010;35:190-97. 35. Lenarz T, Stover T, Buechner A, et al. Hearing conservation surgery using the Hybrid-L electrode. Results from the first clinical trial at the Medical University of Hannover. Audiol. Neurootol. 2009;14:22-31. 36. Driscoll CW, Carlson ML, Fama AF, et al. Evaluation of the Hybrid-L24 electrode using microcomputed tomography. Laryngoscope. 2011;121(7):1508-16. 37. Buchner A, Schussler M, Battmer RD, et al. Impact of low-frequency hearing. Audiol. Neurootol. 2009;14(Suppl. 1):8-13. 38. Chung K, Zeng FG. Using hearing aid adaptive directional microphones to enhance cochlear implant performance. Hear. Res. 2009;250(1-2):27-37. 39. Buechner A, Brendel M, Saalfeld H, et al. Results of a pilot study with a signal enhancement algorithm for HiRes 120 cochlear implant users. Otol Neurotol. 2010;31(9):1386–90. 40. Helbig S, Baumann U, Helbig M, et al. A new combined speech processor for electric and acoustic stimulation—eight months experience. ORL J Otorhinolaryngol Relat Spec. 2008;70:359-65.

Cochlear Implants: An Update 145 41. Helbig S, Baumann U. Acceptance and Fitting of the DUET Device—A Combined Speech Processor for Electric Acoustic Stimulation. Adv Otorhinolaryngol. 2010;67:81-7. 42. Niparko JK, Tobey EA, Thal DJ, et al. Spoken language development in children following cochlear implantation. JAMA. 2010;303:1498–1506. 43. Nikolopoulos TP, O’Donoghue GM, Archbold S. Age at implantation: its importance in pediatric cochlear implantation. Laryngoscope. 1999;109:595–99. 44. DeRaeve L. A longitudinal study on auditory perception and speech intelligibility in deaf children implanted younger than 18 months in comparison to those implanted at later ages. Otol Neurotol. 2010;31:1261–7. 45. Miyamoto RT, Hay-McCutcheon MJ, Kirk KI, et al. Language skills of profoundly deaf children who received cochlear implants under 12 months of age: a preliminary study. Acta Otolaryngol. 2008;128(4):373-7. 46. Houston DM, Miyamoto RT. Effects of early auditory experience on word learning and speech perception in deaf children with cochlear implants: implications for sensitive periods of language development. Otol Neurotol. 2010;31:1248–53. 47. Roland JT, Cosetti M, Wang KH, et al. Cochlear implantation in the very young child: long-term safety and efficacy. Laryngoscope. 2009;119:2205–10. 48. Dettman SJ, Pinder D, Briggs RJ, et al. Communication development in children who receive the cochlear implant younger than 12 months: risks versus benefits. Ear Hear. 2007;28:11S–18S. 49. ACMG Genetics Evaluation Guidelines for the Etiologic Diagnosis of Congenital Hearing Loss. Genetic Evaluation of Congenital Hearing Loss Expert Panel. Genet Med. 2002;4:162-71. 50. Steel KP, Kros CJ. A genetic approach to understanding auditory function. Nat Genet. 2001;27:143-9. 51. Preciado DA, Lawson L, Madden C, et al. Improved diagnostic effectiveness with a sequential diagnostic paradigm in idiopathic pediatric sensorineural hearing loss. Otol Neurotol. 2005;26:610-15. 52. Yoshinaga-Itano C. Early intervention after universal neonatal hearing screening: impact on outcomes. Ment. Retard. Dev. Disabil. Res. Rev. 2003;9(4): 252-66. 53. Moeller MP, Tomblin JB, Yoshinaga-Itano C, et al. Current state of knowledge: language and literacy of children with hearing impairment. Ear Hear. 2007;28(6):740-53. 54. Korver AM, Konings S, Dekker FW, et al. Newborn hearing screening vs later hearing screening and developmental outcomes in children with permanent childhood hearing impairment. JAMA. 2010;304(15):1701-8. 55. Widen JE, Folsom RC, Cone-Wesson B, et al. Identification of neonatal hearing impairment: Hearing status at 8 to 12 months corrected age using a visual reinforcement audiometry protocol. Ear and Hearing. 2000;21:471-87. 56. Moore JM, Thompson G, Folsom RC. Auditory responsiveness of premature infants utilizing visual reinforcement audiometry (VRA). Ear Hear. 1992;13: 187-94.

146 Recent Advances in Otolaryngology—Head and Neck Surgery 57. Zimmerman-Philips S OM, Robins AM. Infant-Toddler Meaningful Auditory Integration Scale. Sylmar, CA: Advanced Bionics Corporation; 1997. 58. Daemers K, Yperman M, De Beukelaer C, et al. Normative data of the A(section) E discrimination and identification tests in preverbal children. Cochlear Implants Int. 2006;7(2):107-16. 59. Govaerts PJ, Daemers K, Yperman M, et al. Auditory speech sounds evaluation (A(section)E): a new test to assess detection, discrimination and identification in hearing impairment.Cochlear Implants Int. 2006;7(2):92-106. 60. Morray JP, Geiduschek JM, Ramamoorthy C, et al. Anesthesia-related cardiac arrest in children: initial findings of the Pediatric Perioperative Cardiac Arrest (POCA) Registry. Anesthesiology. 2000;93:6-14. 61. Cohen MM, Cameron CB, Duncan PG. Pediatric anesthesia morbidity and mortality in the perioperative period. Anesth Analg. 1990;70:160-67. 62. Valencia DM, Rimell FL, Friedman BJ, et al. Cochlear implantation in infants less than 12 months of age. Int. J. Pediatr. Otorhinolaryngol. 2008;72(6):767-73. 63. Lesinski-Schiedat A, Illg A, Heermann R, et al. Paediatric cochlear implantation in the first and in the second year of life: a comparative study. Cochlear Implants Int. 2004;5:146-59. 64. Waltzman SB, Roland JT, Jr. Cochlear implantation in children younger than 12 months. Pediatrics. 2005;116:e487-93. 65. Colletti V, Carner M, Miorelli V, et al. Cochlear implantation at under 12 months: report on 10 patients. Laryngoscope. 2005; 115:445-9. 66. Holt RF, Svirsky MA. An exploratory look at pediatric cochlear implantation: is earliest always best? Ear Hear. 2008;29:492-511. 67. Mulrow CD, Aguilar C, Endicott JE, et al. Association between hearing impairment and the quality of life of elderly individuals. J Am Geriatr Soc. 1990;38: 45-50. 68. Cacciatore F, Napoli C, Abete P, et al. Quality of life determinants and hearing function in an elderly population: Osservatorio Geriatrico Campano Study Group. Gerontology. 1999;45:323-8. 69. Coelho DH, Yeh J, Kim JT, et al. Cochlear implantation is associated with minimal anesthetic risk in the elderly. Laryngoscope. 2009;119:355-8. 70. Eshraghi AA, Rodriguez M, Balkany TJ, et al. Cochlear implant surgery in patients more than seventy-nine years old. Laryngoscope. 2009;119:1180-3. 71. Mahncke HW, Bronstone A, Merzenich MM. Brain plasticity and functional losses in the aged: scientific bases for a novel intervention. Prog Brain Res. 2006;157:81-109. 72. Dickstein DL, Kabaso D, Rocher AB, et al. Changes in the structural complexity of the aged brain. Aging Cell. 2007;6:275-84. 73. Haensel J, Ilgner J, Chen YS, et al. Speech perception in elderly patients following cochlear implantation. Acta Otolaryngol. 2005;125:1272–6. 74. Orabi AA, Mawman D, Al-Zoubi F, et al. Cochlear implant outcomes and quality of life in the elderly: Manchester experience over 13 years. Clin Otolaryngol. 2006;31:116–22. 75. Vermeire K, Brokx JP, Wuyts FL, et al. Quality-of-life benefit from cochlear implantation in the elderly. Otol Neurotol. 2005;26:188–95.

Cochlear Implants: An Update 147 76. Budenz CL, Cosetti MK, Coelho DH, et al. The effects of cochlear implantation on speech perception in older adults.J. Am. Geriatr. Soc. 2011;59(3):446-53. 77. Vermeire K, Brokx JP, Wuyts FL, et al. Quality-of-life benefit from cochlear implantation in the elderly. Otol. Neurotol. 2005;26(2):188-95. 78. Francis HW, Chee N, Yeagle J, et al. Impact of cochlear implants on the functional health status of older adults. Laryngoscope. 2002;112:1482-88. 79. Rance G. Auditory neuropathy/dys-synchrony and its perceptual consequences. Trends Amplif. 2009;9:1-43. 80. Gibson WP, Sanli H. Auditory neuropathy: an update. Ear Hear. 2007;28: 102S-6S. 81. Rance G, Barker EJ. Speech and language outcomes in children with auditory neuropathy/dys-synchrony managed with either cochlear implants or hearing aids. Int J Audiol. 2009;48:313-20. 82. Teagle H, Roush P, Woodard JS, et al. Cochlear implantation in children with auditory neuropathy spectrum disorder. Ear and Hearing. 2010;31:325–35. 83. Roush P, Frymark T, Venediktov R, et al. Audiologic management of auditory neuropathy spectrum disorder in children: a systematic review of the literature. Am J Audiol. 2010;20(2):159-70. 84. Arndt S, Aschendorff A, Laszig R, et al. Comparison of pseudobinaural hearing to real binaural hearing rehabilitation after cochlear implantation in patients with unilateral deafness and tinnitus. Otol Neurotol. 2010;32:39–47. 85. Stelzig Y, Jacob R, Mueller J. Preliminary speech recognition results after cochlear implantation in patients with unilateral hearing loss: a case series. J Medical Case Reports. 2011;5:343–8. 86. Vermeire K, Van De Heyning P. Binaural hearing after cochlear implantation in subjects with unilateral sensorineural deafness and tinnitus. Audiol Neurotol. 2009;14:163–71. 87. Skarzynski H, Lorens A, Piotrowska A, et al. Partial deafness cochlear implantation provides benefit to a new population of individuals with hearing loss. Acta Otolaryngol. 2006;126:934-40. 88. Lorens A, Polak M, Piotrowska A, et al. Outcomes of treatment of partial deafness with cochlear implantation: a DUET study. Laryngoscope. 2008;118: 288-94. 89. Kiefer J, Pok M, Adunka Oet al. Combined electric and acoustic stimulation of the auditory system: results of a clinical study. Audiol Neurootol. 2005;10: 134-44. 90. Skarzynski H, Lorens A. Electric acoustic stimulation in children. Adv. Otorhinolaryngol. 2010;67:135-43. 91. Gantz BJ, Hansen MR, Turner CW, et al. Hybrid 10 clinical trial: preliminary results. Audiol Neurootol. 2009;14 Suppl 1:32-8. 92. Reiss LA, Turner CW, Erenberg SR, et al. Changes in pitch with a cochlear implant over time. J Assoc Res Otol. 2007;8: 241–57. 93. Turner CW, Gantz BJ, Vidal C, et al. Speech recognition in noise for cochlear implant listeners: benefits of residual acoustic hearing. J Acoust Soc Am. 2004;115:1729-35.

148 Recent Advances in Otolaryngology—Head and Neck Surgery 94. Qin MK, Oxenham AJ. Effects of simulated cochlear-implant processing on speech reception in fluctuating maskers. J Acoust Soc Am. 2003;114:446-54. 95. Duquesnoy AJ. Effect of a single interfering noise or speech source upon the binaural sentence intelligibility of aged persons. J Acoust Soc Am. 1983;74: 739-43. 96. Qin MK, Oxenham AJ. Effects of simulated cochlear-implant processing on speech reception in fluctuating maskers. J Acoust Soc Am. 2003;114:446-54. 97. Nelson PB, Jin SH, Carney AE, et al. Understanding speech in modulated interference: cochlear implant users and normal-hearing listeners. J Acoust Soc Am. 2003;113:961-8.

Chapter Implantable Hearing Aids

10

Arnaud Devèze

Introduction Deafness is a major public health problem. In most of the cases, the main etiology is the presbycusis, or age-related hearing loss. Among other consequences, physiological aging of the sensorineural tissue is responsible for the loss of both external and internal haired cells of the organ of Corti and the apoptotic degenerescence of spiral ganglion primary acoustic neurons.1,2 As per WHO estimation, 278 million people worldwide suffer from moderateto-severe hearing impairment on both ears.74 The main rehabilitation procedure is the conventional hearing aids (HA) that have tremendously improved their performances over the past 10 years, mainly through improvement in signal processing algorithms.3 However, the use of hearing aids is far from being optimal and approximately <1 hearing impaired out of 20 is wearing hearing aids. The main limitations are cost related, while other limitations are the social stigma, the occlusion effect of the ear canal, and the lack of benefit in noisy environments, etc.4-7 Acoustic implants have been created on two different axes. First, the cochlear implants (CI) that represent the artificial cochlea and are aimed to restore the lack of the sensorineural epithelium within the inner ear when the capacity for hearing aid improvement with hearing aids to restore hearing is insufficient (severe-to-profound hearing loss). The second axis is represented by the active middle ear implants (AMEIs) that are real implantable hearing aids in the way that these devices aimed to amplify the remnants of hearing function as the conventional hearing aids but through a direct coupling to middle ear structures.8-14 The market of hearing rehabilitation is considerable and the perspectives for development of auditory devices in general stimulate research and development programs. Nowadays, a ‘positive competition’ promotes the improvement in acoustic features of the two main categories of implants: on one hand, cochlear implants target to treat less severe hearing loss (preservation of hearing, atraumatic insertions, bimodal stimulation…)15 and on the other hand AEMI are being improved to


Fig. 10.1: Different options of hearing rehabilitation. (HA: Conventional hearing aids; MEI: Middle ear implant; CI: Cochlear implant; E + A CI: Electric and acoustic cochlear implant; BC: Bone conduction hearing solution).

treat more severe hearing dysfunction. These two trends delineate an area of severe loss that represents an increasing number of eligible patients (Fig. 10.1). A third category of hearing implant is represented by bone conduction (BC) hearing aids. This category has the advantage to be easy to fit in place and to avoid any drawbacks of difficult coupling to the middle ear. Its main disadvantage is the limitation in its amplification output, and to be thus limited to patients with a relatively good cochlear function (for application, keep in mind a 50 dB threshold in average BC threshold). This option seems valid since two new devices have been released, to overcome some limitations of the previous devices, namely skin complication due to the need of transcutaneous placement of titanium screwed abutment. Beside the great majority of hearing impaired due to sensorineural deficit (aging), a small but significant amount of patients suffer from conductive or mixed hearing loss, their middle ear being dysfunctional after disruption of their tympano-ossicular system, concurrently with an impairment of the sensorineural function at different levels. The main causes for such a situation are the sequels after chronic otitis media, cholesteatoma development, ear trauma, or congenital malformations of the ear. Here, the rehabilitation using hearing aids is limited by the alteration of the tympano-ossicular system, unable to conduct the sound up to the cochlea. Few options remain and BC devices represent a good solution unless the sensorineural component is deteriorated to limit the amplification. In such a case, the only reliable option is the use of AMEI with the problem of adequate coupling to the middle ear structures.

Implantable Hearing Aids 151

Fig. 10.2: The different options of hearing rehabilitation.

To be exhaustive on the different possibilities of hearing rehabilitation, we should mention the auditory implants that stimulate directly the central auditory pathway, onto the cochlear nerve nucleus and the inferior colliculus, and that both relay the transmission of sound to the central nervous system. The options are indicated in case of absent cochlea and absent cochlear nerve, and may help partially the deaf patient to interact with its environment. However, it is unlikely that these implants permit an adequate production of articulated sounds in children, except in some exceptional postlingual patients.16 Figure 10.2 summarizes the different options applicable in the auditory rehabilitation.

What are the drawbacks of conventional hearing aids that AMEI should overcome? The technical specifications for AMEI should be tailored to fit the following requirements: invisibility, no or less feedback, no occlusion effect, entirely or at least semiadaptable to modification of the environmental sound, and with gain superior to the current powerful HA. The market of AMEI, and so of hearing aids, does not convey to profound hearing loss that necessitates a cochlear implant, but to the giant population of presbycusis, with its millions of unsatisfied people (for all the forthcoming reasons), aging in a better global health state. This is a huge challenge and justifies the amount of money spent in research and development programs.


Fig. 10.3: Larsen effect. Acoustic feedback model. From Counter.13

Social Stigma and Cosmetic Issues The conventional hearing aid remains nowadays a visible sign of a handicap that affects communication: hearing. Thus, the benefits of wearing hearing aids to enhance communication may be countered by negative stigma associated with hearing aids. This explains why patients prefer to abandon the aid and adopt palliative attitudes and behaviors trying to compensate their deficit. This behavior is mainly linked to the apprehension of other’s reaction to the handicap. Making the handicap visible, hearing aids can affect the image people hold of themselves.17,18 Thus, auditory implant in general should be as invisible as possible. This explains why the Carina from Otologics was so popular at first impression, and this invisibility overcomes the burden for maintenance and daily charging of the battery. Moreover, this explains why the Esteem from Envoy Medical is nowadays popular and being implanted worldwide although disruption of the ossicular chain, which is a critical ethical issue, is mandatory for the implantation. Ideally, the future AMEI must be a fully implantable one.

Audio Feedback This paradoxical effect has been described by Larsen (Fig. 10.3) and is created when a sound loop exists between an audio input and the audio output (from the same hearing aid). This effect depends on the quantity of amplification needed to compensate the hearing deficit and is more likely to appear for severe hearing loss. It can be corrected by isolation of the microphone of the hearing aid that impacts the comfort of this later, or by modulation of the signal processing that impacts the quality of the amplification. The feedback is a clear limitation of the use of auditory implant for treating severe hearing losses, and in addition, may limit the use of implantable microphone, more sensitive to feedback, being close to the transducer.19

Difficulties of Maintenance of Hearing Aids The esthetic demand, truly a quest for invisibility, pushes the development of smaller prosthesis allowed by improvement in chip technologies.


However, HA aim to treat in the great majority of case of elderly people whom capabilities to manipulate such small prostheses is reduced, linked to loss of hands agility and associated visual deficit.20 Recent prosthesis integrated automatic fitting and adaptation to changing sound environment. AMEI must include the same properties and in addition remote that permits to control the device.

Discrimination in Noisy Environment It is the main complaint of hearing impaired, if none the first one. In noisy environment, the hearing aid does not reach the fidelity of a normal cochlea and does not restitute all the acoustic cues, moreover if anti-feedback algorithms are activated. The only way to compensate this issue is to rehabilitate both ears through a bilateral amplification.21 This is a reason why counseling of patients selected for a middle ear acoustic implant must include the need for a contralateral wear of an hearing aid, concurrently with the activation of the implant.

Discomfort and Occlusion Effect All hearing aids, and moreover those that aim treating severe loss, include a mold that is placed into the external auditory canal, more or less occlusive according to the hearing loss. This mold is quite constantly responsible for discomfort. This occlusion effect alters the acoustic transmission through various phenomena:22,23 • A reduction in the transmission of low-pass frequency range that is no longer naturally transmitted to the middle ear • Modifications of resounding properties of the external canal that is shortened • A high-pass band filter, because of the compliance of the air column trapped after the mold. These three consequences affect the transmission of low-pass and highpass sound transmission, and increase the transmission of sound through the bony canal. Patients frequently complained form self-perception of their voice amplified and echoing; this effect pushes some of them abandoning the aid. Open-fit prostheses have been developed to overcome such a problem but the absence of occlusion limits the amplification capabilities.24 This drawback of HA is undoubtedly a major argument in the development and use of AMEI that let the canal free of any device.

Active middle ear implants AMEI could be named as well implantable hearing aids since they are acoustic prosthesis that are implanted in the middle ear and coupled with the ossicular

154 Recent Advances in Otolaryngology—Head and Neck Surgery chain (or to the remaining vibrating structure) to drive the sound up to the cochlear fluid. AMEI aimed to improve the transfer function of the middle ear to the cochlea. Many types exist nowadays but few are routinely implanted, being reliable, relatively easy to position, and/or efficient. Two main categories coexist: the semi-implantable AMEI that necessitates an external part that includes the battery and the microphone to transfer the acoustic cues to the internal part that drives the ossicular chain, and the fully implantable ones where all the components of the implant are surgically positioned into the temporal bone and the middle ear. Fully implantable models necessitate a remote to control their use.

Bone conduction implants BC is a reliable and efficient way to conduct the sound to the inner ear, bypassing the ear canal and so being independent for many ear canal or middle ear diseases. The main BC hearing system is represented by the so-called BAHA now trademark from cochlear (previously Entific). BAHA cannot be called an auditory implant and has the disadvantage to function through a percutaneous abutment (the implant itself ), screwed into the cortical of the temporal or parietal bones. To avoid skin-related and stigmarelated issues of this percutaneous implant,25 challengers have developed recently BC implants that are made of two parts: a magnetic part is inserted underneath the skin, screwed into the bone, and an external part that is composed by the processor, microphone, and battery that are magnetically communicated with the magnetic part and transmit the auditory vibrations. At present there are four device brands available: Vibrant (Med-EL) released the BoneBridge that is a real auditory implant, Cochlear (BAHA), Oticon Medical (Ponto), and Sophono that developed the Alpha 1 and Alpha 2 devices. Among the devices cited above, the BoneBridge is a real implant and a mention of the technique is outlined below.26

History of the Main Commercially Available Implantable Hearing Aids Since 1899 Collins has the paternity of the idea to use artificial device to help the hearing (Fig. 10.4). The French surgeons André Djourno and Charles Eyriès are undoubtedly recognized as the first to develop an electric implantable auditory stimulator that became later the cochlear implant. Djourno developed in 1950 an electric stimulator and Eyriès implanted this latter close to the cochlea in 1957. Personal conflict regrettably conducted to the abandon of the project, to be taken by House.10,27 The history of implantable auditory prostheses began in 1935, when Wilska suggested placing small magnets onto the tympanic membrane controlled by a magnetic field generated by a coil in the outer auditory canal.28 Suzuki and Yanagihara29–31 were the first to insert a semi-implantable


Fig. 10.4: Hearing aid from Collins, 1899.

piezoelectric device in a human with at present > 10 years’ long-term results. Approval for this ‘Rion device E-type’ was at first limited to university institutions in Japan. The very first commercially available middle ear implant was developed by John M. Fredrickson, MD, in the 1970s and 80s while he was a surgeon and researcher at the Washington University School of Medicine in St Louis, Missouri. He invented and created the middle ear transducer (MET), and later cofounded Otologics Company with José Bedoya.9 The first commercially available AMEI was the Vibrant Soundbridge created by Ball in 1993.8,13 Envoy Medical Corporation was founded – originally as St Croix Medical – in 1995 to design, manufacture, and bring to market the world’s first, and only, fully implantable hearing restoration device not to use a microphone or speaker. Envoy Medical began its operations in March of 1996 but got the CE mark in 2006, and then the FDA approval in 2009. The Direct System Soundtec was developed by SOUNDTEC, Inc, which was founded in 1997 by Dr. Jack Hough.32 It got its FDA approval in 2001 but some issues conducted the device not to be developed and the last publication of clinical results last 2005.33 Nowadays the principle of the Soundtec has been taken over by Ototronix company that developed the Maxum implants. Hanz Peter

156 Recent Advances in Otolaryngology—Head and Neck Surgery zenner developed in 1998 what he called the TICA for totally implantable communication assistance. Rudolf Hausler published the principle of the Direct Acoustic Cochlear Stimulator (DACS) in 2005,34 and transferred the technology to Cochlear company who developed the CODACS that has got recently the CE mark.

The different types of currently available implants and their characteristics Various technologies have been chosen, each of them with some advantages and some drawbacks with regard to the following points: energy choice to motor the driver, coupling mode, fully or partial implantability. We will summarize the main commercially available implants.

The Vibrant Soundbridge (VSB) (Med-El, Innsbruck, Austria) This system is one of the most reliable devices with about 2000 recipients worldwide. It is a semi-implantable electromagnetic system, including a floating mass transducer (FMT) weighing 25 mg that amplifies the movements of the ossicular chain (Figs 10.5A to C). The VSB is made of two parts: • The VORP (vibrating ossicular prosthesis) that includes the magnet for communication with the external part, a conductor link and the FMT itself. The VORP is implanted during a surgical procedure. • The external audio processor that includes the microphone and the battery that is placed outside the skull and is removable. The FMT works as a magnet mobilized in an electromagnetic field created by coils (Figs 10.6A and B). Its output is optimized around 1500 Hz (Figs 10.6A and B). The FMT is coupled with the ossicular chain using a clip that can be crimped onto the long process of the incus in case of intact ossicular chain, and onto the stapes head in case of disrupted chain. The light mass of the FMT limits the negative effect on the normal biomechanics of the middle ear, although some impact can be measurable.35 The FMT shall be placed as well directly in contact with the round window membrane; in such a situation, the clip has to be taken off. Some additional tips can be used to improve the coupling of the FMT (Figs 10.7A to C). Undoubtedly, the VSB is the easiest AMEI to use.

Indications The VSB is indicated to treat moderate-to-severe sensorineural loss of 65–85 dB thresholds as well as conductive and mixed hearing losses, unless the BC threshold is below 45 dB especially in low frequencies (Figs 10.8A and B).


A

B

C Figs 10.5A to C: The Vibrant Soundbridge from Med-El. Description of the external audioprocessor (A); The internal part (B); and magnification of the FMT and the clip (C).


A

B Figs 10.6A and B: Principle (A) and output (B) of the FMT.

Advantages: • Simple surgery • Small size • Reversibility of the implantation • Versatility • Reliability Disadvantages: • Limited output for severe loss and severe mixed hearing loss.


A

B

C Figs 10.7A to C: The vibrant soundbridge from Med-El. Conventional coupling onto the long process of incus for sensorineural hearing loss (A) and alternative coupling with or without additional titanium prosthesis; ((B) stapes capitulum; (C) round window). Footplate positioning is not represented but is reliable as well.

The Middle Ear Transducer (MET; Previously Otologics LLC, Boulder, CO, USA, and now Cochlear, Australia) It is the second most implanted devices with approximately 700 units for the MET, and 550 for the fully implantable version, the Carina.


A

B

Figs 10.8A and B: Audiological indications of the VSB. Sensorineural loss (A) and conductive and mixed hearing losses (B). Note that amplification is thought to be less effective in conductive loss and a 45 dB threshold should be considered as a limit on low frequency.

B

A

C

Figs 10.9A to C: Last generation of the middle ear transducer (MET) transducer (A) and positioning onto the incus trough a limited epitympanotomy (B). (C) Different prostheses added to the transducer on demand.

The system is composed of an electromagnetic transducer that is maintained into the mastoid bowl using a mounting bracket that is screwed onto the cortical bone9,73 (Figs 10.9A to C). The system has got a significant output with a peak around 2000 Hz (Fig. 10.10). A subcutaneous processor that communicates with an external button, which includes a battery and the microphone, drives the transducer. The system exists in a fully implantable form, named the Carina. The Carina includes a subcutaneous microphone


Fig. 10.10: Microstructure of the middle ear transducer (MET) (1st generation) and output.

and a rechargeable battery (Fig. 10.11). The transducer is placed in contact with the ossicles: with the body of the incus in the common indications (SNHL) or with the stapes capitulum, the stapes footplate, the round window membrane (Figs 10.12A to D),36-38 or even directly the vestibule39 using additional tips that are coupled with the transducer using a dedicated crimper (Figs 10.13A and B). Since its first development, Otologics has released fourth generation of implant and two of transducer, to gain significantly in reliability and performances.

Indications The indications are different whether the implant is the semi- or the fully implantable one. Hence, the fully implantable design limits the performances of the transducer because of the feedback cancellation algorithms that aim to limit the perception of both the body-sound noise and the sound of the transducer by the implantable microphone. The MET is undoubtedly a powerful


Fig. 10.11: Middle ear transducer (MET)—Carina fully implantable implant.

A

B Figs 10.12A and B


C

D Figs 10.12A to D: Different types of coupling of the middle ear transducer (MET) transducer (A) onto the incus body; (B) the stapes capitulum; (C) the footplate; (D) the round window membrane (experimental pictures).

implant that has shown its capabilities to treat severe loss.40 The Carina has some limitations in performances but the range of applicability is similar to the VSB’s (Figs 10.14A and B). Advantages: • Reversibility • Performances • Stability of the coupling over time (bone screwing) • Fully implantable (Carina) • Versatility Disadvantages: • Surgical placement difficult (learning curve) • Limited amplification of Carina


A

B Figs 10.13A and B: Example of coupling an additional PORP prosthesis (Soft Clip from Kurz) with the transducer (A) and intraoperative coupling of the tip onto the stapes head, viewed through a facial recess approach (B).

A

B

Figs 10.14A and B: Indications range of the middle ear transducer (MET) (A) and the Carina (B).


A

B

Figs 10.15A and B: Esteem implant with the placement of the sensor and the driver (A) and range of application of the processor (B).

The ESTEEM (Envoy Medical, St Paul, MN, USA) It is a fully implantable piezoelectric device fixed onto the ossicle using biologic cement. The two main advantages of its design are as follows: • It uses the tympanic membrane as a microphone, and this avoids a lot of issues with adjustment and feedback • The piezoelectric transducer function is a two-way mechanism: it catches the energy from the mobilization of the drum to give it back to the middle ear. Thus, the implant does not necessitate recharging the battery. The tympanic vibration is transmitted to a sensor that is attached to the incus. This sensor conveys the energy to the processor that treats the sound and gives the filtered energy to the transducer (The Driver) attached to the stapes capitulum. The implant is aimed to treat severe SNHL (Figs 10.15A and B). A limited amount of energy is necessary to the filtering process and explains that the battery life last 5–8 years. The main problem is that the Sensor and the Driver must work separately, and thus, the ossicular chain has to be disrupted. The reversibility principle is violated. Another point is that the surgery is difficult and the learning curve needs several implantations. The time for surgery ranges from 2.5 to 7 to 8 hours. One of the most crucial steps is the complete removal of the mucosa layer that covers the stapes capitulum, and this step is risky for the sensorineural function. In addition, the mastoid is to be fully filled with cement.

166 Recent Advances in Otolaryngology—Head and Neck Surgery Advantages: • Ideal implantable microphone • Energy saver • Quality of sound Disadvantages: • Nonreversible process since reparation of the ossicular chain may be necessary in case of failure • Long and difficult surgery, with risk of the facial nerve • Limited amplifications capabilities • Not suitable to treat mixed hearing losses.

The DACS (Direct Acoustic Cochlear Stimulator, Cochlear, Australia) The CODACS is a powerful semi-implantable electromagnetic transducer that aims electively stimulating the inner ear fluid through a classic stapes piston attached to the vibrating tip, called the artificial incus (Figs 10.16A and B).41 Surgically speaking, the transducer is firmly attached to amounting bracket that is screwed into the cortical bone of the mastoid. This permits significant output to be delivered and reliable fixation. The implant was developed initially to treat advanced otosclerosis, but it may be useful to treat sensorineural as well as mixed hearing loss, with modification of its design. However, the implant is still under evaluation for CE mark approval and does not fit with the reversibility principle of the active auditory implants since it necessitates penetration of the inner ear fluid. Advantages: • Powerful implant Disadvantages: • Difficult and risky surgical placement • Nonreversible in its actual indication

The TICA (Total Implantable Cochlear Amplifier) It is a piezoelectric fully implantable device that includes a rechargeable battery and an implantable microphone that received its CE mark in 1999 under the trademark Implex.42,43 The transducer uses a piezoelectric diaphragm coupled with the incus body. A microphone located underneath the skin of the external auditory canal catches the sound and has the advantage to use the resonance feature of the external canal that amplifies the 3 KHz frequency range. The system suffers from a significant feedback that necessitates disrupting the neck of the malleus. In addition, the subcutaneous microphone may induce skin reaction.28


A

B

Figs 10.16A and B: The CODACS Implant. (A) Global drawing of the placement and positioning of the external part; (B) Magnification of the transducer and the attachment tool that is screwed onto the cortical bone.

A

B

Figs 10.17A and B: Total implantable cochlear amplifier (TICA) and range of application.

The range of application is that of a powerful hearing aid and it seems the implant lacks output in the low frequencies (Figs 10.17A and B). This system was only used by its developer with significant results.42,43 Advantages: • Surgery is easy • Fully implantable Disadvantages: • Nonreversible • Placement of the microphone • Feedback and need for disrupting the chain.


Fig. 10.18: Principles of the Soundtec.

The SOUNDTEC (Ototronix, USA) This system shares the same principle as the VSB, since an electromagnetic transducer using a magnet and coils is fixed onto the stapes head after disruption of the incudostapedial joint, without any comments on how the chain will be restored. However, there is no wire linking the transducer to the processor and the transducer is driven by a magnetic field emitted by an auditory prosthesis placed into the external canal (Fig. 10.18). Thus, the benefit of the Soundtec over conventional aids in terms of canal discomfort is here null. The Soundtec is not widely used nowadays. Advantages: • Surgery is easy Disadvantages: • Not really an AMEI • Nonreversible • Need for hearing aid inside the ear canal • Need for disrupting the chain • Low amplification in compared with hearing aids.

The BoneBridge (Med-El, Austria) The BoneBridge is the first active implanted bone-conductive hearing prosthesis. Thus, a description of the device has its place in this chapter. The implant is made of two parts, the external part resembles the external processor of the VSB in its shape as well as in its function. The internal part is an active real vibrating system and includes two parts (Figs 10.19A and B):


A

B

Figs 10.19A and B: (A) Description of the internal part of the BoneBridge; (B) Positioning of the implant and external processor.

•

The BC-FMT is a cylinder-shaped magnetic part, and is screwed into the mastoid area. This BC-FMT is 9 mm deep, 16 mm large, and the distance between the two screws is 24 mm • The processor itself is the one of the Vibrant Soundbridge and lies underneath the skin, and do not require any bony bed. The size of the BC-FMT is significant and the implantation needs preoperative radiologic evaluation since it might not fit in all the mastoid areas. The preoperative CT scan is mandatory and, even though the technique is not difficult, it is strongly recommended to carry out a preoperative simulation of the positioning of the implant. This helps performing a safe and quick surgery, which takes in our experience less than half an hour (Figs 10.21A and B). The implant is indicated for conductive hearing loss, mixed hearing loss for BC thresholds above 45 dB, and for single sided deafness as well (with the contralateral thresholds to be above 20 dB) (Figs 10.20A and B). The implant is said to be MRI compatible since it is not deteriorated by the magnetic field, and patients do not feel any troublesome symptoms when in the MRI scan. However, significant artifacts occur around the implant. Advantages: • Surgery is easy • Coupling is excellent and does not require middle ear surgery or exploration • ‘MRI compatible’ • Fully reversible • Suitable for conductive hearing loss, mixed hearing loss, and single-sided deafness Disadvantages: • Low amplification and selection of patients needs careful evaluation of BC thresholds as for BC devices.


A

B

Figs 10.20A and B: Audiologic indications of the BoneBridge for conductive and mixed hearing losses (A) and single sided deafness (B).

The ideal AMEI: discussion on limitations and challenge to improve the output and use of implantable auditory prostheses To limit the interfaces in the acoustic transmission was one of the aims of AMEIs. The principle is to drive directly the ossicular chain, bypassing the external canal (Figs 10.22A and B). Theoretically speaking, being closer to the inner ear reduces undoubtedly the energy loss and limits the effect of distortion and feedback. Doing so avoid occluding the external canal and may improve the acoustic comfort. The main difference from cochlear implants is that being extracochlear, the implantation is a reversible process. We will see in the discussion that the AMEI is far from being optimal and do not satisfy the reversibility principle in all cases. Given this common principle, the main differences between AMEI and hearing aids are the following, all four impacting significantly the output to the cochlea: • The vibration mode (electromagnetic, piezoelectric); • The coupling mode (single contact, loop, cement…) • The site for coupling (incus body, incus long process, stapes capitulum, footplate, round window membrane, third window…) • The invisibility (semi- or fully implantable). Again, the reversibility of the implantation is crucial and needs to be taken into account. Reversibility should remain an unviolated principle of the AMEI use as there is no certainty that the induced degradation of the middle ear function may be in all cases. The ideal implant will be a sum of a balance combination of the five parameters cited above, and the current differences in the manufacturers’ choice demonstrate which of the priorities have been selected.


A

B Figs 10.21A and B: (A) Preoperative simulation using the raw data from the CT scan and the dedicated software from Med-El; (B) Intraoperative picture showing the system implanted (left side).

A

B Figs 10.22A and B: Comparison of the amplification with conventional hearing aids and AMEI.13

The Vibration Mode The electromagnetic transducer function as an induction current mobilizes a magnetic vibrating driver. This vibration is delivered to the ossicular chain

172 Recent Advances in Otolaryngology—Head and Neck Surgery or remnants. These types of transducer necessitate a significant amount of energy and their output depends on the size and number of coils. This is a reason why the FMT from Otologics, in some way, lacks output on high frequency; increasing its output will necessitate to increase its weigh and so the negative impact on the biomechanism of the middle ear.35 However, the MET from Otologics (now cochlear) or the CODACS are screwed onto the skull and their outputs are significantly higher. The piezoelectric transducers (from the Greek ‘piezein,’ to press) function on the deformation of a crystal that generates an electric current and reciprocally the crystal moves when an electric current is applied. The two main advantages are first the energy saver phenomenon that is particularly of interest for fully implantable devices (see Esteem from Envoy Medical). Second, the crystal has a high reproducibility of high frequency that is critical for age-related hearing loss. The main disadvantages are their stiffness at rest and so their impact on the biomechanism of the middle ear because their appropriate function necessitates a perfect attachment.

The Coupling Mode This is one of the most critical points. We can distinguish: • The single contact with the ossicular chain: this is the choice of the MET that touches the incus body or the TICA. The advantages are the reversibility of such a coupling. However, to get the best coupling is not a simple task, since the feeling of the surgeon is always approximate with two consequences: the underloading that will be inadequate in transmitting the output or the overloading that may create a conductive hearing loss or damage to the middle ear or inner ear structure. The MET is coupled adequately using the transducer loading assistant (TLA, see Refs 19,44) The TICA is not a reversible process since its placement necessitates interrupting the neck of the malleus • The crimping to the ossicular chain using a loop: this is the choice of the VSB • This may be the perfect coupling in terms of energy transfer, and a reversible one since the attachment can be easily reopened. Among others, Huber,45,46 Huttenbrink,47 Grolman,48 Daniel A’Wengen,49 Tange,50 and Neudert51 demonstrated that tight attachment might significantly improve the energy transfer in ossicular chain reconstruction. We had the opportunity to validate this assumption concurrently with AMEI and demonstrated that improving the coupling by clipping the ossicular chain or remnant dramatically improves the output.52 We strongly recommend to adequately coupling the transducer tip with the ossicular chain or with the remaining vibrating middle ear structure as far as possible. This improves significantly the amplification


•

•

Cementation to the ossicular chain: this is the choice of the Esteem,53 or of the abandoned Rion31 in which the transducer is coupled with the stapes capitulum using biocement. In such a coupling, the transfer function is optimal but the fixation of the stapes is maximal without any degree of freedom, producing an additional conductive hearing loss. The reversibility is here impossible, first by the disruption of the chain that is mandatory for the implantation, and second by the cementation of the stapes Direct stimulation of the inner ear fluid: this option has been chosen by the CODACS from cochlear but can be achieved with other devices such as the MET or the Carina.39 In such stimulation, a piston or piston-like tip is inserted into the vestibule. The output is fully achieved through the transducer; the middle ear is bypassed as the stapes footplate is perforated. It is also feasible to drive the inner fluid directly through a third window, drilled out on the cochlea. This may be an option in selected cases with stapes fixation.75

The Coupling Location Directly linked to the mode of coupling, the placement of the transducer is so critical that inadequate coupling may lead to insufficient output and bad results. The powerfulness of the implant is not always capable to overcome coupling issues. Again, we can distinguish the coupling that preserves the biomechanism of the middle ear and so is reversible (incus body, incus long process, round window membrane), from those who do not (stapes capitulum, stapes footplate, perilymphatic fluid insertion), either because of previous disruption of the chain or secondary to voluntary and mandatory disjunction of the chain to allow the implant to be functional. This latter situation is a subject of controversies. As long as the transducer is positioned onto a vibrating structure that induces mobilization of the inner ear fluid of the cochlea, the implant will be functional. One could say that quite every option is feasible. Many papers, either experimental or clinical, support this.11,28,36–39,41,52,54-60 Given that, it is obvious that round window, footplate, or perilymphatic coupling are somewhat less reliable comparing to incus or stapes capitulum coupling. For instance, we demonstrated that only a diligent and optimized coupling may allow significant output in round window stimulation37 and this is supported by the uncertainty of clinical results of round window implantation.38 However, driving the stapes capitulum represent the best coupling option. It has been demonstrated experimentally61,39,52 and explains the technical choice of the Esteem as well as the VSB who we transducer are located close or at the stapes capitulum. In addition, implantation in case of mixed hearing loss, whatever the site for coupling (round window, stapes, footplate…), gives the opportunity to maximize the performances of the transducer, since there is no risk of feedback.


Fig. 10.23: Sources of battery consumption. From Counter.13

A

B Figs 10.24A and B: Energy loss due to active middle ear implants (AMEI) applica tion, in case of coupling to the ossicular chain (A) or to the round window membrane when the ossicular chain is intact (unusual situation, (B)). From Counter.13

To be practical, for sensorineural indications, to be closer to the stapes improves the results52 and coupling with the long process of the incus or with the stapes capitulum is the best option. For mixed hearing loss cases, choosing the normal auditory pathway will help to decide where to implant and the following strategies may be followed respectively upon availability: stapes capitulum, stapes footplate, round window membrane, and third window.

The Energy Issue The implantable prosthesis is highly costly in terms of energy, much more than a conventional hearing aid, through • The processor • The transducer • The microphone • The dissipation of energy due to the feedback that may be partly reduced by round window coupling (Figs 10.23 and 10.24) For semi-implantable system, the battery is external and needs to be replaced regularly according to the output, so the degree of hearing loss. For fully implantable models, the energy supply is a real challenge and this explains why there are only two implants (Carina and Esteem), which are reliable and fully implantable. The battery daily charge of the Carina is approximately 40 minutes to an hour according to output. This burden is not a subject of complaint from patients who do really appreciate the invisibility of their aid. According to the manufacturer and considering a daily use of at least 16 hours, the battery life of the Carina is said to last 25–30 years (Fig. 10.25).


Fig. 10.25: Battery life of the Carina. Factory data. From Otologics, LLC.

The Esteem is a piezoelectric system and has the advantage of saving the energy for the incus motion. This avoids daily charge of the system and patients can really ‘forget’ that they have got an AMEI. However, the battery lifetime is one of a pacemaker, lasting for 5 to 7 years approximately.

The Microphone This is a critical point and Otologics was the only manufacturer (the microphone from the TICA is a source of skin issues) to succeed facing this challenge with an electromagnetic subcutaneous microphone. Esteem has developed the best microphone ever, since the drum itself constitutes the microphone. The only drawback is that this option is only valid for intact drum and ossicular chain (so sensorineural hearing loss). The microphone of the Carina can be used in any situation, and explains why this implant was chosen for rehabilitation of external ear artesia.62 There are two main issues with the microphone of the Carina. First body and environmental noises are sometimes troublesome (generally patients adapt themselves with time). Second, the feedback is here a main issue since the microphone is screwed into the mastoid and catches the vibration directly. This needs to apply feedback cancellation algorithms that impact negatively on performances and limit the application of the implant to moderate hearing

176 Recent Advances in Otolaryngology—Head and Neck Surgery losses.19 The improvement in coupling is of great interest since it permits to improve the performances using the same output, so without additional risk of feedback.52

The Cost-effectiveness The ‘unaffordable’ cost of AMEI is one of the main limiting factors of their use. We lack clinical studies to prove their cost-effectiveness. Snik et al.63 conducted the only one study that demonstrated the cost-effective benefit of AMEI in mixed hearing loss in 2006. They demonstrated that AMEI might be cost-effective in patients with external ear canal stenosis. However, the difference is tight and the challenge is real facing BC solutions and cochlear implants.

What is the Place of AMEI in the Portfolio of Auditory Aids? Nowadays, otolaryngologist and, mainly, patients are particularly enthusiastic because deafness has become disease of the past (apart from some exceptions!), since several options are available for treating such handicap. AMEI represents an excellent option in this portfolio, but suffer from challenging alternative options: • Conventional hearing aids technology has tremendously improved in the past 10 years and more and more patients suffering from severe loss are satisfied with their aids. Nowadays, one can consider that a new technologic improvement occurs every 6 months.3,24,21 Facing conventional hearing aids, the only benefit of AMEI is the improvement in the highfrequency range that is significantly higher since conventional hearing aids are limited over 4–6 kHz, the greater output for powerful devices such as the MET or the CODACS that can treat severe loss efficiently)40 • BC hearing aids or BC acoustic implants represent an excellent alternative in conductive loss. The coupling is here excellent and reliable: there is no issue with any kind of external canal or middle ear anatomy or effusion. The main limitation of BC options is the cochlear function, since the output of BC systems, whatever the device, is limited for patients with an average 45–55 dB in BC thresholds. Thus, AMEI is an excellent alternative for mixed hearing loss patients, with BC thresholds from 45 to 75–80 dB. • Cochlear implant technology as well has improved and nowadays hearing preservation is no longer a chimera. Hence, patients with severe loss show great benefit from cochlear implantation, even with a moderate contralateral hearing loss. In addition, nowadays, mixed hearing loss without possibility of adequate coupling (obliterative otosclerosis, extensive tympanosclerosis…) is excellent indication of cochlear implant. That is the reason why implantation using powerful AMEIs such as the MET or the CODACS represents a good alternative since they are reversible


processes and do not alter the cochlear function definitively. The main question to ask is how long the use of AMEI will benefit the patient? Would not it be worth to indicate a cochlear implant directly, and avoid wasting time and money?

What are the main indications of AMEI nowadays? AMEIs are useful in many indications and the only real limitations are the possibility to couple the implant and the cost. Sensorineural hearing loss is the most controversial indication since hearing aid can be applied efficiently, and when hearing aids are not satisfactory, it is not 100% sure AMEI will be doing better, and comparative QOL studies lack to demonstrate a difference.40,64 Conductive loss is an excellent indication of AMEI, but the etiology may impact the coupling possibility and the alternative of BC implant is attractive, moreover with the new released devices. Mixed hearing loss represents, in our mind, one of the best indications, since the powerfulness of the AMEI will overcome the BC deficit, and the amplification will improve the acoustic cues dramatically. Here, BC solutions are limited by their low amplification capabilities (consider that the BC implant will be giving an air-conduction threshold at the level of the preoperative BC). Again, facing mixed hearing loss, conventional hearing aids are frequently unable to help the patients with satisfaction. From an acoustical point of view, mixed hearing loss situations are the best indication if the coupling of the transducer is accurate, since the risk of feedback is minimal and conversely the amplification can be maximized to achieve significant results and satisfaction. We propose a Table 10.1 listing the different indications of AMEI and the alternatives.

What is the preoperative selection workup? The selection of patients is achieved after a strict evaluation, and we consider four categories of assessment to help the selection of both the patients and the implants. A. Clinical assessment: 1. What is the history of disease? a. Simple chronic otitis (is there any Eustachian tube dysfunction) b. Cholesteatoma (consider MRI follow-up) c. Blunting and/or ear canal trouble d. Open mastoid cavity (consider the need for rehabilitation of the canal or exclusion)

178 Recent Advances in Otolaryngology—Head and Neck Surgery Table 10.1: Main indications and limitations of AMEIs Indication

Qualified as

Implants

Alternative

Issues

Cholesteatoma and benign tumoral processes

Good indication

Any kind depending on the bone conduction (BC) thresholds

Hearing aids if OCR achieved good closure of air-bone gap. Bone conduction hearing solution

(1) MRI issues and residual disease: Keep a 3-years period after cholesteatoma surgery with normal MRI to avoid impossibility of following up the patient (2) Achieve adequate coupling:

Simple chronic otitis

Excellent indication

Any kind depending on the BC thresholds

Hearing aids with OCR. Bone conduction hearing solution

Ear should not be discharging or graft the drum with a thick cartilage

Blunting, lateralization, and EAC obliteration

Excellent indication

Any kind depending on the BC thresholds

Hearing aid for limited blunting or bone conduction hearing solution for more severe lateralisation and obliteration

No issues in the great majority of cases. The middle ear is usually erated

Open mastoid cavity and discharging ears

Good indication

Prefer small transducer since the anatomy is usually not suitable for large AMEI

Hearing aids are rarely fittable, and BCs are the best alternative

Discharging ears are frequently superinfected and the main issue is to avoid superinfection around the implant. Two options: reconstruction of the ear canal or obliteration with external canal blind sac closure. In both cases, the follow-up of the patient is impaired by the impossibility to carry out MRI scan

(OCR: Ossicular chain reconstruction; EAC: External auditory canal).


e. Otosclerosis (inadequate coupling should be expected) f. The number of previous surgeries g. Any treatment that impacts the implantation (radiation therapy?) 2. Is there any specific disease that may restrict the indication of implanting a medical device? a. Tumoral process b. Brain disease that must be followed by MRI scan 3. What are the local conditions? a. Drum b. The mastoid and temporal bone c. The quality of the skin 4. Are there any obstacles to fit a hearing aid or a BC hearing aid? a. External canal stenosis b. Chronic or recurrent eczema or discharging ear c. Past-history of radiation therapy affecting the external canal or temporal bone d. Previous failure of BAHA application e. Insufficient bone thickness B. Radiological assessment: 1. CT scan (diagnosis of etiology and anatomic work-up to anticipate the coupling) a. External canal vacuity b. Middle ear and mastoid aeration c. Specific disease (otosclerosis, tympanosclerosis…) d. Ossicular chain or ossicular remnant e. Access to round window area f. Mastoid size g. Tegmen dehiscence and position (epitympanum space) h. Lateral sinus and jugular bulb position and providence i. Position of facial canal and size of facial recess approach 2. MRI scan (diagnosis of etiology and central nervous system workup) a. Mastoid, middle ear, and temporal bone abnormal signals that may contraindicate implantation (cholesteatoma, tumoral process…) b. Brain disease that may need further investigation or follow-up (high intracranial pressure, multiple sclerosis, vascular disease like aneurysm, meningiomas, tumoral process, metastasis…) C. Audiological assessment: 1. Etiology and evolution of hearing loss a. Bilateral or unilateral hearing loss, only hearing ear b. Sensorineural, conductive or mixed hearing loss c. Stable or rapidly progressive deterioration of thresholds, fluctuating…

180 Recent Advances in Otolaryngology—Head and Neck Surgery 2. Hearing aid trial and assessment a. At least 3 months of hearing aid use, with appropriate fitting b. What types of aids (air conduction, BC) 3. Audiologic workup a. Pure tone average (PTA) without hearing aids (headphones): determine air-conduction and BC thresholds in both ears with appropriate masking b. PTA with hearing aids: separate ears and with both ears in free field c. Speech discrimination with headphones without aids d. Speech discrimination in free field with aids, separate ears e. Speech discrimination in free field with aids, both ears f. Speech discrimination in noise (SNR 0, 5, 10 dB), without and with aids, both ears in free field D. Quality of life (QOL) and general considerations: 1. Age and perspective of hearing impairment – quality-adjusted life year (QALY) index What is the residual hearing and for how long this status will last? In other words, what is the ‘quality and quantity of good hearing’ that may be improved by the chosen option? This is particularly important and at the basis of QALY calculation. A QALY is designed to aggregate the total health improvement in a group of individuals, while capturing improvements in QOL (health utility) and quantity of life.63,65 Consider that severe loss with ageing people will not benefit for a long time for AMEI application, and cochlear implant may be considered as a first option. 2. Satisfaction and use of hearing aids First, determine what are the dissatisfaction of the patients with regard to hearing aid use and amplification. Then, apply specific questionnaires to evaluate the benefit or dissatisfaction. Many questionnaires are available nowadays. We could recommend the Glasgow Hearing Aid Benefit Profile – GHABP,66 the Abbreviated Profile of Hearing Aid Benefit – APHAB,67 the International Outcome Inventory - Hearing Aid – IOI-HA,68and the Speech, Spatial and Qualities of Hearing Scale – SSQ.*69 General QOL questionnaire may be useful as well and the easiest and reliable evaluation may use the World Health Organization materials, available in different languages** (WHODAS for WHO Disability Assessment Schedule), or the Glasgow Benefit Inventory – GBI70 or the SF-36.71 3. Comprehension of what AMEI implicates, maintenance, and burden and exchange of experience. It is critical and in our mind mandatory that the patient is informed clearly about the future implant, its maintenance, the need to change or charge the *http://www.ihr.mrc.ac.uk/products/display/ssq **http://www.who.int/classifications/icf/whodasii/en/


batteries. In addition, we strongly recommend that future recipients meet implanted patients and exchange their experience. This is relatively easy to achieve during a fitting session.

How to Select the Implants According to the Criteria Cited Above? After the decision to implant the patient has been taken, many factors intervene in the choice of implant. 1. The hearing function Regarding sensorineural hearing loss, AMEIs can be considered to preserve speech discrimination score (SDS) function, otherwise, cochlear implants have to be selected. This being said, the BC threshold indicates what types of implant can be selected. For moderate loss, all types can be applied. For severe loss, the MET or the CODACS should be selected, as their output is powerful enough to overcome severe impairment. For conductive loss and BC threshold better than 30 dB, all types of implants can be chosen, since low amplification is sufficient to reach comfortable level of improvement. Mixed hearing loss is more challenging, as the SDS is irrelevant in the assessment and the best criterion is the BC threshold: • For BC threshold between 30 and 45 dB, all types of implant are applicable, from BC to the other AMEIs (except the Esteem that necessitates a normal drum) • For BC threshold between 45 and 70 dB, the Carina, the MET, the CODACS are usable, since BC devices are unable to overclose the BC threshold and the VSB application is limited to 45 dB at 500 Hz. • For BC thresholds between 70 and 85 dB, only the MET and the CODACS may be applied, or cochlear implantation can be chosen. 2. The anatomic condition Undoubtedly, the easiness of coupling is crucial and the versatility of the implant is a major concern, especially in mixed hearing loss cases. All implants are versatile enough to adapt to different anatomic situation. The VSB can be modified (bending the crimp, adapt some prosthesis) to fit in different situations. The MET and the Carina can be coupled with dedicated titanium tips to adapt to different anatomic situation. The CODACS is still under evaluation but additional tips can be used as well.72 3. The easiness of implantation In the same vein, surgeon preference may be toward an easy, fast and reliable technique. Only the VSB achieves such qualities, and the MET, the Carina, the Esteem, and the CODACS are more complicated to insert. However, all these implants share reliable anchoring and powerful output, which is an argument of choice. Training of the surgeon may help overcoming some difficulties and facilitating the use of high-power AMEIs.


Conclusion AMEIs have a great capacity of amplification and should have a place in the auditory aids portfolio. Different techniques of coupling, difficult surgeries, inappropriate indications have sometimes led to disappointment of both surgeons and recipients. However, a diligent technique and a careful selection of patients increase the level of satisfaction. On one hand, very powerful devices will help to rehabilitate efficiently patients before the indication of cochlear implantation, while on the other hand, fully implantable system can satisfied demanding people through their esthetic wills. The main limitation remains. Their cost and clinical studies evaluating the cost-effectiveness as well as the auditory benefit may help to prove their relevance. As an auditory prosthesis, an AMEI will benefit from the technological improvement. The main ways to improve their performances and their use are as follows: • Increasing the output is a challenge limited by the risk of feedback • Improving the signal process algorithm will benefit from the hearing aid companies knowledge and may reduce the feedback that negatively impacts the performances, and the quality of implantable microphone • Optimization of coupling is a challenge both for the engineers and the surgeons, to reduce the size, improve the coupling, and preserve as far as possible the reversibility of AMEI implantations, while treating more severe loss • Simplification of surgery will help the AMEI to be placed by general otologist and not being used in a small numbers of centers • It is crucial to obtain reimbursement of implantable hearing aids. To achieve this goal, it’s critical to pursue research and clinical studies with appropriate primary endpoint and adequate control group.

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immunohistochemical methods for detecting hypoxia in mouse and rat cochleae. Acta Histochem. 2007;109:177–84. 2. Riva C, Donadieu E, Magnan J, et al. Age-related hearing loss in CD/1 mice is associated to ROS formation and HIF target proteins up-regulation in the cochlea. Exp Gerontol. 2007;42:327–36. 3. Edwards B. The future of hearing aid technology. Trends Amplification. 2007;11:31–45. 4. Erler SF, Garstecki DC. Hearing loss- and hearing aid-related stigma: perceptions of women with age-normal hearing. Am J Audiol. 2002;11:83–91. 5. Junker R, Gross M, Todt I, et al. Functional gain of already implanted hearing devices in patients with sensorineural hearing loss of varied origin and extent: Berlin experience. Otol Neurotol. 2002;23:452–6.

Implantable Hearing Aids 183 6. Stone MA, Moore BC, Meisenbacher K, et al. Tolerable hearing aid delays. V. Estimation of limits for open canal fittings. Ear Hear. 2008;29:601–17. 7. Roup CM, Noe CM. Hearing aid outcomes for listeners with high-frequency hearing loss. Am J Audiol. 2009;18:45–52. 8. Ball GR. Implantable magnetic hearing aid transducer. US Patent. 5456654, 1993. 9. Kasic JF, Fredrickson JM. The Otologics MET ossicular stimulator. Otolaryngol Clin North Am. 2001;34:501–13. 10. Seitz PR. French origins of the cochlear implant. Cochlear Implants Int. 2002;3:77–86. 11. Sterkers O, Boucarra D, Labassi S, et al. A middle ear implant, the Symphonix Vibrant Soundbridge: retrospective study of the first 125 patients implanted in France. Otol Neurotol. 2003;24:427–36. 12. Jenkins HA, Niparko JK, Slattery WH, et al. Otologics middle ear transducer ossicular stimulator: performance results with varying degrees of sensorineural hearing loss. Acta Otolaryngol. 2004;124:391–4. 13. Counter P. Implantable hearing aids. Proc Inst Mech Eng H. 2008;222:837–52. 14. Mosnier I, Sterkers O, Bebear JP, et al. Speech performance and sound localization in a complex noisy environment in bilaterally implanted adult patients. Audiol Neurootol. 2009;14:106–14. 15. Gantz BJ, Hansen MR, Turner CW, et al. Hybrid 10 clinical trial: preliminary results. Audiol Neurootol.2009;1:32–8. 16. Merkus P, Lella FD, Trapani GD, et al. Indications and contraindications of auditory brainstem implants: systematic review and illustrative cases. Eur Arch Otorhinolaryngol. 2013;13, doi:10.1007/s00405–013–2378–3. 17. Hetu R. The stigma attached to hearing impairment. Scand Audiol. 1996;25: 12–24. 18. Kent B, Smith S. They only see it when the sun shines in my ears: exploring perceptions of adolescent hearing aid users. J Deaf Stud Deaf Educ. 2006;11: 461–76. 19. Jenkins HA, Pergola N, Kasic J. Intraoperative ossicular loading with the Otologics fully implantable hearing device. Acta Otolaryngol. 2007;127:360–64. 20. Lupsakko TA, Kautiainen HJ, Sulkava R. The non-use of hearing aids in people aged 75 years and over in the city of Kuopio in Finland. Eur Arch Otorhinolaryngol. 2005;262:165–9. 21. Palmer CV, Ortmann A. Hearing loss and hearing aids. Neurol Clin. 2005;23:90118, viii. 22. Stenfelt S, Goode RL. Bone-conducted sound: physiological and clinical aspects. Otol Neurotol. 2005;26:1245–61 23. Stenfelt S, Goode RL. Transmission properties of bone conducted sound: measurements in cadaver heads. J Acoust Soc Am. 2005;118:2373–91. 24. Kim HH, Barrs DM. Hearing aids: a review of what’s new. Otolaryngol Head Neck Surg. 2006;134:1043–50. 25. Wazen JJ, Young DL, Farrugia MC, et al. Successes and complications of the Baha system. Otol Neurotol. 2008;29:1115–59. 26. Sprinzl G, Lenarz T, Ernst A, et al. First European multicenter results with a new transcutaneous bone conduction hearing implant system: short-term safety and efficacy. Otol Neurotol. 2013;34:1076–83.

184 Recent Advances in Otolaryngology—Head and Neck Surgery 27. Djourno A. Eyries C. Prothèse auditive par excitation électrique à distance du nerf sensoriel à l’aide d’un bobinage inclus à demeure. Presse Med. 1957;65:1417. 28. Beutner D, Huttenbrink KB. Passive and active middle ear implants. GMS Curr Top Otorhinolaryngol Head Neck Surg. 2009;8:Doc09. DOI: 10.3205/cto000061. 29. Suzuki J, Kodera K, Yanagihara N. Middle ear implant for humans. Acta Otolaryngol. 1985;99:313–7. 30. Yanagihara N, Aritomo H, Yamanaka E, Gyo K. Implantable hearing aid. Report of the first human applications. Arch Otolaryngol Head Neck Surg. 1987;113:869–72. 31. Yanagihara N, Sato H, Hinohira Y, Gyo K, Hori K. Long-term results using a piezoelectric semi-implantable middle ear hearing device: the Rion Device E-type. Otolaryngol Clin North Am. 2001;34:389–400. 32. Hough JV, Dyer RK Jr, Matthews P, et al. Early clinical results: SOUNDTEC implantable hearing device phase II study. Laryngoscope. 2011;111:1–8. 33. Silverstein H, Atkins J, Thompson JH Jr, et al. Experience with the SOUNDTEC implantable hearing aid. Otol Neurotol.2005;26:211–7. 34. Busch S, Kruck S, Spickers D, et al. First clinical experiences with a direct acoustic cochlear stimulator in comparison to preoperative fitted conventional hearing AIDS. Otol Neurotol. 2013;34:1711-8. 35. Needham AJ, Jiang D, Bibas A, et al. The effects of mass loading the ossicles with a floating mass transducer on middle ear transfer function. Otol Neurotol. 2005;26:218–24. 36. Lefebvre PP, Martin C, Dubreuil C, et al. A pilot study of the safety and performance of the Otologics fully implantable hearing device: transducing sounds via the round window membrane to the inner ear. Audiol Neurootol. 2009;14: 172–80. 37. Tringali S, Koka K, Deveze A, et al. Round window membrane implantation with an active middle ear implant: a study of the effects on performance on round window exposure and transducer tip diameter in human cadaveric temporal bones. Audiol Neurootol. 2010;15:291–302. 38. Martin C, Deveze A, Richard C, et al. European results with totally implantable Carina placed on the round window: 2-year follow-up. Otol Neurotol. 2009;30:1196–203. 39. Deveze A, Koka K, Tringali S, et al. Active middle ear implant in case of stapes fixation: a temporal bone study. Otol Neurotol. 2010;31:1027–34. 40. Tringali S, Perrot X, Berger P, et al. Otologics middle ear transducer with contralateral conventional hearing aid in severe sensorineural hearing loss: evolution during the first 24 months. Otol Neurotol. 2010;31:630–6. 41. Hausler R, Stieger C, Bernhard H, et al. A novel implantable hearing system with direct acoustic cochlear stimulation. Audiol Neurootol. 2008;13:247–56. 42. Zenner HP, Leysieffer H. Totally implantable hearing device for sensorineural hearing loss. Lancet. 1998;352:1751. 43. Zenner HP, Limberger A, Baumann JW, et al. Phase III results with a totally implantable piezoelectric middle ear implant: speech audiometry, spatial hearing and psychosocial adjustment. Acta Otolaryngol. 2004;124:155–64.

Implantable Hearing Aids 185 44. Tringali S, Koka K, Deveze A, et al. Intraoperative adjustments to optimize active middle ear implant performance. Acta Otolaryngol. 2011;131:27–35. 45. Huber AM, Ma F, Felix H, et al. Stapes prosthesis attachment: the effect of crimping on sound transfer in otosclerosis surgery. Laryngoscope. 2003;113:853–8. 46. Huber AM, Veraguth D, Schmid S, et al. Tight stapes prosthesis fixation leads to better functional results in otosclerosis surgery. Otol Neurotol. 2008;29:893–9. 47. Hüttenbrink KB, Zahnert T, Wüstenberg EG, et al. Titanium clip prosthesis. Otol Neurotol. 2004;25:436–42. 48. Grolman W Tange RA. First experience with a new stapes clip piston in stapedotomy. Otol Neurotol. 2005;26:595–8. 49. Wengen DF. A new self-retaining titanium clip stapes prosthesis. Adv Otorhinolaryngol. 2007;65:184–9. 50. Tange RA, Grolman W. An analysis of the air-bone gap closure obtained by a crimping and a non-crimping titanium stapes prosthesis in otosclerosis. Auris Nasus Larynx. 2008;35:181–4. 51. Neudert M, Zahnert T, Lasurashvili N, et al. Partial ossicular reconstruction: comparison of three different prostheses in clinical and experimental studies. Otol Neurotol. 2009;30:332–8. 52. Devèze A, Koka K, Tringali S, et al. Techniques to improve the efficiency of a middle ear implant: effect of different methods of coupling to the ossicular chain. Otol Neurotol. 2013;34:158–66. 53. Chen DA, Backous DD, Arriaga MA, et al. Phase 1 clinical trial results of the Envoy System: a totally implantable middle ear device for sensorineural hearing loss. Otolaryngol Head Neck Surg. 2004;131:904–16. 54. Colletti V, Soli SD, Carner M, et al. Treatment of mixed hearing losses via implantation of a vibratory transducer on the round window. Int J Audiol. 2006;45:600–08. 55. Venail F, Lavieille JP, Meller R, et al. New perspectives for middle ear implants: first results in otosclerosis with mixed hearing loss. Laryngoscope. 2007;117:552–5. 56. Lupo JE, Koka K, Holland NJ, et al. Prospective electrophysiologic findings of round window stimulation in a model of experimentally induced stapes fixation. Otol Neurotol. 2009;30:1215–24. 57. Linder T, Schlegel C, DeMin N, et al. Active middle ear implants in patients undergoing subtotal petrosectomy: new application for the Vibrant Soundbridge device and its implication for lateral cranium base surgery. Otol Neurotol. 2009;30:41–7. 58. Tringali S, Pergola N, Berger P, et al. Fully implantable hearing device with transducer on the round window as a treatment of mixed hearing loss. Auris Nasus Larynx. 2009;36:353–8. 59. Nakajima HH, Merchant SN, Rosowski JJ. Performance considerations of prosthetic actuators for round-window stimulation. Hear Res. 2010;263:114–9 60. Zahnert T, Bornitz M, Hüttenbrink KB. Experiments on the coupling of an active middle ear implant to the stapes footplate. Adv Otorhinolaryngol. 2010;69:32–7.

186 Recent Advances in Otolaryngology—Head and Neck Surgery 61. Bornitz M, Hardtke HJ, Zahnert T. Evaluation of implantable actuators by means of a middle ear stimulation model. Hear Res. 2010;263:145–51. 62. Siegert R, Mattheis S, Kasic J. Fully implantable hearing aids in patients with congenital auricular atresia. Laryngoscope. 2007;117:336–40. 63. Snik AF, van Duijnhoven NT, Mylanus EA, et al. Estimated cost-effectiveness of active middle-ear implantation in hearing-impaired patients with severe external otitis. Arch Otolaryngol Head Neck Surg. 2006;132:1210–1215. 64. Rameh C, Meller R, Lavieille JP, et al. Long-term patient satisfaction with different middle ear hearing implants in sensorineural hearing loss. Otol Neurotol. 2010;31:883–92. 65. Torrance GW, Feeny D. Utilities and quality-adjusted life years. Int J Technol Assess Health Care. 1989;5:559–75. 66. Gatehouse S. Glasgow Hearing Aid Benefit Profile: derivation and validation of a client-centered outcome measure for hearing aid services. J Am Acad Audiol. 1999;10:80–103. 67. Cox R, Alexander G. The abbreviated profile of hearing aid benefit. Ear Hearing. 1995;16:176–86. 68. Cox R, Alexander G, Beyer C. Norms for the international inventory for hearing aids. Int J Audiol. 2003;14:403–13. 69. Gatehouse S, Noble W. The Speech, Spatial and Qualities of Hearing Scale (SSQ). Int J Audiol. 2004;43:85–9. 70. Robinson K, Gatehouse S, Browning GG. Measuring benefit from otorhinolaryngological surgery and therapy. Ann Otol Rhinol Laryngol. 1996;105:415–22. 71. Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): conceptual framework and item selection. Med Care. 1992;30:473–83. 72. Maier H, Salcher R, Schwab B, Lenarz T. The effect of static force on round window stimulation with the direct acoustic cochlea stimulator. Hear Res. 2013;301:115–24. 73. Jenkins HA, Atkins JS, Horlbeck D, et al. Otologics fully implantable hearing system: Phase I trial 1-year results. Otol Neurotol.2008;29:534–41. 74. WHO. Deafness and hearing impairment. Factsheet updated February 2013. http://www.who.int/mediacentre/factsheets/fs300/en/index.html. 75. Lupo JE, Koka K, Jenkins HA, et al. Third-window vibroplasty with an active middle ear implant: assessment of physiologic responses in a model of stapes fixation in Chinchilla lanigera. Otol Neurotol. 2012;33:425-31.

Chapter Endoscopic Ear Surgery

11

Muaaz Tarabichi, Marchioni Daniele, Livio Presutti

Introduction Although it has been two decades since the first use of operative endoscopy for the exploration of old mastoid cavities, the endoscope is used infrequently in the day-to-day surgical management of ear disease around the globe for several reasons.1 The role of the endoscope as defined by many prominent otologists is so marginal that most surgeons have not felt compelled to master newer techniques and instrumentation for its use.2–6 In effect, the use of the endoscope did not significantly benefit either the patient or the surgeon. In addition, most physicians have focused on the use of smaller diameter endoscopes for ear surgery, which is very frustrating and eliminates the main (and possibly the only) advantage of endoscopy (the wide field of view provided by the endoscope is greater than that of the microscope). This author first used the endoscope in ear surgery in 1993 during years of practice in the United States. In recent years, it has replaced the microscope as the instrument of choice for use in middle ear surgery.7–10 The endoscope offers a new perspective of cholesteatoma and related surgical procedures by increasing the surgeon’s understanding of that disorder and its progression through the temporal bone. Clinicians who use the endoscope during ear surgery realize how the microscope and its limitations have colored the clinical perception of cholesteatoma and have dictated its management.

History The introduction of the binocular operating microscope, which was a landmark event in the development of modern otology, clearly changed the scope and character of ear surgery. Despite continuous technical improvements, basic optical principles and their limitations have remained the same over the last decades. The use of the endoscope in various surgical procedures was extrapolated to otologic surgery, and the diagnostic and photographic use of that instrument in the examination of the tympanic membrane and the ear canal has been widely publicized.2

188 Recent Advances in Otolaryngology—Head and Neck Surgery Transtympanic middle ear endoscopy was initially reported by Nomura3 and Takahashi et al.4 Poe and Bottrill used transtympanic endoscopy for the confirmation of perilymphatic fistula and the identification of other middle ear pathologic conditions.5 Kakehata used microendoscopy and transtympanic endoscopy for evaluation of conductive hearing loss and inspection of retraction pockets.11–13 Thomassin et al. reported on operative ear endoscopy for mastoid cavities and designed an instrument set to be used for that purpose.1 Badr-el-Dine and El-Messelaty reported on the value of endoscopy as an adjunct in cholesteatoma surgery and documented a reduced risk of recurrence when the endoscope was used.14–15 The reduction in residual disease was further confirmed by Yung16 and Ayache.17 Abdel Baki reported on using endoscopic technique to evaluate disease within the sinus tympani.18 Mattox reported on endoscopy-assisted surgery of the petrous apex.19 Magnan and Sanna,20 Bader-el-Dine and El-Garem,21–23 and Rosenberg et al.24 reviewed the role of the endoscope in neurotologic procedures. McKennan described the second-look endoscopic inspection of mastoid cavities that was achieved through a small postauricular incision.6 Presutti and Marchioni have described primary transcanal endoscopic ear surgery in a similar fashion to the experience reported here.25–26

Instrumentation In the procedures described in this report, 4 mm wide-angle 0° and 30° Hopkins II telescopes that were 18 cm in length were most often used. More recently, a smaller 3 mm endoscope that has a very similar field of view to the 4 mm endoscope is being used. Other smaller diameter scopes were used sparingly. Video equipment consisted of a 3-chip video camera and a monitor. All procedures were performed directly off the monitor and were recorded. Instruments used in conjunction with routine microscopic ear surgery (Fig. 11.1).

Discussion The rational, advantages, limitations, technique, and long-term results of the technique will be discussed in the following sections.

Rationale for Endoscopic Ear Surgery Acquired cholesteatoma is usually a manifestation of advanced retraction of the tympanic membrane that occurs when the sac advances into the tympanic cavity proper and then into its extensions such as the sinus tympani, the facial recess, the hypotympanum, and the attic.27 Only in advanced cases does a cholesteatoma progress further to reach the mastoid cavity proper. Most surgical failures associated with a postauricular approach seem to

Endoscopic Ear Surgery 189

Fig. 11.1: Operating room setup. The surgeon is operating while watching the monitor, which is positioned across the operating room table. The surgical assistant also has a clear view of the monitor.

occur within the tympanic cavity and its hard-to-reach extensions rather than in the mastoid.28-29 Therefore, the most logical approach to the excision of a cholesteatoma involves transcanal access to the tympanic membrane and tympanic cavity and the subsequent step-by-step pursuit of the sac as it passes through the middle ear. Mainstream ear surgery has usually involved the mastoid and the postauricular approaches because operating with the microscope through the auditory canal is a very frustrating and almost impossible process. The view during microscopic surgery is defined and limited by the narrowest segment of the ear canal (Fig. 11.2). This basic limitation has forced surgeons to create a parallel port through the mastoid to gain keyhole access to the attic, the facial recess, and the hypotympanum (Fig. 11.3). In contrast, transcanal operative endoscopy bypasses the narrow segment of the ear canal and provides a wide view that enables surgeons to look ‘around the corner,’ even when a 0° endoscope is used (Fig. 11.2). Another anatomic observation that supports transcanal access to the attic, which is the most frequent site of cholesteatoma,30 is the orientation of the ear canal in relation to the attic. Figure 11.4 shows a coronal computed tomographic (CT) section through the temporal bone, which reveals that an axis line drawn through the ear canal ends in the attic rather than the mesotympanum. The only structure that is in the way is the scutum, and its removal allows wide and open access to the attic, which is the natural cul-de-sac of the external auditory canal. Rediscovering the ear canal as the access port for


Fig. 11.2: The view from the microscope during transcanal surgery is defined and limited by the narrowest segment of the ear canal. In contrast, the endoscope bypasses this narrow segment and provides a very wide view that allows the surgeon to ‘look around corners,’ even when the 0° scope is used.

Fig. 11.3: The limited view provided by the microscope during transcanal procedures has forced surgeons to perform postauricular mastoidectomy, in which a port parallel to the attic is created after a considerable amount of healthy bone has been removed to enable anterior keyhole access to the attic.

cholesteatoma surgery is the main story and the main advantage of endoscopic ear surgery. This allows a more natural and direct access and pursuit of cholesteatoma within the middle ear cleft. In contrast, traditional approaches to the attic and facial recess have provided primarily keyhole access through postauricular mastoidectomy, and many surgeons use the ear canal to access the anterior part of the attic, even during postauricular tympanomastoi dectomy. Other areas, such as the hypotympanum and sinus tympani, are minimally accessible even with extensive postauricular mastoidectomy.


Fig. 11.4: A coronal computed tomographic section of the temporal bone, which shows that an axis line drawn through the ear canal ends in the attic rather than the mesotympanum. This almost universal anatomic orientation enables a natural transcanal access to the attic.

The wide view provided by the endoscope enables minimally invasive transcanal access to all those areas and facilitates the complete extirpation of disease without the need for a postauricular approach or incision.

Transcanal Endoscopic Anatomy of the Tympanic Cavity As discussed earlier, the transcanal endoscopic approach provides a fresh new way of looking at the anatomy of the tympanic cavity and more specifically the cholesteatoma bearing areas of that cavity. The endoscope also allows a better understanding of the ligaments and folds of the middle ear and how they affect ventilation of these different spaces. This section would highlight the anatomy of some areas and review the concept of the epitympanic diaphragm that plays an important role in the pathophysiology of attic cholesteatoma.31–33

Facial Recess Using transcanal endoscopic approach, the facial recess becomes very accessible and shallow depression on the posterior wall of the tympanic cavity (Fig. 11.5). In contrast, the postauricular posterior tympanotomy provides a keyhole access to this important area. The pyramidal eminence, along with the vertical segment of the facial nerve, forms the medial wall of the recess and it helps mark the depth of the vertical segment of the facial nerve in that area. The bony annulus that forms the lateral wall of the recess can be taken down safely as long as the pyramidal eminence is continuously observed and kept in view. The relationship of the bony annulus to the vertical segment


Fig. 11.5:Left ear. Endoscopic view through a transcanal endoscopic access after minor removal of bone; the facial recess (FR) is very shallow and more of a flat depression, more or less at the same level as the pyramidal eminence (PE ) and the vertical segment of facial nerve (FN).

of the facial nerve is very variable as we move inferiorly beyond the pyramidal eminence and great care should be paid when removing bone from the inferior/posterior aspect of the ear canal and bony annulus. Retrotympanum: When observing the anatomy of the retrotympanum, it is useful to start by identifying the footplate and the round window. The footplate is located within the posterior sinus that extends around it and posterior to it. The round window is located within the sinus subtympanicum that extends posterior and inferior to it. In between these two sinuses lie the sinus tympani (Fig. 11.6). It is a useful exercise during surgery to start superiorly with the posterior sinus and the footplate, and move inferiorly, identifying the ponticulus, the sinus tympani, the subiculum, and ending up with the sinus subtympanicum where the round window is located (Fig. 11.7). Inferior to that you can find the hypotympanum that is separated from the sinus subtympanicum by the finiculus (Fig. 11.8). Attic: The attic forms a compartment that is distinct and separate from the mesotympanum both anatomically and in terms of aeration. Attic retraction pocket present often as an isolated finding with normal ventilation and findings within the mesotympanum. The concept of the epitympanic diaphragm had been advocated and advanced by multiple clinicians and histologists and pathologist of the temporal bone.31-33 However, this concept did not make much of an inroad on the clinical side because of the difficulty in communicating and understanding the difficult anatomy. The endoscope allows a much better understanding of the anatomy of the attic and the reason that this area is distinct and separate from the rest of the middle ear in term of ventilation.


Fig. 11.6: Left ear. View of the retrotympanum. (IS: Incudostapedial joint; PE: Pyramidal eminence; PO: Ponticulus; ST: Sinus tympani; SU: Subiculum; RW: Round window).

Fig. 11.7: A schematic drawing of the retrotympanum in a right ear. It is useful to start superiorly at the oval window and move inferiorly: from the posterior sinus, then the sinus tympani, the sinus subtympanicum, and the hypotympanum. (FN: Facial nerve; PR: Promontory; Sty: Styloid prominence; TE: Temen of the round window; P: Ponticulus; SU: Subiculum; JB: Jugular bulb; OW: Oval window; ET: Eustachian tube; PE: Pyramidal eminence; PP: Posterior pillar of round window niche; F: Finiculus; AP: Anterior pillar of round window niche).

The attic is reasonably busy place with the bulk of the ossicular chains and many suspensory ligaments and folds. In the lateral attic, the lateral incudomallear and the lateral mallear folds form a lateral wall that does not allow for ventilation of the attic via the mesotympanum laterally (Fig. 11.9). The anterior part of these lateral folds form the medial wall of Prussak space. The anterior attic is often separated from the anterior mesotympanum and


Fig. 11.8: Left ear. Overview picture of the tympanic cavity with special attention to the retrotympanum. (FN: Facial nerve; SU: Subiculum; SS: Sinus subtympanicus; SE: Styloid eminence; RW: Round window; F: Finiculus; CA: Carotid artery; HC: Hypotympanic air cell; PE: Pyramidal eminence).

Fig. 11.9: Left ear. The lateral attic is closed off from the mesotympanum by the lateral incudomallear ligament (LIML). Please note the relatively straight insertion line of the LIML and the downward sloping insertion line of the lateral mallear ligament (LML).

the eustachian tubes by the tensor tympani folds. There are two main variations in this structure: The first is an almost horizontal orientation where the folds attach to the tensor tendon posteriorly and to the tympanic wall anteriorly, very close to the anterior tympanic spine (Figs 11.10 and 11.11). The second is when the supratubal recess is well developed and when it pushes the folds almost to a vertical position (Fig. 11.12). The attic and the supratubal


Fig. 11.10: Right ear. Poorly developed supratubal recess in a surgical case. Using a 70° endoscope and looking up and backward. The tensor fold in these settings is almost a horizontal structure. (HM: Handle of malleus; TTM: Tensor tympani muscle; TF: Tensor fold; ABA: Anterior bony annulus).

Fig. 11.11: Right ear. Close-up view of the tensor fold seen in Figure 11.32. (TF: Tensor fold; TTM: Tensor tympani muscle bony encasement).

recess are two distinct areas anatomically and developmentally. Anatomically, the supratubal recess is often a smooth walled cavity; in contrast, the attic wall has numerous tags and excrescences. The transverse crest is a semicircular bony ridge that starts at the medial wall of the attic, runs across the roof, and then the lateral wall of the attic marks the border between the tags and excrescences-filled anterior attic and the smooth-walled supratubal recess (Fig. 11.13). Its medial limb starts from the area of the cochleariform


Fig. 11.12: Left ear. The anatomy of the tensor fold in a specimen with a welldeveloped supratubal recess. The tensor fold is composed of two segments, a vertical part that attaches to the COG and a horizontal part that forms a partial floor of the supratubal recess. (STS: Supratubal recess; COG: The surface of Sheehy’s cogs that separates the supratubal recess from the anterior attic; TFA: The vertical segment of the tensor fold that when complete will close off the attic from the eustachian tube; TFB: The horizontal segment of the tensor fold that forms a partial floor of the supratubal recess anteriorly; TTM: Tensor tympani muscle’s bony encasement; CA: Carotid artery; ET: Eustachian tube; HM: Handle of malleus; BA: Bone annulus).

Fig. 11.13: Left ear. The tensor tendon is transected and the handle of the malleus is removed, so was the anterior spine, anterior mallear ligament, and the chorda tympani. Note the distinction between the smooth wall of the supratubal recess and the numerous tags and excrescences of the anterior attic. (COG: Sheehy’s COG; TM: Remnant tensor fold. Single arrows, insertion point of the partially removed vertical segment of the tensor fold; double arrows, insertion point of the completely removed horizontal segment of the tensor fold; STR: Supratubal recess; ET: Eustachian tube; CF: Cochleariform process; 1G: First genue of the facial nerve and neighboring geniculate ganglion; LC: Lateral semicircular canal; TF: Tensor fold).


Fig. 11.14: Intraoperative view from posterior toward the anterior attic in a left ear. (FN: Horizontal segment of the facial nerve; HM: Handle of malleus; CT: The cut edge of the chorda tympani; TT: Tensor tympani tendon; TF: The posterior aspect of the tensor fold; COG: Sheehy’s COG).

process and forms the COG, a commonly recognized surgical term and a bony protrusion on the medial anterior attic wall.34 The tensor fold always inserts more anteriorly than the COG and that leaves a space for the entrapment of cholesteatoma (Fig. 11.14). Developmentally, the middle ear spaces are formed from four pouches or sacs (the saccus anticus, saccus medius, saccus superior, and saccus posticus) that bud out from the eustachian tube.35 The attic is formed from the saccus medius, which divides into three saccules, anterior, medial, and posterior. The supratubal recess maybe formed by the saccus anticus. The anterior saccule of the saccus medius meets the slower growing saccus anticus at the level of the semicanal of the tensor tympani, thus forming the horizontally lined tensor tympani fold. The space thus formed above the tensor fold and anterior to the tensor tendon is the anterior attic compartment.36 Alternatively, the saccus anticus may occasionally extend upward to the tegmen, pushing the tensor fold into an almost vertical position and in the process, forming a well-developed supratubal space.36 The expansion from the bony eustachian tube to form the supratubal recess begins at a late fetal stage and continues throughout childhood.37 By contrast, growth of the tympanic cavity, the attic, and the mastoid antrum is virtually complete by birth.38 In the presence of an intact tensor fold, there is a fully formed diaphragm that separates the attic from the mesotympanum (Fig. 11.15). This diaphragm is formed by the lateral incudomallelar and mallelar folds laterally and the tensor folds anteriorly. The only ventilation port is through the anterior and posterior isthmus. The anterior isthmus is the area in between the


Fig. 11.15: Left ear. The anterior attic is separated from the supratubal recess and the eustachian tube by the tensor fold, so there is no direct communication or ventilation anteriorly between the attic and the eustachian tube.

Fig. 11.16: Left ear. IM, the isthmus forms the only pathway for attic ventilation in the presence of a complete tensor folds; TT: Tensor tympani tendon; ISJ: Incudostapedial joint.

incudostapedial joint and the tensor tympani tendon (Fig. 11.16).32 The posterior isthmus is the area posterior to the incudostapedial joint and is often extremely narrow and has many other structures such as the chorda and the pyramidal eminence. So the anterior isthmus, or the ‘isthmus,’ is the main point of attic ventilation with a very long channel that extends medial to the ossicles and then superior to the ossicles to ventilate the lateral and


Fig. 11.17: Left ear. The incus has been removed to demonstrate the long and narrow channel for ventilation of the attic through the isthmus, medial attic, and the upper attic; (AS: Articular surface of the head of malleus; LC: Lateral semicircular canal; AA: Aditus antrum; CD: Corda tympani; TT: Tensor tympani tendon).

anterior attic (Fig. 11.17). This long channel is also populated by other partial folds and suspensory ligaments that provide other opportunities for impaired ventilation.

Basic techniques and management algorithm There are three basic approaches to the endoscopic management of cholesteatoma that echoes principles and lessons learned from traditional tympanomastoid surgical procedures. These are: (1) ‘transcanal management of limited cholesteatoma,’ (2) ‘open endoscopic management of cholesteatoma,’ and (3) ’extended transcanal approach to cholesteatoma.’ While preoperative planning based on high-resolution CT and endoscopic examination is important, the decision is finally made in the operating room and patients need to understand the range of possible interventions. The first question to be answered is whether the ear canal is an adequate port for the complete removal of cholesteatoma. If the answer is yes, then a wide tympanomeatal flap is elevated, atticotomy performed, sac identified, and pursued along with removal of overhanging bone, basically all the steps involved in ‘endoscopic management of limited cholesteatoma.’ If the answer is no, then the ear canal access is improved through an ‘extended transcanal approach’ by removing the skin and enlarging the canal. Then issue of the mastoid will need to be addressed. A limited cholesteatoma that extends to the aditus antrum can be completely removed through a transcanal approach. If the mastoid is involved, then a decision needs to be made whether the disease will be addressed through a postauricular


Fig. 11.18: The management algorithm for endoscopic transcanal management of cholesteatoma.

mastoidectomy or whether it will be exteriorized by ‘endoscopic open cavity management of cholesteatoma’ with aggressive bone removal superiorly and posteriorly all the way to the mastoid cavity proper (see Fig. 11.18)

Endoscopic Transcanal Management of Limited Cholesteatoma The attic (especially its anterior part) is poorly visualized via traditional approaches. An endoscopic approach enables the surgeon to retrace the sac, starting from the mesotympanum and continuing through its twists and turns around the ossicles and ligaments. This improved access also facilitates the better preservation of the ossicles while ensuring the complete removal of the matrix in toto rather than piecemeal and through different access ports.

Technique A wide posterior tympanomeatal flap is elevated. The sac is then pursued under direct vision, and the bony rim is curetted or drilled just enough to enable dissection to continue under direct vision. Appropriate ossicular chain work is performed, and the attic defect is closed by means of a composite tragal graft.


Results Seventy-three ear procedures were performed on the 69 patients; 65 of those individuals underwent unilateral surgery. The results of preoperative CT scanning of the temporal bone, which was performed in 46 ears, suggested cholesteatoma with the presence of bony erosion in 26 ears. Seven ears showed evidence of total opacification of the middle ear and mastoid air cells (without bone erosion), and isolated opacification of the middle ear and attic was evident in 11 ears. The results of audiologic testing showed an air-bone gap of 20 dB or more in 51 ears. The transcanal endoscopic approach was adequate for the removal of disease in all patients. There were no iatrogenic facial nerve injuries. Bone thresholds were stable; i.e. no change of 10 dB or more was noted in average bone conduction thresholds at 500, 1000, 2000, or 3000 Hz. In 24 ears, the cholesteatoma was dissected from the malleus head and the body of the incus, both of which were preserved. The incus or its remnant was removed in 49 ears, and the head of the malleus was removed in 43 ears. Primary ossicular reconstruction was performed in 38 ears and was delayed in 17 ears. Follow-up was performed at 43 months, on average. Revision for recurrent and clinically evident disease was performed on 5 ears. In 8 ears, a revision procedure was performed to correct a failed ossicular reconstruction or a persistent perforation. In one of those reconstruction failures, a small incidental pearl attached to the underlayer of the tympanic membrane was noted. Moderate-to-severe retraction in other areas of the tympanic membrane was evident in 28 patients, none of whom required further intervention.

Case History A 46-year-old male patient presents with a long-standing history of problems. Initial evaluation showed severe retraction bilaterally and some granulation tissue and drainage from the right ear. After a week of medical treatment, his right ear showed clear evidence of severe retraction and debris within the cholesteatoma sac (Fig. 11.19). An endoscopic transcanal approach was undertaken, a wide tympanomeatal flap was elevated, and the middle ear was entered (Fig. 11.20). A wide atticotomy was performed with a curette (Fig. 11.21). The cholesteatoma sac was identified; it extended to the lateral attic and was pulled downward laterally to the body of the incus and medially to the removed scutum (Fig. 11.22). Another process of the sac had rotated posteriorly and medially around the incudostapedial joint and the superstructure of the stapes and had advanced medially to the long process of the incus (Fig. 11.23). The sac was pulled out completely and was deflected (Fig. 11.24). It was evident that the sac had eroded the incudostapedial joint (Fig. 11.25). A prosthesis was used to reconstruct the ossicular chain (Fig. 11.26). A piece of tragal composite graft with excess perichondrium


Fig. 11.19: Right ear. Note the retraction and cholesteatoma. H: Handle of malleus.

Fig. 11.20: Right ear. The tympanomeatal flap has been elevated, the middle ear has been entered, and the cholesteatoma sac has been exposed. (C: Chorda tympani; S: Cholesteatoma sac; A: Annulus; R: Round window).

was used to reconstruct the attic defect (Fig. 11.27). The tympanic membrane defect was reconstructed with a perichondrial underlay graft, and the tympanomeatal flap was repositioned (Fig. 11.28). The patient experienced an uneventful postoperative course. One month after the procedure, his tympanic membrane was intact, his hearing was good, and he returned to duty.

Endoscopic Open Cavity Management of Cholesteatoma In canal wall down procedures, which have been viewed as the definitive treatment of cholesteatoma, all disease-containing cavities are exteriorized to


Fig. 11.21: Right ear. A wide atticotomy is performed with a curette.

Fig. 11.22: Right ear. The sac (S) has been pulled down from the attic, lateral to the body of the incus and medial to the scutum. The body of the incus (I) can be seen. The chorda (C) forms a collar around the neck of the sac.

provide natural aeration and direct access to the disease in the clinic setting. However, during the process of accessing the disease, large problematic cavities that require lifelong maintenance are created. In addition, unpredictable healing patterns, fibrosis, and closing of the meatus, which are common complications associated with postauricular canal wall down procedures, often prevent further ossicular reconstruction. Endoscopic techniques allow transcanal exploration of the disease-containing cavities without opening up areas that are not involved in the cholesteatoma. Such techniques enable the surgeon to approach and reconstruct the ear in a highly predictable fashion.


Fig. 11.23: Right ear. The sac has been completely pulled down from the area lateral to the body of the incus (I), but another process of the sac (S) has rotated posteriorly and medially around the incudostapedial joint and medial to the long process of the incus (L). A cuffed forceps (F) is used to pull the sac from underneath the chorda (C).

Fig. 11.24: Right ear. The sac (S) has been completely pulled out and deflected over the tympanomeatal flap with the incus (I) and the chorda (C) in view.

This in turn creates a better framework for ossicular and partial tympanic membrane reconstruction. The transcanal endoscopic approach opens up only diseased areas, preserves many healthy air cells, and leaves the cortical bone intact. It also allows for the creation of two independent cavities; the small reconstructed tympanic cavity that conducts sound in the middle ear and that is small


Fig. 11.25: Right ear. The sac is removed. The cholesteatoma has eroded the incudostapedial joint (I-S). The incus (I), the chorda (C), and the promontory (P) are clearly in view. The anterior edge of the tympanic membrane retraction (T), now a perforation, is also visible.

Fig. 11.26: Right ear. A prosthesis (A) is used to reconstruct the incudostapedial joint. The handle of the malleus (M) and the incus (I) and chorda (C) are visible.

enough to be serviced by the usually dysfunctional eustachian tube, and the larger attic, antrum, and mastoid cavities, which are joined to the ear canal and are exteriorized (Fig. 11.29). Such an approach was described by Tos in 1982.27 The main concern of many surgeons is the possibility of closing the open attic. That concern is driven by the results of traditional open surgery of the mastoid, in which damage to the cartilaginous portion of the ear canal


Fig. 11.27: Right ear. The attic defect is reconstructed by means of a composite tragal graft (G) with excess perichondrium to prevent retraction around the graft.

Fig. 11.28: Right ear. The tympanomeatal flap is repositioned over an underlay graft (UG) to reconstruct the retracted area of the tympanic membrane.

produces a vicious circle: Trauma to the ear canal results in fibrosis and narrowing of the meatus, which forces the surgeon to design a more aggressive meatoplasty, which in turn results in more trauma, secondary fibrosis, and narrowing. A huge meatus must be created to compensate for that eventual fibrosis and narrowing. In contrast, the very limited trauma to the cartilaginous ear canal caused by endoscopic surgery allows surgeons to avoid those complications and results in a small, shallow, benign, problem-free cavities.


Fig. 11.29: Coronal computed tomographic views of a patient who underwent a left ear endoscopic open cavity management of a cholesteatoma. Compare the normal ear with the left operated ear. The neotympanic membrane (NT) is recons tructed up to the level of the horizontal segment of the facial nerve (FN), and the attic is left open (OA).

Technique In the endoscopic open cavity management of cholesteatoma, the wide posterior tympanomeatal flap is elevated as described above. A transcanal atticotomy is performed. The attic is then emptied from the incus and the head of the malleus. Aggressive bone removal is then performed to provide open endoscopic access into the attic and all the way posteriorly into the antrum. Tympanic membrane defects inferior to the horizontal segment of the facial nerve (including atelectatic areas) are reconstructed with a perichondrial graft, which is placed directly on and up to the horizontal segment of the facial nerve superiorly and on a bed of Gelfoam that is packed in the middle ear inferiorly. The ear canal and the open attic are then packed with Gelfoam. This technique should result in a small, closed, reconstructed tympanic cavity and membrane anteriorly and inferiorly (to service the impedance-matching function of the middle ear) and an open attic and antrum posteriorly and superiorly (Fig. 11.29).

Results Eighty-five ear procedures were performed on 78 patients. There were no iatrogenic facial nerve injuries. Bone thresholds were stable (‘stability’ was defined as no change of 10 dB or more in average bone-conduction thresholds at 500, 1000, 2000, and 3000 Hz) except in 1 patient who presented preoperatively with depressed bone thresholds, vertigo, and a perilymphatic fistula. The mean follow-up was 32 months. Closure of the air-bone gap to within 20 dB was accomplished in 47 ears. Six ears required revision surgery, Four of the surgical failures resulted from complete closure of the open attic by a growth of overlying skin rather than by a step-by-step narrowing of


Fig. 11.30: Left ear. A large retraction pocket (RP) with evidence of recurrent prior episodes of infections and the formation of granulation tissue. (HM: Handle of the malleus; TM: Tympanic membrane).

Fig. 11.31: Left ear. A wide tympanomeatal flap is elevated. The premonitory (P) and the incudostapedial joint (I) can be seen. A curette is used (C) to create the extended atticotomy.

the atticotomy. This complication was usually evident early in the postoperative course and was managed by re-excising the overlying skin in a simple procedure.

Case History A 41-year-old patient presents with retraction pocket and recurrent granulation tissue. Figure 11.30 shows the large attic retraction pocket after it was


Fig. 11.32: Left ear. Note the extended atticotomy at the thick sac (S), the chorda tympani (C), and the incudostapedial joint (I).

Fig. 11.33: Left ear. The incudostapedial joint (LI) is dislocated with a small round knife (K). C: Chorda tympani.

emptied of dermal debris. A wide tympanomeatal flap was elevated, and the thick vascularized sac can be seen after the atticotomy was extended (Figs 11.31 and 11.32). The incus and the head of the malleus were removed after the incudostapedial joint was dislocated (Figs 11.33 and 11.34). The anterior epitympanum was cleared of all disease. The remainder of the sac deep to the removed ossicles was removed after further widening of the atticotomy (Fig. 11.35). All diseases were excised, and specific attention was paid to the attic and the tympanic cavity (Fig. 11.36). A prosthesis was used


Fig. 11.34: Left ear. The incus has been removed, and the head of the malleus (HM) is extracted. Note that the head of the malleus is separated from the handle by means of a malleus nipper at a proximal site to preserve the ligaments stabilizing the handle of malleus. (S: Stapes; C: Chorda tympani).

Fig. 11.35: Left ear. The thick sac (S) is being pulled with an alligator forceps (A). (C: Chorda tympani).

to reconstruct the ossicular chain (Fig. 11.37), and a composite cartilage graft was positioned on top of the prosthesis (Fig. 11.38). The tympanomeatal flap was divided longitudinally (Fig. 11.39). The inferior part was repositioned over the ear canal, the superior part was draped over the horizontal segment of the facial nerve (Fig. 11.40), and the attic was packed open.


Fig. 11.36: Left ear. The sac has been removed completely. (A: Attic; P: Promontory; C: Chorda tympani; St: Stapes; LS: Lateral semicircular canal).

Fig. 11.37: The ossicular chain is reconstructed with the use of a prosthesis (P). (C: Chorda tympani; S: Suction).

Expanded Transcanal Access to Middle Ear and Petrous Apex Although the use of the endoscope allows much expanded transcanal access to the middle ear when compared with the microscope, the ear canal in some patients can be very limiting in size and angulation as not to allow for adequate exposure. Addressing these limitations prior to addressing the disease is essential for performing adequate and safe endoscopic procedures. Also, this approach would provide wide access to disease within the anterior middle ear, eustachian tube, and the petrous bone.


Fig. 11.38: Left ear. Composite tragal cartilage (CG) is used on top of the prosthesis.

Fig. 11.39: Left ear. The tympanomeatal flap (TMF) is cut longitudinally with middle ear scissors (S: Middle ear scissors).

Technique After evaluation of the limiting elements in the ear canal in relation to location of the disease, a decision is made on whether to address these limitations. The location of disease and its extent are determined by endoscopic examination and review of CT of the temporal bone. Anterior middle ear, eustachian tube, and significant disease within the hypotympanum will often require an expanded transcanal approach. When enlarging the ear canal, the surgeon needs to be keenly aware of critical structures that lie in close


Fig. 11.40: Left ear. The inferior part of the tympanomeatal flap (TMF-B) is repositioned over the ear canal, while the superior part of the tympanomeatal flap (TMF) is reflected over the horizontal segment of the facial nerve into the open attic (A). Small pieces of Gelfoam (GF) are used to pack the open attic and ear canal. (TM: Tympanic membrane).

Fig. 11.41: Structures to be considered when enlarging the ear canal.

proximity (Fig. 11.41). The bony annulus, the line separating the ear canal from the middle ear, has tremendous variations39 and one should think of all structures that border the tympanic cavity proper when enlarging the ear canal. Posteriorly, the facial nerve and an anterior sigmoid should be considered.40 Inferiorly, a high jugular bulb can come lateral and borders the ear


Fig. 11.42: Right ear with an anterior whitish lesion behind an intact tympanic membrane.

canal.41 Breaching the glenoid fossa anteriorly is usually a none event, but it can present a limiting factor. The technique echoes that of Sheehy’s lateral graft tympanoplasty. The skin of the ear canal removed along with the epithelial layer of the tympanic membrane and the vascular strip preserved. The ear canal would be enlarged as needed. Then the annulus and fibrous layer of the tympanic membrane is elevated either completely or partially to provide access to the areas of interest. Then all overhanging bony annulus is curetted and wide access to the middle ear is gained for removal of any disease. After the necessary ossicular chain work, the remaining part of the tympanic membrane is repositioned and a lateral graft is applied and the skin of the ear canal is repositioned and packed in place.

Case Presentation A 36-year-old male presents with long standing history of right hearing loss and dizziness. Examination showed an anterior whitish lesion behind the tympanic membrane (Fig. 11.42). Audiometry indicated a dead ear on the right normal hearing in the left. CT of the temporal bone showed extensive petrous bone cholesteatoma eroding the cochlea and the carotid artery (Fig. 11.43). Using the ‘expanded transcanal access’ technique, the vascular strip is preserved, the ear canal skin is removed, the fibrous layer of the tympanic membranes is preserved, and the ear canal is then enlarged (Fig. 11.44). The extensive cholesteatoma has eroded the bony encasement of the sinus tympani muscle and carotid and had eroded the middle and apical turns of the cochlea (Fig. 11.45). The cholesteatoma was completely removed from the apex of the petrous bone (Fig. 11.46).


Fig. 11.43: Right ear. Axial computed tomographic images of the temporal bone. (CO: Basal turn of the cochlea; CA: Carotid artery; CH: Cholesteatoma).

Fig. 11.44: Right ear. The skin of the ear canal is elevated in contiguity with the epithelial layer of the tympanic membrane with preservation of the vascular strip and then the enlargement of ear canal. (VS: Vascular strip; FLTM: Fibrous layer of tympanic membrane; CH: Cholesteatoma).

Transcanal transpromontorial exclusive endoscopic approach This endoscopic approach allows eradication of pathologic matter involving petrous apex,41,42 internal ear canal fundus,43 with extension limited to the intracochlear, intravestibular, and pericartoid regions. If the pathologic condition involves the mastoid, an exclusive approach is not feasible.


Fig. 11.45: Right ear. Much of the cholesteatoma eroding the cochlea had been removed. (MAL: Malleus with the handle transected; SFP: Stapes footplate; CO: The eroded middle turn of the cochlea; CA: Eroded carotid artery canal; CH: Cholesteatoma in the petrous apex surrounding the TT (tensor tympani) muscle).

Fig. 11.46: Right ear. The view after complete removal of cholesteatoma; (PA: Petrous apex; CA: Carotid artery; CO: Eroded middle turn of cochlea; FN: Dehiscent facial nerve; SFP: Stapes footplate; PR: Promontory).

• •

Possible indications are as follows: Mesotympanic cholesteatomas with medial extension toward inner ear structures Cholesterol granulomas of the petrous apex –– Small symptomatic or growing acoustic neuromas with exclusive extension to internal ear canal fundus


•

Cochlear schwannomas with or without internal ear canal fundus extension • Facial nerve schwannomas involving timpani tract and geniculate ganglion. Clinical application of this approach is currently limited, although preliminary experiences and results following initial attempts are promising.43,44 Even indications for surgery in some of the pathologic conditions treated by these approaches could change in the future as a result of these minimally invasive operations, compared with the extensive demolition that microscopic techniques require.45

Preliminary Surgical Steps Using a transcanal endoscopic approach, a circumferential incision of the external ear canal skin is made approximately 3 cm from the annulus by a 0° optic. Tympanic membrane and external ear canal skin are then removed en bloc to obtain the widest exposition of the middle ear. Using a 0° endoscope, a circumferential drilling is made to further increase the view and to facilitate maneuvering of surgical instruments. Next, it is fundamental to identify the great vessels that have close relationships to the middle ear (i.e. the jugular bulb and carotid artery). The first is found at the level of hypotympanum and the second at the level of protympanum, close to the eustachian tube. In some cases, an extensive drilling at those levels is required; in other cases the vessels are clearly identified without drilling any bony tissue. Next, the ossicular chain is removed by disarticulation of the incus, the head of the malleus, the tensor tympani tendon at the level of the cochleariform eminence, and the malleus. This allows the surgeon better access to the tympani tract of the facial nerve, to the geniculate ganglion region, and to the greater petrosal nerve, which is located anteriorly.46 The tympanic tract of the facial nerve and the greater petrosal nerve are then skeletonized. The cochleariform process should be removed, uncovering the underlying tensor tympani muscle. This step could be performed in a posterior to anterior direction using a microcurette because the bone at this level is very thin. In some cases, the muscle needs to be cauterized due to the bleeding that these procedures might provoke. When cauterizing, pay attention to the proximity of the geniculate ganglion at this level. Once the tensor tympani canal has been removed, dissection of the muscle itself is done, displacing it anteriorly. In this way an adequate space is achieved to enable surgery directed to the geniculate ganglion and greater petrosal nerve. The relationship between the superior and lateral border of the tensor tympani canal and the facial nerve (in particular the geniculate ganglion in its posterior and inferior aspect) is apparent (Figs 11.47 to 11.49). If the pathologic matter extends anteriorly to the pericartoid region, an increased skeletonization of the greater petrosal nerve should be made in


A

B

C Figs 11.47A to C


D Figs 11.47A to D: After removal of all of the eardrum with the meatal skin flap of the EAC, a good control of the tympanic cavity was achieved. (CT: Chorda tympani; DR: Eardrum; Ma: Malleus; In: Incus; Fn: Facial nerve; S: Stapes; LSC: Lateral semicircular canal; RW: Round window).

A

B Figs 11.48A and B


C

D Figs 11.48A to D: The cochleariform process and the bony wall of the semicanal of the tensor tendon were removed with a curette, uncovering the tensor tympani muscle. (ET: Eustachian tube; PR: Promontory; S: Stapes; FN: Facial nerve; RW: Round window; LSC: Lateral semicircular canal; TTC: Tensor tympani canal; TTM: Tensor tympani muscle; MCF: Middle cranial fossa).

A Fig. 11.49A


B

C

D Figs 11.49A to D: The tensor tympani muscle was transposed anteriorly: this procedure allowed a direct endoscopic view of the geniculate ganglion and great petrous nerve (A); the carotid artery was detected drilling just inferiorly with respect the eustachian tube (B and C); the carotid artery and the jugular bulb ware so exposed (D). (Et: Eustachian tube; pr: Promontory; S: Stapes; fn: Facial nerve; rw: Round window; lsc: Lateral semicircular canal; ttm: Tensor tympani muscle; mcf: Middle cranial fossa; pe: Pyramidal eminence; gg: Geniculate ganglion; gpn: Great petrosal nerve).

222 Recent Advances in Otolaryngology—Head and Neck Surgery a posterior to anterior direction, by also identifying the dura of the middle cranial fossa, which at this level is situated very close to the geniculate ganglion. The greater petrosal nerve represents a fundamental landmark for this procedure, because it has an almost parallel course to the horizontal tract of the carotid artery. If the lesion has an intracochlear or intravestibular extension with or without extension to the fundus of internal ear canal, the identification of the labyrinthine tract of the facial nerve should be performed. The nerve should be followed from geniculate ganglion to its entry into the internal auditory canal with either a transvestibular or a transcochlear approach. The choice of the approach will depend on which lesion is being removed and, in particular, will depend on the internal auditory canal involvement and the bone erosion provoked by the pathologic state.

Transvestibular approach A transvestibular approach is indicated in cases of lesions from the tympanic cavity that cause a wide erosion of the cochlea and vestibule, creating communication with the internal ear canal fundus, and lesions coming from the internal auditory canal fundus with or without cochlear involvement (e.g. small acoustic neuromas from the fundus or cochlear schwannomas). The stapes is removed from the oval window to expose the internal ear spaces at this level (Figs 11.50A to D). The oval window is enlarged in anterior and inferior direction to obtain a good exposition of the medial aspect of the bony labyrinth. The saccular fossa is identified, with the spherical recess, which is the site of medial termination of the inferior vestibular nerve. The spherical recess is a thin cribriform plate that separates vestibule from internal auditory canal fundus and this bony layer is removed by a micro curette (Figs 11.51A to D). This step allows access to the internal auditory canal, with possible consequent cerebrospinal fluid (CSF) outflow. Next, the facial nerve can be identified at the level of internal auditory canal, which lays close to the spherical recess, approximately 1 mm anteriorly and medially. The cochlear nerve lays inferiorly compared with the facial nerve, which terminates in the modiolus. Once the intrameatal portion of the nerve has been identified, the identification of the intralabyrinthine tract of the nerve must be completed, and dissection of it is made in a anterior and superior direction following the facial nerve into the internal auditory canal to the geniculate ganglion. Before this step, identification of the middle turn of the cochlea is suggested. Because it lies close to the vestibule anteriorly, it could represent an important landmark for the identification of the intralabyrinthine tract of facial nerve, which runs just above this structure. Another important consideration is the characteristics of the intralabyrinthine portion of the facial nerve: this tract is thin and more fragile than the other tracts of the same nerve and it is covered by a thick bony layer.


A

B

C Figs 11.50A to C


D Figs 11.50A to D: The stapes was removed opening the vestibule, and the medial wall of the vestibule was investigated endoscopically. (PR: Promontory; S: Stapes; FN: Facial nerve; RW: Round window; LSC: Lateral semicircular canal; MCF: Middle cranial fossa; PE: Pyramidal eminence; GG: Geniculate ganglion; GPN: Great petrosal nervel; OW: Oval window; PSC: Posterior semicircular canal; SPH: Spherical recess; CA: Carotid artery).

A

B Figs 11.51A and B


C

D Figs 11.51A to D: The bony wall around the oval window was removed with a curette, uncovering the medial wall of the vestibule (A and B), the spherical recess was exposed (C); a diamond bur is used anteriorly with respect the vestibule in order to detect the upper portion of the cochlea (D). (PR: Promontory; S: Stapes; FN: Facial nerve; RW: Round window; LSC: Lateral semicircular canal; MCF: Middle cranial fossa; PE: Pyramidal eminence; GG: Geniculate ganglion; GPN: Great petrosal nerve; OW: Oval window; SPH: Spherical recess; JB: Jugular bulb).

For these reasons, the authors prefer to use Piezosurgery dissection during those steps. The dissection substantiates following the nerve toward the internal auditory canal in an anterior and superior direction, removing the bone over the basal turn of the cochlea where the intralabyrinthine tract reaches the geniculate ganglion. Finally, the whole facial nerve can be visua lized and the possible pathologic tissue can be removed while preserving the facial nerve structure.

Transcochlear approach The transcochlear approach has the advantage of the absence of internal auditory canal opening, avoiding CSF outflow. This approach is preferred in

226 Recent Advances in Otolaryngology—Head and Neck Surgery cases of lesions originating from the tympanic cavity, with a medial extension to the cochlea and/or vestibule without internal auditory canal fundus involvement, or of lesions originating from the timpani cavity with intracochlear and pericartoid extension, or even in cases of facial nerve schwannomas. Nerve dissection is verified by an anatomic triangle identification between the middle turn of the cochlea, geniculate ganglion, and vestibule. The stapes is removed, followed by identification of the vestibule through the oval window. Then, a promontory drilling is made anteriorly to the vestibule and inferiorly to the geniculate ganglion (Figs 11.52A to D). This step allows the access to the middle turn of the cochlea, which represents a landmark for the intralabyrinthine tract of the facial nerve (Figs 11.53 and 11.54). As mentioned above, this part of the facial nerve runs just above the cochlea, with a transverse direction from lateral to medial from geniculate ganglion to the internal auditory canal fundus. This is followed by

A

B Figs 11.52A and B


C

D Figs 11.52A to D: Drilling just anteriorly to the vestibule on the promontory region was performed, looking for the basal turn of the cochlea (A, B). The identification of an anatomic triangle (yellow triangle) between the geniculate ganglion superiorly, the basal turn of the cochlea anteriorly and the spherical recess (IAC) posteroinferiorly (C, D). (pr: Promontory; S: Stapes; fn: Facial nerve; rw: Round window; lsc: Lateral semicircular canal; mcf: Middle cranial fossa; pe: Pyramidal eminence; gg: Geniculate ganglion; gpn: Great petrosal nerve; ow: Oval window; sph: Spherical recess; chO: Choclea).

removal, using Piezosurgery instruments, of the bony tissue laying between cochlea anteriorly and inferiorly, the geniculate ganglion anteriorly and superiorly, and the vestibule posteriorly and inferiorly (the latter representing the base of the triangle). Bone removal should be done very gently to avoid damage to the nerve itself, which at this level is very fragile and thin. Dissection should be done carefully, where the nerve penetrates into the internal auditory canal, trying to avoid dural tearing at this level and/ or creating communications with the internal auditory canal fundus. This approach allows the complete control of the facial nerve in its tympanic tract,


A

B

C Figs 11.53A to C


D Figs 11.53A to D: Opening the fundus of the IAC, a direct view of the intrameatal tract of the facial nerve was obtained. (pr: Promontory; S: Stapes; fn: Facial nerve; rw: Round window; mcf: Middle cranial fossa; pe: Pyramidal eminence; gg: Geniculate ganglion; gpn: Great petrosal nerve; ow: Oval window; sph: Spherical recess; chO: Choclea; FN**: Intrameatal tract of the facial nerve; FN*: Labirinthine tract of the facial nerve).

A

B Figs 11.54A and B


C

D Figs 11.54A to D: Once the entire control of the first and second portions of the facial nerve had been obtained, the promontory was drilled until the cerebellopontine angle was wide open. (pr: Promontory; S: Stapes; FN: Facial nerve; rw: Round window; mcf: Middle cranial fossa; lsc: Lateral semicircular canal; pe: Pyramidal eminence; gg: Geniculate ganglion; gpn: Great petrosal nerve; ow: Oval window; sph: Spherical recess; cho: Choclea; iac: Internal auditory canal; FN**: Intrameatal tract of the facial nerve; FN*: Labirinthine tract of the facial nerve; ***: Falciform crest).

geniculate ganglion, greater petrosal nerve, and labyrinthine tract of the nerve. The pathologic tissue can be removed safely and further bone removal is made based on the pathologic condition. At the end of the surgical procedure, in case a communication with intradural spaces was created, some adipose tissue should be placed in the region of CSF leak. It is necessary to close the external auditory canal, Otherwise, a reconstruction with cartilage or fascia of the can be considered.


Conclusion The story of endoscopic management of cholesteatoma is that of the rediscovering of the ear canal as the most logical, direct, and natural access point to the tympanic cavity and beyond.

References 1. Thomassin JM, Korchia D, Doris JM. Endoscopic-guided otosurgery in the prevention of residual cholesteatomas. Laryngoscope. 1993;103:939–43. 2. Hawke M. Telescopic otoscopy and photography of the tympanic membrane. J Otolaryngol. 1982;11:35–9. 3. Nomura Y. Effective photography in otolaryngology-head and neck surgery: endoscopic photography of the middle ear. Otolaryngol Head Neck Surg. 1982;90:395–8. 4. Takahashi H, Honjo I, Fujita A, et al. Transtympanic endoscopic findings in patients with otitis media with effusion. Arch Otolaryngol Head Neck Surg. 1990;116:1186–9. 5. Poe DS, Bottrill ID. Comparison of endoscopic and surgical explorations for perilymphatic fistulas. Am J Otol. 1994;15:735–8. 6. McKennan KX. Endoscopic ‘second look’ mastoidoscopy to rule out residual epitympanic/mastoid cholesteatoma. Laryngoscope. 1993;103:810–4. 7. Tarabichi M. Endoscopic management of acquired cholesteatoma. Am J Otol. 1997;18:544–9. 8. Tarabichi M. Endoscopic middle ear surgery. Ann Otol Rhinol Laryngol. 1999;108:39–46. 9. Tarabichi M. Endoscopic management of cholesteatoma: long-term results. Otolaryngol Head Neck Surg. 2000;122:874–81. 10. Tarabichi M. Endoscopic management of limited attic cholesteatoma. Laryngoscope. 2004;114:1157–62. 11. Kakehata S, Futai K, Sasaki A, et al. Endoscopic transtympanic tympanoplasty in the treatment of conductive hearing loss: early results. Otol Neurotol. 2006;27(1):14–9. 12. Kakehata S, Hozawa K, Futai K, et al. Evaluation of attic retraction pockets by microendoscopy. Otol Neurotol. 2005;26(5):834–7. 13. Kakehata S, Futai K, Kuroda R, et al. Office-based endoscopic procedure for diagnosis in conductive hearing loss cases using OtoScan Laser-Assisted Myringotomy. Laryngoscope. 2004l;114(7):1285–9. 14. Badr-el-Dine M. Value of ear endoscopy in cholesteatoma surgery. Otol Neurotol. 2002;23:631–5. 15. El-Meselaty K, Badr-El-Dine M, Mandour M, et al. Endoscope affects decision making in cholesteatoma surgery. Otolaryngol Head Neck Surg. 2003; 129:490–96. 16. Yung MW. The use of middle ear endoscopy: has residual cholesteatoma been eliminated? J Laryngol Otol. 2001;115:958–61.

232 Recent Advances in Otolaryngology—Head and Neck Surgery 17. Ayache S, Tramier B, Strunski V. Otoendoscopy in cholesteatoma surgery of the middle ear. What benefits can be expected? Otol Neurotol. 2008;29(8):1085–90. 18. Abdel Baki F, Badr-El-Dine M, El Saiid I, et al. Sinus tympani endoscopic anatomy. Otolaryngol Head Neck Surg. 2002;127:158–62. 19. Mattox DE. Endoscopy-assisted surgery of the petrous apex. Otolaryngol Head Neck Surg. 2004;130:229–41. 20. Magnan J, Sanna M. Endoscopy in neuro-otology. Stuttgart: Georg Thieme Verlag, 2003. 21. Badr-El-Dine M, El-Garem HF, Talaat AM, et al. Endoscopically assisted minimally invasive microvascular decompression of hemifacial spasm. Otol Neurotol. 2002;23:122–8. 22. El-Garem HF, Badr-El-Dine M, Talaat AM, et al. Endoscopy as a tool in minimally invasive trigeminal neuralgia surgery. Otol Neurotol. 2002;23:132–5. 23. Badr-El-Dine M, El-Garem HF, El-Ashram Y, et al. Endoscope assisted minimal invasive microvascular decompression of hemifacial spasm. Abstracts of the 9th International Facial Nerve Symposium. Otol Neurotol Suppl. 2002;23(3): 68–72. 24. Rosenberg SI, Silverstein H, Willcox TO, et al. Endoscopy in otology and neurotology. Am J Otol. 1994;15:168–72. 25. Presutti L, Marchioni D, Mattioli F, et al. Endoscopic management of acquired cholesteatoma: our experience. Otolaryngol Head Neck Surg. 2008;37(4):1–7. 26. Marchioni D, Mattioli F, Ciufelli MA, et al. Endoscopic approach to tensor fold in patients with attic cholesteatoma. Acta Otolaryngol. 2008;19:1–9. 27. Tos M. Modification of combined-approach tympanoplasty in attic cholesteatoma. Arch Otolaryngol. 1982;108:772–8. 28. Sheehy JL, Brackmann DE, Graham MD. Cholesteatoma surgery: residual and recurrent disease. A review of 1,024 cases. Ann Otol Rhinol Laryngol. 1977;86:451–62. 29. Glasscock ME, Miller GW. Intact canal wall tympanoplasty in the management of cholesteatoma. Laryngoscope. 1976;86:1639–57. 30. Kinney SE. Five years experience using the intact canal wall tympanoplasty with mastoidectomy for cholesteatoma: preliminary report. Laryngoscope. 1982;92:1395–400. 31. Chatellier HP, Lemoine J. Le diaphragme interattico-tympanique du612 nouveau-né. Description de sa morphologie considérations sur son role613 pathogénique dans les otomastoidites cloisonnées du nourisson. Ann614 Otolaryngol Chir Cervicofac (Paris) 1945;13:534–66. 32. Aimi K. The tympanic isthmus: its anatomy and clinical significance. Laryngoscope. 1978;88(7 Pt 1):1067–81. 33. Palva T, Ramsay H. Incudal folds and epitympanic aeration. Am J Otol. 1996;17:700–8. 34. Palva T, Ramsay H, Böhling T. Tensor fold and anterior epitympanum. Am J Otol. 1997;18:307–16. 35. Hammar JA. Studien Uper Die Entwicklung Des Vorderdarms und Einiger Angrenzenden Organe. Arch Mikroskop Anat. 1902;59:471–628.

Endoscopic Ear Surgery 233 36. Proctor B. The development of the middle ear spaces and their surgical significance. J Laryngol Otol. 1964;78:631–48. 37. Tono T, Schachern PA, Morizono T, et al. Developmental anatomy of the supratubal recess in temporal bones from fetuses and children. Am J Otol. 1996;17:99–107. 38. Schuknecht HF, Gulya AJ. Anatomy of the temporal bone with surgical implications. Philadelphia, PA: Lea & Febiger; 1986:89–90. 39. Adad B, Rasgon BM, Ackerson L. Relationship of the facial nerve to the tympanic annulus: a direct anatomic examination. Laryngoscope. 1999;109:1189–92. 40. Gangopadhyay KP, McArthur D, Larsson SG. Unusual anterior course of the sigmoid sinus: report of a case and review of the literature. J Laryngol Otol. 1996;110:984–6. 41. Moore PJ. The high jugular bulb in ear surgery: three case reports and a review of the literature. J Laryngol Otol. 1994;108:772–5. 42. Marchioni D, Alicandri-Ciufelli M, Mattioli F, et al. From external to internal auditory canal: surgical anatomy by an exclusive endoscopic approach. Eur Arch Otorhinolaryngol. 2013;270(4):1267–75. 43. Marchioni D, Alicandri-Ciufelli M, Gioacchini FM, et al. Transcanal endoscopic treatment of benign middle ear neoplasms. Eur Arch Otorhinolaryngol. 2013;270(12):2997–3004. 44. Presutti L, Alicandri-Ciufelli M, Cigarini E, et al. Cochlear schwannoma removed through the external auditory canal by a transcanal exclusive endoscopic technique. Laryngoscope. 2013 Apr 1:2862–7. doi: 10.1002/lary.24072. 45. Presutti L, Nogueira JF, Alicandri-Ciufelli M, et al. Beyond the middle ear: endoscopic surgical anatomy and approaches to inner ear and lateral skull base. Otolaryngol Clin North Am. 2013;46(2):189–200. 46. Marchioni D, Alicandri-Ciufelli M, Piccinini A, et al. Surgical anatomy of transcanal endoscopic approach to the tympanic facial nerve. Laryngoscope. 2011;121(7):1565–73.


Chapter

Some Mechanical Aspects of Implant Coupling

12

Albrecht Eiber, Markus HF Pfister

Introduction From an engineer’s point of view, the hearing organ is a very impressive sensor for filtering information out from sound waves in the air. Humans are able to select a specific speaker’s voice from a loud background noise, to cover a tremendously broad range of loudness leading to logarithmic scales or to hear in surroundings with extremely different static pressure. Binaural hearing facilitates the spatial detection of a sound source. Unfortunately, such excellent sensors are particularly vulnerable. Within the multitude of diseases and malformations, those concerning the middle ear that can be reconstructed by ossiculoplasty are of specific interest. A very broad spectrum of passive and of active middle ear implants are on the market and it is difficult for the surgeon to select an appropriate one for surgery. Various factors have to be taken into account to answer this question. Among others, such as the particular diagnosis, the disease itself and the condition of the patient, the skill and experience of the surgeon, the specific instruments in use; and often briskly and controversy discussed, the design and function of the implant itself. All these factors are interconnected to each other and have to be carefully weighted by the surgeon to make an optimal choice. A purposive choice of an implant and its appropriate insertion may be facilitated by considering the mechanical properties and function of the hearing process itself, of the impairment, of the prosthesis design, and of the insertion process. Some of these aspects will be addressed from a mechanical point of view to enlighten the mechanical principles behind. It is not the intention to assess or to compare the implants available on the market.

Mechanics of middle ear Mechanics is a part of physics in which statics is dealing with relationships between forces and deformations and kinetics is dealing with relationships between forces and motions. Specific interests in statics are focused on static equilibrium and static deformations of solid bodies like beams and

Some Mechanical Aspects of Implant Coupling 235

membranes or of fluids. In the dynamical part, the focus is on the motions of a solid body or systems of it in all three dimensions of space due to imposed forces or torques. This is a challenging task because the bodies are in interaction due to kinematical constraints or forces. Specific types of these motions are the vibrations that can be linear or nonlinear, deterministic or randomly, or in a particular simple form, a harmonic vibration. Such vibrations can be seen also in the field of deformable bodies as vibrating solids or as sound waves in fluids like air or inner ear fluid. Due to the complex appearance of sound in our ambience, the middle ear has two different mechanical tasks: 1. The pressure in the ambient air has a constant nominal value depending on the geodetic height. There are variations due to the meteorological conditions but particularly a change of 1 m in the geodetic height causes a pressure variation of 12 Pa, approximately. In terms of sound intensity, this would correspond to a sound pressure level of 115 dB (SPL). The first important task is to compensate these large quasistatical pressure variations below the audible range and prevent the membranes of the inner ear from large displacements. 2. The audible sound signals appear as small pressure variations in the frequency range between 16 Hz and 16 kHz. Their amplitudes are between 2 × 10–5 Pa at the hearing threshold (0 dB) and about 20 Pa (120 dB) at the threshold of pain. This is a remarkable and very large range that can barely found in a technical sensor. The second task is to transform these dynamical pressure variations into an excitation of the inner ear fluid by driving the stapes footplate supported in the oval window. It is accomplished by the motion of the eardrum and of the ossicular chain. To transfer the sound through the middle ear, the tympanic membrane and the ossicles carry out complex three-dimensional motions that are governed by the mass and mass distribution of the elements and by the mechanical properties of the ligaments. The highly nonlinear mechanical characteristics of ligaments and membranes enable the hearing organ to the quasistatic pressure compensation and the handling of loud sound events. A mathematical description of such a dynamical transfer process through the middle ear requires models representing the physics behind the process. The complexity of an appropriate model is dependent on the particular question at hand and on the required accuracy of the result. The complex spatial motions can be described by mechanical models with physical parameters that represent the mechanical properties like mass, stiffness and damping, and geometrical dimensions. Such mechanical models can be established with different complexities being conform to the problem under conside ration. They allow the numerical simulation of natural, diseased, and reconstructed hearing at the computer. In such ‘numerical experiments’, distinct

236 Recent Advances in Otolaryngology—Head and Neck Surgery parameters can be varied and their influence on the dynamical behavior of the entire system, e.g. consisting of natural structures and implants can be investigated. The form and the amplitudes of the vibration patterns of the ossicular chain are dependent on excitation and very typically on the frequency of excitation. Generally, there is a frequency-dependent phase difference between the elements. If the excitation is near the natural frequencies of the system, resonance effects occur and the parts of the chain vibrate in phase or partially in counterphase and the amplitudes of particular parts may reach high values.

Implants Mechanical implants for the middle ear are used for replacing natural structures or functions. Passive implants are driven by natural structures or elements without an additional power supply. Active implants consist of microphone, sound processor, amplifier with energy supply, and an actuator. For both types, the task is the stimulation of the inner ear according to the sound event not only by an appropriate motion of the stapes footplate but also by a fluid displacement in the vestibulum or a fluid displacement at the round window or behind it in the scala tympani. Eventually, a concentration of transmitted sound energy to a particular frequency range is desired to compensate a sensorineural or a mechanical inner ear impairment. In this case, active implants with an additional power source are beneficial. An important issue is the position and the spatial orientation of an implant in the middle ear. Passive prostheses can be inserted between • Two ossicles, e.g. malleus and stapes or incus and stapes • Eardrum and ossicle, e.g. stapes head or footplate • Ossicle and inner ear fluid, e.g. piston prostheses attached at incus or malleus and reaching the fluid via stapes footplate, the round window, or an artificial third window Active implants can be classified due to their driving principle and their situation of attaching it to the natural structures. Piezoelectric actuators deliver a high force level of actuation offering the compensation of severe hearing loss. Mechanically, they can be considered as actuators imposing a prescribed displacement to the ossicular chain. The grave disadvantage is the limited stroke that is quite sufficient for a physiological excitation but not for a compensation of the large quasistatical dislocations of the chain due to quasistatical pressure variations. In contrary, magnetic coil actuators can be considered as actuators imposing a prescribed force to the chain and the disadvantages of the piezoelectric actuators are attenuated to some extent.


The situation of attachment to the natural structures as shown in Figure 12.1 can be quite different, leading to complete different principles of actuation. An actuator needs in any case external energy and can be attached to the natural structures at two points: the base and the driven point, or only at one point: the driven one. In case of two connection points, the actuator imposes a displacement or a force relative to these connection points; it is able to transmit even static displacements or static forces. In case of a one-sided connection, the actuator can only produce inertial forces by moving an internal floating mass. The actuator can freely follow the quasistatical displacements of the chain, but the achievable actuation forces are dependent on the square of excitation frequency that leads to low forces on the lower frequency range. After insertion, it has to be assured that the actuator is firmly fixed at the driven part and there is no other connection or fixation to other parts. In case of a round window application, a good contact to the membrane is necessary and a fixation to the skull must be avoided; only a compliant suspension holding the actuator in place is permitted. For the appraisal of an implant one of the most important features is the ‘handling’ that has following aspects: • Preparation of incision should be minimal invasive, quick to perform, and minimal risky • Application of the implant should be standardized

Fig. 12.1: Different arrangements of active middle ear implants concerning their attachment points and principle of actuation.

238 Recent Advances in Otolaryngology—Head and Neck Surgery • • • •

No necessity of particular tricks or knack No particular demand on surgeon’s training and experience No necessity of specialized instruments for application Possibility to adapt the prosthesis, e.g. length and shape of individual anatomy and surgical conditions during the insertion process without changing the other properties of the implant The fulfillment of these issues will lead to short insertion time and will reduce the risks of the patient. Looking at the surgery results of various surgeons, good results could be observed in case of quick and uninterrupted insertion process even when applying obviously high application forces. The points where the implant is attached to the natural structures define its spatial orientation and thus the axis and direction of transmitted force. This direction is independent of the individual shape of the prosthesis as shown in Figure 12.2. It demonstrates clearly that the spatial motion of stapes will be different for a TORP or for a PORP version. The latter will produce more rocking motion but is better suited for the compensation of large static pressure variations. In the classical theory of hearing, it is assumed that only piston motions of the stapes have an influence on the motion of the basilar membrane, and rocking motions are considered as an acoustical shortcut.

Fig. 12.2: Axes of force transmitted by stapes prostheses for different points of attachment: stapes head (PORP), stapes footplate, or crus anterior (TORP).


This leads to the statement that the hearing sensation is related to the net volume displacement of the perilymph delivered by the motion perpendicular to the stapes footplate. However, recent measurements of compound action potentials (CAPs) on living guinea pigs have shown a considerable sensation by stimulating the stapes with rocking motions.1,2 This could be also verified by numerical simulations using the equations of a mechanical inner ear model. These results have an important impact on the reconstruction of impaired middle ear because the vibration patterns of the middle ear with passive or active implants show significantly pronounced rocking motions in comparison to the natural situation. This explains the positive results of realized reconstructions even in case of unphysiological motion behavior with pronounced rocking components. Independent of the shape of prostheses, the effective lever arm to calculate the driving torque is defined as the orthogonal distance between the force direction and the instantaneous axis of rotation as shown in Figure 12.3. A design variant with a ‘goose neck’ as a pretended longer incus process will not have any benefit concerning the kinematics, i.e. the lever arm is still the same and there is no increased stapes displacement at all. The mechanical effect of such a goose neck may be an increased compliance of the incus– stapes coupling that may protect the hearing from a static overload, but it will attenuate the amplitudes of stapes in the lower frequency range and reduce the transmission of higher frequencies severely.

Fig. 12.3: Different shapes of an incus prosthesis. The effective lever arm is identical for both variants.


Mechanical Coupling of Implants to Natural Structures Mathematical Description of Mechanical Behavior The hearing organ, a marvelous mechanical sensor, transforms dynamical pressure variations in the audible frequency range into motions of the cilia of hair cells in the cochlea. Superposed static pressure or quasistatical pressure variations result in a static displacement of all elements except the basilar membrane and the hair cells so that no hearing sensations occur. In both cases, pressure variations cause the tympanic membrane and particularly the ossicular chain to carry out distinct three-dimensional motions. Therefore, scalar models, e.g. derived from electrical analoga describing unidirectional motions, are not capable to describe the dynamical behavior properly. Mechanical modeling approaches like finite element systems3,4 or multibody systems5 are adequate modeling techniques with well-developed tools for modeling and analysis of the dynamical behavior. But the main challenge in application of these techniques is the estimation or determination of the appropriate constitutive model structures and of the belonging parameter values for the bones and particularly for the muscles and soft tissues. The modeling process is not a uniquely defined task, but it depends strongly on the specific questions at hand and the models should be as simple as possible but as complex as necessary. To avoid an overloaded inscrutable analysis, all primary effects should be taken into account and all secondary ones should be neglected. Thus, the modeling is an iterative process and needs a lot of experience. Considering these demands, the multibody systems approach seems to be of advantage,6 and one of such model is shown in Figure 12.4. It consists of 55 mass points representing the air column in the outer ear canal, 6 bodies for the description of the eardrum, 3 bodies representing the ossicular chain, and bodies representing the inner ear. In more detailed models, some elements like the air column, the ossicles, or the inner ear structures are modeled by means of finite elements and a subsequent application of reduction techniques to reduce the high number of degrees of freedom.7,8 In any case, the soft tissues are described either by linear or in case of high loads and large deflections by nonlinear viscoelastic elements without mass.9 For the description of reconstructed hearing with passive or active implants, the entire system of impaired natural structures and the implant has to be considered. A particular attention has to be drawn to the coupling of implant with the natural structure, which is modeled as a combination of nonlinear springs and dampers to describe their viscoelastic behavior. For specific investigations like sound transfer without quasistatic load variations, the nonlinear description can be linearized with respect to the particular


Fig. 12.4: Multibody system model of middle ear and adjacent structures. The ligaments are indicated by single black lines and the two muscles by double black lines. The arrows show the main degrees of freedom.

static load. Such mathematical models of coupling allow the investigation of the frequency-dependent transfer behavior on the one hand side and they describe the kinematical articulation between the both elements implant and ossicle on the other. In the contact area between implant and bone, there is mucosa, periost, and some fluid acting as an interface layer. To describe and analyze the mechanical effects, a very simplified linear, one-dimensional coupling model is considered. The force transferred through the interface layer is defined by the spring part with coefficient c depending on the deformation x of layer, whereas the damper part with coefficient d is related to the rate of deformation F = cx + dẋ. Assuming a harmonic motion is imposed by the implant as excitation, then the transmitted force is of harmonic form, too as shown in Figure 12.5. ^ This time variant force has an amplitude F and it may be superposed by a static preload F0 leading to the representation ^

F(t) = F0 + F sin (ωt + ϕ). The mechanical properties of the interface layer are of big influence. In ^ the dynamic part F , stiffer and sticky material or narrow gaps will increase the transmissible force. Due to the viscous part, an increased frequency has the


Fig. 12.5: Force transmitted by a viscoelastic coupling region depending on frequency for different stiffness and damping coefficients.

same effect besides a phase shift between excitation and transmitted force. The influence of stiffness and damping depending on frequency of excitation and the phase angle ϕ is shown in Figure 12.5. Due to the nonlinear charac teristics of tissues, and the intermediate layer, the stiffness and damping coefficients are changed by applying a preload F0 and consequently the transfer is changed, too. Now the effect of an excitation by a force on the driven system, i.e. the stapes, is considered. As a simplified example, the stapes is supported in the annular ring and driven by a harmonic force. The aim is to illustrate the influence of stiffness and damping of annular ring on the vibrations of stapes. In Figure 12.6, the transfer function, i.e. response of stapes normalized to the input, is shown. Obviously, it is strongly dependent on frequency of excitation showing a typical resonance phenomenon. The influence of stiffness is twofold: A stiffer annular ring leads to smaller amplitudes on the one hand and shifts the resonance frequency to higher values like in the case of otosclerosis on the other. The damping is caused by the internal energy dissipation in the annular ring and the fluid of inner ear. This damping reduces the amplitudes; particularly it limits the resonance amplitudes and dissipates energy in the process. Damping is necessary to some extent for dying out the vibration after stopping the excitation, otherwise a reverberant sound would be apparent and a quickly varying series of tones could not be perceived.


Fig. 12.6: Dynamic response of stapes on a harmonic force. Transfer function with typical resonance peak for different values of damping.

This clearly demonstrates the low-pass filter characteristic of such a viscoelastic coupling interface. To transmit the high frequencies, a stiff coupling is favorable but it may restrict the articulation in the coupling region to an undesired extent. Now, an other consideration is an actuator that is delivering a desired displacement as excitation, as illustrated in Figure 12.7. It is transmitted via an interface layer to the stapes and again; the influence of stiffness and damping is considered. A part of the actuators stroke y^ а is attenuated in the coupling layer leading to the ratio y^ s /y^ a < 1, and an increased stiffness brings the ratio closer to 1 and shifts the resonance frequency to a higher value. The damping limits again the amplitudes near the resonance, but fortunately for frequencies above the resonance, the negative effect of low-pass filter is reduced. For higher damping values, the transfer is less attenuated.


Fig. 12.7: Transfer function from a displacement transducer to the stapes for different values of damping. In the higher frequency range, a better transfer is achieved for higher damping values.

In reality, the coupling between and the skull can be considered as a viscoelastic coupling, too. The effect from that on the driven stapes is the same and the behavior observed above is more pronounced. Natural tissues show nonlinear characteristics particularly when they undergo to high load levels. Due to the progressive nonlinear characteristic, the stiffness is increased with preload, and it is expected that the damping increases to some extent too. The mechanical models as shown in Figure 12.4 can be extended by introducing passive or even active implants to get a description of the dynamical interactions between natural structures and the implant in the entire system. By modification of the system parameters, the representation of specific diseases is possible. The mathematical equations of these models allow the simulation of the transfer behavior by means of computer programs.

Mechanical Principles of Implant Coupling Coupling of an implant to the natural structure can be considered from a mechanical or from a chirurgical point of view. The surgeon’s demands among other things are as follows: • Good and undistorted sound transfer • Standardized procedure of application, independent of the surgeon’s experience • Easy handling, free visibility of the situation • Long time stable • Low application forces • No damage or erosion of remaining structures (mucosa, bone)


In mechanical tasks this means • Coupling must transfer desired motions not only without restrictions of the natural kinematics but also without adding unphysiological motions of the ossicular chain; i.e. the natural motion patterns of the middle ear structures should be preserved • Coupling must transfer desired forces without distortions producing higher harmonics in the driven element • The design of the prosthesis must be of light weight and filigran for sight and handling • Coupling must fit to anatomically different ossicles • Forces in the coupling region should cause a limited contact pressure in terms of force per contact area to avoid bone degradation These demands hold for passive and active implants. Principally, two bodies can be coupled with each other by 1. Physical unification, e.g. by melting, welding, gluing 2. Forces like magnetical, adhesive, mass attraction ones acting between the volume elements of the bodies (force closure) 3. Enclosure of geometric forms, which may be an one-sided or a two-sided contact leading to forces at the surface of the bodies (form closure) In reality, the bodies (bones and implants) are not ideally rigid but more or less deformable and there are microscopic or even macroscopic interface layers between them in the contact area. Thus, the coupling principles mentioned above appear in a mixed form. Connecting an implant to the ossicle with glue or cement will reduce the degree of freedom. This may lead to severely restricted motion patterns of the ossicular chain, resulting in a distorted hearing impression. The coupling of a middle ear implant with the natural structures is one of the most important influence factors on the hearing result. This is valid for passive prostheses and in particular for active implant. Some mechanical aspects shall be considered now.

Unilateral Contact A very simple and practical contact is achieved by pressing two bodies to each other like the pushing rod against the incus body or a total prosthesis on the stapes footplate. During sound transfer, time-varying forces with positive and negative values have to be transmitted. To maintain this contact, the contact force must be always positive that means a certain static preload force F0 has to be applied. To transmit a low sound intensity, F0 may be low, it must be increased for higher sound intensity. But, due to the nonlinear characteristics of the ligaments, this preload leads to a stiffening of the ossicular chain. As a consequence, the natural frequencies are shifted to higher values and the amplitudes in the lower frequency range are attenuated like in the case of an otosclerosis. Moreover, due to relaxation processes in the ligaments,

246 Recent Advances in Otolaryngology—Head and Neck Surgery this preload originally given by the surgeon may be reduced during months after surgery and the sound transfer is deteriorated in form of attenuated and distorted excitation of the inner ear.

Bilateral Contact A contact with form of enclosure can be realized by a complete or partial embracing of the ossicle by the implant, e.g. by means of loops or clips. Thus, push and pull forces can be transmitted in the contact between the prosthesis and ossicle. To connect the stapes prostheses with the long process of incus, several fastening principles are in use.

Plastic Deformation of Crimp Prostheses The crimp prostheses commonly use a metal band made of gold, steel, platinum, or titanium that is wrapped around the long process of incus. Although the used metal is very ductile, a small part of elasticity remains. As a consequence, the metal loop shows an elastic spring back effect leading to a small gap between the ossicle and the loop, see Figure 12.8, even when it was firmly pressed against the bone. It could be observed that the gap is maximal at the utmost lateral and the medial part of the loop, i.e. in the direction of motion for transmission of sound. Theoretically, this gap is like a play between two one-sided contacts. In praxis, the gap is filled with fluid or mucosa and small forces can be transmitted by these soft coupling. However, from the mechanical point of view, a sound transmission is delivered but not in a well-defined and reproducible manner. Moreover, during the process of crimping, undefined high forces can be applied to the ossicular chain and the risk of damage is considered in the Section ‘Risk of damage.’

Fig. 12.8: Gap between the ossicle and crimp prosthesis after releasing the crimp forceps. The gap is very pronounced in the regions where the force should be transmitted; in some cases an undesired formation of a loop could be observed, right. The photos are taken from an artificial test rig.


Elastic Deformation of Clip Prostheses The region of long incus process where the stapes prosthesis is attached has a cross section with a wide variation in form and diameter.10 Figure 12.9 shows the distribution intraoperatively measured by Dr. Schimanski on over 100 specimen. These results were checked at some excorporated incudes and are in concordance with other investigations.11 For optimal coupling, the contact force between the two branches of the clip prosthesis and the incus should be high enough to transmit the sound forces properly without distortion but not too high to prevent the ossicle from erosion and necrosis. Considering the broad variation in incus diameter, the forces necessary for the application of the clip and the pressure in the contact area will also vary in a wide range. Thus, the clip should have a wide capacity

Fig. 12.9: Cross-sectional dimensions of long incus process.


Fig. 12.10: Different clip prostheses: classical titanium clip, SoftClip titanium, NiTiFlex superelastic Nitinol (Kurz Medizintechnik, Germany).

of elastic deformation before plastic deformations occur and the stiffness should not be too high. With an improved design with extended elastic parts and the use of superelastic material, this demand is optimal fulfilled. Typical clip prostheses are shown in Figure 12.10. For all of these prostheses, the contact points with the incus are in line with the excitation force, and large sections of the circumference are free; the mucosa is not touched allowing the natural blood circulation. The particular design and material has also a big influence on the forces necessary to slip over the prosthesis during application, See Section ‘Clinical aspects.’

Shape Memory Alloy Prostheses Using the shape-memory effect is an elegant mechanism to close the loop. This effect occurs in specific alloys (nickel, titanium) after a specific caloric treatment. An imposed plastic deformation is then reversed after heating over a critical temperature that can be applied, e.g. by a bipolar forceps, a cauterizer or contactless by a laser application. Contrary to the homogeneous plastic deformation in case of pure one-directional deformation caused by tension, the loops of stapes prostheses are subjected to a inhomogeneous bending deformation that is not completely reversible by heating. This leads to certain spring back of the loop after the heating process and an undefined gap between loop and ossicle remains. Using a circular loop design, a strangulation of blood vessels may occur. In a specific design shown in Figure 12.11, these drawbacks are avoided. The thermoactive zones are separated from the mucosa to reduce the heat amount for closing the loops and to prevent the mucosa from direct contact


Fig. 12.11: Loop of the SMA prosthesis NiTiBOND (Kurz Medizintechnik, Germany) with four defined contact zones, three areas for heating and free areas for undisturbed blood circulation.

with heated hot spots of metal. The elastic zones reduce the spring back effect and guarantee a firm contact between implant and ossicle, whereas the strangulation is minimized having free zones for the blood vessels.

Clinical aspects Direct consequences from the issues mentioned above will be discussed concerning the preload of passive and active implants, the forces applied by the surgeon during the insertion of implants, and the admissible forces that can be beard by the ossicular chain. The preload in reconstructions has a direct impact on the transfer of forces through the contact area between implant and natural structures, but it also influences the dynamical behavior of the hearing organ as well as the performance of active implants. While comparing the measured forces of application during the insertion process with the measured admissible forces, a risk of damage can be estimated. This allows an assessment of different types of implants. The measurement setup offers also a possibility to train the surgeon’s proficiency.

Preload A static preload of the ossicular chain and the coupling region can be given by the surgeon during insertion of an implant, but it can also be caused by scar tissue or static pressure differences between outer ear canal, the tympanic cavity, and the vestibulum. Due to the ductus that interconnect the inner ear fluid system with the cranial compartment, the vestibular pressure is depending on the posture and may take different values.

250 Recent Advances in Otolaryngology—Head and Neck Surgery Consequently, the preload originating from specific natural boundary conditions or artificially given by the surgeon during insertion of implants is not constant over time. A reduction in a given preload in a long-term range may be caused by a slow creepage of biological tissues. Due to their relaxation, statically loaded tissues elongate within a period of months. This leads to a lowered preload and may reduce the performance of reconstructions resulting in an increased distortion or reduced excitation of the inner ear. Particularly, powerful active implants, which need a high preload, are very sensitive against such relaxation processes. An increased preload generally leads to a proper contact and a good sound transfer, but due to the nonlinear behavior of the soft tissues, the dynamic behavior of entire system is changed. A shift of the natural frequencies that determine the frequencies of resonance to higher values takes place. As a consequence, the hearing in the lower frequency range is considerably decreased and in the higher frequency range it may be slightly improved. In case of extremely strong preload, the ligaments and membranes became very stiff; they lose their mobility and show characteristics like otosclerosis. Active middle ear implants driven by magnetic coils may reach their limit and the resulting stapes motion may be not high enough to compensate an inner ear hearing loss. Instead, it may happen that the malleus is driven with high amplitudes leading to an increased sound radiation into the outer ear canal. This sound is picked up by the microphone and feedback or ringing effect may occur. This gives a hard limit of the realizable amplification even for very powerful actuators. Now consider an active implant with a driving rod that is pressed, e.g. against the incus body, the stapes, or the membrane of round window. ^ A sinusoidal output force with an amplitude F is assumed that has to be transmitted to the driven part. Due to the unilateral coupling, no pulling force can be transmitted, thus the contact force must be always greater than zero. This condition is fulfilled as long as the pretension F0 is higher than the ampli^ tude F . The condition of firm contact is violated if the preload is reduced, e.g. due to scar tissue, static pressure variations in the outer ear canal, the tympanum, or the cranium, or if the output amplitude of the actuator is increased. In Figure 12.12, three different situations are shown for a simplified actuation of the round window membrane driven by an ideal displacement transducer imposing an amplitude y^ а. No internal dynamics of the inner ear is assumed. In case of no contact, the membrane is not in motion. If the contact is not firm, a liftoff occurs and the driving rod is hammering against the driven part. This causes the appearance of higher harmonics, and the transmitted sound is distorted. Only in case of proper contact without liftoff, the sound transfer is without distortions. In reality, the driven part of the system situation has an internal dynamics with particular natural frequencies, leading to a more complex behavior in


Fig. 12.12: Lift off in the area of unilateral coupling depending on preload and amplitude of force to be transmitted. The travel of actuator against membrane is denoted by yp and the amplitude of actuator by y^ a.

the coupling region. The contact forces are not only dependent on the excitation intensity but they are also from the actual vibration pattern of the entire system. Particularly, in occurrence of resonance, the fluctuations of contact force may be a multiple of the excitation force. Thus, the static preload must be sufficiently higher than the amplitude of excitation.

Application Forces By inserting a prosthesis, forces to the ossicular chain are exerted. The most critical phase in case of classical stapes prostheses is the fastening at the incus process. A technical test rig allows measurements of the application forces in all three spatial directions toward the vestibulum, transversal to and in direction of the incus process as illustrated in Figure 12.13. The spatial components of the application force are registered for offline evaluation and can be replayed together with the records of a video camera. This optical observation from a side view offers a deep insight into the insertion process, particularly the motion in medial–lateral direction is clearly visible. The results in Figure 12.14 from more than 100 applications for crimp, clip, and shape memory alloy prostheses show a high mean value with a broad standard deviation for crimp prostheses. It indicates the high


Fig. 12.13: Technical model for measuring the spatial application forces at the incus process during insertion of a stapes prosthesis. Views are from a microcamera in direction of the artificial incus.

Fig. 12.14: Mean value and deviation with min/max values of application forces for different activities during application and for different types of prostheses.

mechanical load during crimping due to the difficult guiding of the forceps and the simultaneous control of the crimping force itself. The big variance indicates the nonstandardized process of fastening strongly dependent on the experience of the surgeon.


Fig. 12.15: Cyclic load at the long incus process in anterior direction with increasing level and deformation of ligaments. Classification of damage severity in the ligaments in microrupture range with beginning ruptures and rupture range with progressive ruptures.

Admissible Forces In temporal bone experiments, push and pull forces were applied to the long process of incus in medial–lateral and in anterior–posterior direction. The dislocation of ossicular chain under cyclic load with increasing force level was measured and the mechanical characteristics of the ligaments were derived and evaluated.12 Up to a certain level, there was no change from cycle to cycle, but increased loads caused microruptures or even severe progressive ruptures with considerable elongations of the ligaments as it is illustrated in Figure 12.15. The region of severe damage is defined as a pronounced decrease in stiffness and a residual elongation of the system of ligaments. It is still open, how the grade of rupture severity influences the healing process, to which extent the damage can be reversed, and how is the relationship to scar tissue and its influence on pretension in the ossicular chain.

Risk of Damage To estimate a risk of damage, the measured application forces in anterior– posterior and in lateral–medial are compared with the admissible forces as shown in Figure 12.16. Approximating the measured values by a standard deviation, a probability of damage in percent could be derived looking at the overlap of the admissible and the application forces. Due to the high vulnerability and the high application forces in lateral–medial direction, a high percentage of damage results in that direction. The results illustrated in Table 12.1 show clearly that the crimping process is the most difficult and risky part when applying a piston prosthesis.


Fig. 12.16: Measured values of admissible loads to the ossicular chain and application forces for insertion of stapes prostheses, ap denotes the anterior–posterior and lm the lateral–medial direction.

Table 12.1: Probability of damage in percent for crimp, clip, and SMA prostheses due to different activities during application. Different directions are evaluated. Observed direction

Positioning of Crimp/Clip/ SMA Progressive Beginning microrupture rupture

Anterior– posterior Lateral– medial

Crimping Beginning microrupture

Slipover of Clip prostheses

Progressive Beginning Progressive rupture microrupture rupture

< 0.3

0

1.2–9.3

< 0.7

0

0

1.2–14.2

0.1–0.7

14.0–67.9

0.5–7.5

< 8.2

0

Conclusion A lot of articles have been written about the implants to reconstruct a damaged or impaired middle ear. There are passive as well as active implants in use being of different design, working on different principles of function and made from different materials. Therefore, the surgeon’s decision which one he uses in a particular case of impairment may be facilitated by taking the mechanical aspects of the implant itself and the reconstructed ear as a whole into account. Mechanics deals with deformations and motions due to forces; in hearing it appear motions of the ossicular chain and the membranes of the inner ear as well as their static and dynamic deformations in form of vibrations.13 High quasistatic loads or loud sound events show large deformations and amplitudes, whereas physiological sound causes very small vibrations. These different load situations, high quasistatic, and small dynamic forces


lead to two very different tasks for the middle ear. By means of mechanical models, the three-dimensional complex deformations and vibrations can be described and simulated at the computer. The stapes as the input to the inner ear carries out piston and rocking motions;14,15 both of them have influence on hearing. The most important issue in reconstruction is the proper coupling of the passive or active implant to the bones or membranes. There is an interface layer in the coupling region showing a highly nonlinear behavior that governs very sensitive quality and intensity of sound transfer, depending on stiffness and damping of the interface layer. The contact forces in this layer should be high enough for sound transmission but not too high to avoid damages. To avoid liftoff and a distorted sound transfer, a preload is necessary that may vary over time, depending on ambient pressure or posture variations. The attachment process of an implant to bones or membranes should be standardized with a low risk of the patient and should guarantee a good sound transfer. Among crimp, clip, and shape memory prostheses, a high risk could be observed for crimp prostheses. Computer simulations can complete measurements on temporal bones. They offer a deeper insight into the complex mechanics of hearing and allow a systematic optimization of the design and the use of passive and active implants as well.

Acknowledgments Parts of the investigations were financed by funds from the German Research Council DFG and were conducted in close cooperation with ENT departments of universities in Zurich, Switzerland and Cologne, Germany. Special thanks go to the PhD students Christian Breuninger, Michael Lauxmann, Sebastian Ihrle, and Christoph Heckeler. Several students contributed valuable work within their theses.

References

1. Huber A, Sequeira D, Breuninger C, et al. The effects of complex stapes motion on the response of cochlea. Otol Neurotol. 2008;29:1187–92. 2. Eiber A, Huber A, Lauxmann M, et al. Contribution of complex stapes motion to cochlea activation. Hearing Research. 2012;284(1-2): 82–92. 3. Gan RZ, Reeves BP, Wang X. Modeling of sound transmission from ear canal to cochlea. Ann Biomed Eng. 2007;35(12):2190–95. 4. Koike T, Wada H, Kobayashi T. Modeling of the human middle ear using the finite-element method. J Acoust Soc Am 2002;111(3):1306–17. 5. Eiber A. Mechanical problems in human hearing. Stud Health Technol Inform 2008;133:83–94. 6. Eiber A. Mechanical models in hearing. In: de Las Casas EB, Pamplona DC (eds), Computational models in biomechanics. Barcelona, Spain: International Center for Numerical Methods in Engineering; 2003.

256 Recent Advances in Otolaryngology—Head and Neck Surgery 7. Lauxmann M. Nichtlineare Modellierung des Mittelohrs und seiner angrenzenden Strukturen. PhD-thesis, Institut für Technische und Numerische Mechanik, University of Stuttgart, vol 27. Aachen: Shaker Verlag; 2012. 8. Ihrle S, Lauxmann M, Eiber A, et al. Nonlinear modeling of the middle ear as an elastic multibody system applying model reduction to acousto-structural coupled systems. J Comput ApplMath 2012;246:18–20. 9. Fung Y. Biomechanics-mechanical properties of living tissues. New York: Springer; 1993. 10. Schimanski G, Steinhardt U, Eiber A. Development of a new clip-piston prosthesis for the stapes. In: Huber A, Eiber A (eds), Middle ear mechanics in research and otology. New Jersey: World Scientific Publishing; 2007. 11. Tóth M, Moser G, Rösch S, et al. Anatomic parameters of the long process of incus for stapes surgery. Otol Neurotol. 2013;34(9):1564–70. 12. Lauxmann M, Heckeler C, Beutner D, et al. Experimental study on admissible forces at the incudo-malleolar joint. Otol Neurotol. 2012;33(6):1077–84. 13. Decraemer W, Khanna S. New insights in the functioning of the middle ear. In: Rosowski J, Merchant S (eds), The function and mechanics of normal, diseased and reconstructed middle ears. The Hague, Netherlands: Kugler Publications; 1999:23–38. 14. Hato N, Stenfelt S, Goode RL. Three-dimensional stapes footplate motion in human temporal bones. Adiol Neurotol. 2003;8(8):140–52. 15. Eiber A, Heckeler C, Lauxmann M, et.al. Spatial motion in natural and reconstructed middle ears and the impact on sound transmission. In: Shera CA, Olson E (eds), Proc. 11th International Hearing Workshop, Williamstown, Massachusetts; 2011:534.

Chapter Stereotactic Radiosurgery for Acoustic Neuroma

13

Ajay Niranjan, Edward Monaco III, Hideyuki Kano, John C Flickinger, L Dade Lunsford

introduction Radiosurgery is presently a well-established alternative to microsurgical resection of acoustic neuromas (vestibular schwannomas). Many patients and their physicians prefer radiosurgery over surgical resection because of the lower morbidity of the procedure and similar rates of long-term tumor control. Acoustic neuroma radiosurgery with marginal doses of 12 to 13 Gy is associated with a high rate of tumor control with minimal facial and trigeminal morbidity. Hearing preservation rates may be as high as 95% in patients with small volume tumors and excellent pre-procedure hearing. The management options for patients with cerebellopontine angle (CPA) tumors include observation and further follow-up imaging (‘wait and scan’), microsurgery, stereotactic radiosurgery (SRS), and fractionated radiation therapy. To make an informed decision, CPA tumor patients need to be presented with up-to-date information regarding clinical outcomes and complications of different management techniques. During the last two decades SRS has emerged as a highly effective and minimally invasive alternative to surgical removal of small-to moderate-sized CPA tumors. The 30-year evolution of SRS has changed the way majority of these patients are managed at many centers of excellence.1 Advances in dose planning software, detailed intraoperative magnetic resonance imaging (MRI) three-dimensional tumor recognition, and robotic radiation delivery reflect the evolution of radiosurgery technology. Long-term results from multiple international sites especially have established Gamma Knife radiosurgery as an important minimally invasive alternative to microsurgery. The goals of CPA tumor radiosurgery are to prevent further tumor growth, preserve cranial nerve function, maintain or improve the patient’s neurological status, and return the patient to routine activities and work within days. In this report, we focus on the most common CPA tumor, the acoustic neuroma (or vestibular schwannoma).


Gamma knife radiosurgery technique for acoustic neuromas Preradiosurgery Evaluation Patients with suspected acoustic neuromas are evaluated with highresolution MRIs and audiological tests. Audiograms are reviewed to document the hearing level on the side of the tumor compared with the hearing on the contralateral side. Using the Gardner–Robertson (GR) classification, serviceable hearing (Class I and II) is defined as a pure tone average (PTA) or speech reception threshold lower than 50 dB and speech discrimination score (SDS) better than 50%. In the American Academy of Otolaryngology–Head and Neck Surgery classification (AAO-HNS), hearing loss at a higher frequency (3000 Hz) is also included in calculating the PTA. Serviceable hearing (Class A and B) is similar to Class I and II of GR hearing classes. Facial nerve function is assessed according to the House–Brackmann grading system.

Radiosurgery Technique In Gamma Knife radiosurgery, the procedure begins with rigid fixation of an MRI compatible Leksell stereotactic frame (model G, Elekta Instruments, Atlanta, GA, USA) to the patient’s head under conscious sedation and local scalp anesthesia. High-resolution MRIs (axial plane 1–2 mm slices) are acquired with a stereotactic MR-compatible fiducial system attached to the stereotactic frame. For CP angle tumor radiosurgery, a three-dimensional volume acquisition MRI using a gradient pulse sequence (divided into 1 mm thick axial slices) is performed. A narrow slice (0.5–1 mm) T2-weighted threedimensional volume sequence is performed to specially visualize cranial nerves and the cochlea. For patients ineligible for MRI, narrow slice axial imaging is performed using computed tomography (CT).

Radiosurgical Dose Planning Conformal and highly selective dose planning is a critical aspect of gamma knife radiosurgery. A conformal radiosurgery dose plan (the three- dimensional geometry of the dose plan conforms to the three-dimensional tumor geometry) is necessary for hearing and facial nerve preservation. Complete three-dimensional coverage of the tumor with sparing of facial, cochlear, and trigeminal nerves is given priority during dose planning. This is achieved by highly selective dose delivery (the dose delivered to critical structures adjacent to the tumor is low because of rapid fall off of the dose beyond the tumor margin). Brain stem dose is also checked and kept low. Highlights of Gamma Knife CPA radiosurgery planning include use of multiple small volume isocenters, beam weighting, and use of beam plug patterns to

Stereotactic Radiosurgery for Acoustic Neuroma 259

a

b

Fig. 13.1A: Contrast-enhanced axial magnetic resonance images of a 45-year-old man showing Gamma knife radiosurgery dose plan for an acoustic neuroma (a); A margin dose of 12.5 Gy was prescribed to 50% isodose line. Cochlea (white arrow) is outlined using T2-weighted images (b); and a beam blocking was to make sure that cochlea remains outside the 4-Gy isodose line (black arrow).

spare the cochlea and brain stem. Precise three-dimensional conformality between treatment isodose volume and tumor volume is needed to avoid adverse radiation effects.2 CPA tumor dose planning is usually performed using a combination of small beam diameter (4 and 8 mm) collimators. For larger tumors, individual blocking of 24 beam sectors of the 16 mm collimator Perfexion Gamma knife is also used. A series of 4 mm isocenters are used to create a tapered isodose plan to conform to the intracanalicular portion of the tumor. Sector blocking can be used to create sharp fall off toward cochlea (Fig. 13.1A). The dose plan should by highly conformal at the anterior tumor margin because the facial and the cochlear nerve complex generally courses along the anterior superior and anterior inferior side of the tumor. Although there is no clear consensus on the sensitivity of the cochlea, it important to minimize the amount of radiation fall off on the cochlea.3 Most centers attempt to keep the average cochlea dose between 4.2 and 5 Gy.

Dose Prescription In Gamma Knife radiosurgery, a dose of 12–12.5 Gy is typically prescribed to the 50% (or other) isodose line that conforms to the tumor margin. A margin dose of 12.5 Gy is associated with a low complication rate and a high rate of tumor control. After prescribing the margin dose, the dose fall off on cochlea and brain stem is checked to keep them below tolerance level. The dose volume histogram is evaluated to document minimum tumor dose and

260 Recent Advances in Otolaryngology—Head and Neck Surgery to check the volumes of cochlea, brain stem, and fifth nerve receiving any significant dose. At our center, we attempt to keep the cochlear dose below 4.2 Gy in patients with preserved hearing.

Dose Delivery The most recent version of Gamma Knife radiosurgery model is Leksell Gamma Knife Perfexion that is a 192 cobalt-60 sources model. Gamma Knife SRS is also performed with model C or 4C that are 201 sources, cobalt-60 units. Dose delivery is accomplished in a single session by positioning the target serially for each subsequent isocenter until a fully conformal field encompasses the tumor volume.

Postoperative Care and Evaluations Although some physicians decline to use corticosteroids at all before, during, or after radiosurgery, we routinely prescribe an intravenous dose of 40 mg of methylprednisolone at the conclusion of the procedure. Over the years this has seemed to reduce minor headache in the first hours after the procedure. The stereotactic frame is removed immediately after radiosurgery. Patients are usually discharged within a few hours after radiosurgery. We request that patients obtain follow-up brain imaging at 6 months; 12 months; and 2, 4, 8, and 16 years after radiosurgery. Audiological tests (PTA and SDS) are also requested from patients with preserved hearing at the time of radiosurgery.

Radiosurgery: clinical results Tumor Growth Control Multiple reports have documented the clinical outcomes after Gamma Knife radiosurgery for vestibular schwannomas.4–9 Recent reports suggest a tumor control rate of 93–100% after radiosurgery.4–25 In a 5- to 10-year outcome study at the University of Pittsburgh, a 98% tumor control rate was reported for 162 vestibular schwannoma patients who had radiosurgery.19 In the follow-up, 62% of tumors regressed, 33% remained stable, and 6% became slightly larger. Additional management was needed in < 2% of patients. Litvack et al. reported a 98% tumor control rate at a mean follow-up of 31 months after radiosurgery using a 12 Gy margin dose.26 Niranjan et al. reported that all patients (100%) with intracanalicular tumor had imagingdocumented tumor growth control after radiosurgery performed.27 Flickinger et al. reported an actuarial 5-year clinical tumor control rate (no requirement for surgical intervention) of 99.4 ± 0.6%5,11 for acoustic neuroma patients treated between August 1992 and August 1997 at the University of Pittsburgh (Fig. 13.1B).


a

b

c Fig. 13.1B: Contrast-enhanced axial magnetic resonance images and serial audiograms of a 45-year-old man who was treated with Gamma Knife radiosurgery showing a small tumor size and serviceable hearing status at the time of radiosurgery (a); Six-month follow-up shows stable tumor and preserved hearing (b); One and half year follow-up shows tumor regression with presrvation of serviceable hearing (c).


Hearing Preservation Serviceable hearing preservation can be preserved in the majority of patients regardless of tumor volume. In a long-term (5–10 years follow-up) study conducted at the University of Pittsburgh, 51% of patients had no change in hearing ability.11,19 All patients (100%) with an intracanalicular tumor treated with a margin dose of 14 Gy or less maintained a serviceable level of hearing after radiosurgery.27 In a study by Flickinger et al. the 5-year actuarial rates of hearing level preservation and speech preservation were 75.2% and 89.2%, respectively, for patients (n = 89) treated with a 13 Gy tumor margin dose. The 5-year actuarial rates of hearing level preservation and speech preservation were 68.8% and 86.3%, respectively, for 103 patients treated with < 14 Gy as the tumor margin dose.5 Kano et al. evaluated factors related to hearing preservation in 77 CPA tumor patients.28 The median tumor volume was 0.75 cm and the median radiation dose to the tumor margin was 12.5 Gy. At a median of 20 months after SRS, serviceable hearing was preserved in 71%. Among the patients who had GR Class I hearing prior to radiosurgery, 89% retained serviceable hearing. Significant prognostic factors for serviceable hearing preservation were GR Class I hearing, a patient age younger than 60 years, an intracanalicular tumor, and a smaller tumor volume. A cochlear dose of < 4.2 Gy to the central cochlea was significantly correlated with better hearing preservation of the same GR class.

Facial Nerve and Trigeminal Nerve Preservation With the current technique, facial nerve function can now be preserved in almost all patients (Figs 13.2A and B). In the early experience at University of Pittsburgh, normal facial function was preserved in 79% of patients after 5 years and normal trigeminal nerve function was preserved in 73%. These facial and trigeminal nerve preservation rates reflected the higher tumor margin dose of 18–20 Gy used during the CT-based planning era before 1991. In a recent study using current techniques (MR-based dose planning, a 13 Gy or less tumor margin dose) with a 0% risk of new facial weakness and 3.1% risk of facial numbness (5-year actuarial rates) was reported. A higher margin dose (> 14 Gy) was associated with 5-year actuarial rates of 2.5% risk of new onset facial weakness and a 3.9% risk of facial numbness.5 None of the patients who had radiosurgery for intracanalicular tumors developed new facial or trige minal neuropathies. For larger tumor volumes that impact on the root entry zone of the trigeminal nerve, mild trigeminal sensory loss may be detected in < 10 % of patients.


Fig. 13.2A: Gamma Plan poster shows a conformal radiosurgery dose plan for a 40-year-old patient who presented with moderate-sized vestibular schwannoma and serviceable hearing. Axial contrast-enhanced axial magnetic resonance images with coronal and sagittal reconstructions were used for planning and a margin dose of 12.5 Gy as prescribed to 50% isodose line.

Fig. 13.2B: Contrast-enhanced axial magnetic resonance imaging obtained 14 years after radiosurgery shows significant tumor regression (left). An audiogram performed 14 years after radiosurgery documents preserved serviceable hearing (right).


Radiosurgery for Younger Patients Radiosurgery has been shown to be a very effective management strategy for younger patients with vestibular schwannomas. In a study of 55 younger patients managed with GK SRS, Lobato-Polo et al. reported a 96% rate of 5-year freedom from additional management.29 Serviceable hearing was maintained in 100%, 93%, and 93% of patients at 3, 5, and 10 years, respectively. A margin dose of 13 or less was significantly associated with hearing preservation (p = 0.017). None of the patients treated with doses lower than 13 Gy experienced facial or trigeminal neuropathy. All patients maintained their previous level of activity or employment after GK SRS.

Radiosurgery for Larger Tumors SRS is an established management option for patients with small- and medium-sized vestibular schwannomas. However, radiosurgery has been performed for several patients with larger tumors who either refused surgery or were found to be high risk for resection due to comorbidities. In a recent study, Milligan et al. assessed its potential role of SRS for larger tumors. The median maximum tumor diameter was 2.8 cm (range 2.5–3.8 cm) in this group of 22 patients.30 The median margin dose of 12 Gy (range 12-14 Gy) was prescribed. These investigators reported 86% rate of 3-year actuarial tumor control, 92% rate of freedom from new facial neuropathy, and 47% rate of functional hearing preservation. Tumor regression was documented in 91% of patients. Yang et al. studied 65 patients with larger CPA tumors (3–4 cm in diameter, median tumor volume 9 mL) who underwent radiosurgery.31 At 6 months, two patients required resection; 89% had stable or smaller volume tumors. Eleven percent had slightly enlarged acoustic neuroma (AN) (one had repeat SRS). Serviceable hearing was preserved in 82% of patients. The value of radiosurgery in selected patients with large tumors is encouraging. However, all the options should be discussed with the patient and an individualized decision should be taken after considering patient’s wishes and goals and surgeons experience.

Stereotactic Radiation Therapy Stereotactic radiation therapy (SRT) or fractionated stereotactic radiation therapy (FSRT) refers to the delivery of a standard fractionation scheme of radiation. Typically a relocatable stereotactic guiding device is used during radiation delivery with SRT. This approach has been adopted by some linear accelerator (LINAC)-based radiosurgery centers in order to reduce complication rates.17, 3,32–37 Fractionation provides no radiobiological advantage for tumor control. It is used to reduce risk of collateral injury to adjacent brain and cranial nerve structures.


Using CyberKnife-based SRT, Ishihara et al. reported 94% tumor control rate at a median follow-up of 31.9 months in a series of 38 patients with CPA tumors. One patient developed transient facial paresis (2.6%) and one developed trigeminal nerve neuropathy (2.6%).17 Fuss et al. treated 51 patients with vestibular schwannomas using SRT.38 The actuarial 5-year tumor control rate was 95% at a mean follow-up of 42 months. One patient developed transient facial nerve paresis and two noted new trigeminal dysesthesias. Chung et al. reported 57% hearing preservation rate at 2 years for 25 patients treated with SRT.39 Sawamura et al. studies 101 patients with vestibular schwannomas treated with FSRT at a radiation level of 40–50 Gy, administered in 20–25 fractions over a 5- to 6-week period.34 At a median follow-up period of 45 months, the actuarial 5-year rate of tumor control was 91.4% and hearing preservation (GR Class I or II) was 71%. The complications of FSRT included transient facial nerve palsy (4%), trigeminal neuropathy (14%), balance disturbance (17%), and progressive communicating hydrocephalus requiring a shunt (11%). Sakanaka et al. reported local tumor control and hearing preservation using hypofractionated stereotactic radiotherapy (hypo-FSRT) for acoustic neuromas.40 Thirteen patients received a margin dose of 30–39 Gy using 10–13 fractions (regimen A), whereas 12 patients received 20–24 Gy in 5–6 fractions (regimen B). These treatments were scheduled to be delivered in three fractions per week. Local control rates were achieved in 100% with regimen A and in 92% with regimen B. Serviceable hearing was preserved in 57% (4/5 patients in regimen B but no patients in regimen A). Kapoor et al. studied 385 patients to assess long-term tumor control after FSRT for unilateral AN.41 Radiologic progression was observed in 116 patients (30.0%). Eleven patients (3%) required salvage (microsurgical) treatment. Adverse radiation effects included 8 patients (1.6%) with new facial weakness, 12 patients (2.8%) with new trigeminal sensory symptoms, 4 patients (0.9%) with hydrocephalus, and 2 patients (0.5%) with subsequent suspected radiation-related neoplasms. Hearing preservation was not assessed. Hansasuta et al. treated 383 patients with multisession SRS and reported a 5-year tumor control rate of 98% for tumors < 3.4 cc.42 Serviceable hearing was preserved in 76%. Eight patients (2%) developed trigeminal dysfunction. Powell et al. evaluated 72 patients with CPA tumors treated with FSRT (45–50 Gy in 25–30 fractions over 5–6 weeks) and reported (11%) rate of hydrocephalus within 19 months of radiotherapy.43 In a recent study, Andrews et al. evaluated hearing preservation in 89 patients treated with SRT.44 A high-dose cohort (HDC) enrolled 43 patients (treated to 50.4 Gy) and low-dose cohort (LDC) consisted of 46 patients (treated to 46.8 Gy). The median audiometric follow-up in HDC and LDC was 13 and 16 months, respectively. All patients who had preradiosurgery GR grade II hearing and

266 Recent Advances in Otolaryngology—Head and Neck Surgery were treated with HDC lost hearing within 7 months of SRT. Eventually, all patients in LDC group lost serviceable hearing by the end of 42 months. Meijer et al. analyzed 129 vestibular schwannoma patients who underwent LINAC-based radiosurgery.45 SRT was performed on 80 patients and SRS was used in 49. These investigators did not find any statistically significant difference in 5-year local control probability (100% vs. 94%), 5-year facial nerve preservation probability (93% vs. 97%), and 5-year hearing preservation probability (75% vs. 61%). Combs et al. studied 200 patients with vestibular schwannoma treated with FSRT or SRS.46 For patients receiving FSRT, a median total dose of 57.6 Gy was prescribed, with a median fractionation of 5 x 1.8 Gy per week. For patients who underwent SRS, a median single dose of 13 Gy was prescribed to the 80% isodose. Local control was not statistically different for both groups. The probability of maintaining the pretreatment hearing level after SRS with doses of ≤13 Gy was comparable with that of FSRT. In the group of patients treated with SRS doses of ≤13 Gy, cranial nerve toxicity was comparable to that of the FSRT group. Kopp et al. studied 115 consecutive cases of vestibular schwannoma treated with radiosurgery or stereotactic fractionated radiotherapy (SFR).47 The SFR group (47 patients) received a total dose of 54 Gy at 1.8 Gy per fraction. The radiosurgery group received a total dose of 12 Gy at the 100% isodose. The tumor control rate was 97.9% in the SFR group for a mean follow-up time of 32.1 months and 98.5% in the radiosurgery group for a mean follow-up time of 30.1 months. Hearing function was preserved in 85% patients in radiosurgery group and in 79% patients in SFR group. The available data on SRT or FSRT is heterogeneous in terms of dose and number of fractions and does not improve outcomes compared with Gamma knife SRS. There is no consensus on dose and fractions regimen of FSRT. Long-term data on FSRT is not available to support its use. At the present time compared with single session radiosurgery, there are limited data on SRT for vestibular schwannomas. For some centers, SRT may be an option for vestibular schwannomas if they have a higher complication rate using LINAC radiosurgery. The long-term outcome data for single session radiosurgery using 12–13 Gy margin dose is available from several institutions. Overall, we believe that single session Gamma knife radiosurgery is the gold standard for patients with CPA tumors. Highly conformal radiosurgery dose plans are feasible with SRS because of rigid frame-based head fixation. SRS is a single day outpatient procedure, wheels in to wheels out. From frame on to frame off the entire effect is delivered in a single procedure analogous to other surgical procedures. This paradigm is convenient for patient and families. The evolution of SRS has changed the management algorithm for patients diagnosed with C P angle tumors. Radiosurgery is now considered as the


first-line management option for the majority of small-to-medium-sized acoustic (vestibular schwannomas) patients. Surgery may be needed for patients with larger tumors associated with symptomatic mass effect (headache, ataxia, and dysmetria). Such surgery should aim to debulk the mass and preserve existing cranial nerve function. SRS can be used to achieve longterm tumor control for the tumor remnant. SRS is also a valuable alternative for patients who suffer tumor recurrence despite prior gross total tumor removal. Approximately 10% of patients who undergo hearing preservation microsurgery may suffer a tumor recurrence by 10 years after their surgery.

References

1. Niranjan A, Madhavan R, Gerszten PC, et al. Intracranial radiosurgery: an effective and disruptive innovation in neurosurgery. Stereotact Funct Neurosurg. 2012;90(1):1–7. 2. Linskey ME. Stereotactic radiosurgery versus stereotactic radiotherapy for patients with vestibular schwannoma: a Leksell Gamma Knife Society 2000 debate. J Neurosurg. 2000;93 (Suppl 3):90–5. 3. Szumacher E, Schwartz ML, Tsao M, et al. Fractionated stereotactic radiotherapy for the treatment of vestibular schwannomas: combined experience of the Toronto-Sunnybrook Regional Cancer Centre and the Princess Margaret Hospital. Int J Radiat Oncol Biol, Phys. 2002;53(4):987–91. 4. Chung WY, Liu KD, Shiau CY, et al. Gamma knife surgery for vestibular schwannoma: 10-year experience of 195 cases. J Neurosurg. 2005;102 (Suppl) :87–96. 5. Flickinger JC, Kondziolka D, Niranjan A, et al. Acoustic neuroma radiosurgery with marginal tumor doses of 12 to 13 Gy. Int J Radiat Oncol Biol Phys. 2004;60(1):225–30. 6. Hasegawa T, Kida Y, Kobayashi T, et al. Long-term outcomes in patients with vestibular schwannomas treated using gamma knife surgery: 10-year follow up. J Neurosurg. 2005;102(1):10–6. 7. Kondziolka D, Lunsford LD, Flickinger JC. Acoustic neuroma radiosurgery. Origins, contemporary use and future expectations. Neuro-Chirurgie. 2004;50(2-3 Pt 2):427–35. 8. Kondziolka D, Nathoo N, Flickinger JC, et al. Long-term results after radiosurgery for benign intracranial tumors.[see comment]. Neurosurgery. 2003;53(4):815-21;discussion 21–2. 9. Lunsford LD, Niranjan A, Flickinger JC, et al. Radiosurgery of vestibular schwannomas: summary of experience in 829 cases. J Neurosurg. 2005;102 (Suppl):195–9. 10. Delbrouck C, Hassid S, Massager N, et al. Preservation of hearing in vestibular schwannomas treated by radiosurgery using Leksell Gamma Knife: preliminary report of a prospective Belgian clinical study. Acta Oto-Rhino-Laryngologica Belgica. 2003;57(3):197–204. 11. Flickinger JC, Kondziolka D, Niranjan A, et al. Results of acoustic neuroma radiosurgery: an analysis of 5 years’ experience using current methods.[see comment]. J Neurosurg. 2001;94(1):1–6.

268 Recent Advances in Otolaryngology—Head and Neck Surgery 12. Flickinger JC, Kondziolka D, Pollock BE, et al. Evolution in technique for vesti bular schwannoma radiosurgery and effect on outcome. Int J Radiat Oncol Biol Phys. 1996;36(2):275–80. 13. Foote KD, Friedman WA, Buatti JM, et al. Analysis of risk factors associated with radiosurgery for vestibular schwannoma. J Neurosurg. 2001;95(3):440–9. 14. Harsh GR, Thornton AF, Chapman PH, et al. Proton beam stereotactic radiosurgery of vestibular schwannomas. Int J Radiat Oncol Biol Phys. 2002;54(1):35–44. 15. Horstmann GA, Van Eck AT. Gamma knife model C with the automatic positioning system and its impact on the treatment of vestibular schwannomas. J Neurosurg. 2002;97(5 Suppl):450–5. 16. Inoue HK. Low-dose radiosurgery for large vestibular schwannomas: longterm results of functional preservation. J Neurosurg. 2005;102(Suppl):111–3. 17. Ishihara H, Saito K, Nishizaki T, et al. CyberKnife radiosurgery for vestibular schwannoma. Minim Invasive Neurosurg. 2004;47(5):290–3. 18. Kondziolka D, Lunsford LD, Flickinger JC. Gamma knife radiosurgery for vestibular schwannomas. Neurosurg Clinics of North America. 2000;11(4): 651–8. 19. Kondziolka D, Lunsford LD, McLaughlin MR, et al. Long-term outcomes after radiosurgery for acoustic neuromas.[see comment]. N EnglJ Med. 1998;339(20):1426–33. 20. Linskey ME, Johnstone PA. Radiation tolerance of normal temporal bone structures: implications for gamma knife stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2003;57(1):196–200. 21. Linskey ME, Lunsford LD, Flickinger JC. Tumor control after stereotactic radiosurgery in neurofibromatosis patients with bilateral acoustic tumors. Neurosurgery. 1992;31(5):829-38;discussion 38–9. 22. Lunsford LD. Vestibular schwannomas. Neuro-Chirurgie. 2004;50(2-3 Pt 2): 151–2. 23. Noren G. Long-term complications following gamma knife radiosurgery of vestibular schwannomas. Stereotact Funct Neurosurg. 1998;70 (Suppl 1):65–73. 24. Meijer OW, Wolbers JG, Vandertop WP, et al. Stereotactische bestraling van het vestibulair schwannoom (acusticusneurinoom). Nederlands Tijdschrift voor Geneeskunde. 2000;144(44):2088–93. 25. Petit JH, Hudes RS, Chen TT, et al. Reduced-dose radiosurgery for vestibular schwannomas. Neurosurgery. 2001;49(6):1299-306;discussion 306–7. 26. Litvack ZN, Noren G, Chougule PB, et al. Preservation of functional hearing after gamma knife surgery for vestibular schwannoma. Neurosurg Focus. 2003;14(5):e3. 27. Niranjan A, Lunsford LD, Flickinger JC, et al. Dose reduction improves hearing preservation rates after intracanalicular acoustic tumor radiosurgery. Neurosurgery. 1999;45(4):753-62;discussion 62–5. 28. Kano H, Kondziolka D, Khan A, et al. Predictors of hearing preservation after stereotactic radiosurgery for acoustic neuroma clinical article. J Neurosurg. 2009;111(4):863–73. 29. Lobato-Polo J, Kondziolka D, Zorro O, et al. Gamma knife radiosurgery in younger patients with vestibular schwannomas. Neurosurgery. 2009;65(2):294–300;discussion -1.

Stereotactic Radiosurgery for Acoustic Neuroma 269 30. Milligan BD, Pollock BE, Foote RL, el al. Long-term tumor control and cranial nerve outcomes following gamma knife surgery for larger-volume vestibular schwannomas. J Neurosurg. 2012;116(3):598–604. 31. Yang HC, Kano H, Awan NR, et al. Gamma Knife radiosurgery for larger-volume vestibular schwannomas. Clinical article. J Neurosurg. 2011;114(3):801–7. 32. Suh JH, Barnett GH, Sohn JW, et al. Results of linear accelerator-based stereotactic radiosurgery for recurrent and newly diagnosed acoustic neuromas. Int J Cancer. 2000;90(3):145–51. 33. Shirato H, Sakamoto T, Takeichi N, et al. Fractionated stereotactic radiotherapy for vestibular schwannoma (VS): comparison between cystic-type and solidtype VS. Int J Radiat Oncol Biol Phys. 2000;48(5):1395–401. 34. Sawamura Y, Shirato H, Sakamoto T, et al. Management of vestibular schwannoma by fractionated stereotactic radiotherapy and associated cerebrospinal fluid malabsorption. J Neurosurg. 2003;99(4):685–92. 35. Sakamoto T, Shirato H, Takeichi N, et al. Annual rate of hearing loss falls after fractionated stereotactic irradiation for vestibular schwannoma. Radiother Oncol. 2001;60(1):45–8. 36. Poen JC, Golby AJ, Forster KM, et al. Fractionated stereotactic radiosurgery and preservation of hearing in patients with vestibular schwannoma: a preliminary report. Neurosurgery. 1999;45(6):1299-305;discussion 305–7. 37. Meijer OW, Wolbers JG, Baayen JC, et al. Fractionated stereotactic radiation therapy and single high-dose radiosurgery for acoustic neuroma: early results of a prospective clinical study. Int J Radiat Oncol Biol Phys. 2000;46(1):45–9. 38. Fuss M, Debus J, Lohr F, et al. Conventionally fractionated stereotactic radiotherapy (FSRT) for acoustic neuromas. Int J Radiat Oncol Biol Phys. 2000;48(5):1381–7. 39. Chung HT, Ma R, Toyota B, et al. Audiologic and treatment outcomes after linear accelerator-based stereotactic irradiation for acoustic neuroma. Int J Radiat Oncol Biol Phys. 2004;59(4):1116–21. 40. Sakanaka K, Mizowaki T, Arakawa Y, et al. Hypofractionated stereotactic radiotherapy for acoustic neuromas: safety and effectiveness over 8 years of experience. Int J Clin Oncol/Japan Society of Clinical Oncology. 2011;16(1):27–32. 41. Kapoor S, Batra S, Carson K, et al. Long-term outcomes of vestibular schwannomas treated with fractionated stereotactic radiotherapy: an institutional experience. Int J Radiat Oncol Biol Phys. 2011;81(3):647–53. 42. Hansasuta A, Choi CY, Gibbs IC, et al. Multisession stereotactic radiosurgery for vestibular schwannomas: single-institution experience with 383 cases. Neurosurgery. 2011;69(6):1200–9. 43. Powell C, Micallef C, Gonsalves A, et al. Fractionated stereotactic radiotherapy in the treatment of vestibular schwannoma (acoustic neuroma): predicting the risk of hydrocephalus. Int J Radiat Oncol Biol Phys. 2011;80(4):1143–50. 44. Andrews DW, Werner-Wasik M, Den RB, et al. Toward dose optimization for fractionated stereotactic radiotherapy for acoustic neuromas: comparison of two dose cohorts. Int J Radiat Oncol Biol Phys. 2009;74(2):419–26.

270 Recent Advances in Otolaryngology—Head and Neck Surgery 45. Meijer OW, Vandertop WP, Baayen JC, et al. Single-fraction vs. fractionated linac-based stereotactic radiosurgery for vestibular schwannoma: a singleinstitution study.[see comment]. Int J Radiat Oncol Biol Phys. 2003;56(5): 1390–6. 46. Combs SE, Welzel T, Schulz-Ertner D, et al. Differences in clinical results after LINAC-based single-dose radiosurgery versus fractionated stereotactic radiotherapy for patients with vestibular schwannomas. Int J Radiat Oncol Biol Phys. 2010;76:193–200. 47. Kopp C, Fauser C, Muller A, et al. Stereotactic fractionated radiotherapy and LINAC radiosurgery in the treatment of vestibular schwannoma-report about both stereotactic methods from a single institution. Int J Radiat Ocol Biol Phys. 2011;80(5):1485–91.

Chapter Vestibular Rehabilitation

14

Jan Hendrik Wagner, Dietmar Basta, Arne Ernst

Introduction The vestibular system continuously receives information on the threedimensional position and movement of the head and body. The informational feedback of the eyes and the vestibular receptors must be processed separately to allow movements of the head while fixing a target with the eyes. In order to be able to integrate these different sensorimotor inputs, the vestibular system consists of three separate parts: • The peripheral and central part of the vestibular system. The peripheral receptors detect spatial accelerations in three-dimensional, fine tuned, and referenced by two gravity sensors • The three semicircular canals (SCC) on each side detect those rotational movements. They are arranged perpendicularly to each other and filled with endolymph (Fig. 14.1). Before ending into the utricle, the canals widen to build the ampulla, which contains the cupula with vestibular hair cells (Fig. 14.2). • Additionally, there are the two otolith organs, the utricle and the saccule, also standing perpendicular to each other. They detect linear acceleration forces in the vertical (saccular) and horizontal (utricular) plane (Fig. 14.1). • The vestibulo-ocular reflex circuits (VOR) of the vestibular system that give visual control over the position in space • The vestibulospinal (proprioceptive) part of the vestibular system, which consists of somatosensory receptors that provide information about the position and tension of joints and muscles (and therefore procure the positional and motional perception), which serve for tonus control of the spinal extensors (Fig. 14.3)

Mechanisms of compensation of a vestibular loss A clinically manifested, acute vestibular disorder leads to a tonus imbalance between the three different parts of the vestibular system and to a dominance


Fig. 14.1: Schematic diagram of adequate acceleration forces for vestibular receptors. 1: Lateral semicircular canal (SCC); 2: Superior SCC; 3: Posterior SCC; 4: Utricule; 5: Saccule; 6: Endolymphatic duct; 7: Endolymphatic sac; 8: Ductus reunions; 9: Cochlea; 10: Ampulla.

Fig. 14.2: Crista ampullaris of the semicircular canal (SCC): Deflection of the cupula and change of firing rate. Depending on the direction of endolymph acceleration, the firing rate of the hair cells is reduced or accelerated.

of one side. Symptomatic, acute, unilateral vestibular loss (UVL) produces severe vertigo in combination with intense vegetative symptoms (nausea and vomiting) because there is a strong angular and linear acceleration stimulus directed toward the healthy side.1 Especially in young patients, vestibular compensation of such a unilateral receptor deficit can be expected within a

Vestibular Rehabilitation 273

Fig. 14.3: Vestibulospinal pathway. Information of the vestibular receptors is conducted to motor neurons via the vestibulospinal pathway. (LVST: Lateral vestibulospinal tract; MVST: Medial vestibulospinal tract; MLF: Medial longitudinal fasciculus; VIII: Vestibular nuclei).

short period of time through regular vestibular input from the contralateral side (about 10–20 days). However, about one-third of all UVL patients does not fully compensate and suffer from long-term dizziness. That is why the process is not considered to be restitution, but compensation through habituation. If there is more than one receptor affected (usually: the lateral SCC) or in case of bilateral vestibular loss (BVL), it is mainly the nonvestibular information coming from the vestibulospinal (proprioceptive, somatosensoric) afferents that make habituation possible, if it is possible at all. But there are several factors that may cause delayed or incomplete compensation. Specific lesions (like otolith disorders) or the combined injury of peripheral and central vestibular structures (i.e. after traumatic

274 Recent Advances in Otolaryngology—Head and Neck Surgery brain injury) may cause such a delay. Additionally, the sensory components undergo a variety of structural and functional changes during aging. This includes diminished muscle strength and volume, loss of muscle fibers, motor units,2 endplates, and synapses. Furthermore, deterioration of the peripheral vestibular sensors was reported.3 Investigations of age-related differences in posture and movement control showed that the elderly tend to adopt cautious movement strategies (hip strategy vs. ankle strategy in the young) that are typically defined by slower motor responses. In these cases of delayed or incomplete compensation, a specific balance rehab program is mandatory.

Mobile posturography Specific tests for diagnosis of all peripheral vestibular receptors have been developed and are used in a daily routine: Head thrust test and caloric irrigation for the SCC, cervical vestibular evoked myogenic potentials (cVEMP) for the saccule, and eccentric rotation for utricular testing. But receptor disorders do not necessarily reflect a patient’s vestibular performance or even the tendency to fall. Balance deficits of various origins can be better characterized by assessment of postural control, which shows an increase in body sway and a higher risk to fall in vestibular impairment.4 Postural control is often estimated by stance tasks on a force plate under different sensorimotor conditions. This technique allows indirect approximation of the center of body mass and is not necessarily related to everyday balance performance. An alternative approach would be the direct measurement of body sway during daily-life conditions close to the center of body mass. Nowadays, ‘mobile posturography’ systems are available that investigate daily-life activities to determine the mobility of an individual patient. The Vertiguard system (Fig. 14.4) consists of two gyrometers in a battery-driven main unit that is fixed on a belt at the center of body mass (hip). Patients perform the Standard Balance Deficit Test (SBDT) or the Geriatric Standard Balance Deficit Test (gSBDT) with the device attached. The main unit continuously records the Coriolis force during body movements in pitch and roll by inbuilt gyroscopes and compares those values with individually preset thresholds for the stimulator activation in the specific direction. Preset thresholds are task specific. They were determined for the individual patient based on the maximum age and sex-related normative sway in the specific SBDT condition and sway direction.

Vestibular rehab (training) programs Various exercise programs (home or supervised) have been described, including physical training, Cawthorne–Cooksey interventions, alternative


Fig. 14.4: Mobile posturography with the Vertiguard-system: gyroscopes measure the body sway while the patient is performing everyday balance tasks. The recorded sway is then analyzed and compared to age and sex-related normative sway in the specific SBDT condition.

strategies – such as Tai Chi – and simulator-based training with virtual reality. But even when they are proved to be more effective compared with control or no intervention in recent Cochrane Reviews,5,6 these vestibular rehabilitation strategies are always long lasting and are not always successful. Patients with isolated otolith disorders7 or complex disorders that involve several receptors often keep complaining of ‘‘walking on pillows,’ ‘‘unsteadiness’’ in the dark or of reduced visual control even after the training. They are frequently unable to drive a car or to work for a longer period of time at a personal computer. Current studies have shown that rehabilitation strategies including a sensory feedback signal could be much more effective. The first feedback applications consisted of stance tasks with visual feedback,8,9 galvanic feedback,10,11 or vibrotactile feedback.12,13 Because patients tend to fall mostly in

276 Recent Advances in Otolaryngology—Head and Neck Surgery dynamic (i.e. movement) conditions, those stance tasks in balance rehabilitation should be accompanied by gait (or dynamic) tasks including daily-life situations. Earlier studies showed a high effectiveness of a free-field auditory neurofeedback training to reduce the body sway in patients with different peripheral vestibular disorders.14,15 This auditory neurofeedback application, however, is limited to the laboratory situation and those patients with good hearing (which is frequently not the case in the elderly or in patients with a vestibular disorder). Therefore, an intuitive tactile neurofeedback stimulus could be superior for encoding of the individual sway information during the training of everyday-life conditions. The underlying neural mechanisms for the training effect might involve operant learning16 and the multisensory convergence of enhanced processing of different sensory modalities.17 The results of a multicenter study18 indicate that a specific vibrotactile neurofeedback rehabilitation program, which is ‘tailored’ to meet the needs of the individual balance deficit, can significantly improve the postural control in stance and gait situations. This could be demonstrated by the significant reduction in body sway in pitch and roll directions during everyday-life test conditions and the significant increase in stability (SOT composite score) in different sensorimotor stance conditions (force plate measurements).

Surgical treatment of vestibular disorders Microsurgery of the vestibular system to treat symptoms of vertigo came up on a larger scale at the beginning of the 1960s.19 With more precise instruments and microsurgical techniques,20 better radiological imaging and a more profound scientific understanding of the pathophysiology of some vestibular diseases,21,22 new surgical treatment options came up and are applied worldwide today. As a principle (and not only because of medicolegal issues), before indicating surgical treatment all other options including drug therapy and vestibular training should have proven ineffective. The following section discusses therapy options for certain diseases.

Meniere’s Disease The Meniere’s trias is characterized by attacks of vertigo, tinnitus, and lowfrequency hearing loss. In stadium IV (from I–IV, AAO-HNS classification), there is a profound sensorineural hearing loss. If drug therapy (i.e. with betahistidine) fails and the vertigo attacks persist, the following therapeutical steps should be discussed with the patient:23 • Intratympanic injection of gentamicin • Saccotomy (surgical exposition of the endolymphatic sac) • Labyrinthectomy (if functional deafness is prevalent)


•

Otoneurosurgical approach for neurectomy of the superior vestibular nerve The saccotomy starts with a regular mastoidectomy, the bony wall to the posterior cranial fossa between sigmoid sinus, and posterior semicircular canal is then thinned out just until the endolymphatic sac is uncovered, laying on the dura of the posterior fossa. If vertigo symptoms return after a while, revision surgery may be an option because scar tissue and bony regeneration can cover the endolymphatic sac again. The labyrinthectomy performed through a transmastoidal approach is the safest measure to prevent recurring vertigo attacks.24 The indication is thus limited to patients with profound sensorineural hearing loss and functional deafness. The neurectomy of the superior vestibular nerve can be performed through a transmastoidal approach (only in deaf patients), a mid fossa approach, or a retrosigmoid approach. Patients often complain of gait disturbance postoperatively. This effect results from deafferentiation of the utricle by the superior vestibular nerve neurectomy.25 Although habituation is generally good (except of elderly patients), unsteadiness may persist especially in darkness and when complex movements are performed.26

Disorders of the semicircular canals Recurrent Benign Paroxysmal Positional Vertigo Canalolithiasis in benign paroxysmal positional vertigo affects the posterior semicircular canal in over 90% of the cases.27 Positional maneuvers (like the Epley maneuver) provoke rotatory nystagmus into the affected ear. If reposition maneuvers (Semont, Parnes, Epley, Brandt) only bring temporary relieve, occlusion of the posterior SCC can be an option. If it is carefully done, hearing preservation is possible in most of the cases.27 For occlusion, the canal is exposed from bone and then plugged with a patch (i.e. bone wax).28

Dehiscence Syndromes Dehiscence syndromes of the superior or posterior SCC can be demonstrated by high-resolution CT scans of the temporal bone. The lack of complete bony coverage of the superior or posterior SCC produces a ‘third mobile window.’ This leads to direct contact between inner ear fluids and intracerebral pressure that becomes symptomatic in some patients. The main symptoms are Tullio’s phenomenon (vertigo after loud acoustic stimulation), gait disturbance, oscillopsia, and recurring hearing loss and attack-like vertigo in some patients (Meniere’s type).29 These symptoms can occur together or separately. As there is no conservative treatment option, surgical therapy should be considered if the vestibular symptoms are

278 Recent Advances in Otolaryngology—Head and Neck Surgery prevailing. The surgical options are plugging the affected semicircular canal via a transmastoid approach28 or resurfacing the canal via a middle fossa approach.30

Vestibular Schwannoma The vestibular schwannoma is the most frequent intracerebral tumor that originates from Schwann cells of the VIIIth cranial nerve (in over 90% from the vestibular portion). Symptoms are slowly progressive sensorineural hearing loss, tinnitus, and vertigo. Only few vestibular schwannoma tend to grow. A ‘wait-and-scan’ strategy with annual MRI scans, or the occurrence of vertigo symptoms reveal the necessity for treatment. Small, intracanalicular schwannoma can be resected by a transmastoid approach with labyrinthectomy. In cases with good residual hearing and for larger, extrameatal tumors, a neurosurgical transtemporal or retrosigmoid approach is appropriate.31

Further otological disorders with vertigo There are multiple other disorders originating from the peripheral vestibular systems that lead to vertigo and offer surgical treatment options: • Labyrinthine fistula (mostly after mild traumatic brain injury, occasionally with sensorineural hearing loss): Covering the round and oval window niche with connective tissue and fibrin glue • Temporal bone fractures (isolated promontorial wall fractures occur): Covering the fracture line with temporalis fascia and fibrin glue • Labyrinthitis (inflammatory complication of mastoiditis): Mastoidectomy and therapy with antibiotics (that cross the blood–brain barrier) • Vestibular irritation by middle ear prosthesis (i.e. post-traumatically dislodged stapes piston): Revision surgery, removal of the prosthesis, and covering of the round and oval window with connective tissue and fibrin glue and accompanying corticoid therapy • Endolymphatic sac tumors (very rare, may lead to vertigo attacks): otoneurosurgical removal.32

Summary The majority of vestibular disorders can be treated by rehab programs, but few should undergo surgery. Neurofeedback therapy has been shown to be most effective in the rehab of vestibular impairment.

References 1. Curthoys IS. Vestibular compensation and substitution. Curr Opin Neurol 2000; 13:27–30.

Vestibular Rehabilitation 279 2. Horlings CGC, van Engelen BGM, Allum JHJ, et al. A weak balance: the contribution of muscle weakness to postural instability and falls. Nat Clin Pract Neurol 2008; 4:504–15. 3. Sturnieks DL, St George R, Lord SR. Balance disorders in the elderly. Neurophysiol Clin 2008; 38:467–78. 4. Colebatch JG. Consequences and assessment of human vestibular failure: implications for postural control. Adv Exp Med Biol 2002; 508:105–10. 5. Hillier SL, McDonnell M. Vestibular rehabilitation for unilateral peri pheral vestibular dysfunction. Cochrane Database Syst Rev 2011:CD005397. doi:10.1002/14651858.CD005397.pub3 6. Passier L, Doherty D, Smith J, et al. Vestibular rehabilitation following the removal of an acoustic neuroma: a systematic review of randomized trials. Head Neck Oncol 2012; 4:59. 7. Basta D, Singbartl F, Todt I, et al. Vestibular rehabilitation by auditory feedback in otolith disorders. Gait Posture 2008; 28:397–404. 8. Pavlou M, Lingeswaran A, Davies RA, et al. Simulator based rehabilitation in refractory dizziness. J Neurol 2004; 251:983–95. 9. Viirre E, Sitarz R. Vestibular rehabilitation using visual displays: preliminary study. Laryngoscope 2002; 112:500–503. 10. Danilov YP, Tyler ME, Skinner KL, et al. Efficacy of electrotactile vestibular substitution in patients with peripheral and central vestibular loss. J Vestib Res Equilib Orientat 2007; 17:119–130. 11. Barros CGC, Bittar RSM, Danilov Y. Effects of electrotactile vestibular substitution on rehabilitation of patients with bilateral vestibular loss. Neurosci Lett 2010; 476:123–6. 12. Kentala E, Vivas J, Wall C, 3rd. Reduction of postural sway by use of a vibrotactile balance prosthesis prototype in subjects with vestibular deficits. Ann Otol Rhinol Laryngol 2003; 112:404–09. 13. Wall C, 3rd. Application of vibrotactile feedback of body motion to improve rehabilitation in individuals with imbalance. J Neurol Phys Ther JNPT 2010; 34:98–104. 14. Dozza M, Horak FB, Chiari L. Auditory biofeedback substitutes for loss of sensory information in maintaining stance. Exp Brain Res Exp Hirnforsch Expérimentation Cérébrale 2007; 178:37–48. 15. Hegeman J, Honegger F, Kupper M, et al. The balance control of bilateral peripheral vestibular loss subjects and its improvement with auditory prosthetic feedback. J Vestib Res Equilib Orientat 2005; 15:109–17. 16. Taub E, et al. An operant approach to rehabilitation medicine: overcoming learned nonuse by shaping. J Exp Anal Behav 1994; 61:281–93. 17. Foxe JJ, Schroeder CE. The case for feedforward multisensory convergence during early cortical processing. Neuroreport 2005; 16:419–23. 18. Basta D, et al. Efficacy of a vibrotactile neurofeedback training in stance and gait conditions for the treatment of balance deficits: a double-blind, placebocontrolled multicenter study. Otol Neurotol Off Publ Am Otol Soc Am Neurotol Soc Eur Acad Otol Neurotol 2011; 32:1492–99.

280 Recent Advances in Otolaryngology—Head and Neck Surgery 19. Loew F. In Cranial Nerves; 1–5 (Springer Berlin Heidelberg, 1981). 20. Fisch U, Mattox DE. Microsurgery of the skull base. Thieme, 1988. 21. Ernst A, et al. Management of post-traumatic vertigo. Otolaryngol Head Neck Surg Off J Am Acad Otolaryngol-Head Neck Surg 2005; 132:554–8. 22. Vibert D, Häusler R. Long-term evolution of subjective visual vertical after vestibular neurectomy and labyrinthectomy. Acta Otolaryngol (Stockh.) 2000; 120:620–2. 23. Sajjadi H, Paparella MM. Meniere’s disease. Lancet 2008; 372:406–14. 24. Badke MB, Pyle GM, Shea T, et al. Outcomes in vestibular ablative procedures. Otol Neurotol. 2002; 23:504–9. 25. Lehnen N, Aw ST, Todd MJ, et al. Head impulse test reveals residual semicircular canal function after vestibular neurectomy. Neurology 2004; 62:2294–96. 26. Silverstein H, Jackson LE. Vestibular nerve section. Otolaryngol Clin North Am 2002; 35:655–73. 27. Parnes LS, McClure JA. Posterior semicircular canal occlusion in the normal hearing ear. Otolaryngol-Head Neck Surg Off J Am Acad Otolaryngol—Head Neck Surg 1991; 104:52–7. 28. Agrawal SK, Parnes LS. Human experience with canal plugging. Ann N Y Acad Sci 2001; 942:300–305. 29. Minor LB, Solomon D, Zinreich JS, et al. Sound- and/or pressure-induced vertigo due to bone dehiscence of the superior semicircular canal. Arch Otolaryngol—Head Neck Surg 1998; 124:249–58. 30. Pletcher SD, Oghalai JS, Reeck JB, et al. Management of superior canal dehiscence syndrome with extensive skull-base deficiency. ORL J Oto-RhinoLaryngol Its Relat Spec 2005; 67:192–95. 31. Somers T, Van Havenbergh T. Multidisciplinary management of vestibular schwannomas: state of the art. B-ENT 2012; 8:235–240. 32. Cohen JE, Spektor S, Valarezo J, et al. Endolymphatic sac tumor: staged endovascular-neurosurgical approach. Neurol Res 2003; 25:237–40.

Chapter Tinnitus T herapy

15

Timea Tóth, Markus HF Pfister, Peter A Tass

History of tinnitus medicine The medical papyri of ancient Egypt (Ebers papyrus) are the oldest known written sources on the medical treatment of tinnitus. For instance, columns 91–92 (Ebers, 764–770) include great detail regarding the ‘treatments for the ear, if its hearing is poor,’ ‘for the ear, if it gives foul water,’ and the ‘treatment for a bewitched ear’.1 The latter presumably refers to an ear with tinnitus. The Fayyum Medical Book (Crocodilopolis), another document from ancient Egyptian medicine probably dating from a later period, described tinnitus as a ‘worm in the ear.’ One section discusses as ‘treatment for humming ear’ the administration of ‘reed stalk, sap of black reed, a measure of herbst, salt, one hulwart in chips, oleoresin, oil ointment, and sap of lotus’ to the hearing organ.2 The Corpus Hippocraticum is a collection of more than 60 manuscripts on medicine, which originate from Hippocrates’ time in ancient Greece. It is an eminent compendium of medical science in antiquity and has retained its importance even to this day. It is remarkable to mention that tinnitus and deafness are not presented as autonomous symptoms but always appear as parts of a symptom complex.1,3 Aristotle, the tutor of Alexander the Great, was another Greek scientist who made major contributions to the history of medicine. He described tinnitus not as a symptom of a disease but as a physiological sensation. In his Problemata Physica, Aristotle proposed the idea of masking tinnitus by an external acoustic stimulus and suggested it as a treatment.1,4 In the Renaissance, the dissection of human bodies was just coming into common practice. During this period of time, many universities were founded in quick succession in Italy, France, Germany, and England. Likewise, impressive advances occurred in Anatomy, and later Pathology, which became the basic sciences of medicine. One of the most important figures in the history of Renaissance medicine is Paracelsus. In his Chirurgia Magna, he deals with deafness and tinnitus. This work also contains the clear statement

282 Recent Advances in Otolaryngology—Head and Neck Surgery that intense noise can damage the hearing and cause tinnitus. However, it does not recommend any treatment for it.1 At the beginning of the nineteenth century, the otological scene changed significantly when the first scientific journals were published. Soon these became an important means of communication among researchers and clinicians. In 1821, Jean-Marie Gaspard Itard presented the earliest clear description of external noise deliberately applied to mask tinnitus.5 Five years later, René Laennec—the French physician who invented the stethoscope—used his invention to examine ears with tinnitus. Since he could not hear anything, he concluded that the tinnitus is an acoustic hallucination.6 By the turn of the twentieth century, the beginning of modern audiology opened a new chapter in the field of tinnitus research. In the United States, E.P. Fowler carried out nearly all the experiments on tinnitus-affected patients that could be devised (i.e. frequency and loudness matches, masking). He was the first one to determine the exact frequencies in cases of tinnitus and found that tinnitus was easily masked at all frequencies. The main conclusions one can draw from his work are (1) the masking effect is significantly stronger as the masking tone approaches the frequency band of the tinnitus; (2) the presence of tinnitus is always more or less associated with hearing impairment; and (3) the pathology of tinnitus is connected with neurophysiological research.7 Experimental models play an important role in understanding the manifestations of function or dysfunction of systems. Various tinnitus models have been reported in the cochlea or central auditory system. Positive theoretical developments were observed in the past years, but the exact mechanism of tinnitus still remains to be elucidated. Initially, tinnitus was understood as an ear disease. However, the modern conception of tinnitus is based on neural activity in the brain. Nowadays it is generally accepted that most forms of subjective tinnitus are attributable to change in the central nervous system (CNS).8,9 This theory supports the fact that cochlear hearing impairment is seen as a probable if not a necessary condition for tinnitus. The clinical heterogeneity of the tinnitus symptoms suggests that different clinical types of tinnitus exist. In addition, other factors like depression, anxiety, alcohol addiction, and panic attack tend to be associated with severe tinnitus. The multidimensional clinical characteristics of tinnitus make treatment difficult since treatment must be based on the identification of the underlying causes. Currently, there are many different approaches to treatment, some of which can be readily integrated into daily clinical practice. Although many treatment trials have shown positive effects for individual patients, the evidence of effectiveness for the collective as a whole is still quite limited. This chapter concerns itself with the currently available treatment options and their clinical efficiency.

Tinnitus Therapy 283

Treatments of tinnitus Tinnitus treatment is as diversified as its pathophysiology. Although numerous pathophysiological mechanisms have already been identified, tinnitus is still not completely understood. Currently, there is growing evidence that neuronal activity changes in different parts of the auditory pathway may lead to an excitatory–inhibitory imbalance. This imbalance can cause hyperactivity in the auditory pathway, leading in turn to the perception of phantom sounds. Different treatments and new therapeutic approaches have been proposed to modulate this neuronal hyperactivity. Among these approaches are pharmacologic therapy, psychological support, biofeedback (BF), and various forms of sound therapies (e.g. noise generators, hearing aids, and music treatment) and neuromodulatory treatment (e.g. coordinated reset (CR) stimulation and neurobiofeedback). Further, tinnitus medical practices have shown that one type of treatment is not enough and instead a combination of them is needed.

Pharmacological treatment Tinnitus has become one of the most challenging tasks faced by the medical field, since it has generally a moderately negative impact on patient’s quality of life. A large number of pharmacological agents (drugs) have been used for the treatment of tinnitus patients, providing moderate relief of symptoms and in some cases tinnitus suppression.10 Despite the numerous clinical trials that have been performed for a considerable number of different drugs, no drug treatment can—as yet—be considered well established in terms of long-term reduction in the tinnitus impact in excess of placebo effects. A further explanation for these results across studies might be the diversity of pathophysiology of tinnitus. Therefore, there is a pressing need to develop new drugs that can provide significant tinnitus relief and, eventually, its complete disappearance.

Treatment of Acute Tinnitus Tinnitus of < 3 months of duration is considered acute. Its immediate treatment with a suitable therapy would likely prevent the development of chronic tinnitus. Above all, one of the most important therapeutic strategies in the acute phase involves the prescription of drugs. The first diagnostic step to be performed in every patient should reveal sufficient clinical information, including—if possible—an understanding of what causes his/her tinnitus. The adequate identification of the possible etiology of acute tinnitus is of utmost importance in determining the optimal treatment of each case. In its early stages, there exists a possibility to suppress tinnitus, as long as it is triggered by reversible acute cochlear damage, and

284 Recent Advances in Otolaryngology—Head and Neck Surgery represents a minimal plastic change that may enable restoration of neural hyperactivity in the central auditory pathway. The Associations of Otolaryngology in many countries recommend the following pharmacotherapies as treatment of acute tinnitus: systemic or intratympanic corticosteroids, vasoactive drugs, nootropics, glutamate receptor antagonists, local anesthetics, rheological infusion, ginkgo preparations, calcium antagonists, and coronary drugs. The means of administration of such drugs can be classified into two categories: systemic delivery and local therapy.

Systemic or Intratympanic Corticosteroids Steroid therapy is one of the most recommended treatments of acute tinnitus. Although there is good evidence for the effectiveness of this treatment, its mechanism remains unclear. Steroids upregulate the expression of antiinflammatory proteins and downregulate the expression of proinflammatory proteins, thus they have anti-inflammatory and immunosuppressive effects. If the cochlear damage is caused by inflammation, steroids can inhibit the inflammatory cascade and spare in this way the cochlea. Moreover, steroids may improve the inner ear milieu by increasing cochlear blood flow through sodium reabsorption.11 The corticosteroid therapy (oral or intravenous) should begin with a high-dose regimen for the first 3 days of treatment. Subsequently, the dosage should be continuously reduced by half. This therapy may last for a period of approximately 10 days depending on the condition of the patient. The use of intratympanic steroid (ITS) is a procedure that can be administered under local anesthesia. It is usually well tolerated by patients and offers the possibility to treat one ear at a time. ITS is an alternative method for tinnitus patients who are contraindicated or intolerant to systemic steroids due to their side effects. Additionally, ITS leads to significantly higher perilymphatic concentrations of steroid in the inner ear compared with the systemic therapy.12 Reported complications of this therapy include tympanic membrane perforation, pain, hearing loss, short-duration dizziness, bitter taste, otitis media, and also tinnitus.

Rheological Therapy: Colloidal Plasma Substitutes, Vasodilators Blood rheological properties substantially influence tissue microcirculation, oxygen and nutrients supply, and tissue regeneration.13 Increased plasma viscosity and decreased erythrocyte filterability are thought to be a cause of tinnitus. Rheological therapy is aimed at the improvement of microcirculation in the cochlea and in the central auditory pathway by lowering plasma and blood viscosities, as well as decreasing erythrocyte and thrombocyte aggregability. The most widely used drugs are Dextran, Haes-Steril 6%, and Pentoxifylline. However, their effectiveness in relieving tinnitus symptoms is still uncertain.


Nootropics Nootropics refer to a class of drugs that improve a variety of cognitive functions such as learning and memory. Piracetam, the most common of the nootropic drugs, is a cyclic derivative of gamma-aminobutyric acid (GABA). It influences neuronal and vascular function, improves memory and brain performance, and acts on cognitive function without causing sedation or stimulation.14 Moreover, Piracetam possesses a pronounced antihypoxic effect. It was found to increase blood flow and oxygen consumption in parts of the brain, but this may be a side effect of increased brain activity.15 Piracetam’s peripheral vascular effect has indicated its use for sudden deafness and tinnitus.16 The minimum total duration of therapy is approximately 4–6 weeks. Nootropic drugs, therefore, can be recommended for the treatment of acute and chronic tinnitus

Local Anesthetic and Coronary Drugs Lidocaine is a short-term anticonvulsant as well as a local anesthetic. It has vasodilatory, antithrombotic, and anti-inflammatory effects. Various ion channels and receptors (voltage-gated Na+, K+, and Ca+ channels, GABA, glutamate, and vanilloid receptors), found in the auditory system, are affected by lidocaine.17 Lidocaine’s main effects are due to the blockage of the above-mentioned channels and receptors in the neuronal cell membrane. Lidocaine is not effective when taken orally because of poor biological absorption. Many studies have shown that (intravenous or intradermal) lidocaine, administered in high doses, can alleviate tinnitus, although the exact mechanism of action is still unknown.18 Some other trials have focused on intratympanic instillation of relatively high topical concentrations of lidocaine, and a positive effect has been reported.19 In this case, the temporary relief of tinnitus symptoms (positive effect) is accompanied by side effects such as nausea and vertigo. By contrast, the treatment with oral antiarrhythmic drugs (i.e. tocainide and mexiletine) has led to reports of nonsignificant effects. Among local anesthetic and coronary drugs, intravenous lidocaine has remained the most recommended therapy to relieve tinnitus; however, it has only a short-lasting effect.

Other Drug Treatments Betahistine is an oral preparation of a histamine precursor (H3 antagonist blood receptor and an H1 agonist receptor) and has been used as a specific treatment of Meniere’s disease. It induces vasodilatation and increases capillary permeability in ischemic areas of the cochlea, leading—in turn—to an increased perfusion of the stria vascularis.20 There is at present insufficiently good evidence on the effect of betahistine on vertigo, hearing loss, and tinnitus in clearly defined Ménière’s disease. Similarly, there is not enough

286 Recent Advances in Otolaryngology—Head and Neck Surgery evidence to support betahistine as a treatment of tinnitus.21,22 Oxidative stress can cause toxic effects such as the production of peroxides and reactive oxygen species (ROS), both of which damage all components of the cell. It has been identified that noise-induced oxidative stress plays a significant role in cochlear hair cell death through an increase in superoxide anion, hydrogen peroxide, and hydroxyl radical in the stria vascularis.23 The endothelium is a major risk of radical-induced lesions and this damage is most observable in microcirculation. High ROS levels in the blood were detected in patients with tinnitus.24 Since antioxidant therapy (vitamin C, vitamin E, coenzyme Q10, β-carotene) reduces oxidative stress and the impairment of inner ear tissues, it may be considered as a supplemental treatment. Ginkgo biloba possesses antioxidant properties, since it neutralizes ROS and also enhances the activity of antioxidant enzymes. Its two bioactive components, flavonoids and terpenoids, have been investigated for their neuroprotective properties and their benefits on cognitive function.25 It can take approximately 9 weeks to see any effects from Ginkgo leaf extract. Several clinical trials have been conducted to study the effect of Ginkgo biloba on tinnitus. Although some positive results were reported in a number of small, methodologically limited studies, the largest and methodologically most robust trial did not show a difference in outcomes between ginkgo extract and placebo.26

Treatment of chronic tinnitus Different types of tinnitus can be distinguished according to their life span: subacute tinnitus, if it lasts between three and 6 months; and chronic tinnitus, if it persists longer than 6 months. The literature concerning the pharmacotherapy of chronic tinnitus is vast. Some (but not all) drugs are reviewed in the following sections.

Antidepressants Abnormal function in auditory and nonauditory areas, such as the limbic system, amygdala, and prefrontal cortex, is involved in the pathophysiology of chronic tinnitus. Negative emotions such as depression, anxiety, and other psychosomatic disturbances, which are under the control of the limbic system, are reported to be associated with tinnitus perception.27 Given this known association, it is not surprising that there is a growing interest to examine psychoactive drugs for tinnitus management. Psychoactive drugs may act on the central auditory system or on the psychological illness, or they have a simultaneous effect on both, thus resulting in a reduction of tinnitus. A patient, who developed depression following the onset of tinnitus, exhibited a significant decrease in both tinnitus and depression symptoms following the use of antidepressants. The types of antidepressants used in


pharmacological treatment of chronic tinnitus are commonly tricyclic antidepressants (e.g. amitriptyline, imipramine, trimipramine, and nortiptyline) or selective serotonin reuptake inhibitors (e.g. paroxetine, sertraline, and fluoxetine). Some trials involving the above-mentioned drugs showed signi ficant reduction in depression scores, tinnitus disability scores, and tinnitus loudness in tinnitus patients with depression and anxiety, as compared with patients administered with a placebo. Even so, there is no evidence that tricyclic antidepressants are effective or ineffective in the management of tinnitus.28

Anticonvulsants Experimental studies in animals and humans have revealed that tinnitus is associated with a synchronized hyperactivity in the auditory and also in nonauditory cortex of brain. The goal of an anticonvulsant is to suppress the rapid and excessive firing of neurons by blocking sodium channels or enhancing the GABA function. GABA is a generally inhibitory neurotransmitter in the central auditory pathway. Decreased GABA activity, which causes abnormal activation of neurons, is presumed as a potential cause of tinnitus. Several GABA-active drugs (benzodiazepine, gabapentin, alprazolam, baclofen) may enhance inhibition by augmenting the action of GABA or by increasing the synthesis of GABA.29 Carbamazepine and lamotrigine may halt the depolarization of cells by blocking voltage-dependent sodium channels, thereby reducing neural firing. There is no evidence from studies performed so far to show that anticonvulsants have a large positive effect in the treatment of tinnitus, but a small effect has been demonstrated.30

Antiglutamatergic Agents Glutamate is the main excitatory neurotransmitter in both the cochlea and the central auditory pathways. The most important glutamate receptors at auditory pathways are AMPA and NMDA; they allow for the transfer of electrical signals between neurons in the brain. Moreover, neuroplastic changes in the CNS are largely dependent on NMDA-mediated neurotransmission. It has been hypothesized that excessive release of glutamate at the synaptic cleft between the inner hair cell and the terminal fibers of the auditory nerve may cause tinnitus. This excessive release of glutamate causes overexpression of NMDA synaptic receptors. Glutamate receptor antagonists reduce this excitatory neurotransmission.31 The systemic use of nonselective glutamate receptor blockers such as caroverine is limited because of neurological and psychiatric side effects.32 The results of selective NMDA blockers therapy (e.g. acamprosate, flupirtine, or memantine) on tinnitus patients are also contradictory.33–35


Other Drug Treatments Some other drugs from different pharmacological classes are prescribed for tinnitus. These include the prostaglandin E1 analog misoprostol, calcium blocker nimodipine, the loop diuretic furosemide, dopamine agonist pramipexole, dopamine antagonist sulpiride, as well as zinc, atorvastatin, melatonin, vitamins, antihistamines, botulinum toxin, and so on. Drugs that are applied for acute therapy are usually used as a treatment of chronic tinnitus as well. All the above-mentioned drugs provide inconsistent benefits for tinnitus patients. Despite the investigation of a large number of pharmaceutics, no drugs exist as an established treatment. In addition, since several subgroups of tinnitus exist and each of them requires different type of therapy, it seems unlikely that there will be a single drug for the treatment of all forms of tinnitus.

Hyperbaric oxygen therapy Although the pathologic mechanisms of tinnitus remain unclear, tinnitus can be associated with inner ear damage. Moreover, pathological changes in the inner ear blood circulation impair the oxygenation in the stria vascularis. From a physiological perspective, the stria vascularis of the basal turns of the cochlea—which is responsible for encoding high-frequency sound—consumes three-to-four times as much oxygen than in the apical turns. Oxygen diffuses from the stria vascularis into the perilymphatic and endolymphatic space supplying the organ of Corti, which have no direct vascular supply. Impairment of microcirculation or increased cellular oxygen consumption by the organ of Corti (e.g. by noise exposure) might induce hypoxia, oxidative stress, anaerobic metabolism, damage of vascular permeability, and eventually apoptotic cell death of sensory and neuronal elements of the organ of Corti.36,37 Since a lack of oxygen appears to be relevant in the pathogenesis of tinnitus, treatments can be designed to improve oxygenation and blood circulation of the inner ear. The pressure of oxygen in the blood depends directly on the partial oxygen pressure of inhaled air. It is well known that oxygen significantly promotes the healing process. Hyperbaric oxygen (HBO) therapy improves the oxygenation in the tissue. During this treatment, patients breathe 100% oxygen at elevated ambient pressure, interrupted sometimes by short isobaric air intervals. This causes the oxygen to dissolve in the plasma and increases the oxygen partial pressure in the blood. HBO therapy is delivered in a chamber pressurized at 1.5–3.0 atmospheres absolute (ATA) for periods between 60 and 120 minutes once or twice daily. The course of treatment varies by diagnosis, but generally includes 20–40 therapy sessions. It is important to mention that satisfactory microcirculation in the affected area is a prerequisite for the treatment.


HBO therapy is one of the most popular and commonly used therapy for divers who suffer from idiopathic sudden sensorineural hearing loss and acute acoustic trauma. In contrast, limited evidence suggests that HBO therapy reduces tinnitus.38 On the one hand, retrospective studies indicate greater improvement if the tinnitus has been present for < 3 months. On the other hand, tinnitus worsening was showed in up to 12% of patients with chronic tinnitus.36 Additionally, the occurrence of several complications, such as barotrauma (including middle ear, sinuses and lungs), pain in the ear, visual disturbance, fluid in the lungs and seizure, has been reported. The current knowledge indicates that HBO therapy can be useful as an adjunctive treatment, specifically for acute tinnitus.

Sound therapy (hearing devices) Externally generated sound to provide tinnitus masking has been used as a therapy since 1976.39 Its aim is to distract the patient from hearing the tinnitus. Sound therapy devices include maskers, noise generators, hearing aids, and tinnitus instruments (combination devices that contain both a noise generator and a hearing aid). The noise from sound therapy devices is usually better tolerated than the tinnitus itself; moreover it can reduce the contrast between the tinnitus signal and the background activity in the auditory system. The first masking devices worked by completely masking the tinnitus (complete elimination of the tinnitus sensation). These highpowered devices used broadband noise (white or pink noise), and produced louder signals than the tinnitus itself. Prolonged exposure to masking stimulation brought with it a definite risk for hearing loss. Other known side effects are as follows: (1) tinnitus loudness might be enhanced when the masker is turned off; (2) the use of broadband loud noise treatment could act as a source of stimulation for the other tinnitus-unrelated part of the central auditory system and prevent hyperactivity of the associated neurons. The maskerinduced increase of tinnitus loudness might be caused by an increase of synaptic connectivity caused by the noisy stimulation. In fact, in a theoretical study it was shown that in neuronal networks with spike-timing dependent plasticity even independent noise (separately delivered to each neuron in an uncorrelated manner) typically strengthens the synaptic connectivity, so that the pathological tinnitus-related synchrony gets at least stabilized or even enhanced.40 The masking noise is better tolerated when the stimulus frequency is near the tinnitus pitch without amplifying the other part of the auditory cortex. Particularly, with the adjustable frequency-specific narrowband (partial) masking, it is possible to select the optimum noise band for masking. During the fitting of noise devices, the aim is always to establish a masking sound level that patients find more acceptable than their tinnitus. It is important to adjust these devices so as to generate the lowest possible sound level of masking. In order to achieve effective treatment, the loudness

290 Recent Advances in Otolaryngology—Head and Neck Surgery level of the masking sound must never be so loud as to be less acceptable than the patient’s tinnitus. The tinnitus is diminished but is still audible. In general, these tinnitus noise generators are highly recommended for tinnitus patients with normal hearing. Hearing aids are proposed for tinnitus patients with hearing loss. They have been presumed to produce masking of tinnitus by amplifying ambient environmental noise. As a consequence, they may cover and decrease the contrast between tinnitus and the silence caused by hearing loss. Additionally, hearing aids increase speech understanding, reduce attention to tinnitus, decrease frustration, and improve quality of life related to hearing difficulties. Hearing aids are also used as a tool to increase the stimulation of the auditory system. Even a mild hearing loss decreases the afferent auditory inputs to central auditory structures and causes changes in the function of parts of the auditory nervous system by decreasing central inhibition and hyperactivity of the neurons responsible for tinnitus.41 Tinnitus pitch is often associated with the frequency range of hearing impairment.42 In that case, tinnitus pitch matching is a useful procedure to predict the effectiveness of hearing aid fitting in masking tinnitus. Whenever possible, hearing aids should be fitted in both ears (better spatial localization and understanding) with open ear canal fit. This allows the ear canal to remain partially open (sufficient ventilation), eliminate the sensation of occlusion, and is also cosmetically appealing. Hearing aids alone do not usually provide adequate masking for patients, specifically for high-pitched tinnitus. Hearing aids with a built-in sound generator (tinnitus instrument) can generate narrowband or broadband noise, and provide adequate masking as well as sound amplification in the high-frequency region.43 These devices have independent volume controls for hearing and masking. If the tinnitus associated with profound hearing impairment can be treated with cochlear implant (CI), then it is possible not only to amplify the sound but also to mask the tinnitus with noise. It is unclear whether the physical and/or psychological changes influence tinnitus relief after CI. The improved quality of life through better hearing and speech understanding may positively affect the tinnitus annoyance. Moreover, patients with decompensated tinnitus benefit more than those with compensated tinnitus, in both elderly and younger groups.44 By stimulating the deafferented ascending auditory nervous system with a CI, tinnitus could be significantly suppressed (or even eliminated).45 EEG data showed that the use of CI not only reduced signs of tinnitus-related activity in the auditory cortex but also in areas of the CNS associated with emotion (limbic system) and attention (dorsolateral prefrontal cortex).46 Additionally, EEG data exhibited a decreased connectivity between distress-related areas and auditory cortex.46 Also, plastic changes in the central auditory system and associated cortical areas induced by CI electrical stimulation have been suggested as possible mechanisms of tinnitus relief. Unfortunately, tinnitus can also become worse than


before CI.47 Furthermore, tinnitus may be present after CI, even though the patient did not report it before CI. There is no strong evidence from the available literature that a significant change in loudness of tinnitus or the overall severity of tinnitus can be achieved by use of sound-generating devices, although the effect may be better than placebo.48

Tinnitus retraining therapy The tinnitus retraining therapy (TRT) was originally developed by Jastreboff and Hazell on the basis of a neurophysiological tinnitus model.27,49 This model proposed that tinnitus is caused by abnormal neural activity, which is typically generated at the periphery of the auditory system and in the dorsal cochlear nucleus (DCN). Each area of the cochlear basilar membrane, on which hair cells are dysfunctional, causes an imbalance of activity in the DCN, specifically disinhibition with increased spontaneous activity. This signal is detected in the subcortical auditory center as a neutral stimulus. If the continuous firing signal of cochlear fibers is further processed in the high cortical levels of the auditory system, it is perceived and evaluated as a phantom sound called tinnitus. If tinnitus is categorized as an unimportant signal, then it undergoes automatic habituation, and the tinnitus-related neuronal activity is not transmitted to the limbic system. If the perception of tinnitus is associated with a negative reinforcement, then the limbic system is activated. In particular, patients tend to treat tinnitus as a signal that something is going wrong with hearing, or with the brain, and as a result start to focus their attention on it. Repeated appearance of the sound, linked to this negative reinforcement, results in an enhancement of reactions in the limbic and the autonomic nervous system. The former acts at the higher, cognitive brain level, and the latter works at the lower, subconscious level. Those patients for whom tinnitus is clinically significant exhibit distress, a high level of anxiety, and a number of psychosomatic problems. These symptoms result from the abnormally high activation of the limbic (emotional activation) and the autonomic nervous (behavioral reactions) systems. The ultimate goal of TRT therapy is to ‘retrain’ the brain to habituate to the tinnitus signal and thereby to get the patient to reclassify tinnitus as a neutral stimulus. The habituation process is a normal function of the brain to select and to block all unimportant stimuli from reaching our awareness at the subconscious level. It also blocks reactions that these stimuli would otherwise evoke. Thus, the goal of TRT is to achieve two types of habituation: habituation of reaction and perception. Habituation of reaction is the primary goal of the therapy. It can be achieved by weakening the functional connections between the auditory pathways and the limbic/autonomic nervous system, eliminating thereby tinnitus-induced emotional reactions.

292 Recent Advances in Otolaryngology—Head and Neck Surgery The secondary goal is to facilitate habituation of tinnitus perception. Once achieved, patients will be aware of their tinnitus only a small proportion of the time and mainly when focusing their attention on it. Based on the neural plasticity, habituation is regarded as a specific learning process in the brain.50 TRT involves the parallel use of retraining or directive counseling together with sound therapy. Directive counseling is a structured educational program that is designed to remove fears and anxieties associated with tinnitus. It involves exhaustive medical counseling about the auditory system, tinnitus etiology, the neurophysiological model, mechanisms of habituation, positive prognosis, and other cognitive strategies, all of which are explained individually to each patient. Counseling in TRT is carried out typically on an individual basis. In each session, the therapist asks the patient about changes in his/her tinnitus perception and, together, they fill in the Initial Interview form. The TRT Initial Interview form is a structured set of questions about tinnitus, hyperacusis, and subjective hearing difficulties.51 The follow-up Interview form is a shortened version of the Initial Interview form. The total length of each session is not fixed; it depends on the clinical response and generally requires 30–60 minutes. The follow-up sessions should take place at monthly intervals for the first 3 months and then at 6, 9, 12, 18, and 24 months. Sound therapy acts by providing the auditory system with constant, monotonous, low-level sound to decrease contrast between tinnitus-related neuronal activity and background neuronal activity. Another role of sound therapy is to interfere with the brain´s ability to detect the tinnitus signal and to reduce abnormal gain in the auditory system, i.e. to reduce the ‘detectability’ of the tinnitus signal at the subconscious level. Reduced detection of the tinnitus signal at the subcortical level will result in a reduced perception of tinnitus at the cortical level. Sound can be provided from environmental enrichment devices (e.g. music, TV, and broadband noise CD), hearing aids, broadband noise generators, or combination devices (i.e. hearing aid plus noise generator). TRT patients must always adjust their sound generators at or just below the tinnitus mixing point. Although sound therapy is considered essential for TRT, the use of sound devices is not obligatory. TRT is applicable for all types of tinnitus, as well as for decreased sound tolerance (hyperacusis). Many studies refer to the use of a modified version of this therapy (e.g. simplified TRT and TRT combined with behavioral therapeutic elements). The reduction in general severity of tinnitus-related distress is usually observed after 3–6 months. There is often no further improvement after 12 months, but the result tends to remain stable.52 Clinical trials have shown that TRT is much more effective as a tinnitus treatment than masking therapy, and that it has no side effects.53 Although it is one of the most promising habituation based-treatments, TRT has not yet sufficient scientific evidence supporting its efficacy in reducing tinnitus-related distress.53


Cognitive behavior therapy Psychopathological effects arise as serious aspects of tinnitus; however, they are not the cause. Additional processes such as attention, cognition, and fear play a role. The majority of patients with tinnitus cannot tolerate the symptom, and may instead relate to psychological and psychosomatic problems. The intensity of stress reactions and neural damage depends strongly on the individual’s personality.54 Several studies related to psychic comorbidity find disturbances among 85% of decompensated chronic tinnitus. The most common disturbances are major depression, anxiety, neuroticism, social phobia, sleep disturbance, etc., all of which have been found to significantly increase the severity of tinnitus.55 Cognitive behavior therapy (CBT) for tinnitus aims to alter maladaptive cognitive, emotional, and behavioral responses to tinnitus but not to eliminate the symptom itself. Some tinnitus patients benefit from this therapy, since CBT has been shown to reduce patient’s discomfort in particular situations in which tinnitus was especially troublesome. Typically, this therapy includes psychoeducation, cognitive restructuring, relaxation and stress management training, use of positive imagery, attention-control training, cognitive restructuring of negative beliefs about tinnitus, behavioral reactivation, and suggestions for using self-help and making lifestyle changes. The classical CBT program consists of face-to-face sessions (sometimes small group supervision sessions) between patient and therapist. Besides the classical method, there are some alternative methods for delivering CBT interventions using facilitated self-help. The CBT-based self-help interventions are typically presented as printed-, audio-, or video material or on web pages. It is not only cost-effective and accessible, but also CBT-based self-help treatment administered via the Internet has shown significant positive results.56 CBT is a problem-focused and action-oriented treatment. It is a kind of interactive conversational therapy that involves two components: cognitive restructuring and behavior modification. Cognitive restructuring assists patients to think differently and to alter their attitudes about their problem. Behavior modification assists patients to identify maladaptive behaviors that contribute to the problem. In addition, behavior modification helps patients to manage their problems by finding ways to modify and correct their behavior. CBT is a time-limited psychological therapy. The average length of a course of treatment is 6–15 weekly sessions of around an hour. The flow of therapy entails several parts.57 The first part includes behavioral analysis and progressive relaxation training. This analysis helps the patient to define and to describe realistically and specifically when the tinnitus adversely affects behavior (e.g. causes anger, fear, and depression). In the ongoing sessions, the patient should be led to understand the differences between tinnitus

294 Recent Advances in Otolaryngology—Head and Neck Surgery experience and maladaptive tinnitus behavior of an irrational nature. Also, the patient should be taught that, for every irrational interpretation, there is an alternative. In this way the patient devises and rehearses strategies to modify his/her response to moods and situations. This part of the therapy includes rapid relaxation, cognitive strategies (dealing with negative thoughts), coping-skills training in relevant situations, and behavioral sleep management.58 In order to evaluate the evolution of patients under CBT, they are asked to write daily diaries and record tinnitus loudness, annoyance, daily mood, and its influence on tinnitus severity and the quality of sleep. The more they change their thinking and behavior, the greater the decrease in tinnitus-related distress. CBT for tinnitus does not consist of only one form of treatment but it depends on what components of treatment are preferred. Classical CBT is characterized by a high therapeutic freedom. As such, the therapeutic processes for different patients are not standardized and are difficult to compare or reproduce. Structured tinnitus-specific CBT using standardized tinnitus-specific interventions reduces the problem of comparability and reproducibility. A study that reviewed a large amount of clinical data on CBT showed that there is a positive effect on the control of tinnitus, particularly decompensated chronic tinnitus. Furthermore, CBT has been found to be effective in decreasing tinnitus annoyance and associated distress, as well as improving depression score and the patient’s quality of life. However, there is no evidence of efficacy of CBT in reducing tinnitus loudness.59

Biofeedback and neurofeedback If the cause of tinnitus is stress related, then a possible approach to reducing its effects is to modify the stress response. BF is one method to learn to recognize cues for altering our body and to modify our response to stress. BF training is made effective by the learning process of feedback and results in a reduction of a person´s physiological (e.g., muscle tension) and psychological (e.g., mental stress) reactivity.60 Also, it helps patients to increase self-control over bodily functions and improve their feelings of self-efficacy. BF involves various relaxation exercises designed to reduce body and mental activity. The hypothesis is that when muscles are in a state of complete relaxation, then anxiety and stress are expected to be reduced. When the ability to relax is learned, the patient has the opportunity of replacing an anxiety response to tinnitus with a relaxation response. BF training involves the use of different equipment that allows the subject to detect moment by moment how stress, anxiety, or relaxation affects his or her physiology. BF devices sense and amplify physiological signals from the body and constantly ‘feed back’ information to the patient about the


occurring process. The information is used to alter specific physiologic processes and increase the patients’ awareness of the influence of emotional and physiological stress on tinnitus. Electromyographic (EMG) BF uses an EMG sensor to measure the electrical activity from muscle tension. Results from studies appear to suggest that there is a relationship between muscle tension and tinnitus-distress.61 In the case when tinnitus is cause of distress, the muscles show contraction. The electrodes are placed typically on the frontal or masseter area and the EMG signal is transformed in graphic form and sounds to provide a prompt audio-visual feedback to the patient. For example, feedback may consist in the form of a series of ‘clicks’ that reduces in frequency as muscle tension reduces and increase in frequency as muscle tension increases. The BF data (e.g., lower muscle tension levels) indicate to the subject that the relaxation practice is in fact bringing about muscle relaxation. The subject can repeat the same relaxation exercises at home without the machine, after he or she has learned this technique. Thermal BF provides information about skin temperature, which is a good indicator of blood flow changes due to dilation and constriction of blood vessels.62 When the surface temperature is high, this typically means that the patient is in a relaxed state. Thermal BF works by attaching a temperature sensor to a patient, normally the fingers or hands. The body temperature is shown on a digital screen to the patient, where he or she can continuously track body temperature. Skin conductivity BF works with a very slight battery current, and indicates the sweat gland activity related to autonomic arousal.63 Reduction in sympathetic arousal shows decreased sweat gland activity. The BF training consists of approximately 8–15 sessions of 20–50 minutes each. Neurofeedback (NF) is a type of BF, also called EEG BF, because it is based on electrical brain activity measured in the EEG. NF uses sensors that are placed on the scalp to measure brain waves that represent the summed activity of neurons in the cortex.64 NF is a computerized learning strategy that trains patients to self-regulate their abnormal brain-wave patterns. It has proven to be an effective tool for modifying the characteristics of spontaneous and evoked brain activity. The EEG signal is recorded, processed, and converted into auditory or visual signal for the patient. The aim is to teach patients techniques to gain control over their brain activity. The subject is asked to alter specific components (rhythms) of the brain waves. Modulation of specific abnormal brain oscillations in temporal, frontal, or in limbic areas increases the amplitude of alpha activity and/or decrease the amplitude of beta and/or gamma activity. This modulation seems to be a potential route for improving tinnitus.65,66 However, a review of different NF techniques led to the conclusion that NF primarily increases alpha power, while the pathological delta activity is not significantly altered.67 Hence, NF does not seem to specifically counteract tinnitus specific EEG changes.67


Fig. 15.1: Neurofeedback by real time functional MRI (rtfMRI). Setup of an fMRI brain-computer interface and flow of data in feedback experiments. Data transfer, preprocessing, statistical analysis, and display of feedback are performed on-line with respect to image acquisition. (Image: M. Cohen; http://www.brainmapping. org/).

While EEG biofeedback allows modifications of large cortical areas, it gives only an unreliable localization of active brain areas and very limited access to deep subcortical brain areas. The high spatial resolution of realtime functional magnetic resonance imaging (rtfMRI) NF, on the other hand, allows to detect modification of specific circumscribed neuronal areas, and furthermore involves to the continuous monitoring of change in the brain in real time.68 These rapid decoding data provide participants with feedback, on a moment-to-moment basis, about activity within predetermined brain regions (Fig. 15.1). rtfMRI can noninvasively record blood-oxygen-leveldependent (BOLD) signal changes related to neuronal activity.69 The physiological target of rtfMRI feedback training for tinnitus is the mean BOLD signal in the auditory cortex. Data transfer, preprocessing, statistical analysis, and display of feedback are performed online with a delay of < 2 seconds. Through operant training with rtfMRI visual NF allows patients to achieve learning control over specific brain areas (e.g., auditory cortex and limbic system). In addition, self-regulation of the local BOLD response leads to changes in connectivity of the target region.68 In the case of tinnitus patients, it was shown that patients could successfully learn to decrease the activations in the auditory cortex and that this improved his or her tinnitus symptom.70 Therefore, rtfMRI may provide valuable insights into the relationship between physiology and behavior. Although the loudness of tinnitus levels was not reduced by BF training, the subject’s ability to deal better with the stress of tinnitus was enhanced. Other benefits described by patients included greater awareness of one’s bodily reactions and the ability to practice relaxation. BF therapy provides the greatest benefits for patients whose tinnitus is caused by muscle contraction and mental distress.


Magnetic and electrical brain stimulation There is a growing consensus that excessive neuronal activity within both cortical and subcortical areas may account for tinnitus as a phantom perception of sound in the central auditory system. Positron emission tomography (PET) investigations showed asymmetry in the auditory cortices of tinnitus patients with higher levels of spontaneous neuronal activity on the left side of the brain, irrespective of tinnitus laterality.71 Neuronal changes are not only limited to the auditory pathways but also synchronized hyperactivity of frontal and parietal areas seems to be responsible for tinnitus.72 The dorsolateral prefrontal cortex (DLPFC) exerts early inhibitory modulation of input and has a bilateral facilitator effect on auditory attention. Its effect on tinnitus intensity results mainly from the DLPFC´s inhibitory modulation of the auditory cortex.73 It is supposed that tinnitus can occur as the result of a dysfunction in the top-down inhibitory process and it is also believed that stimulation of the cerebral cortex either inhibits or interrupts and interferes with the tinnitus signal.74 One of these stimulation methods is neuromodulation, which is based on the modification of neuronal activity.

Transcranial Magnetic Stimulation Transcranial magnetic stimulation (TMS) is a noninvasive neuromodulation therapy for tinnitus, which induces electric currents in the brain to stimulate specific regions. It involves the use of intermittent, brief magnetic fields, which depolarize cortical neurons via electromagnetic induction. Fast oscillating magnetic fields are created by a strong electric current circulating within a coil, and some of this electrical energy penetrates painlessly through the cranium into the first few millimeters of the cortex without attenuation. Electrical currents induced into the superficial cortical neurons can alter the neuronal activity depending on the stimulation frequency at the applied area. Moreover, the method permits a safe and selective stimulation of specific regions of the brain. Direct stimulation of the cortex with lowfrequency TMS (< 10 Hz) has been shown to suppress metabolic activity and to decrease cortical excitability, thus reducing cortical hyperactivity, while high-frequency (>10 Hz) TMS results an increase in excitability.75 TMS not only modulates this specific cortical area but also it has an effect on remote regions functionally connected to the stimulated area.76 TMS produces immediate effects (within seconds), which is well demonstrated with the speech area. If it is placed precisely over Broca´s area, it immediately blocks fluent speech.77 Different TMS coil types are now available. Figure-eight coils are often used because they generate a focused pattern of activation. Repetitive TMS (rTMS) involves the repeated application of the TMS stimulus in a single sitting. Low-frequency (1 Hz) rTMS was proposed as an

298 Recent Advances in Otolaryngology—Head and Neck Surgery effective treatment with longer-lasting effects on tinnitus suppression. When rTMS is applied at a low frequency for longer periods of time, it induces relatively long-lasting inhibitory changes in cortical excitability and modulates thalamocortical processing as well. Daily application of low-intensity rTMS to the left temporoparietal region can (transiently) relieve chronic tinnitus.78 High-frequency rTMS induces an immediate, short-lasting interruption of tinnitus perception only during the time of stimulation; however, the stimulation frequency seems not to be as critical as previously suggested. Additionally, the combined multisite stimulation treatment, which combines highfrequency DLPFC stimulation and low-frequency stimulation of the temporoparietal cortexes, results in a greater reduction in tinnitus severity and has pronounced long-term effects.79 So-called tonic and burst rTMS treatments have been developed as new stimulation types. Tonic stimulation mainly suppresses unilateral pure tone tinnitus, whereas burst stimulation is more successful in temporarily suppressing bilateral noise-like tinnitus.80 There is evidence that the effect of rTMS might be dose-dependent, also with single or multiple stimuli. Experience shows that tinnitus-related neuroplastic changes might be less pronounced in patients with normal hearing and with a short history of complaints, and a beneficial treatment outcome has been predicted.81 Ten daily sessions of rTMS seem to be a safe and effective method for reducing tinnitus for a period of several months. Even so, the exact mechanisms of rTMS treatment are not clear. It is supposed that rTMS disrupts the malfunctioning network and thereby facilitates the intrinsic ability of the brain to restore its normal function. In addition, the changes in the cortical excitability pattern may reflect a neurobiological response to rTMS treatment. Analysis of magnetoencephalography (MEG) data showed that, when using rTMS, strong reductions in tinnitus loudness are associated with increases in alpha power in the stimulated auditory cortex, which is a predictor for treatment outcome on an individual level.82 Temporal or multisite rTMS protocols are in general safe and welltolerated methods of treatment. However, the magnitude of tinnitus improvement shows great interindividual variability and only moderate effectivity.83 Some side effects, such as slight local sensations of pain during stimulation, or transient headache after stimulation, are reported by about 10–20% of stimulated patients. Furthermore, in the case of hyperacusis, emitted noise (approximately 70 dB) during rTMS stimulation might be uncomfortable. Even though the most effective stimulation parameters, such as stimulation frequency, TMS coil position, or number of pulses per session are still unknown, rTMS may nevertheless provide a new therapeutic tool for chronic tinnitus.


Fig. 15.2: Device for transcranial direct current stimulation. (Image: company neuroConn).

Transcranial Direct Current Stimulation Another form of neuromodulation treatment is transcranial direct current stimulation (tDCS). tDCS delivers low currents (0.5–2 mA) via scalp electrodes placed on the skin over the brain area of interest. tDCS does not induce neuronal action potentials but modifies the spontaneous neuronal excitability and activity. A part of this current is shunted through the scalp and the rest flows into the cerebral cortex, thereby increasing or decreasing cortical excitability in the brain regions. tDCS is usually applied through two surface electrodes, one as an anode and the other as a cathode, which are placed on the skin over the brain areas of interest (Fig. 15.2).84 A weak current flow between the electrodes modulates neuronal membrane potential but without inducing neuronal firing. Depending on the polarity of the stimulation, the anodal electrode increases cortical excitability by depolarization, thereby enhancing the activity of neurons in the underlying cerebral cortex, while cathodal tDCS decreases cortical excitability by induced hyperpolarization.85 The therapeutic effect typically outlasts the stimulation by an hour or longer after a single treatment session. Bilateral tDCS over the temporoparietal cortex (anode over the left, cathode over the right) or over the DLPFC (anode over the right, cathode over the left) can modulate tinnitus perception. Electrodes in the reverse position are found to have no influence on tinnitus. Treatment with tDCS is easy to apply and is less expensive than rTMS. tDCS is also generally well tolerated, and does not induce noise. Possible minor side effects are headache, dizziness, nausea, and skin irritation under the electrodes. The apparatus can be used as a portable unit, but no standard treatment protocol of tDCS in tinnitus management is available at the moment. Also, tDCS treatment parameters remain to be optimized.


Transcutaneous Electric Nerve Stimulation Another method applying current to the nervous system used for tinnitus suppression is transcutaneous electric nerve stimulation (TENS). It is reported that there are connections from the somatosensory system to the DCN.86 The inhibitory role of the DCN on the central auditory nervous system may alleviate tinnitus. The use of TENS therapy in areas close to the ear increases the activation of the DCN through the somatosensory pathway. Therefore, if tinnitus is caused by a somatosensory injury (cochlear lesion), than it can be better suppressed by TENS. TENS is applied to the temporomandibular joint, external pinna, tragus, and second cervical nerve (C2). The unit is usually connected to the skin using two or more electrodes. The patient can use this device at home and can vary the intensity of the current. The benefit of TENS for tinnitus is, however, controversial.

Direct Electrical Cortical Stimulation If rTMS therapy on the auditory cortex is successful in suppressing the tinnitus, direct cortical stimulation through electrodes is likely to be helpful for patients. Deprivation of sensory input is an initiator of neural plasticity causing topographic map reorganization in the sensory cerebral cortex. Direct cortical stimulation can also induce reorganization that can modify tonotopic and somatotopic maps.87 A direct intracranial implanted electrode array on the auditory cortex area can permanently modulate the neuronal hyperactivity. Direct stimulation of the auditory cortex can affect other downstream structures within the auditory pathway. It is also likely that electrical stimulation to nonauditory areas, such as DLPFC or hippocampus can change tinnitus perception. The first surgical intervention was performed extradurally on the primary auditory cortex in 2004.88 Surgery is performed using stereotactic conditions with a neuronavigation system uploaded with fMRI or MEG data. The electrodes are positioned on the primary and on the secondary auditory cortex. They are activated and powered by a subcutaneously internal pulse generator implanted in the abdomen or by an external pulse generator.89 The stimulation parameters are selected postoperatively. Most often the stimulator is programmed in cycle mode to prevent epileptic fits. This treatment is a significant step forward, but this kind of invasive neuromodulation surgery carries a potentially higher risk of injury and is quite expensive. Furthermore, the reported tinnitus relief appears to vary from individual to individual. Better insight into the interactions between external/internal electric stimulation and changes in neurobiological mechanisms may help to further develop and optimize biophysical treatment strategies in the future.


Acoustic Coordinated Reset (CR) neuromodulation A considerable amount of evidence exists that deprivation of the nervous system from auditory input, e.g. caused by hearing loss, can have profound effects on the brain, therefore reorganization of the auditory cortex takes place.90 However, presence of a deafferentation has also been shown in tinnitus subjects with audiometrically normal thresholds.91 This deprivation of sensory input, as a strong promoter of increased neuronal synchrony and neural plasticity in the CNS, seems to be one of the essential causes, leading to phantom auditory sensation, i.e. subjective tinnitus.92 Synchronization in the auditory cortex, together with the firing rate, plays a major role in tinnitus. However, increased neuronal synchrony and the resulting tinnitus sensation may possibly have multiple causes. The development and propagation of overly synchronized neuronal activity through a global tinnitus network is likely.93 Imaging research in animals and in humans has led to the understanding that not only the auditory cortex is involved in tinnitus, but other cortical and subcortical regions are also affected when tinnitus is present. Especially the brain´s limbic regions are responsible for the way in which sensations are experienced in tinnitus.72 The affected limbic system may elevate the perceived importance of tinnitus. Long-lasting changes in brain function are subserved by neural plasticity through connections between neurons. In most cases, these neuroplastic changes are positive and allow humans to adapt to a changing environment. However, maladaptive neuroplastic changes can be responsible for different disorders, e.g., tinnitus.94 These plastic changes can modify the way the information in the CNS. This can promote and stabilize coherent firings of many neurons in selected populations resulting in pathologically synchronized neuronal activity, e.g. between the primary auditory cortex and the limbic system. Thus, limbic structures might also be abnormally activated in individuals with tinnitus.94 Further study using MEG found a significant increase in the spectral power in the delta (1.5–4 Hz) frequency range in tinnitus patients as compared with the healthy controls. In addition, alpha oscillatory activity (8–12 Hz), usually distinctively observed in the healthy population, was strongly reduced in the tinnitus population.93 A greater number of tinnitus subjects concurrently exhibit low alpha and high gamma band activity (30–100 Hz). Enhancements in the gamma frequency band, which can be assumed to be a sign of enhanced synchronized firing of neurons, are involved in the auditory cortex.95 Furthermore, significant correlations of tinnitus-related distress with oscillatory brain activity for both theta (4–8 Hz) and gamma frequency ranges were reported in the auditory cortex and consciousness-relevant brain structures that are necessary for a conscious perception of tinnitus.96

302 Recent Advances in Otolaryngology—Head and Neck Surgery It has been also shown that different auditory modalities may be coded by spatially separate neuronal networks and by different mechanisms. For instance, sound identification and sound localization were shown to depend on specialized and spatially distinct pathways.97,98 Therefore, tinnitus pitch may be processed by a spatially separate functional network, probably spatially similar to the normal pitch processing network. By the same token, one may expect differences in the change of brain synchrony in this pitch processing network, i.e., in auditory, but also in non-auditory areas.99 As a conclusion, tinnitus-related changes have been shown to be associated with an increase in oscillatory brain activity in delta, theta, and gamma frequency ranges as well as reduction in alpha band power. These changes are not only limited to the auditory cortex but also include a complex network of different hubs and connections in the brain. CR stimulation was developed based on methods of statistical physics and nonlinear dynamics.100,101 The aim of the therapeutic application of CR stimulation is to achieve a desynchronization indirectly and, as a consequence, to make the affected neural population unlearn pathological synchrony by shifting the network from the initial (i.e. pathological) synchronized state into an unstable state (cluster state), from where it transiently relaxes into a desynchronized state.102 CR stimulation stimulates the pathologically synchronized population at different sites at different times. In case of an acoustic CR neuromodulation (e.g. in tinnitus), a number of tones with different pitches are used.100,103 The auditory pathway has a complex, hierarchical tonotopic organization.104,105 Through acoustic CR neuromodulation, spatially distinct stimulation is achieved utilizing the tonotopic organization of the central auditory system, e.g. the primary auditory cortex: tones of different frequencies (grouped around the tinnitus frequency) induce a reset in different areas of the tonotopically organized auditory cortex.106 In addition to the spatially distinct delivery, CR stimuli are applied in a temporally coordinated manner, i.e., sequentially and equally distributed within specific time intervals approx. corresponding to the pathological oscillation’s mean period. Duration and strength of stimulation depend on the extent of pathological synchronization in the stimulated neuronal population. A stimulation-induced desynchronization will result in a lower rate of coincident neuronal firing, leading to a decrease in synaptic connectivity in the stimulated neuronal population.102 Thus, on a long time scale, neuronal networks will be shifted from a synchronized state (pathological attracting state) with strong synaptic connectivity to a desynchronized state (physiological attracting state) with weak connectivity.102,107,108 The CR stimuli are confined to the synchronized focus. The goal of CR stimulation is to specifically counteract a synchronized focus in the tonotopically organized auditory cortex located in an area corresponding to the dominant tinnitus frequency by desynchronization. Stimulation signals


Fig. 15.3: Acoustic coordinated reset neuromodulation. The concept of CR neuromodulation comprises a spatial and temporal coordination of the applied stimuli to induce desynchronization leading to anti-kindling: utilizing the tonotopic organization of the primary auditory cortex (left, brain adapted from Chittka and Brockmann, 2005)123 short sinusoidal tones of different frequencies (f1 to f4) induce a reset in different target areas grouped around the tinnitus focus. Three CR cycles, each comprising a randomized sequence of four tones (right), are followed by two silent cycles. That pattern is repeated periodically (the blue arrow shows the time). The random variation of the tone sequences and the 3:2 ON-OFF pattern optimize the desynchronizing CR effect. (Source: Figure adapted from Tass et al. RNN 2012 with permission by the authors and Forschungszentrum Jülich, Germany).106

(CR tones) are generated based on a specific formula reflecting the logarithmic tonotopic organization of the auditory cortex and on the matched tinnitus frequency.106 This calculation results in a four-tone sequence (CR cycle). Two CR tones are placed below and two tones above the patient´s tinnitus frequency. Three CR cycles, each comprising a randomized sequence of the four equidistantly delivered tones, are followed by two silent cycles. That pattern is repeated periodically (Fig. 15.3).102 The stimulation signal is in fact soft and pleasant to the ear, as it is only slightly higher than the auditory threshold of the tinnitus patient. The device is very lightweight and about the size of a matchbox. It is connected to a pair of special earphones that fit comfortably in the ear. The patient should wear the neurostimulator for 4 to 6 hours every day or split this period into several sessions not shorter than 1 hour each to take advantage of cumulative effects. CR therapy significantly changes the tinnitus frequency; therefore, the stimulator tones should be readjusted regularly.106 Acoustic CR neuromodulation decreases pathologically elevated delta, theta, and gamma band activity both in the primary and secondary auditory cortex as well as in the limbic and in frontal brain areas, and enhances alpha oscillatory activity in auditory and prefrontal areas.106 These changes are significantly correlated with the degree of tinnitus symptoms change.99 Intriguingly, after 12 weeks of CR therapy nearly all of the pathological interactions within the tinnitus-related network of brain areas were gone.109,110 Additionally, 12 weeks of CR therapy also caused a partial normalization of the cross-frequency coupling (i.e. the interaction between different brain rhythms) within and between nodes of the tinnitus-related network of brain areas.

304 Recent Advances in Otolaryngology—Head and Neck Surgery CR treatment is safe and well tolerated for chronic tonal tinnitus. There were no observations of long-lasting or severe side effects, resulting directly from treatment with the CR neurostimulator. Incorrect adjustment can lead to relevant side effects such as headaches or a transient increase in the signs and symptoms of tinnitus. CR therapy results in a statistically and clinically significant reduction in tinnitus loudness, annoyance, and distress in approx. 75% of the patients.106 However, patients profit differently from the acoustic CR neuromodulation. The audiometrical calibration of the CR therapy tones relies on a tinnitus pitch matching procedure. The latter, however, is known to have limited accuracy and reliability.111–113 Accordingly, an EEG based calibration of the CR therapy tones is being established for further improvement of the CR approach.

Music therapy During the last years, music has been used to investigate human cognition and cerebral information processing. Music affects many brain functions, such as perception, cognition, emotion, and learning. Even the passive act of listening to music activates a broad range of cortical and subcortical functions. Over the last years supporting evidence has been found for the hypothesis that musical training has pronounced effects on human brain plasticity, and furthermore that listening to music can result in physiological changes correlated with relaxation and stress relief.114–116 Music itself is not only a dynamic broadband acoustic stimulus but can also trigger positive emotions and focus the attention of the listener. This is because of the wide range of neural structures that are activated, including the cerebellum, frontal lobe, limbic, and paralimbic structures and auditory cortex.116,117 With regard to music therapy for tinnitus, several approaches have been proposed that are based on a mere relaxing effect exerted by music or a supposed cognitive effect of the music itself. The neuromusic therapy, according to the Heidelberger model for chronic tinnitus, consists of music- and psychotherapeutic interventions and techniques. These are structured into the following modules: counseling, resonance training, neuroauditive cortex training, and tinnitus reconditioning. In the course of resonance training, the patient learns a vocal exercise, namely the intonation of the individual tinnitus sound, stimulating the craniocervical resonating cavities. The neuroauditive cortex training makes use of tone sequences that are unknown, standardized atonal music sequences in the range of the tinnitus frequency. They are performed live on a piano and have to be vocally imitated by the patient. This training aims at a neuronal reorganization of the auditory cortex. Tinnitus reconditioning is a music-based training program in relaxation and self-control and involves the creation of a ‘well-being image’ as an anchor for physiological relaxation. During the relaxation exercise, the tinnitus sound is integrated intermit-


tently into the background music. These result in a systematic desensitization that is intended to decouple tinnitus from psychophysiological reaction patterns.118,119 Another kind of music therapy is the so-called tailor-made notched music treatment (TMNMT), which removes (notches) the music out of the frequency regions associated with the tinnitus. Patients are given the opportunity to listen to their favorite music via supplied closed headphones with comfortable loudness, but the frequency band of one octave width centered at the individual tinnitus frequency is removed from the music energy spectrum via a digital notch filter. This training is intended to reverse maladaptive plastic processes in the auditory cortex contributing to the perception of tinnitus.120 This target notched music introduces a functional deafferentation of auditory neurons corresponding to the eliminated frequency band, and because this frequency band overlaps the individual tinnitus frequency, the notched music no longer stimulates the cortical area corresponding to the tinnitus frequency. Thus, the neurons, which are not stimulated due to the notch, are presumably actively suppressed via lateral inhibitory inputs originating from surrounding neurons.120 Thus the deprivation from auditory input in the frequency range of the tinnitus frequency may cause long-term depression of auditory and nonprimary auditory cortical neurons corresponding to the tinnitus frequency. It may therefore alleviate tinnitus loudness and annoyance.121,122 The TMNMT approach is enjoyable, low cost, and alleviates tinnitus perception, but it can only be effective if the frequency of the tinnitus is determinable by the patient and if the hearing impairment of the patient is no greater than moderate. As a consequence, more research is needed to better understand the relationship between chronic subjective tinnitus and increased neuronal synchrony, pathological plasticity, hearing loss, and reorganization in other auditory and nonauditory brain structures. While the spectrum of tinnitus symptoms is wide, it is expected that the diagnosis and treatment of patients with tinnitus will require multidisciplinary collaboration. Such collaboration may involve otologists, neurologists, orthopedists, psychologists, psychiatrists, neurosurgeons, and dentists. Individualized effective treatment with the help of a multidisciplinary approach may prove to be most effective for patients with tinnitus.

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Chapter Geriatric Otolaryngology—An Emerging Subspecialty

16

Karen M Kost, David E Eibling

INTRODUCTION Since the beginning of recorded human history, young children have outnumbered older people. In what is a global trend, people over the age of 65 will soon outnumber children under the age of five. In 2006, almost 500 million people worldwide were 65 and older, accounting for 8% of the world’s population. By 2030, that total is projected to increase to 1 billion, amounting to one out of every eight of the Earth’s inhabitants. Significantly, the most rapid increases in the 65 and older population are occurring in developing countries, which will see a jump of 140% by the year 2030. In the United States alone, 20% of the population will be 65 or older by the year 2030. An important feature of population aging is the progressive aging of the older population itself.1,2 Over time, more older people are surviving to even more advanced ages. The “oldest old” are often defined as people aged 85 and over. Because of chronic disease, the oldest old have the highest population levels of disability that require long-term care. As a result, they also consume public resources disproportionately. The oldest old constitute 7% of the world’s population aged 65 and over: 10% in more developed countries and 5% in less developed countries. In the United States, the “oldest old” are estimated to make up 14% of the population by 2040. Although people of extreme old age at 100 years of age or more, referred to as centenarians, constitute a small portion of the total population in most countries, their numbers are growing, having doubled each decade since 1950 in more developed countries.1,2 Global aging is a success story with people living longer and generally healthier lives, particularly in developed countries. Increased life expectancy reflects a number of health transitions occurring around the globe at different rates. Changes affecting life expectancy include a shift from high to low fertility, a steady increase in life expectancy at birth and at older ages, a shift from the predominance of infectious and parasitic diseases to the growing impact of noncommunicable diseases and chronic conditions, economic development, and ongoing medical advances and new drugs (Table 16.1).

314 Recent Advances in Otolaryngology—Head and Neck Surgery Table 16.1: Changes affecting life expectancy Shift from high to low fertility Increase in life expectancy at birth and at older ages Shift from infectious and parasitic diseases to noncommunicable diseases and chronic conditions Economic development Ongoing medical advances New drugs

Sustained growth of the world’s older population, however, also presents challenges. Population aging affects economic growth, formal and informal social support systems, and the ability of states and communities to provide resources for older citizens. Furthermore, the elderly consume a disproportionate amount of the total healthcare resources available. Attempting policy adjustments such as changes in retirement ages and medical benefits may be painful and unpopular. Nations must quickly recognize the scope of the new demographic reality and adjust current policies accordingly.1,2

GENERAL CONCEPTS IN GERIATRICS The Canon of Medicine, written by Avicenna in 1025, was the first book to offer instruction in the care of the elderly, foreshadowing modern gerontology, and geriatrics. In a chapter entitled “Regimen of Old Age,” Avicenna expressed concern with his observation that “old folk need plenty of sleep” and suggested that their bodies should be anointed with oil, and even recommended exercises such as walking or horseback riding. Thesis III of the Canon discussed a diet felt to be suitable for the elderly, and dedicated several sections to the problem of constipation in geriatric patients. George Day published the Diseases of Advanced Life in 1849, one of the first publications on the subject of geriatric medicine. The first modern geriatric hospital was founded in Belgrade, Serbia in 1881 by Doctor Laza Lazarević. In 1909, the term geriatrics was proposed by Dr. Ignatz Leo Nascher from New York, Department recognized as a “Father” of geriatrics in the United States. Geriatric medicine differs from standard adult medicine because it focuses on the unique needs of the elderly person. This fundamental difference was formally recognized, when in July 2007, the Association of American Medical Colleges (AAMC) and the John A. Hartford Foundation3 hosted a National Consensus Conference on Competencies in Geriatric Education. At this conference, a consensus was reached on minimum competencies, or learning outcomes, that graduating medical students required in order to assure competent care by new residents to older patients. Twenty-six minimum geriatric competencies in eight content domains were established

Geriatric Otolaryngology—An Emerging Subspecialty 315

Table 16.2: Eight domains of geriatric competencies Cognitive and behavioral disorders Medication management Self-care capacity Falls, balance, gait disorders Atypical presentation of disease Palliative care Hospital care for elders Healthcare planning and promotion

and endorsed by the American Geriatric Society (AGS), the American Medical Association (AMA), and the Association of Directors of Geriatric Academic Programs (ADGAP). The domains are (Table 16.2) cognitive and behavioral disorders; medication management; self-care capacity; falls, balance, gait disorders; atypical presentation of disease; palliative care; hospital care for elders, and healthcare planning and promotion. Each content domain specifies three or more observable, measurable competencies. The elderly are physiologically different from younger adults, with an expected, but variable decline of almost all organ systems. In many cases, these changes may be slowed or stopped with appropriate interventions. Indeed, there is evidence that age-specific medical care can reduce the rate of decline. With age, there is a relative loss of muscle mass (termed sarcopenia) and increase in body fat. Exercise dramatically reduces these changes. Similarly, although bone density decreases after age 30, exercise is a well-recognized means of slowing the process. In some cases, pharmacologic intervention is also necessary. Common cardiovascular changes with age include a rise in systolic blood pressure and decreased cardiac output, both of which, again, may be mitigated by exercise. Visual acuity often declines with time, and may be accelerated by macular degeneration and/or cataracts. Hearing loss is an extremely common complaint in the elderly and can most often be attributed to presbycusis. Other causes include noise-induced hearing loss, ototoxicity, and cerumen impaction. The vestibular system is affected by peripheral degenerative changes and slowing of central processing. Geriatricians distinguish between these effects of normal aging and disease. The extent to which older individuals are affected by symptoms and disease is often a reflection of lifestyle choices and the degree of available functional “reserve”. The importance of this concept is recognized daily in healthcare centers. Healthy, high-functioning older individuals may present with a seemingly small medical problem, which, because of diminished functional reserves in multiple organ systems, leads to a cascade effect with multiorgan involvement and possibly critical illness.

316 Recent Advances in Otolaryngology—Head and Neck Surgery Table 16.3: Tools for assessing functional reserve Comprehensive geriatric assessment (CGA) Activities of daily living (ADLs) Instrumental activities of daily living (IADLs) Exercise tolerance or gait speed Frailty (0–5)

Several validated “barometers” currently exist to objectively determine functional reserve (Table 16.3). These include the comprehensive geria tric assessment (CGA), the activities of daily living (ADLs) or instrumental activities of daily living (IADLs), exercise tolerance or gait speed, and frailty, assessed on a scale of 0–5. Disease often presents very differently in the elderly, with a vague and nonspecific history that may include falls and confusion. Older individuals may minimize symptoms, or delay seeking medical care. The multiple medications taken by many of these patients (polypharmacy) compound the difficulty of arriving at an accurate diagnosis because of possible drug interactions, dosing errors, and central nervous system side effects. In a geriatric patient, acute bacterial sinusitis may present with low-grade fever and confusion, in contradistinction to the higher fever, facial pressure/headache, and rhinorrhea described by younger patients. Functional abilities, independence, and a high quality of life feature prominently in the top priorities of geriatric patients and the physicians caring for them. A multidisciplinary team knowledgeable in the complexities of geriatric care and dedicated to promoting and restoring autonomy and maximizing quality of life in this patient population is required to achieve these goals. In some cases, this may mean enlisting the help of home care services or skilled nurses. Assisted living facilities may constitute a good option for some individuals, with long-term care or hospices reserved for those unable to achieve any independence, even with appropriate care and support. Frailty is an important and relatively common issue in the elderly and alters the risk–benefit ratio of many treatment algorithms designed for younger patients. Accurate evaluations of treatment risks based on validated measures may assist geriatric patients make reasoned and thoughtful choices about their available options. In some instances, they may decline risky or toxic treatments if they are at higher risk of dying from other causes. The presence of frailty significantly increases the risk of postoperative complications, prolongs recovery times, and increases the probability of requiring extended care. Objective assessment of frailty in the elderly preoperatively allows for accurate predictions of recovery trajectories.4 One frequently used, practical


Table 16.4: Frailty criteria, scored 0 (absent) or 1 (present) Unintentional weight loss Muscle weakness Exhaustion Low physical activity Slowed walking speed

frailty scale uses five items (Table 16.4): unintentional weight loss, muscle weakness, exhaustion, low physical activity, and slowed walking speed. Each item is assigned a score of 0 if absent, and 1 if present. A healthy individual would then have the minimum score of 0, while a very frail person would have the maximum score of 5. Elderly individuals with intermediate frailty scores of 2 or 3 are twice as likely as healthy geriatric patients to have postoperative complications, spend 50% more time in the hospital, and are three times as likely to be discharged to a skilled nursing facility instead of to their own homes.4 Very frail elderly patients with scores of 4 or 5 who were living at home before the surgery have even poorer outcomes, with the risk of being discharged to a nursing home rising to 20 times the rate for nonfrail elderly patients. Polypharmacy refers to the concurrent use of several medications, and is a particularly common problem in the elderly. It is defined either by the absolute number of medications taken (more than five) or by the use of excessive or unnecessary prescriptions. In addition, more than half of seniors take “supplements” in the form of vitamins, minerals, or herbal preparations. Polypharmacy is associated with an increased risk of adverse drug reactions, drug interactions, and patient noncompliance. This is the result of the number of medications taken as well as altered pharmacokinetics in the elderly, which include a change in the distribution, metabolism, and excretion of drugs. More specifically, a decrease in serum albumin, particularly in the cases of malnutrition, may affect drug binding, oxidative metabolism by the liver is diminished, and renal drug clearance is reduced. Although the lists of geriatric syndromes vary, the following are frequently recognized: dementia, delirium, falls, hearing impairment, sarcopenia, malnutrition, frailty, incontinence, and visual impairment.

GERIATRIC OTOLARYNGOLOGY The effect of the shifting demographics on medical and surgical subspecialties, including that of otolaryngology, has been noted for some time. Dr. J. LoCicero, formerly the chairman of the interspecialty group formed by the AGS, recognized the brewing crisis in elderly care. The AGS realized, almost 20 years ago, that it could not, by itself, handle the increasing volume of geriatric

318 Recent Advances in Otolaryngology—Head and Neck Surgery Table 16.5: Most common diagnoses in patients over 65 years Hearing loss Disorders of the external ear Other ear disorders, mainly tinnitus Nonsuppurative otitis media/eustachian tube disorders Vertiginous syndromes/vestibular disorders

patients. It therefore, reached out to several specialties, including otolaryn gology, to embrace this focused subspecialty area, foster research and education, and ultimately better prepare otolaryngologists for the evolving needs of this older patient population. Recognition of the scope of the new demographic reality led to the birth of The American Society of Geriatric Otolaryngology (ASGO) in 2007, a result of the foresight and leadership of its first president, Jerome C. Goldstein, MD. Elderly patients account for a large and disproportionate number of outpatient visits. In 2010, almost 15% of outpatient otolaryngology visits were from patients over the age of 65. That number is expected to dramatically increase to 30% by the year 2030.5 It appears that the cross-section (profile) of otolaryngological pathologies encountered during these outpatient visits is not uniform across various age groups. A 2012 study by Creighton et al. demonstrated that as patients age, otologic complaints increase. The most common diagnoses in patients over the age of 65, in order of frequency, were hearing loss, disorders of the external ear, “other” ear disorders consisting mainly of tinnitus, nonsuppurative otitis media/eustachian tube disorders, and vertiginous syndromes/vestibular disorders5 (Table 16.5).

DYSPHONIA IN THE ELDERLY As the number of individuals aged 65 and older increases, it is not surprising to note an increase in the number of older patients seeking consultations for dysphonia. The increase, however, is not proportional, with a reported incidence of vocal complaints in the geriatric population lying somewhere between 12% and 35%.6 A large number of these patients, from 20% to 35%,7,8 use their voices for work, suggesting that vocal quality is a high priority within this subgroup of older patients. In all geriatric patients, dysphonia directly affects quality of life, and may significantly impair the ability to communicate, particularly with hearing-impaired spouses, family, and friends. Indeed, dysphonia and hearing loss frequently coexist in the elderly: those with hearing loss are more likely to have dysphonia than their counterparts without hearing loss.9 Furthermore, dysphonic seniors suffer from social isolation, anxiety, and depression, indicating a need to address both dysphonia and hearing loss when treating these patients.10,11


Those over the age of 65 are subject to the same vast array of vocal diagnoses as younger adults, including benign vocal fold lesions (polyps, nodules, cysts, papillomas), chronic inflammatory laryngitis (reflux-related conditions, autoimmune disorders, medication-induced conditions), acute inflammatory laryngitis (viral, fungal and bacterial), muscle tension disorders, neurologic disorders (essential tremor, Parkinson’s disease, post-stroke, spasmodic dysphonia, amyotrophis lateral sclerosis), vocal fold immobility, vocal malignancies, and vocal fold atrophy. The latter diagnosis is unusual in younger patients, except in the setting of muscle wasting diseases or extreme weight loss. The severity of the dysphonia in the geriatric patient is a function of not only the primary vocal diagnosis but also several other factors including the functional status of the patient, coexisting morbidities, pulmonary reserve, medications, and cognitive function. A number of physiological changes occur in older patients which may individually, or as a group, influence vocal quality. These include anatomic, musculoskeletal, neurological, and hormonal changes. The aging voice is associated with a change in vocal quality that may be perceived in terms of reduced volume, increased breathiness, a change in pitch, and reduced vocal range. Examination with videostrobolaryngoscopy may reveal changes associated with vocal atrophy, including variable degrees of bowing, noted as a concavity of the medial edge of the vocal fold during both adduction and abduction, prominent vocal processes, and a reduction in amplitude of the mucosal wave.12,13 Microscopic changes noted in the superficial layer of the lamina propria in mice include a relative reduction in hyaluronic acid and increase in collagen. In addition, there is an increase in the density and ratio of collagen and reticular fibers that are organized into thick bundles.14,15 In the human thyroarytenoid muscle, a loss of muscle tone and endurance, as well as a decrease in the number of type II muscle fibers has been noted.16 Described changes within the cricoarytenoid joint include surface irregularities and disorganization of collagen fibers.17 In a recent study by Davids et al.,6 geriatric patients accounted for 21% of referrals. In this older group, the most common diagnoses noted were vocal fold atrophy in almost 25%, neurological vocal dysfunction in 23%, and vocal fold immobility in 23.1%.6 Management options offered to patients consisted of reassurance, voice therapy, injection laryngoplasty, and thyroplasty. Almost 40% of patients were reassured and decided to forego additional treatment. Fully 57% elected to have voice therapy, with a statistically significant improvement in voice-related quality-of-life (VRQOL) scores posttreatment. Similarly, the much smaller proportion of patients who chose injection laryngoplasty also had significant improvement in VRQOL scores following injection. These results indicate that the voice changes associated with vocal fold atrophy can be effectively treated with the simple interventions of voice therapy, injection laryngoplasty, or a combination of both.


DYSPHAGIA IN THE ELDERLY With advancing age, physiologic modifications in swallowing, referred to as presbyphagia, do occur and are often subtle and unnoticed. These changes are multifactorial, and often involve some degree of sarcopenia, with generalized muscle loss, as well as reduced activity and exercise.18 Changes at the level of the upper aerodigestive tract include a loss in mucosal sensitivity and a reduction in isometric pressures of the tongue. Pharyngeal stasis is a frequently observed finding with the swallowed bolus in proximity with the airway for longer than in younger patients, and an overall slowing of the swallow.8 Neuromuscular dysfunction of the cricopharyngeus with failure in relaxation may also occur in the elderly. At the level of the esophagus, esophageal stasis and intraesophageal reflux are frequently observed findings in asymptomatic elderly patients in both supine and upright positions. A decline in taste and olfaction may also contribute to changes in deglutition with aging. The result of all these changes is that “functional reserves” are ultimately reduced, and the added presence of disease is sufficient to tip the scales into the transition from presbyphagia to dysphagia. Neurological disorders, neuromuscular diseases, malignancies of the upper aerodigestive tract, connective tissue/autoimmune diseases, and metabolic disorders may all contribute to or cause dysphagia (Table 16.6). Although medications frequently contribute to dysphagia, they are often neglected as an important potential cause. Antibiotics and/or steroids may produce a fungal pharyngitis and esophagitis. Anticholinergics, antihistamines, diuretics, opiates, and some antipsychotics feature prominently among the groups of medications causing xerostomia and drying of the upper aerodigestive tract. Psychoactive drugs such as the commonly used benzodiazepine anxiolytics may alter perception and slow cognitive function. Many geriatric patients are on at least one medication from each of the groups mentioned, thus compounding the negative effects on swallowing. It is estimated that overall at least 15% of the elderly suffer from dysphagia. For the elderly admitted to hospital, the number doubles to 30%, and rises sharply to 68% for those patients living in nursing homes. The incidence of dysphagia after stroke alone is above 60% for patients aged 65 years and over.19-25 In addition to 'aging', there are several conditions which contribute to this high incidence of dysphagia. Furthermore, the risk of stroke, dementia and Parkinson's disease increases with aging, and all of these conditions are associated with a high incidence of dysphagia.

Dysphagia and Stroke The morbidity and mortality associated with dysphagia in stroke patients is truly impressive. Over 50% of patients experience dysphagia subsequent to


Table 16.6: Disorders that cause or contribute to dysphagia Neurological diseases • Stroke • Dementia • Parkinson’s disease • Multiple sclerosis • Amyotrophic lateral sclerosis • Huntington’s disease • Guillain-Barré syndrome Connective tissue/Autoimmune diseases • Rheumatoid arthritis • Systemic lupus erythematosis • Scleroderma • Sarcoidosis Miscellaneous causes • Deconditioning • Radiotherapy • Chemotherapy • Malignancies of the upper aerodigestive tract • Medications • Tracheostomy • Osteophytes • Zenker’s diverticulum

a stroke. Although many patients recover some swallowing function within a month following the event, a significant number have persistent symptoms of dysphagia, placing them at risk of complications such as aspiration, pneumonia, malnutrition, dehydration, and death. Furthermore, these patients require prolonged hospitalizations, and rehabilitation, and are likely to need long-term assistance. The impact on the quality of life of the patients and their caregivers is enormous. Approximately 50% of post-stroke patients with dysphagia will have aspiration, which is silent, or unnoticed, in half of them. The unfortunate consequence is aspiration pneumonia, which will develop in 20% of these patients with aspiration within the first year. Although most survive the first pneumonia, the mortality risk rises incrementally with each subsequent episode. Ultimately, aspiration will be the direct cause of death in about 20% of these patients within the first 3 years following stroke.26


Dysphagia and Dementia The incidence of dysphagia in institutionalized patients with dementia has been estimated to be 45%, with this number rising as the dementia progresses. Several factors may contribute to swallowing difficulties, including slowed swallowing, cognitive impairment, and generalized weakness. The result is longer feeding times, decreased intake, and increasing malnutrition, predisposing to aspiration and pneumonia. In a study by Mitchell et al. in which 323 patients with advanced dementia were followed for 18 months, dysphagia developed in 86% of the residents.27 The 6-month mortality for those patients who had dysphagia was 38.6%, and even higher at 47% for those who had pneumonia, indicating that the onset of these problems is associated with a short life expectancy. Given these findings, the authors noted that “aggressive treatments” such as the insertion of feeding tubes or hospitalization of patients with pneumonia were of questionable benefit.27 In this study, patient proxies who were informed of prognosis were concerned primarily with comfort, and were much less likely to favor these “aggressive” interventions.

Dysphagia in the Elderly Living at Home Dysphagia has been reported to affect 38% of older patients living independently. This creates nutritional challenges, with many turning to nutritional supplements to try and meet their caloric needs.26 Nonetheless, many become malnourished, placing them at risk of the development of frailty. Although both dysphagia and malnutrition are associated with an increased risk of developing community-acquired pneumonia in geriatric patients, the nature of the relationship is unclear. The geriatric patient with dysphagia is best evaluated and managed with a multidisciplinary team, composed of an otolaryngologist, speech-language pathologist, nutritionist, and possibly an occupational therapist. Although there are a number of ways in which dysphagia can be assessed, the most frequently used include a functional endoscopic evaluation of swallowing (FEES) and/or a modified barium swallow. Compensatory management of dysphagia involves the use of various techniques such as postural adjustments, swallow maneuvers, and diet modifications to facilitate safe oral intake. Altering head and body posture is intended to change the speed and flow direction of solids and liquids. There are several swallow maneuvers: the “supraglottic swallow” or the “super supraglottic swallow” incorporates voluntary breath holds to protect the airway and increases the safety or efficiency of swallowing and the effortful or “hard” swallow, which increases the lingual force on the bolus, and is intended to reduce residue and aspiration.26 The available data on both postural changes and swallowing maneuvers is both limited and contradictory. Therefore, these techniques should be tried in the presence of the


multidisciplinary team using FEES to assess their efficacy in each individual patient. Dietary modifications in the form of thickened liquids are frequently recommended, the objective being to improve control of the speed, direction, duration, and clearance of the bolus with less aspiration. Experience has shown they are intensely disliked, are poorly accepted with low compliance, and there is little data to support their use. The “Frazier water protocol” provides specific water intake guidelines and appears to be effective in addressing the risk of dehydration with a thickened liquid diet.26 The texture of solids may be modified to facilitate swallowing. The National Dysphagia Diet has been developed in an attempt to standardize the various versions of modified/restricted diets. Unfortunately, convincing evidence that they actually make a difference in dysphagia and aspiration is currently lacking. For elderly patients with dysphagia unable to nourish themselves, targeted feeding by individuals trained in presenting food slowly in an environment free of distractions results in higher caloric intake.26 In selected geriatric patients with severe dysphagia and aspiration, insertion of a percutaneous endoscopic gastrostomy (PEG) may be a reasonable option. In elderly patients who have dementia or are hospitalized, PEGs do not protect against aspiration, and are associated with a high mortality. Moreover, they are associated with depression and a host of local complications such as wound infections, leakage, and tube occlusion. By far, the most effective means of treating dysphagia is through resistance-type exercises directed toward improving swallowing function. Although there are several rehabilitative approaches (Table 16.7), they have all been shown to be valuable in improving impaired swallowing, and minimizing or preventing dysphagia-related morbidities such as aspiration and pneumonia. The following are examples of swallowing exercises: (1) Lingual exercises: strengthen the lips and tongue, with a resultant increase

Table 16.7: Swallowing exercises Lingual resistance exercises

• Strengthen tongue • Increase tongue mass • Increase swallow pressure

Shaker head-lift

• Strengthens suprahyoid muscles • Increases laryngeal elevation • Improves upper esophageal sphincter opening

Expiratory muscle strength training (EMST)

• Strengthens submental muscle • Strengthens expiratory muscles • Reduces penetration/aspiration

McNeill dysphagia therapy program (MDTP)

• Swallowing is the exercise • Improves strength, movement, and timing of swallow

324 Recent Advances in Otolaryngology—Head and Neck Surgery in swallow pressure and decreased aspiration. (2) Shaker head-lift: involves repetitive and sustained head raises from a lying position. Beneficial effects include strengthening of the suprahyoid muscles, improved elevation of the larynx, and increased opening of the upper esophageal sphincter with overall improved swallowing. (3) Expiratory muscle strength training (EMST): strengthens the submental muscle and the muscles of expiration, improves expiratory pressures, improves airway protection, and reduces penetration/ aspiration. (4) McNeill dysphagia therapy program (MDTP): uses swallowing as the exercise, with a progressive increase in resistance and results in reported improvement in swallowing movement, timing, and strength. Adjuncts to strengthening exercises include the use of electrical stimulation, which is currently of uncertain benefit, and surface electromyography feedback (sEMG). The latter has been reported to help elderly patients adopt new swallowing maneuvers quickly, and reduce therapy time. Overall, swallowing rehabilitation exercises are effective in both prevention and treatment of dysphagia and the inevitably linked morbidity of malnutrition, pneumonia, and death in the elderly population. Indeed, geriatric patients with acute post-stroke dysphagia treated with intensive swallowing exercises improve their oral intake, gain weight, and are significantly less susceptible to malnutrition and pneumonia compared with those treated with postural maneuvers and dietary modifications. These same benefits of swallowing exercises also extend to patients, the majority of whom are 65 or older, undergoing chemotherapy and radiotherapy for head and neck cancer. “Pharyngocise”, as it is sometimes called, results in significant benefit in maintenance of swallow muscle composition and preservation of swallowing function, salivation, and chemosensation.28 In summary, then, early identification, prevention, and intervention with resistance-based swallowing exercises in geriatric patients with dysphagia help avert associated morbidities, and promote weight gain, nutrition, improved functional status, and quality of life. For dysphagia with intractable aspiration, when all else has failed, surgery may be required. Occasionally, relatively simple procedures that may improve swallowing include augmentation of a paralyzed vocal fold, and cricopharyngeal myotomy or chemodenervation for cricopharyngeal spasm. Often, however, more radical surgery involving definitive separation of the airway and digestive tract is necessary. Options include glottic closure, laryngotracheal separation, and laryngectomy.

PRESBYCUSIS Significant hearing loss is common in the elderly, affecting > 80% of the “oldest old” (> 85) and is multifactorial. It is generally accepted that three


major factors contribute to age-related hearing loss (ARHL). These include hair cell loss, stria vascularis atrophy, and central loss due to degradation of executive function. All three are a sequel of normal aging processes, but are accelerated by many environmental and disease states including trauma (including noise trauma) neurodegenerative disease, diabetes, and vascular disease to include that due to tobacco exposure. In addition, as much as 50% of ARHL may have a genetic component.29 The impact on quality of life is well documented and is recognized by all otolaryngologists as well as others who treat older adults. More recently, however, evidence has appeared linking hearing function to cognitive decline. Although changes in central cognitive functioning have been correlated with speech discrimination for many years, only recently has the effect of hearing loss on central function become apparent.

Executive Function Allocation of brain resources is termed “executive function” and is reliant on short-term memory, attention, inhibition, and decision making (what should I listen to?). Loss of executive function is an early sign of dementia, and can be measured by a number of tests. Central testing utilizing “speech-in-noise” testing is a sensitive measure of this ability, and many geriatric otolaryngologists have the opinion that such testing should be standard testing procedure in older individuals. Such testing is far more sensitive than standard speech discrimination scores, and likely correlates with patient’s complaints that “I can hear but I don’t understand when it is noisy”.30 Two common speechin-noise tests include the dichotic sentence identification (DSI) test and the synthetic sentence identification (SSI) test often with the ipsilateral competing message (ICM) test. Performance on these tests may predict the ability of older adults to adequately utilize hearing aids, in common conversational tasks. More significant is the observation that adults who do worse on these tests have a 7- to 12-fold increase in the risk of developing Alzheimer’s disease within 3–10 years.31

Impact of Hearing Loss on Cognitive Decline Recent studies, particularly the longitudinal Baltimore Longitudinal Study of Aging (BLSA), have demonstrated that degree of hearing loss may affect the progression of cognitive decline in older adults.32 Lin et al.32 quantified the correlation factor noting that a 25 dB hearing loss was equivalent to approximately 7 years of aging. They and others point out that the association seems to be independent of other factors known to affect cognitive decline, suggesting a cause-and-effect relationship. These findings are particularly intriguing as they suggest that aural rehabilitation may delay the progression of cognitive decline.


Recommendations for the Practicing Otolaryngologist The implications of these findings are significant as they suggest a number of new roles for the otolaryngologist who treats older adults. First, a heightened awareness of the possible long-term effects of hearing loss mandates an aggressive approach to the identification and characterization of hearing loss in older adults. At the very least, routine audiologic evaluation including central testing is indicated for those with complaints pertaining to the understanding of speech in noisy environments. Second, earlier comprehensive aural rehabilitation to include more than merely fitting aids would seem to likely improve not only current quality of life but also longer term social functioning. One example of the need for comprehensive testing in this population is the observation that many older adults do better with a single aid than with two, a finding that suggests interindividual variation that mandates new forms of “personalized medicine”. Third, findings of impaired executive function on central hearing testing suggest referral for additional testing to assist the patient and his caregiver(s) in recognizing and preparing for possible cognitive decline. Finally, there may be a benefit in earlier cochlear rehabilitation in older adults with severe progressive hearing loss, in that earlier implantation may preserve executive function that will enhance postimplantation performance.

BALANCE IN THE ELDERLY Balance disorders are common in the elderly, affecting as many as 30% yearly. Older adults are susceptible to a wider range of disorders affecting balance than those common in younger individuals. Although older adults are affected by common vestibular disorders, approximately 60% of all balance disorders in the elderly are nonvestibular.

Vestibular Causes of Balance Disorders Older adults are affected by the common vestibulopathies encountered in the general population. Differentiation of an initial episode of Meniere’s disease, migrainous vertigo, or vestibular neuronitis from more a serious lifethreatening brain stem abnormality mandates a low threshold for imaging. Episodic vertigo may suggest a search for a cardiac abnormality or vascular studies to investigate posterior brain circulation. Impending syncope (with or without vertigo) due to orthostatic hypotension is not uncommon in the older adult population, and may be manifested by complaints of imbalance on arising from a sitting or reclining position. The history is contributory as the condition is often accurately related by the patient and is almost universally associated with the pre-existing diagnosis of hypertension.


Postlabyrinthitis vestibulopathy is frequently noted in elderly indivi duals and does improve with vestibular rehabilitation, as in younger age groups. Benign paroxysmal positional vertigo (BPPV) is commonly encountered in the elderly and responds to otolith repositioning. Patients with frequent exacerbations may benefit from self-performed repositioning using commonly available instructions such as those available on the Internet.

Presbystatis Progressive loss of balance function accompanies the normal aging process. No single locus is responsible for this condition as multiple systems are involved in the maintenance of posture. The inevitable slowing of neural reflexes due to reduced sensation, neural pathway slowing, and reduced motor effector activity leads to more unsteady standing and gait. Older persons are more likely to fail to recover from a trip, leading to an increased risk of fall. There is credible evidence that the progression of presbystatis can be slowed by movement, particularly formal vestibular exercises or a variety of exercise activities such as Tai Chi.33

Falls Falls are a major source of morbidity in older adults. Many factors can be identified that increase the risk of falling, but defective balance function remains the final common pathway. Falls are responsible for about two thirds of all injuries in the elderly and are the sixth most common cause of death in this population. Approximately 40% of community-dwelling older adults fall each year, and 1 in 40 require admission. The average number of falls for patients in long-term care is 1.7 per bed-year, meaning the average person in long-term care will fall more than three times in a 2-year period. Five percent of falls lead to fracture (more for inpatients), and 50% of patients admitted for acute care following a fall will die within a year.34 As a result of the impact of falls, considerable effort has been directed toward fall prevention, particularly in the in-patient arena. Falls have been defined as a “geriatric syndrome”,35 which elevates the problem to one that receives widespread attention. Essentially all hospitals and long-term care institutions have a fall prevention program in place. The 2010 Clinical Practice Guideline published jointly by the American and the British Geriatric Societies is instructive in its recommendations (AGS 2010 available at http:// americangeriatrics.org/health_care_professionals/clinical_practice/clinical_guidelines_recommendations/2010/). The recommendations can be summarized easily in three sections. The first recommendation is to assess fall risk on all older patients. This is not as difficult as it might seem since the data is clear – those patients who have fallen will likely fall again. Second, the history should include a detailed review of the medications the patient is on

328 Recent Advances in Otolaryngology—Head and Neck Surgery since there is strong evidence linking medication usage to fall risk, particularly in the elderly. Third, the physical examination should include an assessment of gait and balance, since impaired balance strongly correlates with fall risk.36 Finally, multifactorial intervention should include elimination or reduction in medications, modification of home environment, and exercise.

Polypharmacy As alluded to above as well as in the discussion of dysphagia, medications often are key etiologic factors leading to impairments of balance and increased risk of falls. Polypharmacy, defined as either a specific number or more commonly as “more drugs than the patient needs”, is extremely common in the older patient population. Studies have consistently demonstrated that as many as 40% of older patients are taking potentially inappropriate medications,37 despite widespread awareness and publication of guidelines such as the Beers Criteria, updated in 2012.38 The reasons for this ongoing challenge are multiple, but often are due to the fact that it is far easier to start a new medication than to withdraw medication the patient perceives to be necessary. Most otolaryngologists have encountered this adage with elderly dizzy patients who request the ubiquitous meclizine (Antivert) even when it is likely contributing to their “dizziness”. Hajjar37 points out that among all specialists, geriatricians seem unusually ‘adept at (and take pleasure in) spotting and discontinuing unnecessary drugs.’ Eliminating all psychoactive medications (including the ubiquitous SSRIs) and reducing as many other medications as possible are two prominent recommendations of the 2010 AGS CPG. Often, this recommendation must come from the otolaryngologist consultant who is evaluating an elderly person with the complaint of dizziness.

Recommendations Evaluating and managing the dizzy elderly patient, although challenging, is a critical service that otolaryngologists should provide to their patient population. Not only do the sequelae of falls and self-induced isolation lead to longterm morbidity and social isolation, management by nonotolaryngologists is impaired by the knowledge gap that exists among colleagues in other specialties. Many are unaware of the role of polypharmacy, particularly the role that psychoactive medications play in the impairment of balance and their contribution to falls. Many are not aware of the existence of, or significance of, the Beers Criteria or the AGS CPG. Otolaryngologists should be aware of the potential significance of balance disorders in their elderly patients, and consider doing formal fall assessments by asking about falls, reviewing medication lists for drugs likely to be implicated, and making specific recommendations for adjusting or discontinuing medications and enrolling patients in vestibular rehabilitation or other informal exercise programs. Finally, the role


of exercise in enhancing balance and quality of life in health elderly cannot be discounted, and otolaryngologists can assist in this regard with appropriate counseling of essentially all of their adult patients.

SUMMARY Geriatric otolaryngology is not simply “otolaryngology as practiced on older people” but can be interpreted to mean “otolaryngology as a tool to enhance the quality of life of older people”. Being aware of and recognizing the impact of voice disorders, swallowing abnormalities, hearing loss, and balance difficulties in older patients has the potential to dramatically improve their quality of life. Older patients present with unique problems, often with different goals than those articulated by younger patients. Identifying these goals will guide the otolaryngologist seeking to assist patients in maximize their functional and social activities in their later years.

REFERENCES 1. Kost K. American Society of Geriatric Otolaryngology (ASGO) AAO-HNS Bulletin 2011;30(9). 2. National Institute on Aging, National Institutes of Health, U.S. Department of Health and Human Services and the U.S. Department of State, (http://www.nia. nih.gov/). 3. http://www.jhartfound.org/ 4. Makary MA, Segev DL, Pronovost PJ, et al. Frailty as a predictor of surgical outcomes in older patients. J Am Coll Surg. 2010;210:901–8. 5. Creighton FX Jr., Poliashenko SM, Statham MM, et al. The growing geriatric otolaryngology patient population: a study of 131,700 new patient encounters. Laryngoscope. 2013;123:97–102. 6. Davids T, Klein A, Johns M. Current dysphonia trends in patients over the age of 65: is vocal atrophy becoming more prevalent? Laryngoscope. 2012;122:332–5. 7. Kost K, Yammine N. Dysphonia in the elderly: findings from the McGill Voice Laboratory. 8. Takano S, Kimura M, Nito T, et al. Clinical analysis of presbylarnyx-vocal fold atophy in elderly individuals. Auris Nasus Larynx. 2010;37:461–4. 9. Cohen SM, Turley R. Coprevalence and impact of dysphonia and hearing loss in the elderly. Laryngoscope. 2009;119:1870–73. 10. Golub JS, Chen PH, Otto KJ, et al. Prevalence of perceived dysphonia in a geriatric population. J Am Ger Soc. 2006;54:1736–9. 11. Roy N, Stemple J, Merrill RM, et al. Epidemiology of voice disorders in the elderly: preliminary findings of prevalence, risk factors, and socioemotional effects Ann Otil Rhinol Laryngol. 2007;116:858–65. 12. Honjo I, Isshiki N. Laryngoscopic and voice characteristics of aged persons. Arch Otolaryngol. 1980;106:149–50. 13. Linville SE. Vocal aging. San Diego, CA: Singular Publishing Group; 2000.

330 Recent Advances in Otolaryngology—Head and Neck Surgery 14. Sato K, Hirano M, Nakashima T. Age-related changes of collagenous fibers in the human vocal fold mucosa. Ann Otol Rhinol Laryngol. 2002;111:15–20. 15. Kolachala VL, Torres-Gonzalez E, Mwangi S, et al. A senescence accelerated mouse model to study aging in the larynx. Otolaryngol Head Neck Surg. 2010;142(6):879–85. 16. Malmgren LT, Lovice DB, Kaufman MR. Age-related changes in muscle fiber regeneration in the human thyroarytenoid muscle Arch Otolaryngol Head Neck Surg. 2000;126:851–6. 17. Casiano RR, Ruiz PJ, Goldstein W. Histopathologic changes in the aging human cricoarytenoid joint Laryngoscope. 1994;104:533–8. 18. Humbert IA, Robbins J. Dysphagia in the elderly. Phys Med Rehabil Clin N Am. 2008;19:853–66. 19. Steele CM, Greenwood C, Ens I, et al. Mealtime difficulties in a home for the aged: not just dysphagia. Dysphagia. 1997;12:43–50, discussion 51. 20. Lee A, Sitoh YY, Lieu PK, et al. Swallowing impairment and feeding dependency in the hospitalised elderly. Ann Acad Med Singapore. 999;28:371–6. 21. Mann G, Hankey GJ, Cameron D. Swallowing function after stroke: prognosis and prognostic factors at 6 months. Stroke. 1999;30:744–8. 22. Smithard DG, O’Neill PA, Parks C, et al. Complications and outcome after acute stroke. Does dysphagia matter? Stroke. 1996;27:1200–04. 23. Kawashima K, Motohashi Y, Fujishima I. Prevalence of dysphagia among community-dwelling elderly individuals as estimated using a questionnaire for dysphagia screening. Dysphagia. 2004;19:266–71. 24. Serra-Prat M, Hinojosa G, López D, et al. Prevalence of oropharyngeal dysphagia and impaired safety and efficacy of swallow in independently living older persons. J Am Geriatr Soc. 2011;59:186–7. 25. Roy N, Stemple J, Merrill RM, Thomas L. Dysphagia in the elderly: preliminary evidence of prevalence, risk factors, and socioemotional effects. Ann Otol Rhinol Laryngol. 2007;116:858–65. 26. Sura L, Madhavan A, Carnaby G, Crary MA. Dysphagia in the elderly: management and nutritional considerations. Clin Interv Aging. 2012;7:287–98. 27. Mitchell Sl, Teno JM, Kiely DK, et al. The clinical course of advanced dementia. N Engl J Med. 2009;361:1529–38. 28. Carnaby-Mann G, Crary MA, Schmalfuss I, et al. “Pharyngocise”: randomized controlled trial of preventative exercises to maintain muscle structure and swallowing function during head-and-neck chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2012;83:210–9. 29. Parham K, Lin FR, Coelho DH, et al. Comprehensive management of presbycusis: central and peripheral. Otolaryngol Head Neck Surg. 2013;148:537–9. 30. Gates GA, Gibbons LE, McCurry SM, et al. Executive dysfunction and presbycusis in older persons with and without memory loss and dementia. Cogn Behav Neurol. 2010;23:218–23. 31. Gates GA, Beiser A, Rees TS, et al. Central auditory dysfunction may precede the onset of clinical dementia in people with probable Alzheimer’s disease. J Am Geriatr Soc. 2002;50:482–8.

Geriatric Otolaryngology—An Emerging Subspecialty 331 32. Lin FR, Ferrucci L, Metter EJ, et al. Hearing loss and cognition in the Baltimore Longitudinal Study of Aging. Neuropsychology 2011;25:763–70. 33. McGibbon CA, Krebs DE, Parker SW, et al. Tai Chi and vestibular rehabilitation improve vestibulopathic gait via different neuromuscular mechanisms: preliminary report. BMC Neurol. 2005;(18):5:3. 34. Rubenstein LZ. Falls in older people: epidemiology, risk factors and strategies for prevention. Age Ageing. 2006;35 Suppl 2:ii37–ii41. 35. Inouye SK, Studenski S, Tinetti ME, et al. Geriatric syndromes: clinical, research, and policy implications of a core geriatric concept. J Am Geriatr Soc. 2007;55:780–91. 36. Furman JM, Raz Y, Whitney SL. Geriatric vestibulopathy assessment and management. Curr Opin Otolaryngol Head Neck Surg. 2010;18:386–91. 37. Hajjar ER, Hanlon JT, Sloane RJ, et al. Unnecessary drug use in frail older people at hospital discharge. J Am Geriatr Soc. 2005;53:1518–23. 38. Prevention of falls in older persons summary of recommendations. 2010 AGS/BGS Clinical Practice Guideline, (http://www.americangeriatrics.org/ health_care_professionals/clinical_practice/clinical_guidelines_recommendations/2010/).


Chapter

Genetics in Otolaryngology

17

Nicolas Gürtler, Benno Röthlisberger

Introduction During the last 20 years, genetic research has enormously contributed to the expansion of medical knowledge in all fields, including otolaryngology. This expansion was mainly achieved by new technical and biostatistical methods. The ‘Sanger sequencing’ published in 1977 allowed for easier and more rapid determination of DNA sequence.1 The deciphering of the human genome, with a first working draft published in 2001, and of many nonhuman organisms, was facilitated by this new method. By linkage analysis, a statistical-genetic method based on the typing of microsatellite markers in affected members of a family, the disease gene could eventually be localized to a specific region on a specific chromosome. The database of the human genome or mice was searched for candidate genes. The final step included confirming the mutation by looking at the segregation of the mutation with the disease in the family or by mutation analysis in cell-or animal-based studies. Animal models such as zebrafish and mouse contributed further to decipher structure and function of genes.2 Especially, the mouse boasts a long list of models for studying hearing loss. This chapter reviews the latest technology in genetic research and new findings resulting from the application of these novel methods, which have an impact on the study, diagnostic, and therapeutic management and prognosis of otolaryngologic diseases. The focus is laid on implication for the clinical work for selected diseases, especially hereditary hearing impairment (HHI). A comprehensive approach to genetics in otolaryngology is beyond the format of this book-chapter. Hundreds of syndromes exist, which show clinical features associated with the field of otolaryngology; their genetic etiology is constantly being unraveled. For more detailed information, the reader is kindly referred to the corresponding literature or websites such as Orphanet. Orphanet (http://www.orpha-net.ch) is an Europe-based portal, which lists information about rare diseases, expert clinics, medical labora tories, ongoing research projects, clinical trials, registries, orphan drugs,

Genetics in Otolaryngology 333

and an assistance-to-diagnosis tool in the field of rare diseases in each of the countries in Orphanet’s consortium. Lastly, genetics in otolaryngology represents a very rapidly evolving field.

Hereditary hearing impairment History Childhood hearing loss can be traced back to genetic causes in 50–60%.3 Hearing impairment in the elderly is also influenced by genetic factors, of which type and frequency have not yet been properly defined. Thirty percent of hereditary hearing impairment is classically categorized as syndromic, with approximately 400 forms of deafness accompanied by other clinical abnormalities, and nonsyndromic, which accounts for the remaining 70% where hearing impairment is an isolated problem. Nonsyndromic HHI is further classified by mode of inheritance. Autosomal-recessive transmission (designated by prefix DFNB) is implicated in approximately 80%, autosomaldominant (DFNA) in approximately 20%, X-linked (DFN) and mitochondrial in less than approximately 2% of cases.2 The study of HHI has seen a tremendous progress during the last 15 years since the first discovery of deafness genes (GJB2, DIAPH1). The breakthrough would not have been achieved without the application of novel genetic research tools. Mostly, classic linkage mapping or association studies have led to the discovery of > 100 loci, > 50 genes, and over 1000 different mutations (www.hereditaryhearingloss.org; www.deafnessvariationdatabase.com). Although HHI is mostly monogenic, the high heterogeneity with currently > 80 genes known is reflected by difficulties encountered in the diagnostic approach to the patient with HHI.4 One single gene, GJB2 encoding for the protein connexin 26, is responsible for up to 40% of sporadic prelingual onset in Europe and the United States.5,6 Its single coding exon offers an easy and cost-effective way to analyze the gene by direct sequencing. However, other genes, like myosins, are much larger and time- and cost-intensive for analysis. While a few mutations, such as the c.235delC mutation in GJB2 in the Japanese, have a high prevalence in specific populations, a multitude of mutations associated with HHI—for instance > 90 mutations are known for GJB2 (www.davinici.crg.es)—renders any analysis based on the search of only specific mutations of limited value.

Development of Next-Generation Sequencing In 1977, two groups independently introduced methods for DNA sequencing relying on gel electrophoresis to separate DNA fragments with single-basepair resolution.1,7 The subsequent automation of the Sanger method (dideoxy sequencing) resulted in a dominance of this sequencing approach over the

334 Recent Advances in Otolaryngology—Head and Neck Surgery Maxam-Gilbert protocol. Sanger sequencing remained the gold standard and in fact the only sequencing method used for > 20 years. While initially only single genes were deciphered, later on entire genomes were sequenced by this method. The first draft of the complete human genome was sequenced in factory-like facilities by Sanger sequencing with hundreds of capillary electrophoresis instruments and published in February 2001 (International Human Genome Sequencing Consortium, 2001). Although the per-base cost of dideoxy sequencing declined continuously due to technical improvements, it became evident in the beginning of this century that this trend of declining sequencing costs will not continue further by using the same technology. Laboratories, scientists, and physicians worldwide were increasingly obstructed by limitations in throughput, speed, and especially cost from obtaining sequencing information needed for research and diagnostics. For these reasons, alternative faster and cheaper technologies were urgently needed.8 In 2005, Margulies et al. introduced genome sequencing in microfabricated high-density picoliter reactors.9 In contrast to conventional Sanger sequencing, this method allowed for massively parallel sequencing, resulting in a significantly greater throughput compared with the best conventional capillary electrophoresis instruments. The machine, invented by 454 Life Sciences (http://www.454.com/), used a novel fiber optic slide containing 1,600,000 individual wells and was able to sequence 25 million bases at a 99% or better accuracy in a 4 hour run. Sequencing on this platform was performed by using the pyrophosphate-based sequencing method initially published by Ronaghi in 1998.10 Pyrophosphate is released during the DNA polymerase process and subsequently made visible by an enzyme. Possibilities for genetic research and diagnostics dramatically improved with this new method. The costs to sequence the 6 Gb of a diploid human genome with the 454 technology dropped to one hundredth of the cost of traditional capillary electrophoresis methods, 3 million compared with 3 billion $ (http://web. ornl.gov/sci/techresources/Human_Genome/index.shtml).11 And while the human genome project to sequence a human genome by Sanger sequencing lasted 13 years (1990–2003), a genome was sequenced by the new method within only 2 months. Being faster and significantly less expensive, this meant a huge step forward to the much-anticipated personalized genome sequencing. The platform 454 was not the only new technology that allowed for highthroughput sequencing. Also in 2005, George Church’s lab described another sequencing method using so-called multiplex polony sequencing to potentially deciphering complete individual human genomes.8 With this approach, an epifluorescence microscope converted to rapid nonelectrophoretic DNA sequencing automation was used. First, single DNA molecules were amplified to 1-micrometer beads by emulsion polymerase chain reaction (PCR). Second, millions of beads were immobilized in a polyacrylamide gel


Table 17.1: NGS platforms and technical performance Instrument

Reads

Maximum throughput (Gb)

Illumina HiSeq 2500/2000

3,000,000,000

600

2–11 days

2 × 100

Life technologies SOLiD

2,800,000,000

320

6–10 days

75

Life technologies Ion Proton

80,000,000

10

2–4 hours

200

4–39 hours

Illumina MiSeq

30,000,000

8.5

Life technologies Ion PGM

5,500,000

2

Roche 454 GS FLX+

1,000,000

0.7

100,000

0.04

Roche 454 GS-Junior

Time/run

2.3–7.3 hours

Maximum read length

2 × 250 400

10–23

1000

10 hours

> 400

and subjected to automated cycles of sequencing by ligation and four-color imaging. This technique finally evolved into the SOLiD platform (Table 17.1). Today, all of the so-called Next-Generation-Sequencing (NGS) commercial platforms used are essentially based on the concept of ‘cyclic array sequencing’.8 In principle, all approaches are similar to capillary electrophoresis: the bases of small DNA fragments are sequentially identified from signals emitted as each fragment is resynthesized from a DNA template strand. NGS platforms just achieve a higher throughput and lower costs by decoding a two-dimensional array bearing millions of different DNA templates immobilized on an array (either a picotiter plate as in 454, or an agarose thin layer). Modern NGS instruments are capable of producing hundreds of gigabases (up to 600 Gb) of data in a single sequencing run, meaning that a whole human genome can be sequenced in a single run (Table 17.1). Different methods for capturing and enriching a subset of the whole human genome make it possible to sequence only a part of the human genome in many individuals for the same price as sequencing one single human genome. Whole exome sequencing means that capturing and sequencing is restricted to the 1% of the human genome that is protein coding. The potential of whole exome capture followed by massively parallel DNA sequencing for genetic diagnosis has been shown for the first time in 2009.12 Basically, the capture of any subset of genes is feasible, e.g. the capturing of all known deafness genes. In fact, in many cases with a particular suspected disease, targeted sequencing of specific genes or genomic regions is preferred, since targeted sequencing yields much higher coverage and therefore higher sensitivity as well as reducing costs and time.13

NGS in Hereditary Hearing Impairment The finding in 1997 that up to 50% of autosomal-recessive nonsyndromic hearing loss in some populations may be due to mutations in the GJB2 gene significantly improved the prospects of genetic testing for hearing loss.6

336 Recent Advances in Otolaryngology—Head and Neck Surgery However, typically, GJB2 mutations are found in only 10–20% of deaf children, which means that far more patients with HHI will have mutations in other genes than GJB2. Since sequencing of dozens of known deafness genes by Sanger sequencing is laborious and expensive, this approach never found its way into routine diagnostics. The introduction of NGS in 2005 and moreover the introduction of NGS in genetic diagnosis by Choi in 2009 led the pathway for NGS as a diagnostic tool in HHI.12 The power of NGS to offer highly sensitive and specific cost-effective and comprehensive moleculardiagnostic analysis of patients with HHI has been shown for the first time in 2011.14 Shearer et al. concluded that targeted capture plus massively parallel sequencing had a sensitivity and specificity comparable to Sanger sequencing. Although, to be precise, it has to be noted that some of the requested target regions were not covered due to repetitive regions and the proportion of covered protein coding regions of the investigated 54 known deafness genes was slightly below 100% (up to 97.7%), this approach did not completely reach the gold standard set by Sanger sequencing. However, this limitation must be weighed against the decreased cost and time for sequencing many genes in parallel and the fact that sequencing of all known deafness genes was for the first time made affordable. In this pilot work, Shearer et al. identified the pathogenic mutation in five of six investigated idiopathic hearing loss patients. Since then, several other groups published their results (Table 17.2).14–20 In addition, other groups evaluated the NGS method by investigating either patients with known mutations or families where the responsible gene was located by linkage studies.21–24 In contrast to the pilot work by Shearer et al. Brownstein included in their research not only all known human deafness genes but also all mouse deafness genes (total of 246 genes) and found pathogenic mutations in 6 of 11 patients.15 The reason to include the mouse genes in their panel was the hope to discover additional human deafness genes that are orthologues of known mouse genes. However, in none of the 11 patients such an additional gene could be found. Diaz-Horta chose to analyze not only a panel of deafness genes but instead successfully sequenced the whole exome, meaning nearly all protein coding genes.16 Again, the reason to include other genes in addition to all known human deafness genes in their ‘panel’ was the hope to find new deafness genes. While mutations in known deafness genes have been detected in 12 of 20 patients in this study, mutations in yet unknown deafness genes have not been found. It has to be noted that while in the work by Shearer > 97% of the bases of all known deafness genes were covered by restricting capturing to the 54 known deafness genes, an average of only 93%, 84% and 73% of bases were covered 1X, 10X and 20X within autosomal- recessive nonsyndromic hearing loss genes, when whole exome sequencing was performed.14,16

2011 NimbleGen capture array Agilent SureSelect Target Enrichment

2011 Agilent SureSelect Target Enrichment

2012 RainStorm microdropletbased technology (RainDance)

Shearer

Brownstein

Schrauwen

Illumina HiSeq2000

Illumina GAIIx

454 GS FLX Illumina GAII

Gene enrichment method Sequencing platform

Year

Author

34

246

54

24 ARNSHL European

9 × ARNSHL 2 × ADNSHL Jewish Palestinian Arab

2 × ARNSHL 4 × ADNSHL

24

Contd...

9/24 (37.5%)

6/11 (55%)

11

GJB2, GJB6, PCDH15, USH1C, MYO3A, SLC26A4, POU4F3, TJP2, LOXHD1, CDH23, MYO7A, MYO15A, OTOF, PJVK, SLC26A4, TECTA, TMHS, TMPRSS3, OTOA, PTPRQ, GPSM2 GJB2

5/6 (83%)

Detection rate (%)

6

No. of patients

No data

No. of Recruitment of Prescreening genes patients analyzed

method, number of genes analyzed, recruitment of patients, prescreened genes, number of patients, and detection rate

Table 17.2: Next-Generation Sequencing employed in hereditary hearing loss: list of author, year of publication, gene enrichment


2012 Sequence Capture not specified

2013 NimbleGen capture array

2013 Agilent SureSelect Target Enrichment

Baek

Yang

Shearer

Illumina HiSeq2000 Illumina MiSeq Illumina GAIIx

Illumina HiSeq2000

Illumina HiSeq2000

Illumina HiSeq2000

93 simplex 7 ADNSHL 1 maternally 24 multiplex 39 × ARNSHL 29 × ADNSHL 32 × sporadic

66

5 × ADNSHL, multiplex

20 ARNSHL 20 parental consanguinity (17 Turkey, 3 Iran)

79

80

Whole Exome

100

125

GJB2, SLC26A4, MT-RNR1

GJB2 in 23 patients

8

20

No. of patients

GJB2, SLC26A4

GJB2

No. of Recruitment of Prescreening genes patients analyzed

(ARNSHL: Autosomal-recessive nonsyndromic hearing loss; ADNSHL: Autosomal-dominant nonsyndromic hearing loss).

2012 SureSelect Human All Exon 50 Mb kit (Agilent)

Diaz

Gene enrichment method Sequencing platform

Year

Author

Contd...

42/100 (42%)

33/125 (26.4%)

5/8 (67%)

12/20 (60%)

Detection rate (%)



This reduction in coverage with resulting significant reduction in sensitivity for the genes of primary interest, i.e. known deafness genes, was accepted for the benefit of the possibility to find a hitherto unknown deafness gene. For the detection of germ line heterozygous variants, some laboratories use a factor of 10–20X as a minimum for covering all bases of a targeted panel. However, according to the American College of Medical Genetics and Genomics Standards and Guidelines it may be more useful to track minimum mean coverage as well as the percentage of bases that reach an absolute minimum threshold. For example, a laboratory might ensure that exome sequencing reaches a minimum mean coverage of 100X for the proband and 90–95% of bases in the laboratory’s defined target reach at least 10X coverage.25 In a pure diagnostic setting, where a low rate of false negatives is of a high priority, a reduction in sensitivity by lowering coverage is not preferred, since it would potentially reduce the detection rate of mutations. Limiting the analysis to a small number of genes comes with the advantage of higher coverage and lower costs. However, as many deafness genes have yet to be discovered, the detection of mutation in novel genes will be missed by pursuing this approach. As new genes are being discovered, such as the latest genes KARS and COL4A6, additional experiments with panels including these new genes must be performed in unsolved cases.26,27 In contrast, if the whole exome was sequenced in an individual, simply a reevaluation of the stored sequencing results with no additional laboratory costs could be performed. The current data available suggests that exome capturing kits would be useful if identification of new genes is intended, and the targeted approach is preferable in a pure diagnostic setting. Theoretically, higher sensitivity can also be achieved by exome analysis, but this currently comes with much higher costs. Although capture-based methods have demonstrated to be an adequate method to enrich a set of genes, there are some shortcomings if compared with amplification by PCR, such as problems with GC-rich regions, repetitive elements, and difficulties to reliably resolve genes with high sequence homology. These weaknesses of capture-based methods result in a lower sensitivity and specificity in comparison with Amplicon sequencing, which is the approach to sequence DNA templates amplified by PCR. However, conventional multiplex PCR rather than capture methods is only used in routine diagnostics for smaller sets like NGS sequencing of BRCA1/2 or other small sets of genes with a limited number of exons. With larger sets of genes involving dozens of genes and hundreds of exons, this traditional multiplex PCR approach would simply be too laborious and too expensive. With these difficulties in mind, Schrauwen et al. introduced another approach, which was subsequently also utilized by other groups.17,22,23 All exons of all known deafness genes were amplified by, using an adopted microdroplet-PCR-based approach (RainStormTM, RainDance Technologies), which resulted in a coverage rate of 99.9%.

340 Recent Advances in Otolaryngology—Head and Neck Surgery Not surprisingly, in the seven HHI-NGS papers published so far, there is a substantial range in the detection rate of mutations in patients with HHI. The overall detection rate varied from 26.4% to 83% (Table 17.2). This discrepancy can be explained by a variety of reasons. In some studies, patients were prescreened for GJB2 mutations, while in others they were not. In addition, the recruitment of patients varied from one study to another, resulting in different proportions of sporadic and familial cases. The influence of these factors was analyzed by Shearer et al.19 While they reported an overall diagnostic rate of 42%, this varied by clinical features from 0% for sporadic cases with asymmetric hearing loss to 56% for persons with presumed bilateral autosomal-recessive HHI. For patients with autosomal-dominant HHI, the mutation was detected in 31% of the cases. The difference between the rate of recessive and dominant HHI could be explained by the fact that for 41 of 55 autosomalrecessive nonsyndromic hearing loss loci the gene was identified, while in autosomal-dominant HHI this is the case for only 27 of 47 known loci. Of course, the real number of genes not yet been discovered obviously is unknown. Another potential reason for the discrepancy of the detection rate could be the number of analyzed known deafness genes, which varied from 24 to all 80 known deafness genes. In two studies, additional genes were investigated; 162 mouse deafness genes in one study and the whole exome in another, although in both of these studies no novel gene was found.15,16 Besides the possibility that the responsible gene was not investigated at all in the particular study, it is also possible that the pathogenic mutation was missed, even if the gene has been investigated, because the mutation lies within a region that has not been analyzed (e.g. intronic regions, and promoter). Finally, in all studies mutations were potentially missed due to different reduced sensitivities of the method used, as outlined above. Finally, also differences in the in silico analysis of the raw data could partially explain the differences of the detection rates published so far. For example, recessive deafness requires the presence of mutations on both alleles either in homozygous or compound heterozygous form, which is easily detected by biostatistical analysis of results obtained by NGS. Analysis of siblings or small families results in a higher detection rate, as detection and verification of mutations is facilitated by the possibility of comparison. As mentioned above, Shearer et al. reported a diagnostic rate of 34% in sporadic patients in comparison to recessive cases with 56%.19 While all these reasons could explain at least part of the variations in the detection rate, these differences cannot be due to the use of different platforms, since all studies were performed on Illumina machines, i.e. Illumina HiSeq and Illumina GAII. Because of its very high price, these NGS platforms were only implemented in sequencing core facilities and not in smaller labs. The introduction of smaller and much cheaper benchtop NGS-sequencers like Roche’s GS Junior in 2010 with very moderate


40 Mb sequencing capacity and later Illumina’s MiSeq and the Ion Torrent Personal Genome Machine both capable of gigabase-scale sequencing with relatively short run-times in 2011 changed the whole NGS-laboratory landscape (Table 17.1). Much lower reagent costs per run contributed to the affordability of NGS technology for smaller diagnostic and research labs. For example, in our small routine diagnostic lab in a tertiary hospital, we introduced NGS on a Roche GS Junior in 2010 and expanded NGS in 2012 with the acquisition of an Illumina MiSeq. Among other panels we also established a HHI-panel with all known nonsyndromic deafness genes and some syndromic deafness genes with a total of 89 genes. As expected, by sequencing 89 genes instead of investigating only GJB2 the detection rate could be dramatically increased (data not published, Fig. 17.1). NGS represents an ideal diagnostic tool for this heterogenous disease HHI at increasingly lower costs. However, reimbursement for this new technology remains a problem in many countries. Nevertheless it can be anticipated that this will change in a foreseeable future and sequencing of all HHI genes soon becomes routine diagnostics.

Oncology Head and Neck Cancer Most of the tumors in the head and neck—the exception being, e.g. lymphomas—show a complex tumor-forming process involving more than one gene and complex pathways.28,29 Squamous cell carcinoma (SCC) is the predominant type of carcinoma in the head and neck. Although genetic changes, such as the PIK3CA mutations, have been reported before the availability of NGS, massive parallel sequencing has very much enlarged our knowledge of the genomics of SCC in a short time. In 2011, two seminal studies employing whole exome sequencing of head and neck SCC (HNSCC) appeared.30,31 In one study, 18,000 genes were sequenced in 32 tumor samples— tumor sites not specified—which showed a mutation range of 19 ± 16.5 mutations obtained per tumor. Fourteen genes were altered in at least two tumor samples, of which six were found in a frequency of > 4%.30 In another study, whole exome sequencing (corresponding to about 20,000 genes) was applied in 74 patients with cancers in oral cavity, oro-and hypopharynx, larynx, and sinonasal site. On average, almost 100 nonsynonymous mutations (not altering the amino-acid) were identified with an additional 30 synonymous, which can be regarded as mostly neutral in respect to protein function. In total, 24 genes were proposed to be related to the tumorigenesis of HNSCC.31 Some of these findings were confirmed by other NGS-based studies. The analysis of 535 cancer-associated genes in 6 HNSCC cell lines revealed a mutation range of 38 ± 7.32 Thirty-five genes

Fig. 17.1: Example of a sequence result obtained by next-generation sequencing showing a mutation in the gene TECTA.



Table 17.3: Most important genes revealed by Next-Generation Sequencing implicated in the tumor-formation of head and neck squamous cell carcinoma including their role and possible therapeutic agent (according to www.cancer.org) Gene

Novel (Yes/No)

Role

Therapeutic agent/Clinical trial

TP53

No

TPS

Advexin (P53-gene replacement)/Yes

CDKN2A

No

TPS

CDKI AT7519 (binds to and inhibits cyclin-dependent kinases)/no

HRAS

No

Onc

--

PTEN

No

TPS

--

PIK3CA

No

Onc

--

NOTCH1

Yes

Onc/TPS

γ-Secretase inhibitor, anti-Notch1 monoclonal antibody OMP-52M51/No

FBXW7

Yes

TPS

--

NOTCH2

Yes

?

--

IRF6

Yes

TPS

--

TP63

Yes

Onc?

--

CDH1

Yes

TPS

--

EZH2

Yes

Onc/TPS

--

MED1

Yes

TPS

--

MLL2

Yes

TPS

--

SYNE1

Yes

?

--

SYNE2

Yes

?

--

RIMS2

Yes

?

--

PCLO

Yes

?

--

CASP8

Yes

TPS

--

DDX3X

Yes

Onc/TPS

--

PRDM9

Yes

?

--

Ripk4

Yes

?

--

Dicer1

Yes

?

--

(Onc: Oncogene; TPS: Tumor suppressor gene; ?: Role unknown). Of note: the term TPS is controversial, as TPS can have a variety of functions in different pathways.

were detected harboring more than one mutation. Validation was performed either by comparison with the COSMIC database (Catalogue of Somatic Mutations in Cancer) or by PCR or Sequenom MassArray gentotyping. In particular, the notch genes, the known tumor-suppressor genes TP53, CDKN2A, and the oncogene PIK3CA, have been shown to be implicated (Table 17.3).

344 Recent Advances in Otolaryngology—Head and Neck Surgery These figures (number of genes involved and frequency of mutations) underline the complexity of HNSCC. Another challenge consists in attributing the alterations found in the various genes to a possible pathogenic effect. To this purpose, various techniques can be employed: computation of statistical significance of detected mutated genes by biostatistical methods, comparison with findings from other tumors, comparison with results from animal models, and effect of mutation on the protein. Results obtained through bioinformatics, although a powerful tool with a very high accuracy in predicting pathogenic effect of a DNA-alteration, need to be corroborated by other methods, such as cell- or animal-based studies. Nichols reported a mutation in the PIK3CA gene (3140A->G), which has been predicted by SIFT (Program called ‘Sorting Intolerant From Tolerant’) analysis to be a tolerated variant, but the high oncogenic potential was already proven in an earlier in vivo study.32,33 Additional information was derived from these studies. Inactivating mutations in tumor suppressor gene are much more common than activating ones in oncogenes. Most mutations were found in tumors with a history of tobacco exposure in contrast to nonexposure and human papilloma virus (HPV)-negative samples. A further classification could be done according to the genes involved. Alterations in TP53 for instance are rarely detected in HPV-positive tumors.29 These findings have implications for diagnostics, monitoring and therapy. Diagnostics is increasingly improved by genetic methods. Recently, the distinction of mammary analogue secretory carcinoma, a neoplasia of the salivary glands, from low-grade cystadenocarcinoma was made possible through identification of a t(12;15) (p13;q25) ETV6-NTRK3 translocation.34 The detection of TP53 mutations in dysplastic lesions, such as oral lichen planus, may represent an indication for an increased risk for development of malignancy.35 In view of the difficulties encountered in immunohistochemical detection of TP53, a rapid molecular-genetic assessment method of TP53 mutations in dysplastic lesions would be more accurate and may lead to a formulation of a more aggressive therapeutic approach in treating dysplastic lesions and ultimately benefit the patient. A list of important genes implicated in the formation of HNSCC as revealed by NGS can be found in Table 17.3. Additionally, the oncogenic role and therapeutic agents of the various genes, which are already available and are currently under evaluation for therapeutic purposes, are listed in Table 17.3. On general, mutations in oncogenes can be more easily targeted and the function blocked than restoring function of tumor suppressor genes. Tumor suppressor genes may play an up- or downregulating role in different pathways. Without elucidation of these pathways, defining the role of tumor suppressor genes and prediction of a potential therapeutic effect is much more difficult. In addition, the type of mutations (i.e. deletions and insertions) might require different strategies in targeting the mutated gene.


Miscellaneous Oculopharyngeal Muscular Dystrophy Oculopharyngeal muscular dystrophy (OPMD) is a hereditary myopathy, which occurs worldwide. Patients present the onset of symptoms (ptosis, dysphagia and proximal lower extremity weakness) around the age of 50 years. Molecular genetic testing by direct sequencing represents a highly accurate and rapid way to confirm the diagnosis. A novel method, based on fragment length analysis, which allows rapid mutation detection in large sets of patients and/or control subjects, can be equally employed.36 Confirmation of the diagnosis is helpful in the management and counseling of the patients. OPMD-related dysphagia is best relieved by cricopharyngeal myotomy, although successful long-term treatment has also been reported for dilatation.37,38

Paraganglioma Head and neck paragangliomas (HNP) are tumors derived from parasym pathetic ganglia and mostly nonsecretory. Less than 10% have been reported to be malignant. HNP can occur in sporadic cases, in familial form or rarely associated with syndromes (Von Hippel-Lindau, Neurofibromatosis 1 and type 2 multiple endocrine neoplasia with corresponding genes VHL, NF1, and RET).39 Since Baysal detected germ line mutation in the succinate dehydrogenase gene (subunit D; SDHD) in families with Paraganglioma syndrome 1, additional three genes have been identified for paraganglioma syndrome 2–4 and subsequently mutations have been found in sporadic and familial cases.39,40 TMEM127 is the latest gene discovered in a female patient with two HNP. 41 Genetic screening for patients with HNP is recommended for various reasons. Familial HNP due to SDHB shows a higher risk for malignancy. As SDHD mutation carriers may develop pheochromocytoma, magnetic resonance imaging (MRI) follow-up is counseled.42 Even with the exclusion of the syndrome-associated genes and the rare SDHAF2 gene genetic screening of the remaining three genes require the analysis of 22 exons. While algorithms have been developed to reduce costs, these are associated with a failure to detect SDH mutations in at least 5%.41 Recently, one group has employed NGS to improve diagnosis in patients with HPN and pheochromocytoma.43 Besides the cluster of SDH genes the genes RET, VHL, and TMEM127, which all have been reported in HNP, were analyzed. In 19 patients with HPN 5 pathogenic, 2 likely variants and 12 of unknown significance were identified in genes SDHA, SDHB, SDHC, SDHD, and TMEM127. The authors also showed NGS to offer a reduction in costs, analysis time, and increase in diagnostic yield due to a higher number of analyzed genes. Patients with HNP profit from better counseling by

346 Recent Advances in Otolaryngology—Head and Neck Surgery applying molecular-genetic analysis. The syndromic form can be separated from the nonsyndromic one. Patients with mutations in SDHC should be examined just once by MRI of the thorax and abdomen, as the risk of development of pheochromocytoma is very low. Patients harboring SDHB mutations exhibit a high risk of malignant tumors. Regular follow-up by MRI, eventually 18F-DOPA-PET, is recommended.39 Carriers of SDHB and SDHD mutations may show an early onset of tumors before the age of 18 years. Some authors advocate beginning with screening at the age of 6 years.44

Conclusion Next-Generation sequencing (NGS) represents a new, powerful moleculargenetic method to sequence and analyze a large number of genes or even genome in a time- and cost-efficient way with a high accuracy. Heterogenetic and complex diseases such as HHI or HNSCC are ideal fields for employing NGS. Disease pathways are being more rapidly elucidated. Diagnosis will be facilitated, earlier and more accurate. Therapies will be more targeted to the specific etiology. For a patient with HHI comprehensive analysis of all known genes involved in HHI based on NGS technology is already available. Neoplasia becomes more and more stratified and even diagnosed along their genetic profile. The complex of tumorigenic process of HNSCC is being unraveled in an accelerating way leading to a more tailored approach to the single patient with HNSCC. Patients profit from better counseling with diseases such as HNP. Plans for follow-up in regard to length and examinations may be better established.

References 1. Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A 1977;74:5463–7. 2. Gurtler N, Lalwani AK. Etiology of syndromic and nonsyndromic sensorineural hearing loss. Otolaryngol Clin North Am 2002;35:891–908. 3. Morton CC, Nance WE. Newborn hearing screening---a silent revolution. N Engl J Med 2006;354:2151–64. 4. Hilgert N, Smith RJ, Van Camp G. Forty-six genes causing nonsyndromic hearing impairment: which ones should be analyzed in DNA diagnostics? Mutat Res 2009;681:189–96. 5. Gurtler N, Kim Y, Mhatre A, et al. GJB2 mutations in the Swiss hearing impaired. Ear Hear 2003;24:440–7. 6. Kelsell DP, Dunlop J, Stevens HP, et al. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 1997;387:80–3. 7. Maxam AM, Gilbert W. A new method for sequencing DNA. Proc Natl Acad Sci U S A 1977;74:560–4.

Genetics in Otolaryngology 347 8. Shendure J, Ji H. Next-generation DNA sequencing. Nat Biotechnol 2008; 26:1135–45. 9. Margulies M, Egholm M, Altman WE, et al. Genome sequencing in microfabricated high-density picolitre reactors. Nature 2005;437:376–80. 10. Ronaghi M, Uhlen M, Nyren P. A sequencing method based on real-time pyrophosphate. Science 1998;281:363–5. 11. Wheeler DA, Srinivasan M, Egholm M, et al. The complete genome of an individual by massively parallel DNA sequencing. Nature 2008;452:872–6. 12. Choi M, Scholl UI, Ji W, et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A. 2009;106: 19096–101. 13. Grada A, Weinbrecht K. Next-generation sequencing: methodology and application. J Invest Dermatol 1038;133(8):248. 14. Shearer AE, DeLuca AP, Hildebrand MS, et al. Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing. Proc Natl Acad Sci U S A 1104;107:21104–9. 15. Brownstein Z, Friedman LM, Shahin H, et al. Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in Middle Eastern families. Genome Biol 1186;12:2011–2. 16. Diaz-Horta O, Duman D, Foster J 2nd, et al. Whole-exome sequencing efficiently detects rare mutations in autosomal recessive nonsyndromic hearing loss. PLoS One 2012;7(11):e50628. 17. Schrauwen I, Sommen M, Corneveaux JJ, et al. A sensitive and specific diagnostic test for hearing loss using a microdroplet PCR-based approach and next generation sequencing. Am J Med Genet A 1002;2013:145–52. 18. Yang T, Wei X, Chai Y, et al. Genetic etiology study of the non-syndromic deafness in Chinese Hans by targeted next-generation sequencing. Orphanet J Rare Dis 2013;8:85. 19. Shearer AE, Black-Ziegelbein EA, Hildebrand MS, et al. Advancing genetic testing for deafness with genomic technology. J Med Genet 2013:26. 20. Baek JI, Oh SK, Kim DB, et al. Targeted massive parallel sequencing: the effective detection of novel causative mutations associated with hearing loss in small families. Orphanet J Rare Dis 2013;7:60. 21. De Keulenaer S, Hellemans J, Lefever S, et al. Molecular diagnostics for congenital hearing loss including 15 deafness genes using a next generation sequencing platform. BMC Med Genomics 1186;5:1755–8794. 22. Shahzad M, Sivakumaran TA, Qaiser TA, et al. Genetic analysis through OtoSeq of Pakistani families segregating prelingual hearing loss. Otolaryngol Head Neck Surg 2013:14. 23. Sivakumaran TA, Husami A, Kissell D, et al. Performance evaluation of the nextgeneration sequencing approach for molecular diagnosis of hereditary hearing loss. Otolaryngol Head Neck Surg 1007;148:1007–16. 24. Tang W, Qian D, Ahmad S, et al. A low-cost exon capture method suitable for large-scale screening of genetic deafness by the massively-parallel sequencing approach. Genet Test Mol Biomarkers 1089;16:536–42.

348 Recent Advances in Otolaryngology—Head and Neck Surgery 25. Rehm HL, Bale SJ, Bayrak-Toydemir P, et al. ACMG clinical laboratory standards for next-generation sequencing. Genet Med 1038;2013:92. 26. Rost S, Bach E, Neuner C, et al. Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6. Eur J Hum Genet 1038;2013:108. 27. Santos-Cortez RL, Lee K, Azeem Z, et al. Mutations in KARS, encoding Lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89. Am J Hum Genet 1016;93(1):132–40. 28. Bhaijee F, Pepper DJ, Pitman KT, et al. New developments in the molecular pathogenesis of head and neck tumors: a review of tumor-specific fusion oncogenes in mucoepidermoid carcinoma, adenoid cystic carcinoma, and NUT midline carcinoma. Ann Diagn Pathol 1016;15:69–77. 29. Loyo M, Li RJ, Bettegowda C, et al. Lessons learned from next-generation sequencing in head and neck cancer. Head Neck 2013;35(3):454–63. 30. Agrawal N, Frederick MJ, Pickering CR, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 2011;333(6046):1154–57. 31. Stransky N, Egloff AM, Tward AD, et al. The mutational landscape of head and neck squamous cell carcinoma. Science 1157;333(6046):1157-60. 32. Nichols AC, Chan-Seng-Yue M, Yoo J, et al. A pilot study comparing HPV-positive and HPV-negative head and neck squamous cell carcinomas by whole exome sequencing. ISRN Oncl 2012;2012:809370. 33. Bader AG, Kang S, Vogt PK. Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci U S A. 2006;103:1475–9. 34. Skalova A, Vanecek T, Sima R, et al. Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol 2010;34(5):599–608. 35. Ebrahimi M, Nylander K, van der Waal I. Oral lichen planus and the p53 family: what do we know? J Oral Pathol Med 2011;40:281–5. 36. Gurtler N, Plasilova M, Podvinec M, et al. A de novo PABPN1 germline mutation in a patient with oculopharyngeal muscular dystrophy. Laryngoscope 2006; 116:111–4. 37. Gomez-Torres A, Abrante Jimenez A, Rivas Infante E, et al. Cricopharyngeal myotomy in the treatment of oculopharyngeal muscular dystrophy. Acta Otorrinolaringol Esp 1016;63:465–9. 38. Manjaly JG, Vaughan-Shaw PG, Dale OT, et al. Cricopharyngeal dilatation for the long-term treatment of dysphagia in oculopharyngeal muscular dystrophy. Dysphagia 2012;27:216–20. 39. Boedeker CC. Paragangliomas and paraganglioma syndromes. GMS Curr Top Otorhinolaryngal Head Neck Surg. 2011;10:Doc03. 40. Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000;287:848–51. 41. Neumann HP, Erlic Z, Boedeker CC, et al. Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res 2009;69(8):3650–6.

Genetics in Otolaryngology 349 42. Fishbein L, Nathanson KL. Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Cancer Genet 2012; 205:1–11. 43. Rattenberry E, Vialard L, Yeung A, et al. A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma. J Clin Endocrinol Metab 2013;98: 2013–1319. 44. Burnichon N, Rohmer V, Amar L, et al. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab 2009;94:2817–27.


Chapter

Botulinum Toxin in Otorhinolaryngology

18

Saskia Rohrbach, Rainer Laskawi

Overview In otorhinolaryngology, botulinum toxin A (BTX) is used in many diseases to treat movement disorders and disorders of the autonomic nervous system.1–4 Besides well-known indications (Table 18.1), which are treated by otorhinolaryngologists, i.e. different facial hyperkinesis or more complex dystonic disorders, there are a lot of new options for the treatment with BTX.5 In the following text, we will give a short overview about ‘classical’ indications, which are currently well established in the clinical use and then predominantly focus on recent developments of the BTX treatment. This review is not intended to be exhaustive but a subjective view of the authors.

How botulinum toxin acts There are seven different serotypes of BTX (A-G) of which type A was the first to be used in therapeutic interventions. They cause a blockage of the discharge of acetylcholine at the cholinergic synapse through a change of the structural combination of different proteins (syntaxin, SNAP 25, synaptobrevin 2).6 The effect takes place at the neuromuscular synapse and at the sympathetic and parasympathetic ganglion cell. It also causes a blockage at postganglional parasympathetic and sympathetic cholinergic neurons. That means that BTX injections are able to reduce movements of muscles and secretion of glands.

Table 18.1: ‘Classical’ indications for the use of BTX Movement disorders (‘classic’)

Autonomous nervous system (‘classic’)

Facial movement disorders:

Gustatory sweating

Blepharospasm, hemifacial spasm, and synkinesis

Hyperlacrimation

Spasmodic dysphonia Esthetic medicine

Hypersalivation

Botulinum Toxin in Otorhinolaryngology 351

BTX is assembled as two chains that are combined through two sulfide bridges. The heavy chain (molecular weight 100 kDa) binds to specific receptors at the presynaptic nerve terminal. There are probably different receptors for the binding of the different serotypes. The toxic domain is the light chain (molecular weight 50 kDa). Except for an accumulation of presynaptic vesicles, there are no morphological changes seen.7,8 Through new sprouting of nerves, the paralytic effect is terminated. This mechanism has different durations in neuromuscular versus autonomous synapses.9 The basis for this difference is yet to be determined. The different BTX ‘A’ types that are sold are onabotulinumtoxin as Botox, abobotulinumtoxin as Dysport, and incobotulinumtoxin as Xeomin.

Well-established BTX indications Facial Movement Disorders, Esthetic Use of BTX Dyskinesis like hemifacial spasm, blepharospasm, synkinesis, or Meige syndrome (combination of blepharospasm and oromandibular dystonia) are the most common facial indications of BTX applications in otorhinolaryngology.3 Hemifacial spasm is an ‘overactivity’ of mimic muscles of one half of the face, and is mostly caused by a contact between the root entry zone of the facial nerve and a vessel close to the brainstem. The contact is not regularly seen in MRIs, which should be initiated before the treatment. Also tumors or inflammations are able to cause a hemifacial spasm. Women are affected about twice as often as men. If a nerve/vessel contact is seen, a neurosurgery with the positioning of a patch between the nerve and the vessel10 is the only case for a curative approach. Most patients are quenched by this option and prefer a conservative treatment with BTX.11 Blepharospasm, a focal idiopathic dystonia with an involuntary closure of both eyes, mostly occurs between the 5th and 7th decade of life. Women are threatened more often than men. Some patients are affected so much that they are functionally blind. A more complex form of segmental cranial dystonia is Meige syndrome, in which a blepharospasm and oromandibular dystonia with or without tongue movement and the muscles of the neck or of the larynx are affected. BTX injections are the first-line treatment and very effective.12,13 Synkinesis of the face after defective healing of the facial nerve, e.g. after Bell’s palsy or hypoglossal-facial nerve-anastomosis, can also be successfully treated with BTX injections, first described by Roggenkämper and coauthors.14,15 Synkinesis occurs in muscles that are not intended to be moved. While the lips are puckered, the eye of the affected side closes concomitantly and vice versa.

352 Recent Advances in Otolaryngology—Head and Neck Surgery Therapy includes the subcutaneous injection of all hyperkinetic muscles as the orbicularis oculi muscle, the glabella, the frontalis muscle, the orbicularis oris muscle, the mentalis and depressor labii inferioris muscles, and the zygomatic and risorius muscles. Doses range from 1.25 to 5 units of onabotulinumtoxin A per point, depending on the intensity of the hyperkinesis, the mass of muscles and the constitution of the patient. Doses for facial indications range from 20 to 60 units onabotulinumtoxin A. The medial part of the upper eyelid should not be injected to prevent a ptosis and not to paralyze the levator palpebrae muscle. The medial corner of the lower eyelid must not be injected to protect the active transport of the tears and the corner of the mouth to prevent a ‘hanging mouth angle.’ The effect lasts about three months. When spasms or synkinesis return, reinjections have to be performed. Electromyography is generally not needed. In some special cases, as in the levator inhibition type, it can be helpful. In these cases, a lid to frontalis suspension (sling operation) might be indicated.16 In our experience, the combination of surgery and BTX treatment leads to the best outcome in cases of levator inhibition type. In cases of a spastic entropion, BTX injections into the lower eyelid musculature are also a helpful option.17 Concerning the use of BTX in mimic muscles, its use in the esthetic medicine gained more importance.18–20 Lower eyelid wrinkles, bunny lines, drooping nasal tip, perioral wrinkles, masseter hypertrophy, drooping mouth corners, dimpled chin, platysmal bands, and décolleté wrinkles can be treated.18–20 Reducing the innervation level of certain areas of mimic muscles leads to a straightening of wrinkles in this area of the face and to a ‘younger facial expression’.18–20 In addition, another new aspect is the use of BTX injections (into the cranial mimic musculature) to treat depressions. Recent publications reported about significant success rates of this therapy.21

Laryngeal Dystonia Dystonic laryngeal movements can cause spasmodic dysphonia. The main form shows adduction of the vocal folds (>90%) with a staccato voice interruption of pressed quality. Only some show abduction of the vocal folds with a breathy voice and a feeling of dyspnea because of air loss through the open glottis.22 Women are affected more often than men.23 Many patients have a long experience of voice training or psychotherapy without any dramatic changes of voice dysfunction. BTA is the treatment of choice.24,25 In the adductor type, the vocalis muscle and the thyroarytenoid muscle are the goal to inject, and in the abductor type, the cricoarytenoideus posterior muscle is injected. Different ways to reach the region are possible: transorally in local or general anesthesia and transcutaneously with electromyography.


Doses range from 1.25 to 5 units onabotulinumA/incobotulinum A per point. In cases of bilateral injection, a low starting dose is recommended.26 Side effects can involve local pain, a breathy voice, and dysphagia. Some rare indications are the granuloma of the arytenoid cartilage27 and a synechia of the posterior commissure.28–30 Some groups reported about positive effects on dyspnea in bilateral vocal fold paresis through weakening of both cricothyroid muscles. The vocal folds then stood in an intermediate position so that the patient could breathe better until a regeneration of the laryngeal nerve occurred. As other rare indications in the larynx BTX have been used to weaken the abducing muscles of the larynx in multiple sclerosis, to prevent resynechia after dissection, to reduce phonation with the false vocal folds, and to influence stuttering.

Gustatory Sweating (GS) Gustatory sweating (GS) is a well-known sequela after parotid gland surgery (for example, Fig. 18.1). Although a number of surgical methods have been described to prevent GS, this postoperative phenomenon cannot be avoided in all cases. GS does not only occur after parotid gland surgery but also, e.g. after trauma, infections, or central nervous diseases.31 Based on our experience, the classification in three different subtypes seems to be suitable to

Fig. 18.1: Patient after parotidectomy: Minor’s test35 shows the colored area of gustatory sweating. After marking the sweating area squares are drawn on the skin surface with a waterproof pen to reach the whole affected area more easily with intracutaneous botulinum toxin injections (for detail see ref. 37).

354 Recent Advances in Otolaryngology—Head and Neck Surgery include the origin into the description of GS.31 In 1994, we first reported about the possibility to treat sweat glands and GS with intracutaneous BTX injections.32 Many authors confirmed this method in the meantime and BTX injections became the ‘first-line treatment’ in GS. In the following years, other forms of hyperhidrosis also were treated using BTX injections.33,34 Before BTX treatment, patients are asked to eat an apple to provoke sweating during Minor’s test.35–37 So the area of pathological sweating can exactly be identified. We prefer a subdivision of the affected area in small boxes to ensure a treatment of the whole sweating area. After a few days, the affected area is dry when patients eat or chew. Interestingly, in some patients the therapeutical effect lasts for years.37,38

Sialorrhea There is evidence that BTX injections can successfully reduce the saliva flow in patients with drooling caused by different reasons.39–42 This is an important treatment option for adults and children suffering from this problem.43–48 The technique we use is the ultrasound-guided injection of BTX into the parotid and submandibular glands.43–47 The doses we use are 3 × 7.5 units onabotulinumtoxin/incobotulinumtoxin for each parotid gland and 15 units onabotulinumtoxin/incobotulinumtoxin for each submandibular gland. The effect of a reduced saliva flow lasts about 12 weeks.43–47 In otorhinolaryngology, bi- and unilateral applications of BTX have proven success in swallowing problems after tumor surgery with aspiration of saliva or the inability to swallow saliva. In disturbances of wound healing after extended laser resections of laryngeal tumors, it can improve wound healing.43,45–47 More recent and special indications with uni- and bilateral application of BTX are described later (see below ‘more recent and rare indications’).

More recent and rare indications Recently, some new indications for the use of BTX in otorhinolaryngology have been described.

BTX to Reduce Sweating in Patients with Hearing Aids, Active Middle Ear, and Cochlear Implants Sweating in the temporal and occipital skin region may be a serious problem for patients with hearing aids, active middle ear implants, or cochlear implants49 (Fig.18. 2). Affected patients often report about the impossibility to use their hearing aids or their speech processor and sometimes complain about a complete loss of function of their device. They describe a real reduction of the ‘wearing comfort.’ Some patients invent ways to wear their devices in order to prevent damage (Fig. 18.3).


Fig. 18.2: Patient with excessive sweating of the lateral scalp wearing her hearing aid (right side). The sweating skin led to a complete loss of function of her devices on both sides during sweating. Botulinum toxin injections into the affected skin reduced sweating and the patient could use the devices on both sides without problems.

Fig. 18.3: Patient with severe sweating of the lateral scalp wearing his hearing aid. To prevent contact between sweat and the device the patient hang the hearing aid lateral to the auricle.

In this context, the use of BTX is of great practical relevance.49 Different companies make a lot of products available to protect hearing devices against the negative effects of sweat. It is well known that BTX can reduce sweating by intracutaneous injections (Figs 18.4 and 18.5). Examples for these indications are the use in patients with GS and axillary hyperhidrosis.


Fig. 18.4: Injection technique: Intracutaneous application of botulinum toxin in a patient suffering from excessive sweating with the consequence that the patient could not use his hearing aid. Intracutaneous application is demonstrated by the expanding white skin area (see tip of the needle). This procedure can be used in all cases of hyperhidrosis (e.g. gustatory sweating) independent of the localization in the face.

In our treated patients, an improvement in their complaints occurred that enabled them to use their hearing aids and active middle ear or cochlear implants continuously. In summary, BTX injections are suitable to improve complaints caused by sweating in patients with hearing aids, active middle ear implants, and cochlear implants.

BTX to Reduce Rhinorrhea Intrinsic, Allergic Rhinitis Chronic rhinitis is a common condition affecting over 20% of the population.50 Nasal hypersecretion due to allergic or idiopathic rhinitis (in former times ‘vasomotor rhinitis’) can often not be treated sufficiently by conventional medication. Since most of the nasal glands are innervated by acetylcholine, an anticholinergic drug like BTX should have an effect on nasal hypersecretion. BTX has been injected into the nasal mucosa or applied minimally invasive by sponges in patients with nasal hypersecretion with a reduction in rhinorrhea lasting for about 4–12 weeks.51–53 Studies that compared the effects of conventional antiallergic medications such as cetirizine or ipratropium bromide as an anticholinergic drug did not reveal a dominant positive effect of the one or the other concerning the quality of life or the nasal hypersecretion.54,55


A

B Figs 18.5A and B: Example of a patient with excessive sweating during his work in a paint shop wearing a vibrant sound bridge (A). Figure B demonstrates the treated area around the device. The injection points (red dots) have to be distrib uted over the whole affected skin area. Depending on the therapeutic effect, the treated area can be modified (expanded, reduced).

Rhinorrhea Following Laryngectomy About one-third of laryngectomized patients suffer from nasal problems, which occur postoperatively.56 Due to reduced physiological ventilation, a reactive nasal relative or absolute hypersecretion may occur. As one of the neurotransmitters, the regulation of mucosal nasal glands depends–beside others–on acetylcholine (ACE). So, the inhibition of the release of ACE leads to a decrease in rhinorrhea. BTX can therefore also reduce nasal secretion in patients after laryngectomy, which was shown in a case report by our group.57

358 Recent Advances in Otolaryngology—Head and Neck Surgery A dose of 15 units onabotulinumtoxinA on each side (total dose: 30 units onabotulinumtoxinA) is recommended.57 In the treated patient, we injected BTX into the inferior turbinates.

Facial Pain, Headache Several studies exist that deal with BTX applications in pain syndromes of the head and neck region, and there is some evidence that BTX is effective in the treatment of chronic migraine and other types of headache.58–60 Recently, the treatment of trigeminal neuralgia also has been demonstrated.61,62 Furthermore it is of interest to note that BTX injections also can be used in ‘special situations’ and rare pain syndromes.63 One example of our clinic was the repeated injection of BTX in a patient with immense pain in the lower face following a maxillofacial operation.64 In this patient, a unilateral movement of one lower lip occurred combined with extensive pain and skin alterations after maxillofacial surgery. BTX injections into the lower lip relieved the patient completely.

More recent salivary gland applications Fistulas Salivary fistulas are a serious problem. Early fistulas of the parotid gland tend to close spontaneously, but during their existence they evoke clinical symptoms like a continuous loss of saliva through the fistula. Permanent fistulas

Fig. 18.6: Flow diagram demonstrating the treatment strategy in our department in cases of fistulas following parotidectomies [from ref. 66]. Early and permanent fistulas are treated initially with botulinum toxin injections into the residual parotid gland tissue. Radiotherapy is the last resort.


Fig. 18.7: Case example: Cutting damage of the left cheek. The patient developed a fistula. After intraglandular injection of botulinum toxin, the saliva flow stopped and the wound closed.

need revision surgery in nearly all cases to be closed; in rare cases radiotherapy is the last alternative.65,66 Early or permanent fistulas of the parotid glands themselves or in other regions of the head and neck after surgery (e.g. after laryngectomy) can be treated with BTX. Several authors already demonstrated the benefit of BTX injections in cases of salivary fistulas following parotidectomy.66–70 In our opinion, BTX injections should be the first-line treatment in salivary fistulas after parotidectomy. Independent of a possible subsequent spontaneous closure of a fistula, it is a great advantage for the patients that the saliva flow out of the skin is reduced or even stopped. Therefore, it is not important whether the fistula may close later spontaneously. Figure 18.6 demonstrates our actual treatment regime in cases of parotid gland fistulas following parotidectomy. In some cases, fistulas of the parotid gland or the duct system occur without an earlier operation on the parotid gland. Figures 18.7 to 18.9 show the application of BTX in a patient with a deep cut of the face from which a fistula resulted (Fig. 18.7), a patient after skin excision because of a malignant tumor with a lesion of the Stensen duct (Fig. 18.8) and a fistula following local salivary stone extraction with the need for the opening of the Stensen duct (Fig.18.9). In all cases, the saliva flow has been reduced or stopped. A consecutive optimal wound healing was possible. In addition, the injection of BTX into the salivary glands can be helpful in patients who underwent or have to undergo laryngectomy due to an advanced laryngeal cancer. In cases of expected wound healing problems (e.g. after radiotherapy), BTX injections can be performed before the operation (e.g. laryngectomy) to improve the wound healing by a reduction of the


A

B Figs 18.8A and B: Case example: Saliva flow down the cheek after skin excision because of a malignant tumor with lesion of Stensen duct (A). Surgery and addi tional botulinum toxin injections into the right parotid gland led to wound healing (B).

‘aggressive agent’ saliva. In these cases, we recommend that the injections should be performed at least 3 days before the surgery. In patients who developed a fistula after laryngectomy BTX injections into the salivary glands help to improve the wound healing, the closure of the fistula, and the complaints of the patients.

Flaps/Reconstructive Surgery Oncological head and neck surgery often leads to tissue defects that have to be closed after removing, e.g. a big tumor. To reach a good functional result after surgery, different flaps are suitable to close these defects. Saliva is an aggressive agent prohibiting an uncomplicated wound healing and this is


Fig. 18.9: Case example: Fistula and saliva flow (arrow) after removal of a salivary stone that was located in the Stensen duct. Intraglandular botulinum toxin appli cation led to early closure of the fistula.

of relevance, e.g. in free flaps covering defects in the oral cavity. BTX injections into the salivary glands improve the ambience for the wound healing by reducing the amount of saliva. Recently we described a case in which this procedure helped to optimize the integration of the flap in the adjacent tissue.71 Other authors confirmed this observation.72

Stenosis of Stensen Duct After trauma or infections, a stenosis of Stensen duct may cause problems. This leads to complaints that are based on a stasis of the saliva flow, resulting in pain, swelling, and infections of the affected gland.73 In cases of stenosis of Stensen duct, in which sialendoscopic treatment is not successful, a reduction in the saliva production of the affected gland by BTX injections can be helpful.73 We chose this option in a patient who disliked an extirpation of the parotid gland. We reached a good improvement in the patient’s complaints after repeated ultrasound-guided injection of 3 × 10 units onabotulinumtoxin A (total dose: 30 units) into the affected parotid gland.74

Additional Treatment of Dysphagia A number of patients with neurological diseases suffer from dysphagia (see also later chapter ‘dysphagia’) because of a discoordinated relaxation of the upper esophageal sphincter (UES) (cricopharyngeal achalasia). They often suffer from silent aspiration. First of all the dysphagia has to be treated. In these cases, we inject BTX into the cricopharyngeal muscle to open the UES (see above). Besides, we often combine this treatment with additional BTX injections into the salivary glands (parotid gland, submandibular gland,

362 Recent Advances in Otolaryngology—Head and Neck Surgery technique see above) in patients who have a lot of saliva, because the exclusive relaxation of the upper esophagus sphincter is in many cases not sufficient to reach total recovery. Experimental studies demonstrated a possible ‘protection of the salivary glands’ during radiotherapy after BTX treatment of the glands.75 Further studies will show whether patients will benefit from this interesting method.

Lacrimal Gland Applications There are different conditions that can cause tearing.76 In most of these cases, a stenosis of the lacrimal duct exists. Surgery is the ‘therapy of choice,’ but in some cases patients dislike surgery or surgery is not sufficient. In these cases, BTX injections are suitable to reduce epiphora.77 The spectrum of indications for BTX became wider. It can be applied before a planned lacrimal duct operation, instead of a lacrimal gland operation and in cases of insufficient effect of already realized surgery. We prefer injections into the palpebral part of the lacrimal gland in a dosage of 5.0–7.5 units onabotulinumtoxin A2.

Improvement in Wound Healing Injuries in the head and neck region may lead to unesthetic scars in the face. During early surgical treatment, it is of great importance to consider the special situation in the face (relaxed skin tension lines). Besides, the circumstances for an unproblematic wound healing can be improved using BTX injections.78,79 To reach an optimal esthetic result after surgery in the face or after traumatic skin lesions, it is essential to minimize or prevent any muscle pull on the healing wound. Using BTX injection into mimic muscles next to a facial wound the tension on the healing facial wound can nearly be eliminated.78,79

Dysphagia, Pharyngeal Spasm Dysphagia may have many causes. A serious problem in this context is the occurrence of aspiration with the possible consequence of pneumonia. In some cases, the physiological relaxation of the UES is disturbed during swallowing. In other cases, the opening of the lower esophageal sphincter (LES) is disturbed (achalasia). An uncoordinated opening of the UES typically occurs in central neurological diseases like ischemic or hemorrhagic conditions. A feeding tube or a percutaneous endoscopic gastrostomy often is necessary. Surgical myotomy is one approach.80,81 For achalasia, BTX injections into musculature of the distal esophagus can be performed82,83 as one therapeutically method instead of surgery as the established first-line treatment. In cases of a disturbed UES function, we inject BTX into the cricopharyngeal muscle using instruments for microlaryngoscopy.84–91 During application, patients are intubated


and the region of the UES is exposed.92 Three points of the dorsal pharyngoesophageal circumference are chosen and a dose of 10–20 units onabotulinumtoxin A/incobotulinumtoxin A is injected at each point. In our experience, the success rate is about 73.3% in patients with disturbances of the UES and 76.6% patients with achalasia of the LES.92 This correlates with the results of other authors.84–91 Interestingly, some patients need only one treatment because the reorganization of the nervous functions leads to a ‘physiological’ improvement in the swallowing disturbance. In patients with persisting dysphagia injections have to be repeated. In our department, endoscopic surgery normally is the first-line treatment of Zenker diverticulum (ZD). BTX injections are also reported to treat ZD,93 in combination with surgery94 and as a single option and alternative to surgery in patients who do not want surgery or for whom surgery is not possible. In addition, the possibility to prevent a close contact between the wound margins after incision of the wall of the diverticulum by reducing the movements of the muscle can be taken into account. In these cases, BTX can be injected beneath the incision cleft to hold it wide open and to prevent extensive scar formation. After laryngectomy, some patients are not able to phonate through their implanted voice prosthesis. Persistent spasms of the pharyngeal muscles are thought to be responsible for this problem. BTX injections into the cricopharyngeal muscle area can lead to a functionally adequate movement and a good voice production.95–104

Tinnitus, Autophonia An objective clicking tinnitus can be caused by a palatal myoclonus. It is a rare neurological disorder characterized by involuntary movements of the soft palate musculature. Conventional medical treatments with anxiolytics, antidepressants, and anticonvulsants have limited efficacy so that BTX is injected electromyographically controlled. The salpingopharyngeus and tensor veli palatini muscles are the goal of injection.105,106 In autophonia due to a malfunction of the muscles around the eustachian tube (tensor and levator veli palatini muscles and salpingopharyngeus muscle), BTX has been injected in these muscles. Autophonia disappeared and tympanic ventilation normalized.107

References

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Computer-assisted Surgery of the Paranasal Sinuses and Skull Base

Chapter

19

Edgar Mauricio López-Chacón, Manuel Bernal-Sprekelsen

Introduction Computer-assisted surgery (CAS) or image-guided surgery (IGS) establishes a real-time correlation between the operative field and the preoperative imaging that allows a more precise location of the surgical instrument in the surrounding structures through its three-dimensional (3D) radiologic orientation. This radiologic orientation has increased the thoroughness and depuration of the surgical steps.1,2 Since the introduction of this technology in the mid-1990s, the use of surgical navigation in the paranasal sinus surgery has become an important tool. In a remarkably short time, navigation systems have gone from being a curious novelty to a near-necessity in some complex skull base procedures.3

Technical characteristics Components There are five basic components of the CAS system: a computer workstation, a software, a monitor for image display, a tracking system, and an instrument or instruments to be tracked.1,4,5 The critical component is the digitalizing sensor or tracker. Four types of tracking technology have been used: optical, electromagnetic, electromechanical, and sonic. Actually, only the optic and electromagnetic are being used.5,6 The computer workstation is usually mobile for ease of use in the operating room and placement with respect to the position of the operating table. The monitor typically displays images in axial, coronal, and sagittal planes. The fourth quadrant of the display monitor may give an endoscopic view or a computerized 3D reconstruction model.1,2,6


Steps in the Computer-aided Endoscopic Surgery Preoperative Preparation A detailed medical history, physical examination, and an adequate previous medical treatment will permit CAS to be used in an adequate manner.5 Every navigation system has its own computed tomography (CT) protocol. Many systems now require thin-cut slices of 1.25 mm in an axial orientation, without the need of a fiducial mask.7–9 Once the images are obtained, the majority of systems require processing in an adequate format so that the navigator can read them. The images may be transmitted to the workstation through the hospital’s internal network or through transfer media (magneto optical discs) by manually loading them.1,6,8

Modeling In this step, the preoperative axial images taken are reformatted in order to reconstruct the patients anatomy in a 3D structure of the first three planes. In certain cases, CT images and magnetic resonance imaging (MRI) or MR angiography series can be fused to obtain a greater detail of important structures such as the optical nerve or the carotid artery.5,8 The CAS system offers the opportunity to study the 3D image of the operative situs before the surgery. This is a dynamic process and is similar to the relocation of the patient and surgical material to help aid in the orientation. The human eye is capable of distinguishing 30 of the 4000 shades of the gray scale;1,5,6,8 this is why bone windows or soft tissue windows are used in CT or MRIs. By using different scales of gray, different types of tissue can be differentiated. The images obtained by the CAS system allow the surgical team to work with all the available information even during the surgical intervention.1,5,6,8 Once the images have been reformatted, they need to be uploaded to the workstation of the navigation computer (network, USB drive, for example). Soma navigators allow this process to be done directly in the system computer. It is very important to verify that the images uploaded correspond to the patient; this step should be incorporated in the preincision safety briefing.8,9

Positioning The arrangement of the operating room should be optimal in order for the navigation system to provide its maximum benefit (Fig. 19.1). The arrangement varies depending on the navigation system used, e.g. the four-quadrant arrangement. The monitor display is positioning in a way that allows all involved surgeons to view the intraoperative images comfortably.5,7,8 The navigation display is placed to each side of the endoscopy display. This

Computer-assisted Surgery of the Paranasal Sinuses and Skull Base 373

Fig. 19.1: Operating room setup. Modified from Keschner and Lee.7

permits quick reference to the navigation unit, without compromising access to the images. A correct field disposition reduces the need to switch instruments during the procedure as much as possible.5,7

Registration At the moment there are three types of registration techniques available. • The paired-point requires that the surgeon labels fiducial points on both the patient and the imaging data. These markers can be either implan table or removable tattoos, and can be located in previously determined sites in the image or in anatomical landmarks.1,5,7 Advantages and disadvantages: Implantable fiducials are invasive, as they need to be inserted (usually) into the bone. However, the calibration is straightforward and definitive. Moving the patient´s head during surgery, which is frequently needed during functional endoscopic sinus surgery (FESS), is not a problem. • The second type is the surface-based registration; it needs an IGS system to construct a 3D model of the surface contours of the patients face using imaging data. This allows preoperative scanning without any headset or patient-mounted fiducials by using natural landmarks1,5,6,7 (Fig. 19.2). Advantages and disadvantages: This system avoids invasive applications of fiducials. Calibration is fast and easy, but errors may occur when the skin is being displaced or becomes edematous. • The automatic registration uses a headset that has been located during the preoperative scanning and is the same that will be used during the surgery. Therefore, it should be made specifically for the patient1,5,6,7 (Fig. 19.3).


Fig. 19.2: Surface-based registration.

Fig. 19.3: Headset with automatic registration.

Advantages and disadvantages: The headset avoids the use of invasive fiducials. Patients need to undergo the imaging with the headset and the same one has to be employed during surgery. Calibration is really fast; however, tilting the head during surgery makes it necessary to recalibrate.

Method of Localization Electromagnetic Localization System: This system uses external fiducial markers, which are fixed within a headset that the patient must wear during the preoperative CT scan and during surgery. This headset needs a transmitter to


A

B Figs 19.4A and B: Electromagnetic tracking system.

generate an electromagnetic field near the surgical site and a receiver within the surgical instrument to calculate the position versus the transmitter1,2,5,6,8 (Figs 19.4A and B). The position of the tip of the surgical instrument can be calculated with respect to the headset fiducials, since its technology is based on detections of the electromagnetic field. The use of autoregistration technology allows the headset fiducials to be directly synchronized with the stored preoperative CT or MRI scan fiducials to provide a map of the base of the skull and paranasal sinuses.2,6 At the moment, the headset is capable of compensating the head movements of the patient during the surgery.2,6 Optical Tracking System: The great majority of navigators use this type of system, which is based on the use of infrared light. The camera is located in a


Fig. 19.5: Optical tracking system.

boom about 6 feet from the patients’ head to track the headset or the fiducials and the instruments. The instruments can be tracked in two ways: actively by the emission of infrared light from the instruments captured by the camera, and passively, the camera senses the infrared light reflected by the reflectors on the surgical instruments and the reference apparatus2,5,6 (Fig. 19.5). The majority requires that the patient wears a reference apparatus in the head during surgery, with the exception of the autoregistry systems, which require the use of headsets during the preoperative imaging only.6 Comment: Both tracking systems have advantages and disadvantages. Study the systems carefully. Before deciding for one or the other consider whether the company providing the system will probably still exist in the next 10 years to upgrade software and hardware or simply to repair it.

Accuracy of CAS The accuracy of CAS systems can be affected by many factors such as image acquisition protocols and tracking technologies. The most likely issue to affect accuracy in image-guidance surgery is the registration process. According to the published literature, a registration error within 2 mm is an acceptable accuracy for rhinologic and skull base procedures scan. Fried and Kleefield determined that the InstaTrak system with skin markers had a headset mean accuracy of 1.97 mm and 2.25 mm.10 With the same system, the group of Stammberger reported in an in vivo study of 45 patients a mean of 0.69 mm (SD of 0.35 mm) based on anatomical references.11 Metson and coworkers reported a mean accuracy of 1.69 mm for Landmarks optical system in a study done in 754 patients.4,10,12


Comment: The accuracy of the IGS has been improved. However, do consider the RANGE of that accuracy to be on the safe side. A deviation of around 1–2 mm at the skull base, around the optic nerve, or the internal carotid artery (ICA) can make a huge difference. Never use the navigational system for millimetric decisions, just for orientation. The system should confirm your anatomical knowledge, not the other way round!

Indications for CAS Since the introduction of IGS in the 1990s, several articles have examined its utility. The general perception is that IGS is a critical adjunct in certain cases13 (Figs 19.6 and 19.7).

Fig. 19.6: Axial, coronal, and sagittal views of ethmoid sinus.

Fig. 19.7: Axial, coronal, and sagittal views of sphenoid sinus.

378 Recent Advances in Otolaryngology—Head and Neck Surgery The AAO-HNS policy on intraoperative use of computer-aided surgery14 includes the following indications: • Revision sinus surgery • Distorted sinus anatomy of developmental, postoperative, or traumatic origin • Extensive sinonasal polyposis • Pathology involving the frontal, posterior ethmoid, and sphenoid sinuses • Disease abutting the skull base, orbit, optic nerve, or carotid artery • Cerebrospinal fluid (CSF) rhinorrhea or conditions where there is a skull base defect • Benign and malignant sinonasal neoplasms Comment: A recommendation made by a scientific society may be helpful to orientate in decision making about when or when not to proceed with the help of a CAS. Additionally, it shows, that the learning curve in FESS seems to fasten when navigational systems are used. No study, so far, has shown a reduced rate of complications when using a navigational system. Thus, avoidance or reduction of potential complications is not a clear indication for the use of an IGS. Because the rate of major complications in endoscopic sinus surgery is very low, around 0.25%, a big sample population would be needed to study the impact of using IGS. The control and the study group should each have at least 3017 patients in order to detect 1 to 2% differences of major complications in tough cases with a significance of < 0.05.13 The number of patients that should be treated with IGS to prevent one additional poor outcome and decrease the rate of complications from 0.25% to 0.125% should be of 800.13 Because of the methodological complications in designing a study that shows the benefit of using IGS and the ethical dilemma of performing a complicated surgery without guidance in the control group, the current recommended indications for the use of IGS relay on expert opinions, published literature, and common sense.4,15,16,18

Advantages and Disadvantages Electromagnetic tracking systems that may suffer from disturbances in the electromagnetic field will result in an altered accuracy. Therefore, large metal objects must remain away from the electromagnetic field.4,5,7 Usually, a double mattress on the operating room table is adequate to prevent interferences. The suction aspirators and headset used for tracking are disposable and mildly pliable. Significant force may distort these tools and interfere with accurate surgical localization.4,5,7 The disposable components of the InstaTrak system also add some expense to the use of this system. The headset must be purchased for each patient. The InstaTrak headset fits into the


patient’s ear canals, and sensory and motor neuropathies of the midface have been reported in relation to headset use.17 Electromagnetic tracking systems are also relatively contraindicated for use in patients with pacemakers and cochlear implants.4,18 The main disadvantage of optical systems is their requirement for a direct line of sight from the camera to the patient and instruments.4,5,7 Equipment and operating room personnel must be kept out of this line of sight for the navigation system to function properly. Additionally, the camera must be on average 6 feet away from the patient. In smaller operating rooms, this distance may be difficult to obtain.4 As for teaching, the navigation systems allow the medical resident and junior trainees to visualize and correlate the endoscopic view and the CT.5 Navigation systems used during the ESS were believed to reduce stress by facilitating identification and confirmation of anatomical landmarks, minimizing the disorientation. However, this could not be proven in a clinical study of novel surgeons performing FESS with and without a navigational study.19 The major stress factor, either with or without the use of a navigational system, was strongly related to those surgical steps approaching the skull base.19

Special features CT-MR Fusion CT and MRI contribute in a complementary manner with the complex skull base information. MRI shows the intracranial and extracranial soft-tissue structures and CT depicts bony anatomy well. Image fusion creates images with both CT and MRI characteristics allowing better definition of the lesion and the surrounding bony and soft tissue anatomy facilitating more comprehensive and minimally invasive endoscopic surgery with low morbidity. Leong et al. reported on this technology a series of 25 cases.20 The main indications for CT-MR fusion included neoplasms and multiloculated mucoceles. Comment: CT-MRI fusion is strongly recommended for centers performing skull base surgery for benign and malignant tumors.

Three-dimensional Computed Tomography Angiography Three-dimensional computed tomography angiography (3DCTA) permits the management of complex skull base lesions. Combining images of CT with angiography helps establish location, patency, and relationship of major blood vessels to the lesion. Leong et al. utilized 3DCTA in 22 cases for preoperative planning and in 18 cases for intraoperative navigation to define the relationship of the ICA and skull base lesions.21 Some of the indications for the studies included CSF leak, mucocele, neoplasm, and fibro-osseous

380 Recent Advances in Otolaryngology—Head and Neck Surgery lesion. In all cases, the 3DCTA provided very important information about the ICA in relation with skull base anatomy, allowing the ICA can be directly appreciated without the need to expose it in the operative field. Comment: This feature is of help in cases in which the ICA is supposed to stay in its original position during surgery. For cases in which the ICA gets displaced during or after tumor removal either intraoperative CT or MRI is recommended. As this is not generally available, we suggest the use of microDoppler systems to identify the location of the ICA.

References 1. Bernal-Sprekelsen M, Tomas M. Sistemas de navegación en la cirugía endoscópica. In: Suarez C (ed) Libro del Año Otorrinolaringologia. Saned ediciones. Madrid 1999;108–14. 2. Fried MP, Parkh SR, Sodougui B. Image guidance for endoscopic sinus surgery contemporary review. Laryngoscope. 2008;118:1287–82. 3. Verillaud B, Bresson D. Endoscopic endonasal skull base surgery review. Eur Ann Otorhinolaryngol Head Neck Dis. 2012;129:190–96. 4. Wise SK, DelGaudio JM. Computer-aided surgery of the paranasal sinuses and skull base. Expert Rev Med Devices. 2005;2(4):395–408. 5. Uddin FJ, Sama A, Jones NS. Three-dimensional computed-aided endoscopic sinus surgery. J Laryngol Otol. 2003;117(5):333–9. 6. Sindwani R. Image-guided surgery of the paranasal sinuses and skull base. Mo Med. 2008;105 (3):257–61. 7. Keschner D, Lee J. Use of surgical navigation during endoscopic skull base surgery. Operative Techniques in Otolaryngology-Head and Neck Surgery. 2010;21:44–50. 8. Javer AR, Kuhn FA. Stereotactic computer-assisted navigational sinus surgery: historical perspective an review of the available system. J Otolaryngol. 2001; 30(1): 60–4. 9. Tabaee A. Outcome of computer-assisted sinus surgery: a 5-year study. Am J Rhinol. 2003;17:291–7. 10. Fried MP, Kleefield J. Image-guided endoscopic surgery: results of accuracy and performance in a multicenter clinical study using an electromagnetic tracking system. Laryngoscope. 1997;107(5):594–601. 11. Luxenberger W, Köle W, Stammberger H, et al. Computer assisted localization in endoscopic sinus surgery—state of the art? The InstaTrak system. Laryngorhinootologie. 1999;78(6):318–25. 12. Metson R. Image-guided sinus surgery: lessons learned from the first 1000 cases. Otolaryngol Head Neck Surg. 2003;128(1):8–13. 13. Smith TL, Stewart M, Orlandi R, et al. Indications for image-guided sinus surgery: the current evidence. Am J Rhinol. 2007;21:80–3. 14. American Academy of Otolaryngology—Head and Neck Surgery (AAO-HNS). AAO-HNS policy on intra-operative use of computer-aided surgery. Approved 2005 Sept. Available at : http://www.entlink.net/practice/rules/image-guiding. cfm.

Computer-assisted Surgery of the Paranasal Sinuses and Skull Base 381 15. Citardi MJ, Batra P. Intraoperative surgical navigation for endoscopic sinus surgery: rationale and indications. Curr Opin Otolaryngol Head Neck Surg. 2007;15:23–7. 16. Eliashar R, Sichel J-Y, Gross M, et al. Image guided navigation system—a new technology for complex endoscopic endonasal surgery. Postgrad Med J. 2003;79:686–90. 17. Hwang PH, Maccabee M, Lindgren JA. Headset-related sensory and motor neuropathies in image-guided sinus surgery. Arch Otolaryngol Head Neck Surg. 2002;128(5):589–91. 18. Koele W, Stammberger H, Lackner A, et al. Image guided surgery of the paranasal sinuses and skull base: 5 years experience with the InstaTrak system. Rhinology. 2002;40(1):1–9. 19. Alobid I, Mullol Miret J, Bernal-Sprekelsen M. Increased cardiovascular and anxiety outcomes but not endocrine biomarkers of stress during performance of endoscopic sinus surgery: a pilot study among novice surgeons. Arch Otolaryngol Head Neck Surg. 2011;137(5):487–92. 20. Leong JL, Batra PS, Citardi MJ. CT-MR image fusion for the management of skull base lesions. Otolaryngol Head Neck Surg. 2006;134:868–76. 21. Leong JL, Batra PS, Citardi MJ. Imaging of the internal carotid artery and adjacent skull base with three-dimensional CT angiography for preopera tive planning and intraoperative surgical navigation. Laryngoscope. 2005; 1115:1618–23.

Index 383

Index Page numbers followed by f refer to figure and t refer to table.

A Acoustic neuroma 257, 258, 260, 264, 265 Acquired subglottic stenosis 102 Active middle ear implants 153, 174f Additional treatment of dysphagia 361 Age-related hearing loss 325 Aggressive bacterial sinusitis 20 Allergic rhinitis 356 American Academy of Otolaryngology-Head and Neck Surgery Classification 258 Sleep Medicine 115 Geriatric Society 315 Medical Association 315 Society of Geriatric Otolaryngology 317 Amitriptyline 287 Amyotrophic lateral sclerosis 323 Anterior and posterior cartilage grafts 108 costal cartilage grafts 104 costal cartilage graft laryngotracheoplasty 106 epitympanic space 198f ethmoid air cells 16f bulla 14, 16f cell 13f ethmoidal artery 10 graft 105 mallear ligament 196f Anticonvulsants 286, 287 Apnex system 121 Arteriovenous malformation 76, 88 Articular surface of head of malleus 199f

Association of Directors of Geriatric Academic Programs 315 Audiological tests 260 Auditory neuropathy spectrum disorder 125, 138 speech sound evaluation test 136 Autoimmune diseases 320, 321t Automatic registration headset 374f Autonomous nervous system 350t Autosomal dominant nonsyndromic hearing loss 338 recessive nonsyndromic hearing loss 338 Axial noncontrast computed tomography 14f, 15f

B Basic fibroblast growth factor 84 Benign paroxysmal positional vertigo 327 Bevacizumab 88 Bilateral vestibular loss 273 Blepharospasm 350t Blood-oxygen-level-dependent 296 Blue rubber bleb nevus syndrome 86f Body dysmorphic disorder 54 mass index 117 Bone anchored hearing systems 139 conduction hearing solution 150 implants 154 Botulinum toxin in otorhinolaryngology 350 injections 355f Bronchoscopy 103


C Capillary malformation 76 Carotid artery 194f, 215f, 216f, 224f Castration resistant prostate cancer 70 Central nervous system 282 Cerebrospinal fluid 10, 28, 30f, 222, 378 Cervical slide tracheoplasty 108, 111 vestibular evoked myogenic potentials 274 Cervicofacial lymphatic malformations 85 Chemoradiotherapy 65 Chirurgia magna 281 Cholesteatoma 199, 215 sac 202f Cholesterol granulomas 216 Chorda tympani 202f, 210f, 211f, 219f Chronic rhinosinusitis 45, 46 sinusitis survey 46, 47, 49 Cochlear implant 125, 150 internal receiver 135f speech processor 132f Cochleariform process 196f Cognitive behavior therapy 293, 292 Compensation of vestibular loss 271 Composite tragal cartilage 212f Comprehensive geriatric assessment 316 Computed tomography 9, 258 Computer aided endoscopic surgery 372 assisted surgery 371 of paranasal sinuses and skull base 371 Concha bullosa 14, 16f Cone-beam CT systems 10 Congenital hemangioma 75 Connective tissue 323 Continuous positive airway pressure 114 Contralateral routing of sound 139 Contrast enhanced axial magnetic resonance 259f, 261f, 263f Conventional hearing aids 150 Corda tympani 199

Coronal computed tomographic section of temporal bone 191f noncontrast computed tomography 12f, 16f, 17f, 18f Corpus hippocraticum 281 Cribriform plate 10 Cricotracheal resection 104, 108 Crista ampullaris of semicircular canal 272f Current state of hypoglossal nerve stimulation 117 Cut edge of chorda tympani 197f Cutaneous hemangiomas 82f

D Dehiscence of lamina papyracea 17 syndromes 277 Dehiscent facial nerve 216f Dementia 321t, 322 Dermatologic acquired vascular tumors 75 Dichotic sentence identification test 325 Direct acoustic cochlear stimulator 156, 166, 300 Disorders of external ear 318 semicircular canals 277 Dorsal cochlear nucleus 291 Drug induced sleep endoscopy 116 Dysphagia 320-324, 328, 353, 361 Dysphonia 318 Dystonic laryngeal movements 352

E Elastic deformation of clip prostheses 247 Electroencephalogram 290 Electromagnetic localization system 374 tracking system 375f Encephalocele 34f, 35f Endolymphatic duct 272f sac 272f tumors 278

Index 385 Endoscopic ear surgery 187 open cavity management of cholesteatoma 202 repair of cerebrospinal fluid leaks 23 transcanal management of cholesteatoma 200f limited cholesteatoma 200 Epidermal growth factor receptor 62, 63f, 65-67 Epworth sleepiness scale 117 score 3 Eroded carotid artery canal 216f middle turn of cochlea 216f Esophageal squamous cell carcinoma 70 Ethmoid sinus 377f Eustachian tube 193f, 196f, 198f, 220f, 221f disorders 318 Expansion surgery 105 Expiratory muscle strength training 323t, 324 Extensive pneumatization of sphenoid sinus 18 sinonasal polyposis 378 Extracorporeal membrane oxygenation 109

F Facial movement disorders 350, 351 nerve 193f, 194f, 219f-221f, 224f, 225f, 227f, 229f, 230f, 262 pain 358 recess 191 Fatigue severity scale 117 Fibrosarcoma 89 Fibrous layer of tympanic membrane 215f Fine structure processing 126 Flash lamp pulsed dye laser 85 Flavonoids and terpenoids 286

Flexible bronchoscopy 103 laryngoscopy 103 Floating mass transducer 156 Foramen rotundum 15 Fovea ethmoidalis 16f Frontal cell 15 Functional endoscopic evaluation of swallowing 320 sinus 9 outcomes of sleep questionnaire 117 Fungal sinusitis 20 Furosemide 288

G Gamma knife radiosurgery 257, 258, 259, 260 technique for acoustic neuromas 258 Gamma-aminobutyric acid 285 Gardner-Robertson classification 258 Gastrointestinal tract 86f Genetics and vascular malformations 88 in otolaryngology 332 Geniculate ganglion 221f, 224f, 225f, 227f, 229f, 230f Geriatric otolaryngology 313, 317 standard balance deficit test 274 Ginkgo biloba 286 Glasgow benefit inventory 46 Glioma 89 Glomeruloid hemangioma 74 Goose neck 239 G-protein-coupled receptors 63 Great petrosal nerve 221, 227f, 230f Guillain-Barré syndrome 321t Gustatory sweating 350, 353, 356

H Haller cells 15 Handle of malleus 197f, 208f

386 Recent Advances in Otolaryngology—Head and Neck Surgery Head and neck cancer 341 paragangliomas 345 squamous cell carcinoma 65-67 Hearing loss 318t rehabilitation 150 Hemangiopericytoma 89 Hemifacial spasm 350 Hereditary hearing impairment 332, 333 hemorrhagic telangiectasia 86f High-flow parotid hemangioma 79f Horizontal segment of facial nerve 197f Human papilloma virus 61, 344 Huntington’s disease 321t Hyperbaric oxygen therapy 288 Hyperlacrimation 350t Hypersalivation 350t Hypofractionated stereotactic radiotherapy 265 Hypoglossal nerve stimulation 114 Hypotympanic air cell 194f

I Imipramine 287 Implant coupling 244 Implantable hearing aids 149 Incudomallear joint 198f Incudostapedial joint 193f, 198f, 204f, 205f, 208f, 209f Infantile hemangiomas 75 Infant-toddler meaningful auditory integration scale 136 Inferior part of tympanomeatal flap 213f Injection technique 356f Intensity modulated radiation therapy 65 Internal auditory canal 230f Intracranial pressure 25, 28, 29, 30f Intracutaneous botulinum toxin injections 353f Intrathecal fluorescein 31 Intrathoracic slide tracheoplasty 109 Intratympanic corticosteroids 284

injection of gentamicin 276 steroid 284 Intravenous vincristine 85 Ipsilateral competing message 325

J Janus-activated kinase 68 Jugular bulb 193f

K Kaposiform hemangioendothelioma 75 Kasabach-Merritt syndrome 75

L Labyrinthectomy 276 Labyrinthine fistula 278 Labyrinthitis 278 Lacrimal gland applications 362 Lamina papyracea 10 Laryngeal dystonia 352 Laryngotracheoplasty 102 Lasabach-Merritt syndrome 75 Laser assisted uvulopalatoplasty 114 therapy 88 Lateral incudomallear ligament 194f mallear ligament 194f semicircular canal 196f, 199f, 211, 219f-221f, 224f, 225f, 227f, 230f, 272f vestibulospinal tract 273f Leukemia 89 Lidocaine 285 Lingual resistance exercises 323t Lower esophageal sphincter 362 Lumbar drainage 30f Lymphatic malformation 76, 88

M Magnetic and electrical brain stimulation 297

Index 387 resonance angiography 78f imaging 9, 19, 28, 257, 345, 372 Magnetoencephalography 298 Maintenance of hearing aids 152 Mammalian target of rapamycin 70 Management of cerebrospinal fluid 23 cholesteatoma 207f vascular malformations 87 Margins of meningoencephalocele 33f Mastoiditis 278 Maxillomandibular advancement 115 McNeill dysphagia therapy program 323t Medial longitudinal fasciculus 273f vestibulospinal tract 273f Meniere’s disease 276, 285, 286, 326 Microlaryngoscopy 103 Microstructure of middle ear transducer 161f Microvenular hemangioma 75 Middle cranial fossa 220f, 221f, 224f, 225f, 227f, 229f, 230f ear implant 150, 159, 162f turbinate flap 37 Mobile posturography 274 Monoclonal antibody 67 Multichannel cochlear implants 125 Multiple sclerosis 323 Muscle weakness 317t Music therapy 304, 305 Myofibroma 89

N Nasal health survey 51 septum 50 Nasoseptal flap 36 Neuroblastoma 89 Neurological diseases 321t Noninvoluting congenital hemangioma 76, 76f Non-small cell lung cancer 70 Nonsuppurative otitis media 318t

O Obstructive sleep apnea 1, 114, 116 Oculopharyngeal muscular dystrophy 345 Onodi cells 16 Open endoscopic management of cholesteatoma 199 Operating room setup 189f Optic nerve 10 Optical tracking system 375, 376f Organ of Corti 288 Ossicular chain reconstruction 178 Osteophytes 321t Otorhinolaryngology 350

P Pancreatic neuroendocrine tumor 70 Paraganglioma 345 Parkinson’s disease 321t Parotid gland 359, 361 Pediatric cricotracheal resection 102 Percutaneous endoscopic gastrostomy 323 Pericranial flap 37 Petrous apex 188, 211, 216f PHACES syndrome 80f Pittsburgh sleep quality index 117 Plastic deformation of crimp prostheses 246 Polymerase chain reaction 334 Polysomnography 114 Positive airway pressure 1 Postauricular mastoidectomy 190f Posterior aspect of tensor fold 197f costal cartilage graft 104 laryngotracheoplasty 107f fossa 80f graft 106 pillar 193f semicircular canal 224f wall of maxillary sinuses 14f Presbycusis 324 Presbystatis 327 Pressure-release valve 30

388 Recent Advances in Otolaryngology—Head and Neck Surgery Primary nasal symptoms 49 Problemata physica 281 Progression-free survival 64 Pterygopalatine fossa 14, 15f, 21f Pyogenic granuloma 75 Pyramidal eminence 193f, 194, 224

Q Quality of life after rhinoplasty 50, 52 after septoplasty 50

R Radiosurgery for larger tumors 264 technique 258 Rapid eye movement 116 Rapidly involuting congenital hemangioma 76f Real-time functional magnetic resonance imaging 296f Recurrent benign paroxysmal positional vertigo 277 Removal of bone; facial recess 192f cholesteatoma 199, 216f stenotic segment 109f Resection of meningocele or encephalocele 33 surgery 108 Retrotympanum 192 Revision sinus surgery 378 Rhabdomyosarcoma 89 Rheumatoid arthritis 321t Rhinorrhea 378 Rhinosinusitis disability index 47 outcome measure 46 quality-of-life survey 47 Rosetti infant-toddler language scale 137

S Sagittal noncontrast computed tomography 13f, 17f

Salivary glands 359-361 Sarcoidosis 321t Schwann cells 278 Scleroderma 321t Sclerotherapy 88 Secondary rhinogenous symptoms 49 Semicircular canals 271 Sensorineural hearing loss 125, 159f Septoplasty 50 Shape memory alloy prostheses 248 Sialorrhea 354 Single-sided deafness 139 Sinonasal cerebrospinal fluid 25f, 27f outcome test 46-49 Sinus subtympanicus 194f tympani 193f Sleep apnea quality of life index 117 Slide tracheoplasty 104 Sound therapy 289 Spasmodic dysphonia 350t Sphenoethmoidal recess 13 Sphenoid meningoencephalocele 33f sinus 10, 13f, 377f Spherical recess 224f, 230f Spindle cell hemangioendothelioma 75 Spontaneous CSF leaks 25 Squamous cell carcinoma 61, 341 Standard balance deficit test 274 Stapes capitulum 159f, 160f footplate 216f Staphylococcus aureus 103 Stenosis of Stensen duct 361 Stereotactic fractionated radiotherapy 266 radiation therapy 264 Stroke 320, 321t Sturge-Weber syndrome 87f Styloid eminence 194f prominence 193f Submandibular gland 361 Superior part of tympanomeatal flap 213f

Index 389 Surgical exposition of endolymphatic sac 276 treatment of vestibular disorders 276 Swallowing exercises 323 Systemic lupus erythematosis 321t

T Targetoid hemangioma 75 Temporal bone fractures 278 Temporoparietal fascial flap 37 Tendon of tensor tympani 199f Tensor tympani canal 220f muscle 220f, 221f tendon 197f, 198f Thalidomide 88 Three-dimensional computed tomography angiography 379 Tinnitus retraining therapy 291 therapy 281 Total implantable cochlear amplifier 166, 167f Tracheal resection 104, 108 Tracheostomy 321t Transcanal endoscopic anatomy of tympanic cavity 191 management of limited cholesteatoma 200 Transcranial direct current stimulation 299 magnetic stimulation 297 Transcutaneous electric nerve stimulation 300 Transducer loading assistant 172 Transoral robotic surgery 1 Traumatic CSF leaks 24 Treatment of acute tinnitus 283 chronic tinnitus 286 hemangiomas 85 Meniere’s disease 285 tinnitus 283 Trigeminal distribution facial capillary malformation 87

Trimipramine 287 Tullio’s phenomenon 277 Tympanic membrane 206f, 208f, 213f, 214f Tympanomeatal flap 212f Typical hemangioma 77f infantile hemangioma 76 Tyrosine kinase inhibitor 62, 63f

U Upper esophageal sphincter 361 Uvulopalatopharyngoplasty 114

V Vascular endothelial growth factor 64, 67, 84 malformations 85 strip 215f tumors 74 Vasomotor rhinitis 356 Venous malformation 76, 88 Ventriculoperitoneal shunt 29, 30 Vertical segment of facial nerve 192f Vertiginous syndromes 318 Vestibular causes of balance disorders 326 disorders 318 irritation 278 rehabilitation 271 schwannoma 257, 278 Vestibulospinal pathway 273f Vidian canal 15 Visual analogue scales 51 Visual reinforcement audiometry 136

W Wegener’s granulomatosis 20

Z Zenker’s diverticulum 321, 363

Recent Advances in Otolaryngology

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