Writing Case Reports - A Practical Guide From Conception Through Publication

Clifford D. Packer Gabrielle N. Berger Somnath Mookherjee

Writing Case Reports A Practical Guide from Conception through Publication

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Writing Case Reports

Clifford D. Packer Gabrielle N. Berger Somnath Mookherjee

Writing Case Reports A Practical Guide from Conception through Publication

Clifford D. Packer, MD Case Western Reserve University School of Medicine Cleveland, Ohio USA Gabrielle N. Berger, MD Division of General Internal Medicine Department of Medicine University of Washington School of Medicine Seattle, Washington USA

Somnath Mookherjee, MD Division of General Internal Medicine Department of Medicine University of Washington School of Medicine Seattle, Washington USA

ISBN 978-3-319-41898-8 ISBN 978-3-319-41899-5 DOI 10.1007/978-3-319-41899-5

(eBook)

Library of Congress Control Number: 2016955956 © Springer International Publishing Switzerland 2017 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG Switzerland The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

CDP dedicates this book to his wife, Marie Sullivan. CDP acknowledges his medical students, colleagues, and patients at the Louis Stokes Cleveland VA Medical Center, all of whom helped to make this book possible. GB dedicates this book to all the students and residents who inspire her to “just write it up!” GB wishes to thank her colleagues at the University of Washington School of Medicine and the University of Washington Medical Center for their camaraderie and support. SM dedicates this book to his best friend, Leah Smith. SM wishes to acknowledge the University of Washington School of Medicine, Department of Medicine, and Division of General Internal Medicine for supporting this work.

Preface

Why write a book about writing case reports? One very practical reason is to bridge the gap between aspiration (“we ought to write this up”) and publication. Despite the increasing numbers of case reports published each year, we suspect that this gap remains wide, especially for medical trainees and physicians practicing in the community. Consequently, interesting and potentially important cases that ought to be in circulation are going unpublished. Second, although there are many fine articles on how to write case reports, and one excellent book – Milos Jenicek’s Clinical Case Reporting in Evidence-Based Medicine – we think that prospective case report authors need a practical, single-source guide to the whole process, from case selection through publication. In the twenty-first century, this guide must go beyond the traditional case report to instruct potential authors on its many modern variants: clinical vignette abstracts, case series, clinical images, clinical quizzes, adverse drug reaction case reports, n-of-1 trials, and clinical problem-solving cases. Today’s case report author needs to be versatile; that classic case of Mirizzi syndrome may not work as a straight case report, but it could be a superb clinical image or clinical reasoning case. Our aim is to help authors navigate these many options, select the form and venue that works best for their case, and then write it up in a concise, informative, and publishable style. But perhaps the best reason for writing this book is simply that case reports are fun to write, fun to read, great for teaching, and useful in our clinical practices. I am extremely lucky to have found two co-authors, Gabrielle N. Berger and vii

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Somnath Mookherjee, who not only feel the same way about case reports but have been willing to devote considerable time and energy to writing about them. Over the course of our collaboration, what started out as a simple case reporting handbook has evolved into something more – a handbook with supplemental essays on the history, educational value, career enhancements, scholarly opportunities, social media aspects, and future prospects of the case report. A major goal of any case report is to put the case in context; our parallel goal is to put the art and science of case reporting in context for our readers. Case report authors should understand that they are part of a great historical tradition, that case reports can be powerful educational tools, and that writing case reports can lead to exciting scholarly opportunities, new collaborations, and useful clinical insights. Writing case reports, in other words, can help to make us better teachers and physicians. If even a few medical students, residents, and practicing physicians publish their first case reports with the help of this book, it will have served its purpose. Cleveland, OH, USA

Clifford D. Packer, MD May 8, 2016

Contents

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clifford D. Packer

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2 The Historical Tradition of Case Reporting . . . . . . . Clifford D. Packer

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3 The Educational Value of Case Reports . . . . . . . . . . Clifford D. Packer

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4 Practical Benefits of Case Reporting . . . . . . . . . . . . . Gabrielle N. Berger

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5 Is My Case Good Enough? . . . . . . . . . . . . . . . . . . . . Somnath Mookherjee and Gabrielle N. Berger

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6 How to Get Started . . . . . . . . . . . . . . . . . . . . . . . . . . . Somnath Mookherjee and Gabrielle N. Berger

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7 How to Write a Traditional Case Report. . . . . . . . . . Clifford D. Packer

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8 Special Considerations . . . . . . . . . . . . . . . . . . . . . . . . . Clifford D. Packer

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9 How to Write a Clinical Vignette Abstract . . . . . . . . Jeffrey Wiese and Somnath Mookherjee

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10 How to Write a Clinical Problem Solving Manuscript . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gurpreet Dhaliwal and Gabrielle N. Berger

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11 Submitting a Case Report Manuscript . . . . . . . . . . . . Gabrielle N. Berger and Somnath Mookherjee

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12 The View from the Journal . . . . . . . . . . . . . . . . . . . . . Somnath Mookherjee and Brian J. Harte

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13 It’s Published! . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clifford D. Packer

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14 The Future of the Case Report . . . . . . . . . . . . . . . . . . Clifford D. Packer

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Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Contributors

Gabrielle N. Berger, MD Division of General Internal Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA Gurpreet Dhaliwal, MD Department of Medicine, University of California San Francisco, San Francisco, CA, USA Brian J. Harte, MD Department of Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA Somnath Mookherjee, MD Division of General Internal Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA Clifford D. Packer, MD Case Western Reserve University School of Medicine, Cleveland, OH, USA Jeffrey Wiese, MD Department of Internal Medicine, Tulane University School of Medicine, New Orleans, LA, USA

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Chapter 1 Introduction Clifford D. Packer

Writing Case Reports There are many good reasons to write case reports: to educate other trainees and physicians; to contribute evidence that could be useful to others for patient care; to learn (and teach) scholarly writing skills; to be the first to describe a new syndrome or a serious adverse drug reaction; to analyze clinical reasoning and decision-making; to propose new hypotheses on mechanisms of disease; to participate in innovative research in personalized medicine; to gain academic recognition and career advancement; and to take part in the historical tradition of case reporting that goes back almost 4000 years. This book has two purposes. First, it can be used as a comprehensive handbook or guide for anyone interested in writing a medical case report. Chapters 5, 6, 7, 8, 9, 10, 11, and 12 cover every practical step from conception and case selection (“Is my case good enough?”) to obtaining consent, collecting images and other data, assembling a team of authors, defining a target audience, selecting a journal, and responding to peer review. Chapters 7, 8, 9, and 10 give detailed, step-by-step instructions on how to write traditional case reports, adverse drug reaction case reports, case series, n-of-1 case studies, clinical image or clinical quiz articles, clinical vignettes, and © Springer International Publishing Switzerland 2017 C.D. Packer et al., Writing Case Reports, DOI 10.1007/978-3-319-41899-5_1

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clinical problem-solving cases. These chapters have numerous figures, tables, images, and excerpts of published case reports (including many written by the authors) to illustrate and reinforce the strategies that lead to publication. The second purpose of this book is to give the interested reader some perspective on the historical, educational, social, and cultural aspects of case reporting. Chapter 2 traces the history of case reporting from ancient Egypt to the present day, focusing on the effects of culture and technology on the evolving form and structure of the case report. Chapter 3 discusses the educational benefits of reading and writing case reports, both for trainees and experienced physicians. Chapter 4 covers the practical benefits of case reporting, including contributing to the medical literature, career development, and better patient care. Chapter 13 explores postpublication issues: press releases and media exposure, peer review and editorial writing opportunities, indexing, citations, and use of social media to track article views and comments. Finally, Chap. 14 speculates on the uncertain future of the case report. We hope that readers who want to write case reports will go beyond the “handbook” and take the time to learn more about this ancient yet still vibrant form of medical communication.

The Violinist Who Lost His Vibrato Case reports can arise in unexpected places. One of my first published case reports began with a conversation I had with a violinist at a chamber music party. On hearing that I was a physician, he began complaining to me about the side effects of one of his blood pressure medicines. Normally, this would elicit a polite nod or two, followed by a quick move to the opposite side of the room. However, something about his story intrigued me. When he was prescribed daily atenolol for hypertension, he began to have difficulty with initiating and controlling his vibrato, which

The Violinist Who Lost His Vibrato

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is produced by quick oscillations of the violinist’s hand to create a pleasantly pulsating tone. The problem worsened, and finally came to a head when he began rehearsing the famous solo in Massenet’s Meditation from Thais, a slow piece that requires varied and dramatic vibrato effects. Despite hours of practice, the vibrato was too slow, too “wide,” and difficult to control. In desperation, he turned to a physician with experience in music medicine, who weaned him off the atenolol and started him on an angiotensin-converting enzyme inhibitor for hypertension. His vibrato quickly recovered, and his subsequent performance of the Meditation was completely successful. This conversation led eventually to a case report and review of the literature on beta-blockers, stage fright, and the paradoxical effects of atenolol on the “controlled tremor” of vibrato [1]. Another case report was born when a patient with unexplained hypokalemia rolled into my office with a 2 l bottle of cola in the front basket of his electric scooter. His potassium had been low and almost impossible to replete for 2 years; an extensive work-up had revealed nothing. As I looked at him, I suddenly realized that the big cola bottle was the “MacGuffin” in the case. When I asked him about it, he admitted to drinking 4 l per day. This led to a diagnosis of cola-induced hypokalemia, which was confirmed when his potassium normalized after he reduced his cola intake [2]. What did these two cases have in common? An unexpected association, a mystery solved, but also the excitement of discovery. Vladimir Nabokov, in his Lectures on Literature, wrote that “a wise reader reads the book of genius not with his heart, not so much with his brain, but with his spine.”[3] In a very similar way, experienced physicians detect reportable cases with their spines, by the “telltale tingle” they feel when confronted with true novelty. The purpose of this book is to help physicians and students to sustain and preserve that initial frisson of excitement by learning to write up their cases for publication.

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Evidence Value of Case Reports: “What Actually Happened” “Case reports may remain the ‘lowest’ or ‘weakest’ level of evidence with respect to causality,” writes Riaz Agha, “but they remain the first line of evidence of what actually happened” [4]. Case reports derive their value as evidence from the real-world authenticity of the cases they describe. As Milos Jenicek reminds us, “Everything begins with the personal experience of the physician and his patient, at the office or hospital ” [5]. Randomized trials deal with populations of patients, under carefully controlled conditions; case reports deal with individual patients in the randomness of everyday life. Randomized trials are mainly confirmatory; they “bring a final quantification” of the evidence, Jan Vandenbroucke notes, “but offer little scientific novelty in themselves” [6]. Case reports are all about novelty, serendipity, new ideas, fresh hypotheses, and therapeutic surprises. Rather than providing confirmation, they provide inspiration. Case reports and case series supply most of the ideas and hypotheses that are tested and confirmed in randomized trials. Case reports are the lone prospectors who pan for gold and chip away at rocks with their hammers; randomized trials are the organized mining operations that rush in with their feeders and crushers and leaching tanks when the prospector finds a promising nugget. Case reports are traditionally regarded as the base of the evidence pyramid, with randomized controlled trials at the top (see Fig. 4.1). Evidence-based medicine tells us to use these high-quality randomized trials to guide our decisionmaking. This is all very well when patients present with textbook illnesses, and do not have multiple comorbid conditions. However, if your practice involves patients with complex medical histories who present with confusing and atypical symptoms, you will soon discover that randomized trials do not have all the answers. Fortunately, there are more than 1.7 million case reports indexed in PubMed, and a literature

Impact of Case Reports

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search will usually yield a handful of similar cases that may give some guidance on diagnosis and management. Thus, we turn the evidence pyramid on its head when randomized trials are lacking, and case reports and case series – “what actually happened” – become the best available evidence.

Impact of Case Reports Those who consider writing case reports a quaint, outmoded, and marginal pursuit should consider the dramatic and continuing impact of case reports in the twenty-first century. Whereas randomized trials often take years to plan and execute, case reports can function as “reports from the frontline” with rapid publication and wide dissemination of critical information on the natural history, prognosis, and treatment of emerging diseases. For example, a recent case report, “Zika Virus Associated with Microcephaly” [7], describes the autopsy findings of the 29-week fetus of a woman with symptoms of Zika virus infection. The autopsy revealed microcephaly, almost complete agyria, hydrocephalus, and other major brain abnormalities. Zika virus was found in the fetal brain tissue on reverse transcriptase–polymerase chain reaction (RT-PCR) assay, and the complete Zika virus genome was recovered from the fetal brain. This report provided the best evidence to date that Zika virus infection in pregnant women causes fetal microcephaly. Case reports played a similar frontline role in the recent Ebola virus epidemic in Africa, with critical information on natural history, virology, common complications (including Gram-negative septicemia and encephalopathy), and optimal ICU treatment for survival [8]. Similarly, case reports and case series have made critical contributions in outbreaks of SARS [9], MERS [10], AIDS [11], toxic shock syndrome [12], West Nile Virus [13], and many others. In addition to recognition and description of new diseases, case reports continue to play important roles in pharmacovigilance (see Chap. 8), hypothesis-generation and study of

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mechanisms of disease (Chap. 7), medical education (Chaps. 3, 8, 9, and 10), researching rare disorders and outliers (Chap. 8), personalized medicine (Chap. 8), study of the history of medicine (Chap. 2), quality assurance, and solving ethical dilemmas [6, 14, 15].

Case Reports: Form and Function in the Twenty First Century Over the centuries, case reports have evolved to fit the sociocultural and technological contexts of their times. The twentyfirst century has seen an expanding variety of roles for case reports (Fig. 1.1), probably arising from the rapid growth in computer technology, with increasingly powerful applications in research, education, imaging, and bioinformatics. For example, the study of individual outlier cancer survivors has become one of the hottest areas in cancer research with the advent of rapid and inexpensive genomic sequencing; we can now sequence hundreds of these individuals to find the ones with mutations that predict response to a

Traditional case report “Exceptional responder” trial

Adverse drug reaction case report

N-of-1 trial Study of disease mechanisms

Case series

Educational case report

Clinical image

Pharmacogenomic case study Quality assurance case series

Clinical vignette

Cohort study Clinical quiz Clinical problem-solving case

Clinical reasoning case

Figure 1.1 Taxonomy of the twenty first century case report

References

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specific treatment. Similarly, n-of-1 trials of patients with chronic conditions such as hypertension, sleep apnea, and Parkinson’s disease have benefitted from the development of advanced “phenotypic” monitoring devices to assess treatment response. In medical education, the traditional case report has morphed into a variety of forms, including clinical images, videos, quizzes, poster vignettes, and clinical problemsolving cases, all widely available via electronic media. Case series can now be electronically combined and analyzed for purposes of outcome studies, case definition, quality assurance, and multi-institutional registries. Clearly, we have come a long way from the traditional print journal case reports of 30 years ago. In fact, it can be argued that case reports have changed more in form and function over the past 30 years than in the 2000 years between Hippocrates’ Epidemics and the first modern case reports. How long can case reports continue to grow and reshape themselves and reach ever-increasing numbers of readers? Will the traditional case report stay relevant, or will it wither away and become a forgotten relic in 30 years? We hope that readers of this book – especially medical students, residents, and early-career physicians – will take these questions to heart and preserve the best that case reports have to offer.

References 1. Packer CD, Packer DM. Beta-blockers, stage fright, and vibrato: a case report. Med Probl Perform Art. 2005;20(3):126–30. 2. Packer CD. Chronic hypokalemia due to excessive cola consumption: a case report. Cases J. 2008;1:32. 3. Nabokov V. Lectures on literature. New York: Harcourt Brace Jovanovich; 1982. p. 6. 4. Agha R. Time for a new approach to case reports. Int J Surg Case Rep. 2010;1(1):1–3. 5. Jenicek M. Clinical case reporting in evidence-based medicine. Oxford: Butterworth-Heinemann; 1999. p. 5. 6. Vandenbroucke JP. Case reports in an evidence-based world. J R Soc Med. 1999;92(4):159–63.

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7. Mlakar J, Korva M, Tul N, Popović M, Poljšak-Prijatelj M, Mraz J, et al. Zika virus associated with microcephaly. N Engl J Med. 2016;374:951–8. 8. Kreuels B, Wichmann D, Emmerich P, Schmidt-Chanasit J, de Heer G, Kluge S, et al. A case of severe Ebola virus infection complicated by gram-negative septicemia. N Engl J Med. 2014;371:2394–401. 9. Tsang KW, Ho PL, Ooi GC, Yee WK, Wang T, Chan-Yeung M, et al. A cluster of cases of Severe Acute Respiratory Syndrome in Hong Kong. N Engl J Med. 2003;348:1977–85. 10. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus ADME, Fouchier RAM. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med. 2012;367: 1814–20. 11. Hymes KB, Greene JB, Marcus A, William DC, Cheung T, Prose NS, et al. Kaposi’s sarcoma in homosexual men – a report of eight cases. Lancet. 1981;2(8247):598–600. 12. Todd J, Fishaut M, Kapral F. Toxic-shock syndrome associated with phage-group-I Staphylococci. Lancet. 1978;2(8100):1116–8. 13. Asnis DS, Conetta R, Texeira AA, Waldman G, Sampson BA. The West Nile Virus outbreak of 1999 in New York: the Flushing Hospital experience. Clin Infect Dis. 2000;30(3):413–8. 14. Vandenbroucke JP. In defense of case reports and case series. Ann Intern Med. 2001;134:330–4. 15. Nissen T, Wynn R. The clinical case report: a review of its merits and limitations. BMC Res Notes. 2014;7:264.

Chapter 2 The Historical Tradition of Case Reporting Clifford D. Packer

The Case Report in Ancient and Medieval Times The medical case report as we know it today is not a static form of medical communication. It has evolved over almost 4000 years, and the format, content, and uses of case reports have undergone remarkable changes according to the shifting historical, technological, and cultural contexts. While the tradition of case reporting is ancient, our current way of writing a case report is a relatively recent development. The first known medical case reports, circa 1600 BC, were written and preserved on an Egyptian papyrus. They comprise a series of 48 cases which discuss injuries and disorders of the head and upper torso, and include an accurate description of a maneuver to reduce a jaw dislocation [1]. Another ancient Egyptian medical treatise, the Ebers papyrus (1552 BC), is a 110-page scroll which contains folk remedies, magical potions, and descriptions of a wide variety of diseases, including a disorder of frequent urination that is probably the first report of diabetes mellitus (although an ancient Hindu text from the same period noted that ants were attracted to the urine of people with a mysterious wasting disease) [2]. Egyptian medicine was practiced by physician-priests, and treatment, though often practical and occasionally useful, was inextricably © Springer International Publishing Switzerland 2017 C.D. Packer et al., Writing Case Reports, DOI 10.1007/978-3-319-41899-5_2

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entwined with magic [3]. In contrast, the Hippocratic case histories from the Greek classical era (ca. 400 BC) show no belief in supernatural origins of disease, and are characterized by objective and detailed descriptions of the findings and courses of various illnesses [1]. The physician-narrator was generally an observer, and did not intervene or otherwise participate in the case [4]. This case history from the Epidemics, of a patient with what sounds like a foot infection complicated by cellulitis and overwhelming sepsis, is typical: Criton, in Thasus, while still on foot, and going about, was seized with a violent pain in the great toe; he took to bed the same day, had rigors and nausea, recovered his heat slightly, at night was delirious. On the second, swelling of the whole foot, and about the ankle erythema, with distention, and small bullae (phlyctaenae); acute fever; he became furiously deranged; alvine discharges bilious, unmixed, and rather frequent. He died on the second day from the commencement. [5]

Hippocrates’ crowning achievement was the Aphorisms, a collection of 412 short, pithy maxims which conveyed the collected “teaching points” of his case histories. Aphorisms lend themselves to oral transmission – they live in speech, not on the page – and the best and most memorable of them are like poetry, the haiku of medicine. “It is the oral-poetic nature of a good aphorism,” writes Quentin Shaw, “that flash-welds it into the memory” [6]. The aphorism has persisted as a teaching tool; consider three Hippocratic aphorisms [7], followed by three that I memorized from my own medical training: Dysentery, if it commence with black bile, is mortal. In dropsical persons, ulcers forming on the body are not easily healed. In acute diseases, coldness of the extremities is bad. The pain of biliary colic radiates to a point just below the right scapula. The sun should never set on an empyema. Chest pain that is substernal, exertional, and relieved by nitroglycerine is angina pectoris.

In the modern case report, it is still customary to conclude the discussion with an aphoristic teaching point. As we sum up the case, we invoke the authority of Hippocrates.

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Galen (129–ca.200 AD), the eminent Greek physician and philosopher, took a very different approach to the case history. In contrast to the objective and detached case descriptions of Hippocrates, Galen used the first person to place himself at the center of his cases. His subjects were frequently celebrities – senators, philosophers, even the emperor – and he did not hesitate to describe his brilliance as a diagnostician, the gratitude of his patients, and the shortcomings of other physicians. Regarding Galen’s first work, On the Affected Parts, Cristina Alvarez Millan comments: …we have in these accounts mainly strange conditions and spectacular cures, and more importantly, we also find the literary device of increasing suspense throughout the nosological description, together with a remarkable amount of theatrical rhetoric. Thus, a typical clinical account would be in the following sequence: Galen's fear for the patient, Galen questioning the patient, Galen puzzling over the disease, Galen coming to a conclusion (diagnosis or prognosis), Galen warning the patient, Galen preventing his colleagues from administering a certain treatment, Galen amazing everybody on the scene, Galen explaining the real nature of the matter, and so on. [8]

Galen made many brilliant observations, and his medical teachings were revered for more than a thousand years after his death, until Vesalius and others began to disprove his anatomical and physiological theories. In the middle ages, European medical progress was hampered by rampant scholasticism and religious proscriptions against dissection and experimentation. As the Dark Ages continued in Europe, Islamic medicine took the lead, most impressively in the work and writings of Rhazes (865– 925 AD) and Avicenna (980–1037 AD). The case histories of Rhazes stand out in particular for their accurate and insightful descriptions of disease. Rhazes was the first to differentiate smallpox from measles, and his explanation of why survivors of smallpox are not infected a second time stands as the first theory of acquired immunity [9]. In another case, of a man who had fallen from a horse and sustained a neck injury with loss of sensation in his third, fourth, and fifth fingers, Rhazes was able to localize the lesion to “the nerve

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located after the seventh vertebra” (i.e., C-8) [1]. Rhazes had many students, and clearly used his case reports as didactic tools; in many instances, he went beyond description to include his own comparisons and generalizations from previous cases [10]. There was an interesting parallel rise of the case report in both Europe and China in the late fifteenth century. The first European collection of cases came from the Portuguese Jewish physician Amatus Lusitanus, who published 700 cases from 1551 to 1556. In China, the Stone Mountain Medical Case Histories of Wang Ji, written up and published in 1531 by his disciple Chen Hue, comprised about 100 case histories collected over 15 years. The early Chinese and European case reports had similar formats, and served both to teach a wide audience and to promote the doctors’ practices. An important difference was that the Chinese case reports tended to put respect for authority above experience, while the European case reports emphasized experience and valued debate and argument. Also, the Chinese physicians thought that case reports were for patients as well as physicians, and functioned as part of the treatment; European physicians saw them chiefly as a way to communicate with each other about diseases and treatments [11].

Origins of the Modern Case Report The historian Gianna Pomata has traced the roots of the modern case report to the Observationes (collections of case histories), which originated in the second half of the sixteenth century, and grew to become a primary form of medical writing by the eighteenth century [12]. The Observationes began as a form of self-promotion for town and court physicians, but eventually came to be viewed as a source of medical knowledge. “The original emphasis on therapeutic success,” writes Pomata, “gave way to a new focus on the descriptive knowledge of disease through detailed observation.”

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As the Enlightenment eased religious restrictions, autopsy findings began to be included in case reports, which improved diagnostic accuracy and led to major advances in the study of anatomy and physiology [13]. Pomata links the rise of the case report with “the new epistemological value of observation in the age of the Scientific Revolution” [12]. From the eighteenth century to the mid-twentieth century, even as it continued to change and develop, the case report played a critical role in teaching and discovery as well as in shaping the day-to-day practices of physicians. This is not to say that the case reports of 200 years ago were much like the objective and detached reports of today; eighteenth and early nineteenth century authors still favored the conversational tone of Galen, placed more emphasis on the patient’s subjective experiences, and often employed “dramatic devices” to delay the moment of diagnosis or heighten the narrative tension [4]. Consider Dr. John Warren’s description of a case in his Remarks on Angina Pectoris (1812): I had too soon an opportunity of confirming my suspicions; for on the following Sunday, whilst attending public worship in Brattle Street, Mr. Neal was seized with a most violent paroxysm, under circumstances peculiarly affecting. In the midst of a discourse highly interesting in its nature, and delivered with a great degree of fervor, whilst the eyes of all were fixed upon the preacher, he was observed to raise his hand, and forcibly rub his breast; his voice faltered, and his countenance changed; and, after one or two efforts to proceed, he sallied back on his seat, and became insensible. [14]

In his Essay on the Shaking Palsy (1817), James Parkinson brilliantly linked the disorders of trembling, posture, and gait as a single disease entity. Here he describes the terminal stages of the disease: As the debility increases and the influence of the will over the muscles fades away, the tremulous agitation becomes more vehement. It now seldom leaves him for a moment; but even when exhausted nature seizes a small portion of sleep, the motion becomes so violent as not only to shake the bed-hangings, but

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even the floor and sashes of the room. The chin is now almost immoveably bent down upon the sternum. The slops with which he is attempted to be fed, with the saliva, are continually trickling from the mouth. The power of articulation is lost. The urine and fæces are passed involuntarily; and at the last, constant sleepiness, with slight delirium, and other marks of extreme exhaustion, announce the wished-for release. [15]

Note the personification (“exhausted nature”) and the sentimental “wished-for release” which further dramatize Parkinson’s compelling clinical observations. In a similar vein, several eminent Victorian cardiologists used sensational and sentimental language in their case reports as they described the distressing effects of heart disease on their patients – and themselves [16]. But change was coming: the twentieth century saw the depersonalization of case reports and the standardization of their structure, with the rise of the now-familiar “introduction/case report/discussion” format and the gradual disappearance of the author from the narrative [1]. Osler’s 1902 report of two cases of intermittent claudication [17] is characteristic of this modern transition point in the case report. He begins with a recollection of a horse autopsy he had viewed with some members of the Montreal Veterinary College more than 20 years before. The horse had been afflicted with a “peculiar form of intermittent lameness,” and the autopsy showed “verminous aneurysms…of the iliac arteries.” He cites the case of another horse that had to stop and rest “after being driven for fifteen or twenty minutes;” autopsy showed clots obstructing the arteries in both hind legs. He then gives a thorough review of the literature, including a case reported by Charcot in 1856 of a soldier with classic intermittent claudication, who was found at autopsy to have a bullet encysted near the iliac artery, which had caused an aneurysm with obliteration of the lower part of the artery. Collateral blood flow had allowed a modest level of activity, but more vigorous activity caused ischemic pain that was relieved only with rest. Osler then describes his own case of a young man with a

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syphilitic abdominal aortic aneurysm who developed leg claudication symptoms after the aneurysm was successfully treated with “wiring and electrolysis”: …After walking for a certain distance his legs would, as he expressed it, give out completely; so that he could not move another step, and had to sit down. After resting a few minutes he could then go on again. This was more particularly noticeable when he walked on the street. He had to go very slowly and could not go for any distance. There was no paralysis accompanying the loss of ability to walk. He could move his legs, but there was an uncontrollable feeling that he could not take another step. Accompanying this there was a sensation of dead, heavy weight in the legs, but no cramps. Walking about in the house (and in the yard) did not bring on the condition, but he had had it very frequently in the past few months and he had learned to ward it off by walking very cautiously and slowly and resting at intervals. The femoral artery and the dorsal arteries of the feet were distinctly sclerotic.

Osler concludes with an important teaching point: As shown in the horse and in the first case which I here report, the affection is not always due to simple arterio-sclerosis, but may be due to aneurism, as in Charcot’s case and as is the rule in the horse. [17]

In this terrifically interesting and entertaining interspecies case report, Osler writes in the first person, and brings in his odd (though very apt) experience in veterinary medicine. Yet, this case report is distinctly modern in that it contains an introduction, review of the literature, concise description of two cases, and a strong teaching point. At the end, Osler cannot resist adding “a word as to the name,” and indicates his preference for the term “intermittent claudication” as opposed to angiosclerotic intermittent dysbasia, intermittent muscle paresis, or angiosclerotic paroxysmal myasthenia, as proposed by Charcot, Erb, and Higier. This is the literary Osler expressing a preference, which any reader of Aequanimitas will surely respect. (Osler’s paper brings to mind another interspecies case report, recently published in the New England Journal of

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Medicine, of an HIV-infected man who developed a nonhuman malignancy that arose from proliferating, genetically altered tapeworm cells. This was the first case of human disease caused by transmissible clones of parasite-derived cancer cells [18]).

The Rise, Decline, and (Electronic) Rebirth of the Case Report Over the past 100 years, the popularity of the case report has risen, fallen, and risen again. The twentieth century saw a tremendous surge in the publication of case reports focusing on new diseases, drug side effects, etiology and mechanisms of disease, therapy, prognosis, and education [19]. New diseases first described in case reports include shell shock (1915), Cushing’s syndrome (1932), erythroblastosis fetalis (1932), Ebola virus infection (1977), toxic shock syndrome (1978), AIDS (1981), and thrombophilia due to Factor V Leiden (1993). Significant drug side effects first described in case reports include thalidomide-related birth defects (1961), venous thrombosis due to oral contraceptives (1961), chlorpropamide-induced SIADH (1970), valvulopathy associated with weight-loss drugs (1996), and troglitazone-induced liver failure (1998). Other landmark twentieth century case reports include the first surgical ligation of a patent ductus arteriosus (1939), the first use of lithium to treat mania (1949), and the first heart transplant (1967). Physicians looked to case reports for practical guidance, education, and inspiration. Furthermore, they were frequently able to publish their own interesting cases; over the 30-year period, from 1946 to 1976, case reports comprised up to 38 % of all articles published in general medicine journals [20]. The 1980s, however, marked the beginning of a steep decline in the publication of case reports in many leading journals. This decline correlated with a rise in the publication of “research articles” (articles which included original,

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firsthand data with a clearly delineated research methodology), which increased from 50 % of all psychiatry journal articles in 1969–1970 to 82.4 % by 1989–1990 [21]. Another factor was the popularization and broad acceptance of “evidence-based medicine,” which raised randomized controlled trials to the pinnacle of the evidence pyramid, and vilified case reports and case series as “the lowest forms of intellectual life, even lower than the case-control study” [19]. In their excellent article on the recent history of the clinical case report, Nissen and Wynn [22] describe how the case report was marginalized by editors, whether relegated to the “Letters to the Editor” section, limited by stringent selection criteria, or, in many cases, barred entirely from publication. Case reports are generally cited less often than clinical research studies, and the increasing importance of the impact factor gave editors another reason to avoid publishing them. In addition, the dramatic rise in government and pharmaceutical company funding of randomized controlled trials made the largely unfunded case report a less desirable venue for both authors and journals [22]. All of these factors contributed to the flat overall growth in case report publication from the 1980s through the mid-1990s. And then, in the late 1990s, the case report began to rise again. A number of prestigious journals – The Lancet, the American Journal of Psychiatry, BMJ, the Journal of Clinical Oncology, and others – began to publish case reports again in a variety of formats. Around the same time, some skeptics began to criticize evidence-based medicine as “a hierarchy of clinical epidemiology” that favors large-n quantitative studies to evaluate medical interventions with wide applicability, but fails at the level of the individual patient [22]. In the backlash against evidence-based medicine, interest began to grow in the narrative of the individual patient, which could be studied with qualitative research methods and applied to other patients with similar patterns of illness. Between 2000 and 2013, the rate of PubMed-indexed case report publication increased by 36 %, from 42,000 to 58,000 per year.

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Perhaps the most important factor in the case report’s revival has been the rise of the electronic case report journal. This trend began in 2007, with the Journal of Medical Case Reports, Cases Journal, and BMJ Case Reports; since then, there has been exponential growth with more than 30 online case report journals as of November, 2015. Increasingly, both the advantages and problems of these online journals are becoming more clear [23]. On the one hand, the case report journal can be a gateway to publication and career advancement for both busy clinicians and novices who lack experience in medical writing. In areas of the world with limited resources, where research funding is scarce, open-access case report journals can be a way to post important clinical findings and circulate medical information in the community. Another potential benefit is the creation of a large database of cases, which in theory could be useful in the diagnosis and treatment of individuals with complex and unusual problems not addressed by clinical trials. On the other hand, the quality of both peer review and writing has been inconsistent in some of these journals, with critical information missing, inadequate explanation of events, and unsupported conclusions. Authorship fees can be a hindrance to publication, especially for authors lacking institutional support, and the combination of high fees and substandard peer review raises the specter of “vanity publication” for those willing to pay. Finally, the large database of marginally significant cases in online journals “might drown key sentinel events in a sea of careless publishing” [23]. Several authors have proposed case report guidelines as a solution to these problems [23–25]. They suggest that guidelines could improve both the evidence value of individual case reports and the quality of the database as a whole. The authors of the CARE guidelines, a consensus-based case report guideline and 13-point checklist first published in 2013, assert that “the systematic aggregation of information from case reports will inform clinical study design, provide early signals of effectiveness and harms, and improve healthcare delivery” [22]. This is an exciting development, but one

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could argue that, with 1.77 million case reports already indexed in PubMed, the guideline “ship” has already sailed. Another approach might be to disseminate the CARE guidelines to all physicians in training and teach them to assess the evidence value of each case report at the time it is accessed for patient care. But before we embrace strict guidelines, we should consider what we have learned from the long history of the medical case report. Case reports reflect the cultures, values, and technologies of their times. Therefore, the form and function of the case report must continue to change over time. Who can imagine what medical case reports will look like in 500 years? And why would these future case reports adhere to twenty first century guidelines, any more than we look to the sixteenth century for instruction? The other distinctive thing about case reports is that they are at their best highly creative endeavors, bursting with enthusiasms, intuitions, and hypotheses that are barely restrained by the traditional form. Is there a place within the guidelines for Osler’s stiff-legged horses, or for Rhazes’ intuitive hypothesis on immunity, which was correct but remained unverifiable for centuries? Whatever guidelines we choose, we must not stifle speculation, which is essential not only in case reporting but in all medical writing.

References 1. Nissen T, Wynn R. The history of the case report: a selective review. JRSM Open. 2014;5(4):2054270414523410. 2. Frank LL. Diabetes mellitus in the texts of old Hindu medicine (Charaka, Susruta, Vagbhata). Am J Gastroenterol. 1957;27(1): 76–95. 3. Allen JP. The art of medicine in ancient Egypt. The Metropolitan Museum of Art, New York. New Haven/London: Yale University Press; 2005. 4. Hurwitz B. Form and representation in clinical case reports. Lit Med. 2006;24:216–40.

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5. The Internet Classics Archive. Hippocrates: of the epidemics (trans. Francis Adams). 1994. http://classics.mit.edu/Hippocrates/ epidemics.html. Accessed 29 Oct 2015. 6. Shaw Q. On aphorisms. Br J Gen Pract. 2009;59(569):954–5. 7. The Internet Classics Archive. Hippocrates: aphorisms (trans. Francis Adams). 1994. http://classics.mit.edu/Hippocrates/aphorisms.html. Accessed 13 Nov 2015. 8. Alvarez MC. Graeco-Roman case histories and their influence on Medieval Islamic clinical accounts. Soc Hist Med. 1999;12:19–43. 9. Ashtiyani SC, Amoozandeh A. Rhazes diagnostic differentiation of smallpox and measles. Iranian Red Crescent Med J. 2010; 12(4):480–3. 10. Alvarez MC. The case history in Medieval Islamic medical literature: Tajarib and Mujarrabat as source. Med Hist. 2010;45(2):195–214. 11. BMJ Blogs. Richard Smith: case reports in 16th century Europe and China. Blogs.bmj.com/2013/07/09/richard-smith-casereports-in-16th-century-europe-and-china/. Accessed 29 Oct 2015. 12. Pomata G. Sharing cases: the observations in early modern medicine. Early Sci Med. 2010;15(3):193–236. 13. King LS, Meehan MC. A history of autopsy. A review. Am J Pathol. 1973;73:514–44. 14. Warren J. Remarks on angina pectoris. N Engl J Med. 1812;1(1):1–11. 15. Parkinson J. Project Gutenberg’s An Essay on the Shaking Palsy. www.gutenberg.org/files/23777/23777-h/23777-h.htm. Accessed 3 Nov 2015. 16. Class M. Introduction. Medical case histories as genre: new approaches. Lit Med. 2014;32(1):vii–xvi. 17. William Osler: Original Papers 1898–1906. Intermittent claudication, 1902. digitalcommons. library.tmc.edu/osler/2/. Accessed 3 Nov 2015. 18. Muehlenbachs A, Bhatnagar J, Agudelo CA, et al. Malignant transformation of Hymenolepsis nana in a human host. N Engl J Med. 2015;373(19):1845–52. 19. Vandenbroucke JP. Case reports in an evidence-based world. J R Soc Med. 1999;92(4):159–63. 20. Fletcher RH, Fletcher SW. Clinical research in general medicine journals. A 30-year perspective. N Engl J Med. 1979;301:180–3.

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21. Pincus HA, Henderson B, Blackwood D, Dial T. Trends in research in two general psychiatric journals 1969–1990: research on research. Am J Psychiatry. 1993;150:135–42. 22. Nissen T, Wynn R. The recent history of the clinical case report: a narrative review. J R Soc Med Sh Rep. 2012;3:87. 23. Sun GH, Oluseyi A, Hayward RA. Open access electronic case report journals: the rationale for case report guidelines. J Clin Epidemiol. 2013;66(10):1065–70. 24. Gagnier JJ, Kienle G, Altman DG, et al. The CARE guidelines: consensus-based clinical case reporting guideline development. J Med Case Rep. 2013;7:223. 25. Rison RA. A guide to writing case reports for the Journal of Medical Case Reports and Biomed Central Research Notes. J Med Case Rep. 2013;7:239.

Chapter 3 The Educational Value of Case Reports Clifford D. Packer

Educational Benefits of Reading Case Reports A case report is a clear, concise, and digestible account of a case that can easily be read in one sitting. It offers much more than a description of a unique or unusual patient encounter. A well-prepared case report gives a focused review of the pertinent literature, places the case in context compared with other similar cases, proposes a hypothesis to explain what occurred, and makes a clear teaching point. The attentive reader will gain both deeper understanding of the topic area and insight into specific points of diagnosis and management. Consider, for example, a case report written by one of my former medical students describing an unusual case of airway compromise in infectious mononucleosis [1]. We learn that infectious mononucleosis can, in rare cases, cause lifethreatening airway obstruction due to severe tonsillar hypertrophy, with the key findings of “hot potato voice” and “kissing tonsils” on CT imaging of the neck (Fig. 3.1). In addition, we learn that the differential diagnosis for pharyngeal airway obstruction also includes peritonsillar abscess, epiglottitis, Ludwig’s angina, angioedema, foreign body, neoplasm, and local trauma. A literature review reveals that only 5 of 467 mononucleosis patients in one series had airway © Springer International Publishing Switzerland 2017 C.D. Packer et al., Writing Case Reports, DOI 10.1007/978-3-319-41899-5_3

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Figure 3.1 CT image of “kissing tonsils” [1]

compromise, that most patients with it respond well to corticosteroids, and that very few require tonsillectomy. Finally, the author clearly delineates the clinical reasoning that led to the diagnosis: While this patient already carried a diagnosis of infectious mononucleosis, we could rule out diphtheria as there were no significant pharyngeal exudates and he had been previously vaccinated. Direct visualization of the pharynx with laryngoscopy revealed no foreign bodies, neoplasms, abscesses, and revealed only tonsillar swelling. Cultures for superimposed streptococcus infection were negative. Taken together, these diagnostic findings further confirmed that this patient’s symptoms were due only to infectious mononucleosis without exacerbating processes. [1]

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Thus, in a three-page case report that can be read in less than 10 minutes, the reader learns key points on the differential diagnosis, etiology, epidemiology, diagnostic work-up, imaging findings, and management of pharyngeal obstruction from mononucleosis. Consider also a 2014 case report by Kreuels et al., “A case of severe Ebola virus infection complicated by gram-negative septicemia” [2]. This report meticulously describes the care of a patient with Ebola infection complicated by septicemia, respiratory failure, paralytic ileus, and encephalopathy, who was successfully treated with general intensive care measures. The patient put out 4–8 l of diarrhea per day over the first 72 h, and required 10 l of IV fluid per day along with aggressive potassium repletion. A table gives the 27-day record of vital signs, oxygenation, IV and PO fluid intake, fluid losses from diarrhea and vomiting, urine output, fluid balance, and laboratory test results. There are two figures: a timeline with plasma viral RNA levels, white blood cell count, CRP levels, and antimicrobial treatment (Fig. 3.2); and a second timeline with antibody titers in plasma, and viral RNA load in plasma, sweat, and urine. The practical educational value of this case report is tremendous. First, it documents the natural history of Ebola virus infection. Second, it gives a comprehensive description of a successful treatment regimen, including details of critical infection control measures, which serves as a blueprint for the treatment of other patients. Third, based on the case and their review of the literature, the authors propose certain basic principles in the care of Ebola patients: the vital importance of aggressive IV hydration, the use of serial ultrasonography and other tests to document the adequacy of hydration, and the need to monitor patients for signs of superimposed bacterial infection by means of laboratory tests, such as C-reactive protein. Practical management points and discussion of the clinical decision-making are defining features of case reports [3, 4]. In this case, in the absence of randomized controlled trials, we are given some of the best available evidence on optimal treatment of Ebola virus infection.

Chapter 3. The Educational Value of Case Reports

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Figure 3.2 Timeline of plasma viral RNA load, septicemia, and antimicrobial therapy in a patient with severe Ebola virus disease [2] (Copyright © 2014 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society)

Case reports also create “recognition patterns” that can help clinicians to identify and treat rare and unexpected conditions in their own practices [5], and can be invaluable to physicians confronted with cases that defy the usual diagnostic and treatment algorithms. I once admitted an elderly man to the hospital with weight loss and failure to thrive; his PSA was 200, and a biopsy confirmed prostate cancer. His metastatic work-up revealed multiple pulmonary nodules but no bone or liver metastases. I consulted a pulmonologist who recommended a bronchoscopic biopsy. However, a literature search turned up several cases of men with prostate cancer metastatic only to the lungs, all of whom had complete regression of their lung nodules with hormonal therapy. Based on this evidence, we decided to cancel the bronchoscopy and proceed with treatment [6]. This case illustrates the

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practical educational value of reading case reports, especially for the evaluation and treatment of patients who do not present with the usual textbook symptoms.

Educational Benefits of Writing Case Reports for Medical Students and Residents A few authors have discussed the educational benefits of publishing case reports for medical students and residents. In their article “The case report in context,” Carleton and Webb comment that “the experience of writing a case report can sharpen authors’ writing skills, lend critical experience in the peer review process, and prepare medical professionals for careers as scholarly clinicians” [5]. Petrusa and Weiss explore the benefits of “collaborative writing” of case reports with residents: extending patient care activities to a more scholarly product, improving residents’ writing and critical thinking skills, facilitating fellowship and academic career plans, and documenting faculty teaching efforts, with the published case report as “tangible evidence” of teaching [7]. McNeill et al. developed a series of tutorials to teach junior doctors the principles of medical publishing and academic writing, which included editorial comments on structure and content, perfection of drafts via e-mail correspondence, and advice on journal selection. Their aim was to combine “formal teaching on medical publishing with the experiential learning of writing a case report” in order to develop the skills required to produce publications and thus enhance career prospects [8]. As an internal medicine clerkship director, I have become increasingly aware of the many educational benefits of case reporting; consequently, I have required all of my students to write a case report over the past 7 years. Early in the clerkship, we meet for a 1-hour session to discuss the evidence value of case reports, how to select a case, and how to structure and present the report, which must be at least 400 words with two to three references. In the sixth week, we meet again and the

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students present their case reports to the group, respond to questions, and receive feedback. All students have completed the assignment, and most are able to select a suitable case and write a well-reasoned discussion without my assistance. To date, this project has produced more than 250 case reports, 35 ACP and SGIM abstracts, and 15 published case reports in peer-reviewed general medicine, pharmacology, and psychiatry journals. Student case report topics [9] have included: • Transient transcortical motor aphasia caused by lithium toxicity • Sphingomonas paucimobilis bacteremia in a patient with alcoholic cirrhosis • MSSA-associated metastatic endophthalmitis • Left atrial invasion of squamous cell lung cancer • Diclofenac-associated neutropenia • Pylephlebitis associated with necrotizing pancreatitis and prostatic abscesses • Pantoea agglomerans bacteremia from a rose thorn injury • Prostate cancer metastatic to the clivus, presenting as episodic diplopia • Elephantiasis nostras verrucosa in a 62-year-old man with chronic lymphedema • Occult Citrobacter freundii bacteremia in a man with cirrhosis • Ipilimumab-induced pan-colitis • Type B lactic acidosis caused by metastatic gastric carcinoma • Cannabinoid hyperemesis syndrome • Cushing’s syndrome due to an interaction between oral budesonide and ritonavir • Concurrent reactive arthritis, Graves’ disease, and warm autoimmune hemolytic anemia • Xanthogranulomatous pyelonephritis presenting as fever of unknown origin • MERS (mild encephalitis with a reversible splenial lesion) in the setting of Legionella pneumonia and B12 deficiency

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Of note, 14 of the 15 students who published their case reports required the help of faculty mentors as co-authors; only one student was able to publish as a single author [1]. Since case reports often require multiple revisions before publication, co-authoring with students typically involves several months of mentoring, with much back-and-forth discussion. In almost all cases, the learning is bidirectional, the mentoring is deeply appreciated, and the door is left open for new collaborations after the case report is published. Over time, it has become increasingly clear that my students are learning many useful skills as they select, research, and write up their case reports. Case selection is a complex process that involves advanced observation and patternrecognition skills. Generation of a hypothesis to explain unusual events requires thorough research, clear understanding of pathophysiology, and a dash of creativity. Writing a case report demands rhetorical versatility – an ability to combine the narrative and descriptive elements of the case description with the synthetic and argumentative elements of the discussion. In addition, case reports are “patient-centered” because they tell patients’ stories even as they seek to comprehend and explain their illnesses; students can be taught to consider (and connect) both the scientific and humanistic aspects of their patients through case reports [10]. My students have shown impressive creativity and resourcefulness in developing their hypotheses. One student, for example, had a patient with an atypical presentation of Behcet’s syndrome with renal infarcts and orogenital ulcers. The patient also had a chart history of Ebstein’s anomaly, but had been healthy enough to serve as an active duty soldier, which made the student wonder if he had been misdiagnosed. A literature search revealed that Behcet’s-associated endomyocardial fibrosis can mimic Ebstein’s anomaly, and the student hypothesized that Behcet’s explained the right atrial and tricuspid valve abnormalities seen on echocardiogram. This surmise was confirmed when old surgical records were reviewed.

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Educational Benefits of Writing Case Reports for Practicing Physicians Sir William Osler, the famed Canadian physician, founded the modern teaching service at Johns Hopkins University, wrote the last single-author medical textbook, and became Regius Professor of Medicine at Oxford. Dr. Osler published more than 180 case reports, and had this advice for his fellow physicians: “Always note and record the unusual…Publish it. Place it on permanent record as a short, concise note. Such communications are always of value” [11]. Regarding medical writing and publication, he added: The difficulty is that the young write too much, the mature write too little. There is too much green fruit sent to market, and the fruit of too many of the fine trees is never plucked at all… [12]

Osler felt that mature physicians have an obligation to publish, in order to share their important clinical observations and insights with others. The problem, of course, is that practicing physicians are usually far too busy (or feel they are too busy) to write case reports on their patients. Also, community physicians, although they generally see more patients, may be less confident than academic physicians in their ability to publish. It is our contention that any physician with a sufficiently novel case can and should be able to publish it. The benefits of publication include the expertise gained from thoroughly researching a rare case, the opportunity to disseminate one’s observations or innovations to a wider audience, and the scholarly connection with all physicians, past and present, who have written case reports. The knowledge that one has placed a brick or two at the base of the evidence pyramid (or added an apple to the bushel, to complete Osler’s metaphor) can be profoundly satisfying, especially as the citations begin to roll in. Our chief aim with this book is to help all physicians to comply with Osler’s archival imperative: “Always note and record the unusual…Publish it.”

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References 1. Kakani S. Airway compromise in infectious mononucleosis: a case report. Cases J. 2009;2:6736. 2. Kreuels B, Wichmann D, Emmerich P, et al. A case of severe Ebola virus infection complicated by gram-negative septicemia. N Engl J Med. 2014;371:2394–401. 3. Aitken LM, Marshall AP. Writing a case study: ensuring a meaningful contribution to the literature. Aust Crit Care. 2007;20(4):132–6. 4. Jenicek M. Clinical case reporting in evidence-based medicine. Oxford: Butterworth-Heinemann; 1999. p. 56. 5. Carleton HA, Webb ML. The case report in context. Yale J Biol Med. 2012;85(1):93–6. 6. Packer CD. The MEDLINE search as a diagnostic maneuver. Arch Intern Med. 2005;165(6):703–7. 7. Petrusa ER, Weiss GB. Writing case reports: an educationally valuable experience for house officers. J Med Educ. 1982;57(5):415–7. 8. McNeill A, Parkin CK, Rubab U. Using a case report to teach junior doctors about medical publishing. Med Teach. 2007;29(5):511. 9. Packer CD. Case reports: good evidence, good for teaching. SGIM Forum. 2014;37(8):10, 14. 10. Packer CD, Katz RB, Krimmel JD, Iacopetti CL, Singh MK. A case suspended in time: the educational value of case reports. Acad Med. 2016. PMID:27097050. doi:10.1097/ACM.0000000000001199. [Epub ahead of print]. 11. Thayer WS. Osler, The Teacher Sir William Osler, Bart. Baltimore: Johns Hopkins Press; 1920. p. 51–2. 12. Osler WD. Johnston as physician. Washington Med Ann. 1902;1:158–61.

Chapter 4 Practical Benefits of Case Reporting Gabrielle N. Berger

Introduction Case reports represent an important avenue for clinicians aiming to disseminate novel observations to a broad audience. The value of case reports has been contested in recent decades, in part due to an increased focus on publishing scientific papers that bolster a journal’s impact factor [1]. Despite this trend, case reports remain an accessible and achievable mechanism for many practitioners to publish. This is particularly true for trainees and junior faculty seeking publications for career advancement but who lack the research skills to execute a sophisticated research study [2, 3]. This chapter will address the practical benefits of case reporting with a particular focus on the role of case reports in enhancing the medical literature, patient care, and career development.

Contribution to the Medical Literature For centuries, case reports occupied a highly respected place in the medical literature [4] (see Chap. 2). With its roots planted in the Greek classical era, the modern case report evolved as a critical mode of communication to help practitioners © Springer International Publishing Switzerland 2017 C.D. Packer et al., Writing Case Reports, DOI 10.1007/978-3-319-41899-5_4

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exchange knowledge about pathophysiology and disease. Fundamentally, case reports are based on observations: they allow medical practitioners to catalog their experiences with unusual presentations of disease, innovative surgical and procedural techniques, and the effects of new drugs [5]. While medical case reporting gained relevance for centuries, the emergence of evidence-based medicine ushered in a new era focused on large-scale research to inform clinical care. Within this context, levels of evidence are stratified according to strength and rigor, with systematic reviews and randomized controlled trials occupying the apex of the evidence-based pyramid, while expert opinion, case reports, and case series form the base [6] (see Fig. 4.1). This paradigm shift, with its move away from observational data to guide clinical decision-making, led many to reconsider the merit of case reports. Indeed, the number of case reports published in high-impact journals declined dramatically over the last several decades [1]. Case reports are less likely to be cited as frequently as large research studies, which can adversely affect a journal’s impact factor [7]. Because journals generally strive for the highest possible impact factor, editors are often reluctant to publish case reports fearing a decline in ratings.

Systematic Reviews Randomized Trials Cohort Studies Case Control Studies Case Series, Case Reports Animal Research/Expert Opinion

Figure 4.1 The hierarchy of evidence

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Although observational – and even anecdotal in nature – case reports and case series remain a critical plank in the platform of evidence-based medicine. Publication of novel disease presentations and treatment effects spur additional research and may highlight the emergence of new trends or patterns of disease [8]. Consider the report of five gay men with Pneumocystis pneumonia in a 1981 Morbidity and Mortality Weekly Report (MMWR) published by the Centers for Disease Control (CDC) [9]. This publication was among the first to describe the new disease that came to be known as the acquired immune deficiency syndrome (AIDS). Further, the association between specific opportunistic infections and HIV was first described in case reports, including HIV-related Kaposi’s sarcoma [10] and retinitis due to cytomegalovirus [11]. Even today, highly respected journals publish case reports or series when new diseases are identified. Examples include the emergence of zoonotic Onchocerca lupi infection in the United States [12], or when a previously known disease entity poses a new public health risk, as in the case of variant Creutzfeldt-Jakob disease transmission by blood transfusion [13]. These examples highlight the contributions of case reporting to the medical literature: without the ability to rapidly disseminate new medical observations through case reports and series, there is limited evidence to inform larger, more rigorous studies (see Fig. 4.2, adapted from Pierson [7]).

The Case For Guidelines Case reporting as a mechanism for launching future paths of scientific inquiry has been well described [7, 14]. However, there is general agreement that case reports must be sufficiently rigorous in methodology and reporting standards to influence advanced research studies. Reporting guidelines exist for other study designs, including randomized controlled trials (CONSORT) [15], systematic reviews and metaanalyses (PRISMA) [16], and adverse event case reports [17]. Recent evidence suggests that journals employing the CONSORT guidelines receive randomized controlled trial submissions that are more complete [18].

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Physiologic Studies

Clinical Trail

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Clinical Trail Clinical Trail

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Observation Documentation Hypothesis Generation Interpretation in Clincal Context

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Incorporation into Clinical Practice

e Fig. 4.2 How the observation and documentation of an individual case can lead ultimately to changes in practice. Although it is possible to speculate about mechanisms and the potential for broader application of what happened in a single case, justification for changing the future care of patients requires many more steps and substantially higher levels of evidence than can be derived from one experience

Until recently, there was no similar set of guidelines for case reports. However, the emergence of online outlets for publishing case reports and an interest in increasing the quality of case report submissions led an interdisciplinary team of clinicians and researchers to publish the CARE (CAse REport) guidelines in 2013 [14]. The CARE guidelines provide a checklist for authors to capture key clinical data and translate that data into a concise, evidence-driven case report. Consisting of 13 discrete items, the checklist aims to help authors structure the case report writing process. Adoption of the CARE guidelines or another standardized framework is likely to improve the completeness of case reports and may help reestablish case reporting as a more respected component of the medical literature.

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Contribution to Patient Care Case reports benefit patients directly by allowing clinicians to share clinical experiences that diverge from the standard of care. While most practicing physicians aspire to apply evidence-based medicine in their daily practice, there will always be patients who fall into the “gray zone” of medicine. For example, a patient may present with a confusing constellation of symptoms that does not fit with a known syndrome. In these scenarios, there is often a lack of evidence to guide clinical decision-making. The physician’s ability to compare the patient’s presentation to previous case reports can mean the difference between making a diagnosis and leaving a patient searching for additional answers. The limitations of evidence-based medicine often emerge when patients face decisions about pursuing aggressive treatment, some of which may have significant side effects [5]. Depending on individual goals regarding quality of life, patients may decline a recommended treatment plan despite counseling from their physician about the benefits. In this situation, physicians should use the literature to identify additional treatment options for the patient. Case reports documenting how a physician chose an alternative therapy and the outcome of that therapy can help align their recommendations with the patient’s preferences [19]. In the absence of clear guidelines for managing a particular disease, case reports can help illustrate the complex decision-making process undertaken by other clinicians in similar scenarios. Gaining insight into how colleagues grapple with challenging clinical questions can validate a physician’s own internal struggle over how best to advise a patient. This holds particular relevance for physicians who operate in isolated areas and may not have access to consultation from colleagues or subspecialists. Despite the growing reliance on evidence-based medicine to inform daily practice, many patients do not “follow the textbook” in either their presentation or treatment

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preferences. Knowing where to turn for advice in these situations is essential for physicians aiming to improve care for their patients. Accessing additional clinical experience through case reports remains an invaluable resource for clinicians seeking guidance outside the traditional evidence base.

Career Enhancement Case reports provide a practical, achievable avenue for scholarship for physicians at various stages of training. Many learners and junior faculty aspire to publish in the medical literature to demonstrate academic productivity. Yet medical writing is a skill that must be practiced and honed over time: learning to construct a well-written research manuscript is an iterative process that requires mentorship and tenacity. It also requires a significant amount of time and commitment. Additionally, the likelihood that a manuscript will be accepted for publication often correlates with an author’s level of experience publishing in the medical literature. Authoring case reports is an effective way of gaining experience with medical writing and can influence the success of publishing future research projects. Publishing case reports can be of particular benefit for medical students and residents (see Chap. 3). Case reports are brief; they do not require a background in research methodology or primary data analysis skills. Although it takes preparation and forethought to effectively organize a case report project, writing a case report is a much more attainable goal than trying to spearhead a rigorous research manuscript. In a survey of internal medicine residents who presented work at a national meeting, the median time spent preparing a case report was 50 hours, compared with 200 hours for research abstracts [20]. Medical students just embarking on their careers typically bring a high level of energy and enthusiasm to patient care.

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They are often highly motivated to participate in a case report project that validates this excitement. Case reports are an ideal project for a medical student to lead: the scope of the project is limited but provides an opportunity to develop a range of important research skills, including [21]: • • • • •

Conducting a literature search; Constructing an abstract; Writing a manuscript that adheres to journal expectations; Engaging in multiple rounds of editing with a mentor; Navigating the submission and review process.

Publishing in the medical literature as a student or resident demonstrates intellectual curiosity, a commitment to scientific inquiry, and the ability to follow-through on scholarly projects. Committing to a case report project may be more pragmatic than trying to submit a research manuscript, particularly because it is easier to complete a case report on a limited timeline. The likelihood of project completion is important since a track record of successful publications makes learners more attractive candidates for residency and fellowship. Scholarship is also required for academic promotion. For faculty pursuing a clinician-educator track (or similar pathway) within an academic institution, publishing case reports can help fulfill promotion and advancement criteria. With the exception of pure research tracks at academic medical centers, many promotion committees recognize publication of a case report as a valuable contribution to the literature. Case reports should be listed as a published work on the curriculum vitae, particularly if the report appears in a peer-reviewed journal. Serving as the first or last author on a case report can be particularly beneficial. As first author, the faculty member is viewed as the project lead – the person responsible for most of the writing and moving the project toward completion. In contrast, as last author, the faculty member fulfills the role of project mentor. In this position, the faculty member provides leadership, oversight, vision, and mentorship for junior colleagues.

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Finally, publishing a case report allows a faculty member to develop expertise in a particular condition or disease presentation [2]. The corresponding author may receive inquiries from all over the world regarding similar presentations that other clinicians have struggled with. This correspondence may offer opportunities for collaboration with colleagues at other institutions. Thus, a project that began as a single case report may turn into a case series, which could then form the foundation for larger research studies. This trajectory is just one example of how a case report can serve as a springboard for future scientific inquiry.

Conclusion Case reports remain a critical component of the medical literature, offering many practical benefits for clinicians, patients, and those eager to gain experience with medical writing. Case reports form the foundation of the evidencebased pyramid; they shed light on new disease entities, emerging patterns of disease, potential side effects of drugs, and alternative treatment options for patients whose goals may differ from the standard of care. Case reports also represent an accessible pathway for learners and junior faculty to publish in the medical literature, which is a key component of academic advancement and promotion. While the role of scientific research in informing medical practice cannot be understated, case reports should be similarly valued as an essential component of the medical literature.

References 1. Warner JO. Case reports–what is their value? Pediatr Allergy Immunol. 2005;16(2):93–4. doi:10.1111/j.1399-3038.2005.00266.x. 2. Bhattacharrya S, Miller J, Ropper AH. The case for case reports. Ann Neurol. 2014;76(4):484–6. doi:10.1002/ana.24267.

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3. Stephens J, Wardrop R. Scholarship improved by case report curriculum. Clin Teach. 2016. doi:10.1111/tct.12460. 4. McCarthy LH, Reilly KEH. How to write a case report. Fam Med. 2000. doi:10.1136/bmj.327.7424.s153-a. 5. Nissen T, Wynn R. The clinical case report: a review of its merits and limitations. BMC Res Notes. 2014;7:264. 6. Honeybul S, Ho KM. The role of evidence based medicine in neurotrauma. J Clin Neurosci. 2015;22(4):611–6. 7. Pierson DJ. How to read a case report (or teaching case of the month). Respir Care. 2009;54(10):1372–8. http://www.ncbi.nlm. nih.gov/pubmed/19796418. Accessed 16 Mar 2016. 8. Albrecht J, Meves A, Bigby M. Case reports and case series from Lancet had significant impact on medical literature. J Clin Epidemiol. 2005;58(12):1227–32. doi:10.1016/j.jclinepi.2005. 04.003. 9. Centers for Disease Control (CDC). Pneumocystis pneumonia– Los Angeles. MMWR Morb Mortal Wkly Rep. 1981;30(21): 250–2. http://www.ncbi.nlm.nih.gov/pubmed/6265753. Accessed 25 Mar 2016. 10. Dotz WI, Berman B. Kaposi’s sarcoma, chronic ulcerative herpes simplex, and acquired immunodeficiency. Arch Dermatol. 1983;119(1):93–4. http://www.ncbi.nlm.nih.gov/pubmed/6849574. Accessed 22 Mar 2016. 11. Bachman DM, Rodrigues MM, Chu FC, Straus SE, Cogan DG, Macher AM. Culture-proven cytomegalovirus retinitis in a homosexual man with the acquired immunodeficiency syndrome. Ophthalmology. 1982;89(7):797–804. http://www.ncbi. nlm.nih.gov/pubmed/6289217. Accessed 22 Mar 2016. 12. Cantey PT, Weeks J, Edwards M, et al. The emergence of zoonotic onchocerca lupi infection in the United States – a caseseries. Clin Infect Dis. 2015:civ983. doi:10.1093/cid/civ983. 13. Wroe SJ, Pal S, Siddique D, et al. Clinical presentation and premortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: a case report. Lancet (London, England). 2006;368(9552):2061–7. doi:10.1016/S0140-6736(06)69835-8. 14. Gagnier JJ, Kienle G, Altman DG, Moher D, Sox H, Riley D. The CARE guidelines: consensus-based clinical case report guideline development. J Clin Epidemiol. 2014. doi:10.1016/j. jclinepi.2013.08.003. 15. Schulz KF. CONSORT 2010 statement: updated guidelines for Reporting Parallel Group randomized trials. Ann Intern Med. 2010;152(11):726. doi:10.7326/0003-4819-152-11-201006010-00232.

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16. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi:10.1371/journal. pmed.1000097. 17. Kelly WN, Arellano FM, Barnes J, et al. Guidelines for submitting adverse event reports for publication. Drug Saf. 2007;30(5):367–73. doi:10.2165/00002018-200730050-00001. 18. Turner L, Shamseer L, Altman DG, Schulz KF, Moher D. Does use of the CONSORT Statement impact the completeness of reporting of randomised controlled trials published in medical journals? A Cochrane review a. Syst Rev. 2012;1. doi:10.1186/ 2046-4053-1-60. 19. Browman GP. Essence of evidence-based medicine: a case report. J Clin Oncol. 1999;17:1969–73. 20. Rivera JA, Levine RB, Wright SM. Brief report: completing a scholarly project during residency training perspectives of residents who have been successful. doi:10.1111/j.1525-1497. 2005.04157.x. 21. Pierson DJ. Case reports in respiratory care. Respir Care. 2004;49(10):1186–94.

Chapter 5 Is My Case Good Enough? Somnath Mookherjee and Gabrielle N. Berger

Introduction A common barrier in writing a case report is the author’s lack of confidence that the case is novel enough to warrant publication. The reality is that most cases will be of interest to someone, somewhere (see Chap. 11 for details on finding a journal for your report). Even with this knowledge, it is tempting to forgo the effort required to write and submit a case report manuscript when there is uncertainty regarding its value. This chapter reviews commonly held criteria regarding the suitability of a case for publication and provides a stepwise process to assess your case.

What Makes a Good Case? Many physicians and journal editors have opined on what criteria should be met for a case to be a published as a case report. A helpful summary comes from an article entitled “Two cheers for case reports” [1]. In this 2014 article, the Scientific Editor of the Canadian Family Physician suggests six types of cases that the journal would consider publishing: • Unusual or unexpected presentations of commonly seen illnesses © Springer International Publishing Switzerland 2017 C.D. Packer et al., Writing Case Reports, DOI 10.1007/978-3-319-41899-5_5

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• New associations or variations in disease processes • Presentations, diagnoses, or management of new or emerging diseases • An unexpected event in the course of treating or observing a patient • Unreported or unusual adverse effects or interactions of medications • Novel or useful approach to managing patients with complex chronic conditions This is an exceedingly helpful list for authors considering the suitability of a case for publication. Several important points are highlighted: first, the disease process itself need not be rare – uncommon manifestations or complications of common conditions can be very interesting and have great educational merit. Second, regardless of the rarity of a disease, there is additional value in sharing observations about caring for the patient, particularly when unexpected events occur or novel approaches are taken. Another article presenting tips on “How to write a case report” details the characteristics that may make cases more likely to be published [2]: • Cases that contribute to a change in the course of medical science • Cases that illustrate a new principle or support or refute a current theory and thus may stimulate research • Cases that present a therapeutic or diagnostic observation that elucidates a previously misunderstood clinical condition or response • Cases that demonstrate an adverse response to drug therapies or presumed cause-and-effect presentations that have not been detected or reported • An unusual combination of conditions, cascading events, or presenting complaints that confused the decisionmaking process or created treatment dilemmas • A new observation of the impact of one disease process or condition on another, or of a treatment regime for one condition that results in an unexpected outcome of a different condition

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• Reports that describe the personal influence a particular event had on the patient, the physician, or both While some of these criteria may seem unattainable at first glance, consider that it was a 1981 report on five patients with Pneumocystis pneumonia published in the Centers for Disease Control’s Morbidity and Mortality Weekly Report [3] that helped precipitate the recognition of the emerging syndrome of acquired immunodeficiency syndrome (AIDS). “An essay on the shaking palsy” by Dr. James Parkinson led to defining the disease that now bears his name [4]. All clinicians are faced with atypical presentations and clinical conundrums during their career; it is not unrealistic to imagine that your unusual case might someday “contribute to a change in the course of medical science.” Several themes begin to emerge when considering these two sets of criteria. First, adverse events are of particular interest to journal editors and other clinicians. From the perspective of patient care, learning about adverse events is critical to improving practice and preventing future occurrences. Second, interesting or novel processes of care – whether or not they are accompanied by unexpected outcomes – are often excellent case reports. Looking beyond the disease to consider how a physician arrived at a particular diagnostic or treatment decision can inform colleagues facing similar clinical scenarios. Finally, case reports that specifically consider management questions can be similarly useful. Novel therapeutic strategies fall into this category, for example, the approach detailed in the recent article entitled “I cannot stand this anymore! Chronic cortical stimulation for intractable focal reflex epilepsy” in the Neurological Picture series in the Journal of Neurology, Neurosurgery and Psychiatry [5]. Finally, these lists allude to the concept of physician reflection, specifically, how medical events may shape personal or professional trajectories. There is growing interest in publishing reflection or “perspective” pieces, which are now commonly featured in some of the most high-impact medical journals including the New England Journal of Medicine (NEJM), the Journal of the American Medical Association

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(JAMA), and The Lancet. If a case seems important but remains challenging to fit it into a traditional case report format, it may be appropriate for a reflections piece. Many generalist and specialty journals, in addition to those noted above, provide a venue for reflective pieces based on important interactions with patients, although these are not strictly considered case reports for the purposes of this book. A useful article “Writing and publishing case reports – the road to success” provides ten categories of case reports [6]: • • • • • • • • • •

Totally original condition/new disease Rare and previously sparsely reported condition Unusual presentation of a common disease Unexpected association between two relatively uncommon symptoms/signs Impact of one disease process on another Unexpected event in the course of observing or treating a patient Impact of a treatment regime of one condition on another disease Unexpected complication of treatment or procedure New and unique treatment Honest mistakes in management

These criteria are helpful to look through when considering the suitability of a case for publication. A new theme from this list is the concept of reporting “mistakes” (in contrast to simply adverse events). Of course, before submitting such a manuscript, the author should discuss the situation with institutional risk management representatives. Another method to assess your case is to consider whether its publication would make a positive contribution to medical science. Five potential contributions of case reports include [7]: • • • •

Recognition and description of a new disease Recognition of rare manifestations of a known disease Elucidation of the mechanisms of a disease Detection of adverse or beneficial side effects of drugs (and other treatments) • Medical education and audit

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While the lists outlined above can serve as a useful framework for approaching a case report project, using a strictly mechanistic approach may result in many important cases not being submitted for publication. A review of ten recent issues of the Journal of General Internal Medicine (JGIM) is informative in this regard. Six clinical vignettes were published in these ten issues, including a novel manifestation of a rare disease (Campylobacter-Associated Hemolytic Uremic Syndrome Associated with Pulmonary-Renal Syndrome [8]), an unusual manifestation of a relatively uncommon problem (Elevated Lactate Secondary to Gastrointestinal Beriberi [9]), a somewhat novel treatment for a common problem (Oral Rehydration Therapy and Feeding Replaces Total Parenteral Nutrition: A Clinical Vignette [10]), a rare syndrome (An Unusual Case of Statin-Induced Myopathy: AntiHMGCoA Necrotizing Autoimmune Myopathy [11]), and two more common diagnoses (Narcolepsy with Cataplexy in an Elderly Woman [12] and A Case of Subacute Ataxia in the Summertime: Tick Paralysis [13]). Strictly adhering to any of the case-suitability guidance above may have resulted in these well-written and very educational articles not being published.

A Process to Assess Your Case Building from the lists and criteria described above, we suggest that aspiring authors ask themselves a series of questions about their case to determine suitability for publication [14]. After giving many talks on this topic to faculty and house staff, we have developed a modified five-question algorithm to assess the suitability of a case for publication, which we offer here: 1. Is there a diagnosis? We previously believed that having a diagnosis was mandatory for a case report to be published. But, keep in mind that there are over a million published case reports [15] and over 60,000 are added every year [16]. There is very little

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that is “mandatory” for publication, and even the axiom “there must be a diagnosis,” is flexible. For example, a recent case report entitled “A possible new multiple endocrine neoplasia mutation” described a patient with concurrent primary hyperparathyroidism, papillary thyroid cancer, acromegaly, and renal cell carcinoma who tested negative for MEN-1 and MEN-4 mutations. Despite the title, a new mutation was not in fact identified: the lack of a diagnosis in essence became the diagnosis. The authors accurately and precisely stated, “the currently reported case likely represents a unique and novel variant of MEN-1 or -4,” [17] but did not definitively make the diagnosis. Nonetheless, case reports are certainly more publishable if there is a diagnosis. If a diagnosis is lacking, the authors must be exceptionally rigorous, thorough, and comprehensive so that reviewers do not read the manuscript and say “If only they had done the ________ test, they would have made the diagnosis of ___________.” In addition, most reviewers and readers do not want to read a case and learn at the end that “the diagnosis remains unknown.” Rather, it is preferable to describe the case as a new or variant syndrome that does not meet strict diagnostic criteria. 2. Is the topic something strange, rare, or an uncommon presentation of a common problem? This question captures the majority of case reports and usually is the reason why a case has caught the physician’s eye in the first place. The literature is full of case reports of rare syndromes or rare manifestations of syndromes. These case reports may form the basis for larger case series and even future scientific inquiry. 3. If it is not strange or rare, is it an important clinical issue? High-impact clinical issues are often worthy of publication, even if the syndrome is not particularly rare. For example, “Early repolarization masquerading as STEMI” [18] is an important topic that merits consideration for publication even if the described case scenario is not particularly rare.

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4. Is there a diagnostic, therapeutic, or management dilemma? If the answer to this question is “yes,” AND the case is either rare or important, then it is very likely that the case is suitable for publication. These cases may even be appropriate for publication as a clinical problem-solving (CPS) exercise (see Chap. 10). 5. Is there an important teaching point? Many cases do not quite meet the criteria described above, yet still seem interesting enough to consider publishing. Oftentimes, this is because the “punch line” is thought-provoking, poignant, or makes a critical teaching point. The paper, “Loss of the guide wire: a case report” [19] illustrates this point. For many physicians who place central venous lines, remembering to hold onto the guidewire is an ordinary part of process. But those who read this case report, which describes the consequences of not always holding on to the wire (“the lost guide wire was seen extending from the saphenous vein through the vena cava, right atrium, right ventricle, pulmonary artery and lung tissue to the back of the neck…”) will surely never loosen their grip on the wire. By highlighting the teaching point that “The operator must hold onto the guide wire at all times…,” the authors made an otherwise straightforward case important and publishable.

Conclusion The general publication criteria described above give an overview of how many journals assess the publication value of a case. Use the five-step process to more specifically evaluate the suitability of proceeding with writing a case report. One of the best ways to corroborate conclusions drawn from this process is to describe the case to three or four colleagues. Would they read a report of the case? Do they think it is interesting? Is there something they learned from even the brief description of the case? If

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the consensus is that the case is interesting enough to report, there is very likely going to be an audience and venue in which to publish it.

References 1. Pimlott N. Two cheers for case reports. Can Fam Physician. 2014;60(11):966–7. 2. McCarthy LH, Reilly KE. How to write a case report. Fam Med. 2000;32(3):190–5. 3. Centers for Disease C. Pneumocystis pneumonia–Los Angeles. MMWR Morb Mortal Wkly Rep. 1981;30(21):250–2. 4. Parkinson J.An essay on the shaking palsy. 1817. J Neuropsychiatry Clin Neurosci. 2002;14(2):223–36; discussion 2. 5. Feyissa AM, Britton JW, Van Gompel JJ, Matt SS. I cannot stand this anymore! J Neurol Neurosurg Psychiatry. 2016;87(4):441–2. 6. Chelvarajah R, Bycroft J. Writing and publishing case reports: the road to success. Acta Neurochir (Wien). 2004;146(3):313–6; discussion 6. 7. Vandenbroucke JP. In defense of case reports and case series. Ann Intern Med. 2001;134(4):330–4. 8. Bowen EE, Hangartner R, Macdougall I. Campylobacterassociated hemolytic uremic syndrome associated with pulmonary-renal syndrome. J Gen Intern Med. 2016;31(3): 353–6. 9. Duca J, Lum CJ, Lo AM. Elevated lactate secondary to gastrointestinal beriberi. J Gen Intern Med. 2016;31(1):133–6. 10. Wright SM, Noon MJ, Greenough 3rd WB. Oral rehydration therapy and feeding replaces total parenteral nutrition: a clinical vignette. J Gen Intern Med. 2016;31(2):255–7. 11. Nichols L, Pfeifer K, Mammen AL, Shahnoor N, Konersman CG. An unusual case of statin-induced myopathy: anti-HMGCoA necrotizing autoimmune myopathy. J Gen Intern Med. 2015;30(12):1879–83. 12. Suzuki S, Uehara T, Ohira Y, Ikusaka M. Narcolepsy with cataplexy in an elderly woman. J Gen Intern Med. 2015;30(8): 1222–4. 13. Laufer CB, Chiota-McCollum N. A case of subacute ataxia in the summertime: tick paralysis. J Gen Intern Med. 2015;30(8): 1225–7.

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14. Mookherjee S, Berger G. Case reports: a “how to” guide for attendings. SGIM Forum. 2015;38(6):8–9. 15. Rosselli D, Otero A. The case report is far from dead. Lancet. 2002;359(9300):84. 16. Sun GH, Aliu O, Hayward RA. Open-access electronic case report journals: the rationale for case report guidelines. J Clin Epidemiol. 2013;66(10):1065–70. 17. Buzzola R, Kurukulasuriya LR, Touza M, Litofsky NS, Brietzke S, Sowers JR. A possible new multiple endocrine neoplasia mutation in a patient with a prototypic multiple endocrine neoplasia presentation. Cardiorenal Med. 2016;6(2):129–34. 18. Christianson L, Matthews RV, Rahimtoola SH. Early repolarization masquerading as STEMI. Am J Med. 2014;127(11):e1–2. 19. Guo H, Peng F, Ueda T. Loss of the guide wire: a case report. Circ J. 2006;70(11):1520–2.

Chapter 6 How to Get Started Somnath Mookherjee and Gabrielle N. Berger

Introduction Think about how many times you, a colleague or trainee have said “We should write this case up!” Now consider how many of these cases actually made it to publication. For many authors, there is a gap in the degree of enthusiasm for an interesting case and channeling that energy into submitting a manuscript. This chapter describes four early steps for case preparation and writing that will increase the likelihood of publication. Table 6.1 outlines these key steps.

Obtain Consent From the Hippocratic Oath: “And whatsoever I shall see or hear in the course of my profession, as well as outside my profession in my intercourse with men, if it be what should not be published abroad, I will never divulge, holding such things to be holy secrets.” [1]

Whether or not patient consent is required to publish a case report is a source of confusion. Experienced authors will often dismiss the need for consent, while others insist that consent is mandatory even to submit a clinical vignette abstract to a conference. The confusion is so pervasive that some authors will actually try to submit a case report to a journal even when the patient has refused to give consent [2]. Most authors accept © Springer International Publishing Switzerland 2017 C.D. Packer et al., Writing Case Reports, DOI 10.1007/978-3-319-41899-5_6

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Table 6.1 Key steps to 1. Get consent – always get consent! get a case report started 2. Collect images and data early 3. Create a team 4. Just write something!

that they should not try to publish a case if the patient has asked them to not do so; a more common scenario is one where authors try to publish a case report when they do not believe that consent is needed. For example, a case report describing an ethical dilemma around the care of a child was submitted to the British Medical Journal (BMJ); it was rejected by the journal due to the lack of informed consent from the patient’s parents [3]. The authors subsequently submitted the manuscript to a second journal, where it was published [4]. In a unique published discussion of their positions on the issue, the editors of each journal provided their perspective: The British Medical Journal’s position: “Confidentiality is not an absolute value, and both the common law and the General Medical Council [the United Kingdom’s standard setting organization for physicians] recognize that it can be breached without consent when the public interest is sufficiently engaged. There is, however, a high threshold for such disclosures—such as prevention of serious harm to an individual. Although there is clearly a degree of public interest in the issues raised by Isaacs and colleagues’ case study, it is difficult to see how they begin to reach such a threshold.” [5] The Journal of Paediatrics and Child Health’s position: “In this instance we accepted the argument that seeking parental permission would have further compromised a difficult relationship with the child’s parents, making it even less likely to achieve an appropriate resolution to a challenging clinical and ethical situation. In addition to the specific clinical and ethical issues generated by the management of this case, the case study also raised important ethical issues…” [6]

As this example illustrates, the question of foregoing informed consent hinges on whether the content of the case report is so important for the health of the public that an internationally accepted respect for confidentiality and

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consent may be superseded. This is a very high bar for most case reports, and in practice it would be extraordinarily rare to argue that publishing a single case report is necessary for the good of the society as a whole. The International Committee of Medical Journal Editors (ICMJE) statement on patient privacy provides further guidance on the issue of consent (Table 6.2). Reviewing these guidelines raises several practical issues for authors of case reports. First, precisely what entails “identifying information?” Case reports include interesting, often unusual details in a patient’s history. Depending on these details and the circumstances of the case, the patient could theoretically be identified by the reader. This is especially true in the modern era, where many published

Table 6.2 International Committee of Medical Journal Editors – Protection of Privacy [7] Patients have rights to privacy that should not be infringed without informed consent. Identifying information should not be published in written descriptions, photographs, or pedigrees unless the information is essential for scientific purposes and the patient (or parent or guardian) gives written informed consent for publication. Informed consent for this purpose requires that the patient should be shown the manuscript to be published. Identifying details should be omitted if they are not essential, but patient data should never be altered or falsified in an attempt to attain anonymity. Complete anonymity is difficult to achieve, and informed consent should be obtained if there is any doubt; for example, masking of the eye region in photographs of patients is inadequate protection of anonymity. The requirement for informed consent should be included in the journal’s instructions for authors. When informed consent has been obtained, it should be indicated in the published article.

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case reports are accessible to the public, and technological methods exist to aid in the identification of images, including those that have ostensibly been de-identified [8]. Second, the ICMJE recommends that if informed consent is obtained due to concern for the presence of identifying information, the patient should be shown the manuscript prior to publication. This may prove to be impractical in many cases and impossible in others. The ICMJE recommends that journals include informed consent requirements in the author instructions. A 2004 review of case report instructions from 249 core journals showed that only 29 specifically requested patient consent in order to publish a case report [9]. Among journals that do provide authors instructions on obtaining consent for case reports, there is variability in what is required and under what circumstances. While some have called for a universal patient consent that will allow publication of case reports in all medical journals [10], such a form does not currently exist. Therefore, to maximize the number of journals to which a case report may be submitted, it is logical at the outset to follow the consent requirements of journals with the most conservative requirements. BMJ Case Reports’ author instructions are a useful resource in this regard (Box 6.1). The bottom line regarding consent for case reports: • Always obtain signed consent from patients! • Locate institution-specific consent forms – usually these are located in a forms repository, typically online. • Be sure to obtain consent for any images that you are even considering using – it is easy to decide later not to use the images, but you will not be able to use them at all without prior consent. • Look at the author instructions for five journals where you might submit an eventual manuscript. • Determine if there are journal-specific consent forms that need to be filled out.

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• Explain the process of manuscript submission and review to the patient; ask them to sign any required consent forms for all five of the likely target journals. • Keep a copy of each of these forms, and put another copy in the patient’s medical record. • If identifiable information will be used in the case report, in addition to obtaining consent for publication, remember to ask the patient to review the manuscript prior to submission. Acquire multiple ways of contacting the patient – many months usually pass before the manuscript is submitted, and patients can become difficult to contact.

Box 6.1 Consent Requirements from BMJ Case Reports [11]

“Publication of any personal information about an identifiable living patient requires the explicit consent of the patient or guardian. This is a requirement under the UK’s Data Protection legislation. We expect authors to use the BMJ consent form which is available in several languages. You must have signed informed consent from patients (or relatives/guardians) before submitting to BMJ Case Reports. Please anonymise the patient’s details as much as possible, eg, specific ages, ethnicity, occupations. For living patients this is a legal requirement and we will not send your article for review without explicit consent from the patient or guardian. If the patient is dead the Data Protection Act does not apply, but the authors must seek permission from a relative (ideally the next of kin). If you don’t have signed consent from a deceased patient, guardian or family, the head of your medical team/hospital or legal team must take responsibility that exhaustive attempts have been made to contact the family and that the paper has been sufficiently anonymised not to cause harm to the patient or their family. You will need to upload a signed document to this effect.”

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Collect Images and Data Early The best case reports include images to enhance the clinical story and highlight teaching points. Authors should attempt to acquire these images as soon as they consider writing a case report (after obtaining patient consent). Consider what images will add value to the report: • Take multiple photographs to document specific findings while you still have easy access to the patient (either in the inpatient setting or in an outpatient clinic). • Place a ruler near the image if it will be beneficial to demonstrate the size of the findings. • Document “before and after” images that enhance teaching points, such as before and after an examination maneuver, or before and after a treatment modality. Do not forget about “paper-only” studies or results: • While in Western countries most medical records are electronic, some study results may only be accessible in the paper records. These paper records can be difficult to obtain once the patient has left the hospital. For example, at our institution, nocturnal oximetry reports were placed in the paper record and disappeared into an off-site medical record storage facility once the patient was discharged. • As you are considering a case report, take photographs or make copies of any paper records which will be accessible for a limited time. Capture other images early: • Pathologic, radiographic, and hematologic images are also best captured while the patient is still being cared for by the team planning to write the case report. • You may need the assistance of specialists to select the best images; these collaborators take more initiative if the patient is still under their care.

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• In contrast, approaching the pathology lab months after a discharge to help locate and photograph the right slides can be much more difficult. Think creatively about obtaining other images: • What will be the most impactful and educational for your particular case? • If the patient is going to the operating room, ask the surgical team to take photographs and share them, if possible. • If the patient is scheduled for a unique study that will help make the diagnosis, try photographing the patient during the study itself (in addition to obtaining the diagnostic images). • Consider photographing interesting findings that are external to the patient – for example, a test tube of lipemic blood or unusual appearing bodily fluids.

Create a Team Once you have identified an appropriate case (see Chap. 5), obtained consent, and collected images and data, the next step is to create the authorship team. This can be problematic, especially when multiple specialists and subspecialists are involved in caring for the patient. It is critical to be precise and transparent about the roles and expected authorship. Be prepared to step aside to let another team take the lead on writing up a case if they played a larger role in the patient’s care. Conversely, if you take the lead in a case where others have stepped aside, it is important to quickly follow through on writing the manuscript rather than delaying it for some unknown time in the future. As you select team members, keep in mind that many journals have strict limits on the number of authors for case reports (often no more than four), and many further limit the number of authors for clinical images reports.

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Table 6.3 Case report authorship responsibilities First author Middle author(s) Last/senior author • Obtain consent • Verify appropriate • Perform • Obtain images consent was obtained aspects of • Complete • Advise on the selection literature literature review and use of images to review • Write the first illustrate teaching • Help obtain draft of the points consent and manuscript • Verify literature review images, if • Ensure deadlines • Extensively edit needed are met manuscript for content, • Edit • Submit manuscript manuscript flow, and clarity to journal • Adhere to deadlines • Fast turn • Respond to • Advise on the around reviewers submission process • Assist first author respond to reviewers ICMJE authorship criteria – for all authors; all criteria must be met [12] 1. Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work 2. Drafting the work or revising it critically for important intellectual content 3. Final approval of the version to be published 4. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved

Table 6.3 outlines standard case report authorship responsibilities. Clearly establish roles and authorship by writing down exactly what you propose for the team. Note that while middle authors have considerably fewer tasks (appropriately for their middle author status) than first and last authors, they must agree to quickly turn around the manuscript with edits and comments when asked. If roles and responsibilities were previously discussed with potential co-authors, send a follow-up e-mail delineating what was agreed upon to ensure

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Table 6.4 Example e-mail to establish authorship and responsibilities “Dear Dr. _________, It was a pleasure taking care of Mr. _______ alongside you earlier this month. As we discussed, it would be great to publish this as a case report. I propose that I will take the lead as the first author for this paper. I will obtain consent and obtain the images that we discussed. I will complete a literature review and write the first draft in its entirety by May 1st. I propose that you will be the senior (last) author. If you agree to this, you will verify the completeness of my literature review, review and edit my draft by June 1st, and help with any responses needed to reviewer comments. I suggest that we invite Dr. ________ to be a middle author on this project. Given her expertise, I will ask her to pay particular attention to the novel treatment that will be described in this paper. I will ask her to commit to editing and returning the manuscript to me by June 15th. Please let me know if you are in agreement with this plan. I look forward to working on this with you! Best regards, Dr. __________”

Adapted from Mookherjee and Berger [13]

that everyone shares the same expectations (Table 6.4). See Chap. 10 for more on authorship responsibilities, with an emphasis on clinical problem-solving manuscripts.

Just Write Something! After deciding to turn the case into a case report, spend a few hours reviewing the literature to verify how many prior reports there have been on the topic. Use the references from more recent case reports to quickly identify prior publications germane to the case. Some of the older publications may be otherwise difficult to find using online databases. For most forms of case reports, it is expected (but not always mandatory) to state how many times the syndrome, condition, or finding has been previously reported. Now, it is time to conquer the inertia – Chaps. 7, 8, 9, and 10 provide detailed guidance on the format and content of different types of case reports. Refer to those guidelines and

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simply start writing! Write with the knowledge that whatever is created will inevitably undergo extensive editing. Write without regard to style or voice – this can be polished later (see Chap. 12 for manuscript polishing tips). Simply write something – this is the only way to get the project started!

Conclusion While thousands of case reports are published every year, thousands more are not, due to lack of knowledge and experience in the mechanics of publishing a case. This chapter provides a brief and practical framework to help get a case report started. Pay particular attention to obtaining consent – many case reports have perished due to lack of appropriate consent being obtained in a timely fashion. Remember what draws the eye when reading a case report – an evocative image enhances any report. Purposefully create a team and be explicit regarding roles and responsibilities. Finally, just write something!

References 1. Thompson IE. The nature of confidentiality. J Med Ethics. 1979;5(2):57–64. 2. Nussmeier N, Saidman LJ, Shafer S. A&A case reports: a progress report and an update on requirements for patient consent. Anesth Analg. 2014;119(6):1251. 3. Isaacs D, Kilham HA, Jacobe S, Ryan MM, Tobin B. Gaining consent for publication in difficult cases involving children. BMJ. 2008;337:a1231. 4. Ryan MM, Kilham H, Jacobe S, Tobin B, Isaacs D. Spinal muscular atrophy type 1: is long-term mechanical ventilation ethical? J Paediatr Child Health. 2007;43(4):237–42. 5. Newson AJ, Sheather J. Commentary: consent and confidentiality in publishing–the view of the BMJ’s ethics committee. BMJ. 2008;337:a1232. 6. Oberklaid F. Commentary: consent to publication–no absolutes. BMJ. 2008;337:a1233.

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7. Editors ICoMJ. Protection of patients’ rights to privacy. BMJ. 1995;311(7015):1272. 8. Gibson E. Publication of case reports: is consent required? Paediatr Child Health. 2008;13(8):666–7. 9. Sorinola O, Olufowobi O, Coomarasamy A, Khan KS. Instructions to authors for case reporting are limited: a review of a core journal list. BMC Med Educ. 2004;4:4. 10. Aldridge RW. Simplifying consent for publication of case reports. BMJ. 2008;337:a1878. 11. BMJ Case Reports: Instructions for authors. Available from: http://casereports.bmj.com/site/about/guidelines.xhtml. 12. Guidelines on authorship. International Committee of Medical Journal Editors. Br Med J (Clin Res Ed). 1985;291(6497):722. 13. Mookherjee S, Berger G. Case reports: a “how to” guide for attendings. SGIM Forum. 2015;38(6):8–9.

Chapter 7 How to Write a Traditional Case Report Clifford D. Packer

The Title There are two schools of thought on case report titles. Some authors favor the cute or clever title, which can be humorous, mysterious, or (in the worst-case scenario) a play on words or a pun. The clever or humorous title may be good fun, but it has several drawbacks. It makes the case report obscure, a riddle that most readers will not bother to solve by reading it. It is also less searchable than a straightforward title, which provides the gist of the case at a glance. There is evidence, in fact, that scientific journal articles with amusing titles are cited less than comparable articles with straightforward titles [1]. In my own practice, I once had a patient with a puzzling case of hypokalemia, whom I eventually discovered to be drinking 4 l of cola per day. When I wrote the case report, humorous titles such as “hypokalemia on ice” or “a fizzy mystery” did occur to me, but common sense prevailed and I titled it “Chronic hypokalemia due to excessive cola consumption: a case report” [2]. The best strategy is to describe in the title what is of the greatest interest to the author, the crux of the case, in the plainest possible terms. In other words, as Milos Jenicek has put it, “the title should always get right to the point”

© Springer International Publishing Switzerland 2017 C.D. Packer et al., Writing Case Reports, DOI 10.1007/978-3-319-41899-5_7

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[3]. One of my first case reports was about a young violinist who became unable to control and vary his vibrato when he was started on atenolol for treatment of hypertension. My too-general title was “Beta-blockers, stage fright, and vibrato: a case report” [4]. A better title would have been “Impairment of violinist’s vibrato caused by chronic atenolol treatment: a case report.” Since then, I have been careful to make my titles as specific as possible. When I had a patient with three autoimmune diseases at the same time, my title was “Concurrent reactive arthritis, Graves’ disease, and warm autoimmune hemolytic anemia: a case report” [5]. When another patient came in with a lymphoma-like presentation of vertebral sarcoidosis 16 years after his primary sarcoidosis had resolved, our title was “Vertebral sarcoidosis mimicking lytic osseous metastases: development 16 years after apparent resolution of thoracic sarcoidosis” [6]. The primary teaching point that quiescent sarcoidosis can recrudesce many years later in the form of vertebral bone lesions is clearly spelled out in the title. Some authors recommend that the words “case report,” “case study,” or “case series” be included in the title [7, 8]. This is useful, both to categorize the paper for indexing purposes and to inform the prospective reader about the type of content and evidence that is presented. The author should feel free to use “a case report and review of the literature” if a thorough literature review is included. Other variations are also acceptable: one case report in which we presented a long discussion of the mechanisms of disease for a patient with intractable vomiting was titled “Cannabinoid hyperemesis syndrome: a case report and review of pathophysiology” [9]. The title, then, should be a clear and specific description of the main point of the case, not a riddle wrapped in a mystery inside an enigma. We should reserve the creative titles for case reports formatted as clinical quizzes or clinical problem-solving cases, which will be discussed in Chaps. 8 and 10.

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The Abstract The abstract is nothing more or less than a brief précis of a case report. It may be structured or unstructured, and generally runs from 150 to 300 words. Because it is freely available on the electronic database, the quality of the abstract often determines whether or not researchers will go on to view the full case report, cite it, or use it for patient care. Therefore, the abstract must be a short, well-organized, and readable summary that touches on all the major points of the case. Typically, whether structured or unstructured, the case report abstract has three sections: Introduction, Case Presentation, and Conclusion. The Introduction gives the background for the case report, the context of the case in the literature (i.e., “this is the third case,” “the only case,” etc.), and the rationale for publishing it. The Case Presentation is a succinct summary of the case that includes the age and gender of the patient, key history and physical exam findings, lab testing, imaging, and highlights of the clinical course including response to treatment. The Conclusion describes the clinical impact of the case and gives the important lesson or teaching point. Consider the following two abstracts, where the first is unstructured and the second is structured: Vertebral sarcoidosis is a rare condition that can present with persistent back pain, often with concurrent lung, lymph node, or skin involvement. It can produce lytic or blastic osseous lesions that are indistinguishable from metastatic cancer on bone scan and magnetic resonance imaging (MRI). It usually occurs at the time of initial diagnosis of sarcoidosis, but may in very rare cases appear many years after presumed resolution of thoracic sarcoidosis. We present the case of a 47-year-old man who developed persistent low back pain 16 years after spontaneous resolution of stage I pulmonary sarcoidosis. MRI of the spine showed lytic thoracic and lumbar vertebral lesions. Computed tomography of the chest showed a pleural-based lung mass, multiple pulmonary nodules, and hilar and mediastinal lymphadenopathy. Positron emission tomography with fluorodeoxyglucose was widely positive, including at the vertebral foci noted on MRI. Metastatic lymphoma was suspected, but mediastinal lymph node and

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vertebral body biopsies showed noncaseating granulomas with negative stains for acid-fast bacilli and fungi. After 1 month of treatment with prednisone, the angiotensin-converting enzyme level and erythrocyte sedimentation rate had normalized, and the back pain was substantially improved. We found only 1 case report of a longer interval between resolution of initial sarcoidosis and development of vertebral involvement [6]. INTRODUCTION: Metformin is a widely prescribed biguanide antidiabetic drug that has been implicated as a cause of hemolytic anemia in three previous case reports. We report a case of rapidly fatal hemolysis that was temporally associated with the initiation of metformin treatment for diabetes. Clinicians need to be aware of this rare but potentially serious side effect of metformin. CASE PRESENTATION: A 56-year-old Caucasian man with type 2 diabetes mellitus was started on metformin to improve glycemic control. Shortly afterwards, he developed progressive fatigue, exertional dyspnea, cranberry-colored urine and jaundice. Laboratory studies showed severe hemolysis, with a drop in hemoglobin from 14.7 to 6.6 g/dl over 4 days, markedly elevated lactate dehydrogenase, bilirubin and reticulocyte counts, and a low haptoglobin level. A peripheral blood smear showed no schistocytes, and a direct Coombs test was positive for anti-IgG and negative for anti-C3. Despite corticosteroid treatment and transfusion of packed red blood cells, the patient developed increasing dyspnea, hypotension, further decline in hemoglobin to 3.3 g/dl, and fatal cardiorespiratory arrest 12 hours after admission. CONCLUSION: The serologic findings in this case suggest an autoimmune hemolytic anemia, caused either by a drug-induced autoantibody or a warm autoantibody. Based on the temporal association with metformin and the lack of other clear precipitating causes, we propose that metformin-induced hemolysis with a drug-induced autoantibody is a strong possibility. This mechanism differs from a previously described case with a possible antibody to the erythrocyte-drug complex. It has been shown, however, that hemolysis may occur via multiple mechanisms from the same drug. Clinicians should consider the possibility of metforminassociated immune hemolytic anemia in patients with otherwise unexplained hemolysis [10].

In the unstructured abstract, we learn that vertebral sarcoidosis is rare, that it can mimic metastatic cancer, and that it may occur many years after apparent resolution of the initial episode of sarcoidosis. The structured abstract puts the

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case in context – three previous cases, this is the first report of a fatality – gives key symptoms and laboratory findings, summarizes a hypothesis on the mechanism of metformininduced hemolysis, and finishes with the teaching point that metformin should be considered in patients with otherwise unexplained hemolysis. Both abstracts cover background, clinical context, key findings, and teaching points. The abstract should be written last, since it is much easier to write a summary of a finished manuscript. Remember that the abstract should not contain any new information that is not presented in the body of the case report; it is strictly a summary. It should not act as an introduction to the paper, or include any citations.

The Introduction This section should briefly summarize the background and context of the case report. If the case involves an unusual presentation or natural history of a disease, the usual course of the disease should be described; if the case is a new disease or syndrome, this should be clearly stated. If it is an adverse drug reaction, the properties and common uses of the drug and previous reports of side effects should be mentioned. If the case report presents a new surgical technique, the standard technique should be described. The introduction should also include a brief literature review which puts the case in its clinical context. For example, if five other authors have described a similar clinical presentation, or if there are three previous reports of a similar side effect, or if one other surgeon has tried the new approach, these should be cited and mentioned briefly in the introduction. (Typically, the details of previous case reports and comparisons with the present case are reserved for the Discussion.) The introduction should end with a very brief statement, usually one sentence, of what is being reported in the article, beginning with a phrase such as “in this case,” “we report,” or “we describe.”

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In the introduction, brevity is important. The aim is to orient the reader to the context without getting bogged down in the fine details, which will come later. In the following example, the context and purpose of an adverse drug reaction case are given in four sentences: Romiplostim is a thrombopoietin (TPO) mimetic (median halflife = 3.5 days) currently considered a second-line treatment for idiopathic thrombocytopenic purpura (ITP). Clinical trials have demonstrated efficacy in increasing long-term platelet counts. In a few case reports, romiplostim has been used as an effective bridge to splenectomy. We describe a patient with refractory ITP who developed severe postsplenectomy rebound thrombocytopenia that occurred when a single romiplostim dose was held at the time of surgery [11].

Here is an even briefer Introduction that gets the job done in three sentences: There are 4 published case reports of severe chronic hypokalemia due to long-term, excessive cola consumption. Complications described in the reports include hypokalemic myopathy, hypokalemic nephropathy, and nephrogenic diabetes insipidus. In this case, a patient developed severe chronic hypokalemia and probable hypokalemic myopathy due to consumption of 4 liters of Pepsi-Cola per day [2].

Other examples of effective and succinct introductions: Patients with chronic lithium toxicity typically present with symptoms of agitation, confusion, tremor, ataxia, and hyperreflexia. In rare cases, however, lithium toxicity can present with transient cognitive and language deficits. We report the case of a lithiumtoxic patient who presented with transient transcortical motor aphasia, which resolved 2 days after discontinuation of lithium. This is the first report of focal transcortical motor aphasia in a patient with lithium toxicity [12]. Metformin, a biguanide antidiabetic drug, has been implicated as a cause of lactic acidosis, usually in a setting of renal failure, IV contrast administration, shock, sepsis, hypoxemia, or liver disease. Although metformin can cause mild lactic acidemia in type 2 diabetes mellitus patients with normal renal function, there are very few case reports of lactic acidosis in patients with normal renal function and no other obvious precipitating cause. In the following case, a metformin-treated man with mild and limited

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stroke symptoms and normal renal function developed lactic acidosis in the absence of other risk factors [13]. Spigelian hernias are rare and often challenging to diagnose. Although many case reports have described the presence of a variety of abdominal organs found in Spigelian hernias, there are no reports of an incarcerated appendix repaired laparoscopically. The use of laparoscopic technique in this case provided easy identification of the incarcerated structure and allowed us to perform an appendectomy without a large incision and with minimal dissection of the abdominal wall [14].

The Case Description The biggest mistake my students make when writing up their case reports is putting too much information into their case descriptions. This is understandable, since they are in the habit of presenting their cases comprehensively on the wards. The key to a good case description is focus: include only the parts of the history, physical exam, lab and imaging results, and clinical course that pertain directly to the case report topic. For example, in a patient with hemolysis, the presence or absence of scleral icterus, light stools, dark urine, abdominal pain, fever, and hepatosplenomegaly should be noted; pertinent medications and relevant family, social, and travel histories should be included; and lab results should include the CBC, reticulocyte count, bilirubin, LDH, haptoglobin, G6PD level, peripheral smear, and Coombs test. There should also be a clear timeline for the clinical and laboratory findings, both in the text and in tables or graphs as needed. Other data, such as the patient’s chronic eczema, mild COPD, recurrent UTI’s, and chronic back pain, should not be included unless directly relevant to the case (e.g., if the patient recently started a sulfa antibiotic for a UTI). The course, diagnostic work-up, and treatment of the hemolysis should be central. Unrelated complications and events should be left out. The concept of clinimetrics is very important to consider in the case description [3]. Clinimetrics is concerned with the

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accurate measurement of clinical data, and includes patient demographics, clinical biomarkers such as physical examination maneuvers (many of which have well-established odds ratios), laboratory tests, and reproducible indices such as TNM cancer staging, the Glasgow Coma Scale, the Duke criteria for endocarditis, or the Naranjo Adverse Drug Reaction Probability Scale. Careful adherence to clinimetric principles improves the evidence value of a case report and makes it more useful for clinical decision-making. The case presentation should include all relevant clinical biomarkers and scores for any applicable probability scales or other indices. For example, any case report of endocarditis must include information on blood culture results, presence or absence of a new regurgitant murmur, echocardiogram findings, and the presence of immunologic or vascular phenomena. From these data, a Duke criteria score should be given. Without these data, the case report will be neither useful nor publishable. Therefore, the author must take the time to research all pertinent clinical biomarkers and diagnostic criteria before writing the case description. Table 7.1 lists the essential elements of the case description. All elements should be included whenever possible. Rarely, a case report might be purely descriptive, with no therapeutic intervention, or the clinical outcome might be

Table 7.1 Essential elements of the case description 1. Patient demographics: age, gender, and race 2. Pertinent history, physical exam, laboratory, and imaging findings 3. Timeline of important clinical events (both in text and graph or table form) 4. Diagnostic assessment, including applicable biomarkers, indices, and rating scales 5. Therapeutic interventions 6. Clinical outcome of case

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uncertain. However, case reports that lack one or more of these elements, even if intriguing, are rarely publishable. Consider the following example of a case description with all essential elements. The first paragraph gives the patient demographics, focused history, and a timeline (Fig. 7.1) with hospitalizations and serum potassium values over a 21-month period. The timeline reveals that the hypokalemia resolved during the three hospitalizations, then recurred each time after discharge. Note that all prescribed medications are listed, because it is important that the patient was not taking any medications likely to cause hypokalemia, and that he was taking a potassium supplement: A 52-year-old white male with O2-dependent COPD, hypertension, GERD, idiopathic gastroparesis, and chronic low back pain was noted to have persistent hypokalemia in the 2.7–3.3 meq/L range over more than 2 years. He complained also of chronic generalized weakness and fatigue. He denied nausea or vomiting, but did have occasional loose stools. The hypokalemia persisted despite discontinuation of diuretic treatment for hypertension and fludrocortisone that had been prescribed briefly for orthostatic hypotension. There was no improvement with aggressive oral potassium supplementation in amounts up to 120 meq per day. The patient's serum potassium level normalized on three

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Figure 7.1 Serum potassium values from July 2006 to May 2008. Note normalization of serum potassium levels during hospitalizations in 7/06, 1/07, and 7/07. Also note improvement in potassium level from 3.0 to 3.5 mg/dL between 5/1/08 and 5/16/08, when the patient decreased his cola consumption from 4 to 2 l per day (Reproduced with permission from Packer [2])

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occasions when he was hospitalized and given supplemental potassium (COPD exacerbations in 7/06 and 1/07, pseudoseizures in 7/07), but the hypokalemia promptly recurred after discharge from the hospital [Fig. 7.1]. His medications were paroxetine, trazodone, pregabalin, sustained-release morphine, loratadine, isosorbide mononitrate, lisinopril, metoprolol, simvastatin, omeprazole, metoclopramide, potassium chloride, calcium/vitamin D tablets, alendronate, and mometasone, tiotropium, and albuterol inhalers. He smoked one-half pack of cigarettes per day and did not drink alcohol.

The second and third paragraphs give the physical examination findings and laboratory test results. The physical findings indicate that the patient does not have signs of Cushing’s syndrome, a possible secondary cause of hypokalemia, and include the mild generalized muscle weakness which could indicate hypokalemic myopathy. Laboratory results include serum aldosterone, plasma renin activity, and urine electrolytes, which rule out primary hyperaldosteronism or other forms of renal potassium wasting (in retrospect, a transtubular potassium gradient would also have been useful but was not included): On physical examination, he was a chronically ill-appearing man wearing a nasal cannula. Height was 69 inches, weight 205 pounds. There were no cushingoid facies, buffalo hump, or abdominal striae. Vital signs were temperature 98.6 degrees, pulse 95, respiratory rate 14, blood pressure 128/73. There was no thyromegaly or lymphadenopathy. Lungs showed decreased breath sounds and mild expiratory wheezes bilaterally. Heart sounds were regular with no murmurs, rubs, or gallops. The abdomen was soft and nontender, with no masses or organomegaly. Extremities showed no edema, clubbing or cyanosis. The neurologic examination revealed mild generalized muscular weakness (4+/5) and normal deep tendon reflexes. Laboratory results include serum sodium 137 mg/dL, potassium 3.0 mg/dL, chloride 95 mmol/L, CO2 30.0 mmol/L, blood urea nitrogen 5 mg/dL, creatinine 0.8 mg/dL, calcium 9.3 mg/dL, phosphorus 4.1 mg/dL, albumin 3.6 g/dL, ferritin 126 ng/mL, hemoglobin 12.7 g/dL, white blood cell count 10.6 K/cmm, and platelet count 160 K/cmm. Serum aldosterone was 4.8 ng/dL (normal 4–31 ng/dL) and the plasma renin activity was 0.33 ng/mL/hr (normal 1.31–3.96 ng/mL/hr upright, 0.15–2.33 ng/mL/hr supine). Spot urine potassium was 8.6 mEq/L, urine sodium was < 10 mEq/L, and urine chloride was 16 mmol/L [2].

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Finally, the fourth paragraph gives the diagnostic assessment and reveals the key dietary information which was obtained at that point. The connection between excessive cola consumption and hypokalemia is established. The clinical outcome is the near-normalization of the potassium level when the patient cut his cola consumption in half: In the absence of a clear explanation for this patient's chronic hypokalemia, he was asked to give the details of his diet. He admitted to drinking 4 liters of Pepsi-Cola per day for the past several years. It was his habit to sip cola slowly but almost continuously, throughout the day. When hospitalized, he had stopped drinking cola and his potassium levels had temporarily normalized. In early May 2008, he decreased his cola intake to 2 liters per day, with a resultant increase in the serum potassium from 3.0 to 3.5 mg/dL (Fig. 7.1) [2].

Note that the case description does not discuss the differential diagnosis of the hypokalemia, but simply gives the tests that were done to evaluate it. Also, the case description does not include any information on possible mechanisms of colainduced hypokalemia. Differential diagnosis and mechanisms of disease are reserved for the discussion.

The Timeline The timeline is critical in case reports that involve changes in clinical parameters over time, especially where inferences are made about cause and effect. Timelines are much clearer than long prose passages when it comes to telling the stories of adverse drug reactions or other complex case histories. In Fig. 7.1, the timeline clearly shows chronic hypokalemia with normalization of potassium levels only during hospitalizations. Figure 7.2 is from a case report of a 91-year-old man with thrombocytopenia in the setting of biocompatible dialysis membranes, with daily platelet counts and arrows to indicate the various dialyzer types that were used over a 3-week period [15]. The graph gives conclusive evidence that platelet counts dropped repeatedly when polysulfone membrane

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Figure 7.2 Demonstration of chronological platelet levels measured in this patient. Dashed arrows indicate administration of hemodialysis using either Optiflux 200 or 18NR polysulfone membrane dialyzers (Fresenius). Solid arrows indicate administration of hemodialysis using AM100 dialyzer with alkyl ether polymer-grafted cellulose membrane (Reproduced with permission from Muir and Packer [15])

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dialyzers were used, and then recovered when the patient was switched to a cellulose membrane dialyzer. Timelines of this kind can be very useful in demonstrating cause and effect, especially in adverse drug reaction cases. A simple clinical timeline is often used to show the natural history of a disease process. Figure 7.3 is a timeline of events, symptoms, and diagnosis in a case of human rabies. This was the first report of rabies acquired in the United States, but with symptom onset, medical management, and diagnosis abroad [16]. The timeline includes all key events, from suspected bat bite to postmortem analysis of brain tissue, and gives important details on the patient’s travel history and the rapid progression of symptoms over his last 5 weeks. A great deal of data is neatly and concisely presented on this simple timeline. Although graphs are more visually effective as timelines, tables can also be useful if there are multiple data points that would lead to an overly cluttered graph. Consider Table 7.2, which gives laboratory values from a case of metforminassociated lactic acidosis in a patient with vertebral artery dissection and essentially normal renal function [13]. The table allows for a quick review of day-by-day changes in the important laboratory values as the patient’s lactic acidosis peaked and then resolved over the course of 4 days. The timeline should be referenced and briefly described in the case description. Any critical analysis of the timeline, such as comment on the relatedness of events or the likelihood of causal relationships, should be left to the discussion.

The Discussion The aims of the discussion are simple: to put the case in context, explain what happened, explore the implications, and give a useful teaching point. Table 7.3 gives the essential elements of the discussion, with the specific steps needed to fulfill these four key requirements. There is a logical flow from context to explanation to speculation and the teaching

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Chapter 7.

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The Discussion Table 7.2 Laboratory values 20 days before On Variable admission admission Lactate – 5.2 (mEq/L)

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Adapted with permission from Wolters Kluwer Health [13] From: Metformin-associated lactic acidosis in a patient with vertebral artery dissection Table 7.3 Essential elements of the discussion Context of the case Review of relevant anatomy, physiology, pharmacology, etc. Focused literature review Comparison with other cases: what is new, unusual, or unique about the case? Explanation of events Assessment of cause and effect or relatedness of events (refer to the timeline as needed) Evaluation of differential diagnosis and alternative explanations Proposed explanation or hypothesis, with rationale Critique of the evidence value of the case report (strengths and weaknesses) Critique of management of the case (optional) Speculation Broader implications of the case, possible future research Teaching point A brief, aphoristic, and memorable teaching point to conclude the discussion

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point – explanation is meaningless without context, and the teaching point is not credible without a clear and convincing explanation of the case. Therefore, it is best to write the discussion in the order suggested in Table 7.3.

Context of the Case Establishing the context usually begins with a brief review of the clinical setting. For instance, in an adverse drug reaction involving the cytochrome p450 system, factors leading to enzyme inhibition should be discussed; in a case of a Spigelian hernia, a brief summary of the etiology, anatomy, presentation, and surgical management of these rare hernias should be offered. The next step is the literature review, which should be as specific and focused as possible (see Chap. 5). Use of an advanced search tool such as the MeSH database in PubMed is highly recommended. An excellent way to compare a group of cases is to make a table (Table 7.4) with key demographic and clinical features. Always include the current case (listed as “this case” or “this study”) as the final entry on the table. The accompanying discussion highlights the important differences between the previous cases and the current case, and proposes a mechanism to explain the differences in the Direct Coombs (DAT) test results: The possible mechanism of metformin-induced hemolytic anemia discussed here is different from that proposed by Kashyap and Kashyap in their report. Their patient's DAT was positive for anti-C3 and negative for anti-IgG, which suggests the formation of an antibody against the erythrocyte-drug complex. In contrast, our patient's DAT was consistent with autoantibody formation. This is not necessarily a contradiction, since it has been shown that the same drug can cause many if not all of the mechanisms of DIIHA. In fact, one mechanism may simply be more pronounced and identifiable in a particular patient. Observations of DIIHA caused by third-generation cephalosporins support the notion of multiple mechanisms for the same drug [10].

This type of comparison table can accommodate an almost unlimited number of cases and variables (Table 7.5).

51

68

56

Kashyap and Kashyap

Meir et al.

Packer et al. (this study)

Male

Female

Female

Gender Male

1–2 days

14 days

9 days

Adapted with permission from Packer et al. [10]

Pt. age (years) 46

Case report Lin et al.

Time from starting metformin to onset of symptoms 10 days

Positive (+IgG, −C3)

Negative

Positive (−IgG, +C3)

Direct Coombs “Equivocal”

Table 7.4 Reported cases of metformin-induced hemolytic anemia

N/A

Decreased

Normal

G6PD level Normal

N/A

N/A

Yes

Recurrence of hemolysis with metformin rechallenge Yes

Death

Recovery

Recovery

Outcome Recovery

Context of the Case 81

Prior endoscopic intervention Biliary sphincterotomy

No

ERCP, pancreato– graphy

No

Patient age/ gender 74/ male

73/ male

46/ male

53/ male

Case report Weinman [1]

Tajima et al. [2]

Deeb et al. [3]

Fujimori et al. [4]

AOSPD case reports

Chronic pancreatitis, AML

Chronic pancreatitis

Abdominal pain, fever

Abdominal pain, fever

Abdominal pain, fever

Presenting symptoms Abdominal pain, fever, N/V

3.19

N/A

14.2

WBC 17.9

Dilated pancreatic duct with stones

Dilated pancreatic duct with large stone

Dilated pancreatic duct, tumor at head of pancreas

CT scan results Dilated pancreatic duct with 5 mm stone

Pancreatic duct cannulated and stented

Pancreatic duct stone, stented

Pancreatic stricture, stented

ERCP results Pancreatic duct stone removed, stented

Stenotrop– homonas maltophilia

Klebsiella ornithino– lytica

N/A

E. coli

Culture results

Relapsed 1 month later and required repeat ERCP and drainage

Resolved

Resolved

Clinical course Resolved, doing well at 18 months

Chapter 7.

Chronic pancreatitis, pancreatic CA

Relevant comorbid conditions Chronic pancreatitis, DM

Table 7.5 Reported cases of acute obstructive suppurative pancreatic ductitis

82 How to Write a Traditional Case Report

N/A

50/ male

63/ male

Aoki et al. [6]

Wali et al. (this case)

Chronic pancreatitis, DM

Chronic pancreatitis

Intraductal mucinous neoplasm

Reproduced with permission from Wali et al. [17]

Biliary sphincterotomy

No

70/ male

Fujinaga et al. [5]

Asymptomatic

Abdominal pain, fever

Abdominal pain, fever

6.04

N/A

N/A

Dilated pancreatic duct, pancreatic calcifications

N/A

Mild pancreatic edema, 10 mm pancreatic stone

Pancreatic stricture, stented

Purulent pancreatic fluid, main pancreatic duct stented

Pancreatic duct cannulated

E. coli, S. pneumoniae, and H. pneumonia

N/A

Klebsiella oxytoca

Resolved

Resolved

Resolved

Context of the Case 83

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Here again, the discussion focuses on explaining the differences in clinical presentation and bacteriology between the six previous cases and the current case: The presentation and severity of illness of AOSPD can vary significantly. In prior cases, patients presented with abdominal pain, with severity of illness ranging from meeting criteria for systemic inflammatory response syndrome (SIRS) to septic shock. In contrast, our patient was asymptomatic and had no objective signs of infection at the time of diagnosis and throughout his hospitalization. Our case is also unique because of the polymicrobial nature of the infection. Prior cases were monomicrobial. Two of the three pathogens isolated in our case, Streptococcus pneumoniae and Haemophilus influenza, are generally considered respiratory pathogens…Several theories to explain how respiratory pathogens may infect the pancreas have been proposed. Possible hypotheses include hematogenous or lymphatic spread from nasopharyngeal colonization, enteric spread from transient inclusion of the bacteria in intestinal flora, or the direct introduction of nasopharyngeal flora into the biliary tree and pancreatic duct during endoscopic interventions such as ERCP [17].

Note again how placing the case in context – showing how this case is different from the others – leads naturally to hypothesizing about the reasons for the differences. This process, the identification of unique features in a new case and the development of a hypothesis to explain them, is absolutely fundamental. Context and explanation are the heart and soul of a case report.

Explanation of Events: Developing a Hypothesis “Cases,” writes Milos Jenicek, “are ‘uncontrolled experiments.’ They do not provide proofs, but they generate hypotheses” [3]. A hypothesis is a supposition or proposed explanation made on the basis of limited evidence. It is meant only to be a starting point for further investigation, and is never definitive; its aim is not “proof,” but rather “plausibility.”

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Developing a hypothesis is unquestionably the most difficult part of writing a case report. It requires a deep knowledge of all relevant anatomy, physiology, and pharmacology, a spark of insight, and the creativity and persistence to test, revise, and refine the hypothesis, so that it fits and explains the clinical events. Consider the serendipitous discovery, in 2008, that propranolol is a highly effective treatment for severe infantile hemangiomas. A child with a severe nasal hemangioma developed obstructive hypertrophic cardiomyopathy during corticosteroid treatment, and was started on propranolol. By the next day, the hemangioma had softened, and within weeks it had faded and become almost completely flat. Similar dramatic responses to propranolol were then observed in 10 other children with severe hemangiomas. The authors proposed three possible explanations for this unexpected effect: Potential explanations for the therapeutic effect of propranolol – a nonselective beta-blocker – on infantile capillary hemangiomas include vasoconstriction, which is immediately visible as a change in color, associated with a palpable softening of the hemangioma; decreased expression of VEGF and bFGF genes through the down-regulation of the RAF–mitogen-activated protein kinase pathway (which explains the progressive improvement of the hemangioma); and the triggering of apoptosis of capillary endothelial cells [18].

This is a particularly strong hypothesis because it proposes three plausible mechanisms, which explain both the rapid improvement – via vasoconstriction – and the progressive improvement over time with suppression of angiogenesis and induction of apoptosis. The high explanatory value of the hypothesis greatly strengthens the evidence value of the case series and adds theoretical support for the clinical treatment of hemangiomas with propranolol. Another important function of a hypothesis is “getting it out there.” When a case report is published, the hypothesis is carefully scrutinized and may then be confirmed, debunked, or enlarged upon by experts in the field. This is the reason

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that even a tentative, incomplete, or highly speculative hypothesis can still be useful. Others will evaluate it, propose alternative or additional explanations, and make it stronger. In my case report on cola-induced hypokalemia, I proposed an osmotic diarrhea due to poor GI absorption of highfructose corn syrup as the likely cause of the hypokalemia [2]. A team of Greek authors then included my case report in their review article and proposed several additional mechanisms, including osmotic diuresis, hyperinsulinemia with intracellular potassium redistribution, and caffeine-induced phosphodiesterase inhibition and renal potassium wasting [19]. Similarly, in the case of propranolol treatment for hemangiomas, a good initial hypothesis was made even stronger through other researchers’ insights into propranolol’s molecular mechanisms of action [20]. Thus the importance of publication: not only is the case made available as evidence, but the hypothesis takes on an organic life of its own as it grows and evolves over time. The specific steps in developing a hypothesis are listed in Table 7.6. First, establish the context of the case and specify the rare or unique focus of the case that requires explanation. Second, review all of the case reports, case series, and review articles that pertain to your case, and critically evaluate the existing hypotheses already developed by others. If an existing hypothesis seems sound, use it, but see if you can expand on it or add other possible explanations for what you Table 7.6 Steps in developing a hypothesis Establish the context of the case – what needs to be explained? Review all pertinent case reports, case series, and review articles Identify existing hypotheses, if any Search the relevant basic science literature Modify or add to existing hypotheses, or propose a new hypothesis Present the hypothesis and all supporting evidence in the discussion

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observed. (Remember that you must give full credit with citations for any hypothesis you borrow, or you will risk plagiarism.) If the existing hypotheses do not suffice, or there are none, you will need to develop a new hypothesis. Third, go to the basic science literature to find potential mechanisms, pathways, anatomical variants, etc. to help explain the findings. Often, this step will lead to revision or even rejection of a favored hypothesis and development of a new explanation that fits better with the underlying pathophysiology, pharmacology, or anatomy. Finally, present the hypothesis and all supporting evidence in the discussion section of your case report, making sure that it is clearly presented as a hypothesis rather than a definitive explanation of events. As an example of hypothesis development, consider the case of a 65-year-old man who developed transient transcortical motor aphasia in the setting of lithium toxicity [12]. The key observation in this case was that the patient had halting speech and inability to write, but comprehension and repetition were preserved. As the lithium levels dropped, the neurologic symptoms resolved. Our first task was to put the case in context: A few cases of transient focal speech deficits and apraxia in the setting of lithium toxicity have been reported in the literature, including constructional dyspraxia, Wernicke’s aphasia, pure-word deafness, and dysnomia. Our patient presented originally with confusion and word-finding difficulties, but his focal aphasia persisted after his mental status improved. There were problems with word finding, speech initiation, and handwriting in the setting of preserved comprehension, repetition, reading, and following commands. These findings are most consistent with transcortical motor aphasia (TCMA). Our literature search revealed no prior cases of TCMA associated with lithium toxicity [12].

Next, we needed to evaluate the apparent causal association between the patient’s lithium toxicity and his transient TCMA. Were there any alternative explanations for this episode? A transient ischemic attack (TIA) seemed a reasonable possibility; other TIA mimics such as seizures, migraine headaches, and infectious or metabolic disturbances were

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also considered. We reviewed the TIA literature and found that non-atrial fibrillation patients with transient speech and language disturbances without paresis were more likely to have TIA mimics than true TIAs. Considering the strong temporal association with lithium in the absence of seizure, migraine, infection, or other metabolic disorders, lithium toxicity seemed to be the strongest possibility. Having established the clinical likelihood of TCMA from lithium toxicity, we needed a hypothesis to explain it. This proved to be challenging. The few case reports of speech and language disturbances in patients with lithium toxicity did not give any convincing explanations. We turned to both animal and human studies of lithium accumulation and pharmacokinetics in the brain, including a magnetic resonance spectroscopic study, and looked for correlations with the anatomical regions (Broca’s area and the supplementary motor area) known to be associated with TCMA. We discovered that these areas are watershed zones between the blood supplies of the anterior and middle cerebral arteries: Watershed zones are especially prone to ischemic injury, and may have decreased rates of drug clearance. Given his poor baseline cardiac output and dehydration in the setting of toxic lithium levels, we hypothesize that this watershed area may have been relatively hypoperfused, thereby reducing lithium clearance and causing transient focal symptoms. When he was rehydrated and lithium was held, local perfusion improved and his focal symptoms resolved [12].

This hypothesis may or may not be the true explanation for lithium-induced TCMA, but the process – establishing the context of the case, a thorough literature review, and a reasonable hypothesis built on the basic science – lends plausibility (and publishability) to the case report. In the case of an 81-year-old man with metastatic gastric carcinoma and type B lactic acidosis [21], we faced another challenging hypothesis. Type B lactic acidosis typically occurs in hematologic malignancies; it is rare in solid

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malignancies, and ours was only the second case reported in a patient with gastric cancer. Our review of the literature revealed several possible mechanisms, including thiamine deficiency, the Warburg effect (the tendency of tumor cells to favor glycolysis even in the presence of sufficient oxygen), and rapid tumor proliferation (usually seen in hematologic malignancies) resulting in massive lactate production, which overwhelms the body’s carbonic acid– bicarbonate buffer system. Our observation that this was an extremely aggressive gastric carcinoma – it was a poorly differentiated AFP-positive tumor, with the liver almost entirely consumed by metastases – led to this hypothesis: “Given the extensive tumor burden and aggressive tumor subtype, it is possible that the tumor’s overwhelming anaerobic metabolism approximated that of a hematologic malignancy.” We then proposed two additional mechanisms based on the patient’s extensive liver metastases and chronic kidney disease: Reduced lactate clearance may be an important pathophysiologic factor, as was likely in our case. Normally, the liver is responsible for the clearance of 80–90 % of lactate via the Cori cycle, and extensive hepatic disease is therefore hypothesized to impact lactate metabolism…It is possible that his baseline stage III-IV CKD may have contributed to the systemic lactate accumulation by impairing the secondary mechanism for lactate clearance [21].

This is a good example of adapting the existing hypotheses to a different scenario. The notion that an aggressive gastric tumor can “act like” a hematologic malignancy is the key inference behind the hypothesis. In conclusion, a hypothesis can be original, adapted to fit new circumstances, or borrowed intact. The original hypothesis is the most difficult of the three, but also the most interesting and satisfying to develop. A successful hypothesis requires a thorough literature review, a clear understanding of the context of the case, and the insight and creativity to make a plausible explanation.

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Speculation: The Broader Implications In their article, The Function of the Discussion Section in Academic Medical Writing, Skelton and Edwards conclude that “every paper must reach a conclusion that is not contained in its results” [22]. This is especially true for case reports; if there is no speculation, the case narrative stands alone, without interpretation or explanation. We have just discussed one form of speculation, the hypothesis, which attempts to explain the unusual events of the case. Sometimes, it is advisable to go beyond explanation and speculate about the broader implications of a case report. Often, this broader speculation ties in with the surveillance and pharmacovigilance functions of case reporting, which serve as a kind of “early warning system” for new syndromes and serious adverse drug reactions. To stimulate speculation, ask these questions: What are the implications of this case for the general population? How does it change our understanding of this disease, drug, or procedure? Does it offer any new scientific insights? How might it affect future research? Consider a few examples of speculation in case reports. First, let us return to my patient with cola-induced hypokalemia. In considering the implications of the case for the general population, I came to this conclusion: Excessive soft drink consumption can cause hypokalemia due to a fructose-induced osmotic diarrhea. Given the very high soft drink consumption in industrialized societies, this is probably an underreported and underdiagnosed cause of potassium depletion. In addition to muscle weakness and cramping, hypokalemia lowers the arrhythmia threshold and may increase the risk of sudden death, particularly in people with heart disease [2].

Although the Coca-Cola company was not happy with this speculation (see Chap. 13), it is logical to consider the

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possibility that populations with heavy soft drink consumption might see more complications of hypokalemia. A case report of a lung cancer patient with acute abdominal pain after sexual intercourse led to this conclusion, with implications for cancer patients in general: Physicians should consider adrenal hemorrhage in the differential diagnosis of any cancer patient presenting with acute abdominal pain…Activities that increase intraabdominal pressure, such as heavy lifting and sexual intercourse, may be risk factors for spontaneous adrenal hemorrhage [23].

The authors of a fascinating 2015 case report, of an AIDS patient who developed cancer of nonhuman origin from a clonal population of genetically altered tapeworm cells, appropriately emphasize the foundational implications of their case: The host-parasite interaction that we report should stimulate deeper exploration of the relationships between infection and cancer [24].

In a case report of metformin-induced lactic acidosis in a patient with normal renal function, I speculate on the existence of a subset of susceptible patients: This case report adds to the evidence that metformin can trigger lactic acidosis in a small subset of patients with normal renal function and no other evident risk factors. The cause is unclear, but an otherwise subclinical inborn or acquired error of lactate metabolism might predispose some metformin-treated patients to lactic acidosis [13].

Note, again, the natural flow from context to hypothesis to broader implications. All that remains of the discussion, once all of these pieces are in place, is the teaching point.

The Teaching Point The teaching point, which traditionally concludes a case report, should be simple, clear, and memorable. It should call to mind the pithy and powerful aphorisms of Hippocrates (see Chap. 2). Typically, it begins with a phrase such as

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“Physicians should be aware…” or “Clinicians should consider…,” and consists of a single sentence. It is generally best to have one main teaching point; a second is acceptable if there are two equally important lessons to be learned. More than two teaching points begins to strain the memory of the reader and tends to dilute the message. In writing the teaching point, the author should simply ask: “What is the main point of this case report? What message do I want readers to take away from it?” In the spirit of teaching by example, here are the teaching points from several of the case reports already discussed in this chapter: Physicians should ask their patients about soft drink consumption when faced with unexplained hypokalemia [2]. Physicians should discuss the possibility of impairment of vibrato with string musicians before prescribing a β-blocker for hypertension or other conditions that require long-term, daily use [4]. Clinicians should be alert to the possibility of vertebral sarcoidosis in any patient with a remote sarcoidosis history and persistent back pain [6]. We think it is important to make clinicians aware of the possibility of rare but severe hemolysis with metformin treatment [10]. In lithium-treated patients who develop transient aphasia, physicians should consider the possibility of lithium toxicity, especially in the setting of volume depletion, renal failure, or overdosage [12]. Physicians should be alert to the possibility of lactic acidosis in any metformin-treated patient with an unexplained anion gap metabolic acidosis, regardless of risk factors and renal function [13]. This case demonstrates that there may be a small subset of (dialysis) patients for whom direct contact with polysulfone results in thrombocytopenia [15]. Physicians should be aware that type B lactic acidosis can occur in a variety of nonhematologic tumors, including gastric carcinoma [21].

Note that the teaching point often generalizes and broadens the message of the case, and tends to arise quite naturally from the discussion of context, the hypothesis, and the speculation that precede it.

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The CARE Guidelines and Checklist The CARE (CAse REport) guidelines (Fig. 7.4) were developed in 2013 in response to evidence that many case reports “are insufficiently rigorous to be aggregated for data analysis, inform research design, or guide clinical practice” [7]. The authors used a three-stage consensus process involving 27 participants, which resulted in a 13-item checklist as a case reporting guideline [7, 25]. Compliance with the CARE guidelines not only improves the evidence value of the case report, but may – as the guidelines continue to gain acceptance – also increase the likelihood of publication. I recommend that authors complete the checklist and mention when submitting the case report that it complies with CARE guidelines.

Figure 7.4 The CARE checklist of information to include when writing a case report (2016) (Reproduced with permission from Elsevier [25])

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References 1. Sagi I, Yechiam E. Amusing titles in scientific journals and article citation. J Inform Sci. 2008;34(5):680–7. 2. Packer CD. Chronic hypokalemia due to excessive cola consumption: a case report. Cases J. 2008;1:32. 3. Jenicek M. Clinical case reporting in evidence-based medicine. Oxford: Butterworth-Heinemann; 1999. p. 51. 4. Packer CD, Packer DM. Beta-blockers, stage fright, and vibrato: a case report. Med Probl Perform Art. 2005;20(3):126–30. 5. Chiang E, Packer CD. Concurrent reactive arthritis, Graves’ disease, and warm autoimmune hemolytic anemia: a case report. Cases J. 2009;2:6988. 6. Packer CD, Mileti LM. Vertebral sarcoidosis mimicking lytic osseous metastases: development 16 years after apparent resolution of thoracic sarcoidosis. J Clin Rheumatol. 2005;11(2): 105–8. 7. Gagnier JJ, Kienle G, Altman DG, et al. The CARE guidelines: consensus-based clinical case reporting guideline development. J Med Case Rep. 2013;7:223. 8. Rison RA. A guide to writing case reports for the Journal of Medical Case Reports and Biomed Central Research Notes. J Med Case Rep. 2013;7:239. 9. Iacopetti C, Packer CD. Cannabinoid hyperemesis syndrome: a case report and review of pathophysiology. Clin Med Res. 2014;12(1–2):65–7. 10. Packer CD, Hornick TR, Augustine SA. Fatal hemolytic anemia associated with metformin: a case report. J Med Case Rep. 2008;2:300. 11. Choe MJ, Packer CD. Severe romiplostim-induced rebound thrombocytopenia after splenectomy for refractory ITP. Ann Pharmacother. 2015;49(1):140–4. 12. Katz RB, Packer CD. Lithium toxicity presenting as transient transcortical motor aphasia: a case report. Psychosomatics. 2014;55(1):87–91. 13. Packer CD. Metformin-associated lactic acidosis in a patient with vertebral artery dissection. South Med J. 2006;99(10): 1147–8. 14. Reinke CE, Resnick AS. Incarcerated appendix in a spigelian hernia. J Surg Case Rep. 2010;10:3.

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15. Muir K, Packer CD. Thrombocytopenia in the setting of dialysis using biocompatible membranes. Case Report Med. 2012;2012:358024. 16. U.S.-acquired human rabies with symptom onset and diagnosis abroad, 2012. MMWR Morb Mortal Wkly Rep. 2012;61(39): 777–81. 17. Wali E, Koo P, Packer CD. Acute obstructive suppurative pancreatic ductitis in an asymptomatic patient. Case Rep Med. 2015;2015:919452. 18. Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo J, Taieb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649–51. 19. Tsimihodimos V, Kakaidi V, Elisaf M. I Cola-induced hypokalaemia: pathophysiological mechanisms and clinical implications. Int J Clin Pract. 2009;63(6):900–2. 20. Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action. Br J Dermatol. 2010;163(2):269–74. 21. Krimmel JD, Packer CD. Type B lactic acidosis in the setting of gastric adenocarcinoma with extensive metastases. Med Princ Pract. 2015;24:391–3. 22. Skelton JR, Edwards SJ. The function of the discussion section in academic medical writing. BMJ. 2000;320(7244):1269–70. 23. Wang J, Packer CD. Acute abdominal pain after intercourse: adrenal hemorrhage as the first sign of metastatic lung cancer. Case Report Med. 2014;2014:612036. 24. Muehlenbachs A, Bhatnagar J, Agudelo CA, et al. Malignant transformation of Hymenolepsis nana in a human host. N Engl J Med. 2015;373(19):1845–52. 25. Gagnier JJ, Kienle G, Altman DG, Moher D, Sox H, Riley D. The CARE guidelines: consensus-based clinical case report guideline development. J Clin Epidemiol. 2014;67(1):46–51.

Chapter 8 Special Considerations Clifford D. Packer

Adverse Drug Reaction Case Reports Whenever a patient presents with new symptoms or abnormal laboratory results, an adverse drug reaction (ADR) should be considered in the differential diagnosis. ADRs are common; it has been estimated that 3–8 % of hospitalized patients are admitted because of ADRs, and about 7 % of hospitalized patients will experience a serious ADR during their stay [1]. Most ADRs are of the type known as dose related or “augmented,” in which there is an exaggerated response to the known pharmacologic action of the drug; bleeding with warfarin and orthostatic hypotension from antihypertensive drugs are examples of these common ADRs, which are seldom reportable. Non-dose related or “bizarre” ADRs, which are uncommon, not related to the known pharmacologic action of the drug, and unpredictable, are more likely to be reportable [2]. Examples of this type include anaphylaxis to penicillin, malignant hyperthermia with general anesthetics, and (on a more delayed basis) osteonecrosis of the jaw with bisphosphonates or the teratogenicity of thalidomide. Case reports describing ADRs have a vital role in pharmacovigilance. Before a new drug is approved for general use, phase II and phase III trials assess efficacy and safety in a few hundred to a few thousand subjects. When the drug is released © Springer International Publishing Switzerland 2017 C.D. Packer et al., Writing Case Reports, DOI 10.1007/978-3-319-41899-5_8

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to the general population and used by tens or hundreds of thousands of patients, rare and often unanticipated adverse effects may begin to emerge. These effects can be quite severe, as for example, in the cases of troglitazone-induced liver failure and valvular heart disease associated with fenfluraminephentermine. Case reports of ADRs are a critical part of this postmarketing surveillance – also known as phase IV trials – in which rare adverse effects that were not detected in early clinical trials can be reported and verified. Since ADR case reports rely largely on temporal connections to support causality, a timeline (either a figure or table; see Chap. 7) should be created to show the temporal relationship between the drug and the adverse effect. A simple timeline describing the effects of two different dialyzer types on platelet counts is shown in Fig. 7.2. A more complex timeline (Fig. 8.1), created by one of my medical student co-authors, illustrates the effects of five drugs, platelet transfusions, and splenectomy on the long-term platelet counts of a patient with refractory ITP [3]. The aim of this timeline is to show how platelet counts were affected when romiplostim was held at the time of splenectomy. A large amount of information is given in a single, easy-to-understand figure. This clarifies the timeline and allows the authors to focus on interpretation, as the reader can refer back to the figure for the day-by-day details of treatment and response. The key to writing a convincing and publishable ADR case report is to make a compelling argument for the causal relationship between the drug and the adverse effect. In addition to the timeline, this requires a discussion of differential diagnosis and possible alternative explanations, and use of a validated causality scale to support the argument, such as the Naranjo ADR Probability Scale [4], the WHO-UMC causality categories [5], or the Liverpool adverse drug reaction causality tool [6]. Because it is simple, transparent, and easy to apply, the Naranjo scale (Table 8.1) is probably the most commonly used causality scale. Naranjo adds points for previous conclusive reports of the same reaction, temporal relationships between the drug and the event, lack of alternative causes, response to challenge and dechallenge, and other objective evidence such

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Platelet clinical course 450

400

350

Platelet Count in 109 Liter

300

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200 Splenectomy romiplostim held

Romiplostim held

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0 0

Pred (mg)

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90 100 110 120 130 140 150 160 170 180 190 200 Days

40

Dexa (mg)

40

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0.5

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IVIG (mg/kg) 0.5

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Plat (units) 2

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4 675

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Figure 8.1 Top graph represents patient’s platelet counts throughout the clinical course. Bottom graph represents the temporal relationship of doses of important pharmacotherapeutic agents. Each bar represents a single dose for a given day. Labels include drugs with the corresponding units of doses. Abbreviations: Pred prednisone, Dexa dexamethasone, IVIG intravenous immunoglobulin, Plat platelets, Rom romiplostim, Ritux rituximab (Reproduced with permission from SAGE Publications [3])

as toxic drug levels in the blood. Points are subtracted if there are alternative causes for the reaction, or if the reaction reappeared when a placebo was given. Case reports with “definite” or “probable” Naranjo scores are more likely to be published than those with “possible” scores. For drug interaction case reports, the Horn Drug Interaction Probability Scale (DIPS) has many of the same elements as the Naranjo scale, but also

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Table 8.1 The Naranjo ADR probability scale Yes No Unknown Are there previous conclusive +1 0 0 reports on this reaction? Did the adverse event appear after the suspected drug was administered?

+2

−1

0

Did the adverse event improve when the drug was discontinued and a specific antagonist was administered?

+1

0

0

Did the adverse reaction reappear when the drug was readministered?

+2

−1

0

Are there alternative causes (other than the drug) that could on their own have caused the reaction?

−1

+2

0

Did the reaction reappear when a placebo was given?

−1

+1

0

Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?

+1

0

0

Was the reaction more severe when the dose was increased or less severe when the dose was decreased?

+1

0

0

Did the patient have a similar reaction to the same or similar drugs in any previous exposure?

+1

0

0

Was the adverse effect confirmed by any objective evidence?

+1

0

0

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Adapted with permission from John Wiley and Sons [4] Assessment score: Definite ≥ 9; Probable 5–8; Possible 1–4; Doubtful ≤ 0

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includes questions on whether the observed interaction is consistent with the known interactive properties of both the precipitant drug and the object drug [7]. For authors who are not pharmacologists, answers to these questions will require additional research on the properties of both drugs. In the discussion section of an ADR case report, all previous reports of the drug reaction should be reviewed and compared with the current report; causality including possible alternative explanations should be explored; and a hypothesis for the mechanism of the reaction should be proposed. The following passage gives the argument for azathioprine hypersensitivity in a patient with Crohn’s disease, with recurrent fever, and concludes with the Naranjo score: The differential diagnosis for fever in a patient with IBD on immunosuppressive medications focuses primarily on infectious etiologies. In this patient, possible localizing clues for infection proved to be red herrings: the opacity on CXR was likely from atelectasis, and the rising bilirubin and elevated aminotransferases were due to the hypersensitivity reaction rather than biliary tree disease. In addition to the fever and leukocytosis, our patient’s arthralgias and rash raised concern for extraintestinal manifestations of IBD flare. However, our patient did not have worsening intestinal IBD symptoms; moreover, he clinically improved after each “flare” without any specific intervention targeting IBD. Ultimately, it was only after the third admission with still no evidence of an infectious etiology that the possibility of AZA hypersensitivity was considered in earnest. The association became clear by aligning the timing of his fevers with the timing of AZA ingestion. Further evidence of AZA hypersensitivity included clear clinical improvement each time the AZA was stopped and the escalating clinical and laboratory manifestations that occurred with each rechallenge. This intensifying response with each exposure is a hallmark of hypersensitivity reactions. The Naranjo scale score was 8, supporting the probability that this was a true adverse drug event [8].

As another example, consider this argument in support of iatrogenic Cushing’s syndrome due to an interaction between ritonavir and oral budesonide: Our patient developed edema, weight gain, uncontrolled hypertension, cushingoid facies, hypokalemia, and metabolic alkalosis shortly after initiation of budesonide, with resolution of all symptoms soon after it was stopped. Congestive heart failure, liver

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disease, and nephrotic syndrome were ruled out as causes of the edema, which supported iatrogenic Cushing’s syndrome. Although budesonide concentrations were not measured, the very low serum cortisol level (0.8 μg/dL) in a clinical setting of hypercortisolism provides strong indirect evidence that levels of an exogenous corticosteroid (i.e., budesonide) were high. Adrenal suppression has been described in a number of cases of iatrogenic Cushing’s disease due to ritonavir-steroid interactions. The Naranjo Probability Scale and Horn Drug Interaction Probability Scale score characterized this as a probable drug interaction [9].

Note that the Naranjo scale can serve as an excellent outline for the discussion section of an ADR case report. Point-by-point answers to the ten Naranjo questions (or to as many as are answerable), with full explanations for each answer, will require a full literature review and a thorough investigation of causality – which, according to the published guidelines of Kelly et al. [10], are the two essential features of an ADR case discussion. Many ADR case reports are published, but they vary greatly in terms of quality and clinical usefulness. Several studies indicate that ADR case reports are frequently missing important elements, including route and formulation of the suspect drug, social history, weight, race, allergy history, liver and kidney function, discussion of possible mechanisms for the ADR, and use of objective rating scales to support the causal connection between drug and adverse effect [11–13]. Consequently, guidelines for submitting ADR case reports have been developed that include all relevant patient data and drug information, a full description of the adverse event, a review of previous reports in the literature, and an assessment of competing explanations and biologic plausibility [10]. All of these elements should be included in every ADR case report. Incomplete or unsubstantiated case reports are seldom published and have no role in pharmacovigilance.

N-of-1 Trials The n-of-1 trial is a first cousin of the case report. N-of-1 trials use individual patients as study subjects, with the purpose of finding the best treatment for that individual using his or her

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own data. In essence, n-of-1 trials explore variability in an objective way, and serve as a way to make individual case reports more useful and more generalizable. Some n-of-1 trials use blinding, placebo controls, crossover designs, and washout periods sequentially in a single patient [14]; others involve in-depth studies of the genomic or physiologic characteristics of a single interesting or unusual case. Although randomized controlled trials (RCTs) are generally considered the best evidence for evaluating the effectiveness of treatments or procedures, n-of-1 trials have important advantages, which are becoming increasingly clear in the era of genomic medicine and individualized treatment. Unlike RCTs, which may evaluate thousands of patients but study only a few variables, n-of-1 trials can better comprehend the myriad factors and nuances involved in a patient’s response to treatment. Any physician in active practice performs de facto n-of-1 trials every day, for example, in the selection, dosing, and titration of blood pressure medicines for a number of individual patients. Factors such as race, age, gender, comorbid conditions, renal function, medication adherence, potential side effects, financial constraints, and patient preferences all come into play. These factors are too complex to be assessed in toto by any RCT, however large and well-designed. RCTs may reveal the best treatment for a population of patients, but there are always substantial numbers of individuals who will not benefit – a state of affairs which Nicholas J. Schork has described as “imprecision medicine” [15]. The n-of-1 trial is designed to work in the opposite direction, from the particular to the general, identifying the traits of individuals and small groups of patients that would predict a favorable response to treatment. The treatment can then be generalized to larger populations of patients with the same traits, with more precision and fewer nonresponders. There are several exciting examples of this kind of thinking in oncology, especially in the study of the small numbers of outliers who respond exceptionally well in clinical trials. In the past, these rare super-responders were dismissed as “anecdotal cases,” but more recently, intensive genomic studies of these patients have revealed that specific genetic mutations, such as

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the ROS1 gene rearrangement in non-small cell lung cancer and the mutated EGFR gene in colon cancer, are predictors of excellent treatment responses (to crizotinib and cetuximab, respectively). These findings are driving cancer researchers to revisit “failed” clinical trials to find and reassess more outliers [14]. In 2012, the National Cancer Institute announced the Exceptional Responders Initiative to identify and sequence the tumors from 100 extraordinary responders to any type of cancer therapy [16]. The aim is to collect and curate n-of-1 cases to create a large genomic database that can be used for clinical decision-making [17]. Conversely, reports of adverse reactions to commonly used drugs such as clopidogrel, warfarin, and carbamazepine have led to the discovery of genetic variations which can put patients at risk. This has prompted the FDA to relabel many drugs with pharmacogenomic information [18, 19]. Beyond pharmacogenomics, the use of wireless remote “phenotypic” monitoring devices – such as smartphone apps for heart rate and sleep quality, actigraphs, continuous glucose monitors, esophageal pH sensors, heart rhythm monitors, oximeters, and wrist tremor monitors for Parkinson’s disease – expands the possibilities for accurate and comprehensive physiologic data collection in n-of-1 trials of treatment response [14]. What, then, is the connection between case reports and n-of-1 trials? Case reports tend to focus on the unusual – outliers, adverse drug reactions, new syndromes, atypical presentations – and often raise questions that would be best answered by n-of-1 trials. For example, there are numerous case reports of prazosin as an effective treatment for PTSD-associated nightmares; the results of randomized controlled trials have been mixed [20]. Clearly, some patients benefit, but many do not. Carefully designed n-of-1 trials, with the fullest possible accounting for the many variables in these complex patients, might reveal which patients are most likely to benefit; for those unlikely to benefit, the side effects of prazosin could be avoided. In any case report, it is important to speculate on the broader implications, including directions for future research. Therefore, the potential for n-of-1 trials (or other studies) to resolve questions raised by the case should be noted and considered in the case report discussion.

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In a larger sense, case reports, like n-of-1 trials, work inductively: they go from the specific to the general. N-of-1 trials can be aggregated and subjected to meta-analysis, which can lead to valid general conclusions. Case reports are already aggregated – in a huge database, with more than 1.7 million cases indexed in PubMed – and can be used effectively for clinical decision-making when other sources of evidence are lacking.

Case Series The case series is a group or series of observations involving patients with a similar diagnosis or cluster of symptoms, or a similar response (adverse or beneficial) to a procedure or treatment. In the epidemiology literature, the definition and design of the case series are largely neglected; in one survey of epidemiology textbooks, only five of 27 even mention case series in the index [21]. The minimum number of cases required for a case series is also unclear [22]; although some authors have argued for the “rule of four” [23], many published case series consist of only two or three cases. The case series is distinguished from case-control and cohort studies in that it lacks a comparison or control group, and does not follow patients over time using a well-defined inception point [21, 24]. This limits its statistical analysis to means, medians, ranges, and graphs, whereas case-control studies can include calculations of odds ratios and absolute risk reduction. The aims and functions of case series are similar to those of case reports: to recognize and describe new diseases or rare manifestations of disease, detect drug side effects, study mechanisms of disease, and assist with medical education. In addition, case series are useful in case definition, clues about cause, single physician or hospital reports of outcomes, and in the development of trend or “benchmarking” analyses and multi-institutional registries [25]. Case series can offer more compelling evidence than case reports, because clusters of new or unusual cases are more convincing than isolated cases. Case series can thus function quite

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persuasively as hypothesis-generating studies, which lead to additional trials for confirmation. A good example of this is the 2008 case series which showed the effectiveness of systemic propranolol in treating severe infantile hemangiomas [26]. This led to additional case series, physiologic studies, randomized controlled trials, a meta-analysis, and finally widespread acceptance of propranolol as a first-line treatment. Similarly, it was the case series of Pneumocystis carinii pneumonia and Kaposi’s sarcoma that led to an immune suppression hypothesis and the eventual discovery of the AIDS virus. On the other hand, case series have their disadvantages. One major drawback is the lack of a comparison group, which makes questions of cause and effect, disease frequency, and treatment effectiveness impossible to answer without further studies. Also, case series are subject to selection bias, because the investigator self-selects the cases [27]. Because of these weaknesses, case series can cause useful treatments to be abandoned, or potentially harmful procedures to be adopted [28]. Consider the 1998 series of 12 cases by Wakefield et al. which postulated a relationship between measles, mumps, and rubella (MMR) vaccination and chronic enterocolitis and regressive developmental disorder in children [29]. This paper was found to be fraudulent and was subsequently retracted, and any connection between MMR vaccination and autism was debunked in several epidemiologic studies. However, the harm has persisted because the notion of vaccine-induced autism has gained some traction in the popular culture. This has led to reduced vaccination rates and preventable outbreaks of measles, mumps, and whooping cough over the past several years. Although a series of cases can be collected from multiple sources, a single source may be better because it permits the use of uniform clinimetric criteria to compare and interpret the cases [25]. The authors may report only cases they have observed themselves, or assemble cases from several clinical sites. Case series can be cross-sectional studies, that is, an instant portrait of case characteristics at a set time, or longitudinal, with cases tracked as they arise over time. Longitudinal

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case series give a better understanding of the clinical course and clinical outcomes [25]. When writing up a case series, the basic structure is the same as that for the traditional case report, which is discussed in detail in Chap. 7. For the majority of case series reports, which are descriptive studies involving only a few patients with no statistical testing, a “Methods” section is not required. However, in more complex case series involving large numbers of patients and statistical analysis, a brief “Methods” or “Patients and Methods” section should be added after the introduction and before the case descriptions. This should include the number of cases described, the time period and length of follow-up, inclusion and diagnostic criteria, method of assessment, description of statistical analysis, and patient consent and/or IRB approval, as required. For example, in a case series of rheumatic fever presentation and outcome in Brazil from 1986 to 2007, 178 cases were diagnosed, of which 134 were selected; inclusion criteria were age under 18 years, fulfillment of Jones criteria, and regular follow-up for at least 1 year; all cases were followed up by one author, descriptive statistics were given for continuous variables, and the probabilities of relapse and carditis were assessed with clinical and echocardiogram data and actuarial survival analysis [30]. The case descriptions should be a series of short paragraphs with all essential demographic, clinical, and clinimetric data included for easy comparison. In case series where there are too many reports to list individually, a couple of case descriptions are often included as examples, followed by a summary of all the cases with a listing of the important clinical observations. For instance, in a 1981 series of eight male homosexual patients with Kaposi’s sarcoma, two brief case descriptions are given; of the group as a whole, we learn that seven had generalized lymphadenopathy, six had visceral involvement, one had possible brain involvement, three died from Kaposi’s sarcoma, and one died from overwhelming cryptococcosis unresponsive to antifungal therapy. A comparison table is included with patient age, ethnic group, sites of skin and visceral lesions, CMV and hepatitis B titers, disease duration, chemotherapy, and outcome [31].

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For any case series, a comparison table is essential. Unlike a single case report, where the table compares the object case with similar cases from the literature, the case series uses the table to make an internal comparison of its own cases. Table 8.2 illustrates the serum renin levels, aldosterone levels, and abdominal ultrasound findings for a series of seven Indian children with childhood Bartter’s syndrome [32]. In the discussion, the authors compare the clinical and biochemical features of their patients with other case series of Bartter’s syndrome in children, and note that a series of 13 Arabic children also showed hypokalemia, hypochloremia, metabolic alkalosis, and hyperreninemia in all cases. They conclude – just as in a single case report – with the important teaching points: “Bartter’s syndrome should be suspected in any child with history of failure to thrive and metabolic alkalosis. Early diagnosis and treatment with NSAIDs are lifesaving.” In summary, the case series is a simple, accessible, and inexpensive way to describe new or emerging diseases, treatments, Table 8.2 Serum renin, aldosterone, and renal ultrasound findings in seven children with childhood Bartter’s syndrome Serum Serum renin (ng/ aldosterone Case# ml/h) (ng/l) Ultrasound abdomen finding 1 8.5 330 Normal 2

187

848.7

Bilateral medical renal disease

3

6.05

1400

Normal

4

3.23

86.3

Bilateral mildly increased renal cortical echoes

5

8.6

752

Normal

6

40.71

967

Nephrocalcinosis

7

4

135

Normal

Mean

36.8 ± 42.3

645 ± 482.7

Adapted with permission from Sampathkumar et al. [32]

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or drug side effects, and generate hypotheses for further study. Limitations of case series include potential for selection bias, lack of a control group, lack of generalizability, and potential for harm with incorrect conclusions (the “anecdotal fallacy”). Case series follow the same basic structure as single case reports, except that a “Methods” section is sometimes needed to describe case selection and statistical analysis, and the discussion must include an internal comparison of case characteristics in addition to a review of the literature. As in any case report, the three main objectives are to place the cases in context, develop a hypothesis to explain the findings, and make a teaching point.

How to Write a “Clinical Images” Article A good clinical image that really “tells the story” makes for a more compelling and convincing case report. I have used photographs, CT, MRI, and PET scan images, and pathology photomicrographs in my own case reports. Increasingly, realtime videos, echocardiograms, ultrasounds, phonocardiograms, angiograms, and other media are becoming the norm in the era of the online electronic case report. A good image, whether static or dynamic, can also save hundreds of words of description, which makes for a leaner and more succinct case report. Editors love to publish cases with powerful images; they also love short, concise articles. Increasingly, they are making the image the centerpiece, and shrinking the case report to a mere caption. In many journals, in fact, the “clinical images” article seems to be replacing the traditional case report. Therefore, although I shudder to consider a possible “Fahrenheit 451” future for the case report (all images, no words), I do think it is important for physicians to know how to publish their most captivating clinical images. Contrary to many physicians’ expectations, the rarest, oddest, and most extreme images are not necessarily the most publishable. In fact, a review of the “Images in Clinical Medicine” section of the New England Journal of

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Medicine (NEJM) reveals a substantial number of common medical conditions (measles, rubella, myxedema, SVC syndrome) and findings (pronator drift, upper limb clonus, cannon A waves, pulsus alternans) among the oddities such as a Grynfeltt hernia, ptosis due to impacted fish mandibles over the eye of a swimmer who collided with a school of fish, and bilateral periorbital erythema migrans in a boy with disseminated Lyme disease. In its instructions for authors, NEJM calls for “classic images of common medical conditions,” with the aim “to capture the sense of visual discovery and variety that physicians experience” [33]. This notion of “archetypal images” of common conditions is a common theme in many journals. BMJ is very clear about the kinds of images it does not want: “foreign bodies, results of gross trauma, poor image quality (even if interesting), simply ‘textbook’ presentations, very rare clinical presentations, and submissions which simply criticize other physicians, or the patient” [34]. The Lancet solicits visual information that will be useful to other physicians, as well as interesting, educational, and respectful of the patient; they are “less interested in pictures that simply illustrate an extreme example of a medical condition” [35]. Finally, the Canadian Medical Association Journal (CMAJ) asks for “intriguing, classic, or dramatic images” which illustrate “common presentations of rare conditions, or unusual presentations of common problems” [36]. These instructions give much latitude for various kinds of images, but the common thread seems to be that beyond amazing, amusing, and impressing us, the best clinical images should have something important to teach us. In other words, novelty is important, but so is the clinical lesson, the teaching point. In this way, clinical image articles are very much like case reports. In general, the captions for clinical images are limited to 100–450 words, depending on the journal. The caption, according to the Lancet, should give a brief patient history,

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put the image in context, and “explain what the image shows and why it is of interest to the general reader” [35]. This may involve further discussion of epidemiology, differential diagnosis, management strategies, prognosis, or other issues raised by the image. For example, a recent NEJM “Images in Clinical Medicine” article includes a video of a patient with cannon A waves, an ECG showing AV nodal re-entrant tachycardia with characteristic notching in the terminal portion of the QRS in lead V1, a brief discussion of the pathophysiology and differential diagnosis for cannon A waves, electrophysiology study results, and the clinical course including follow-up after slow pathway ablation [37]. Impressively, all of this information is conveyed in a 222-word caption. Brevity is the key with clinical images: as much as possible, let the picture speak for itself. How does one find publishable clinical images? As Louis Pasteur said, “chance favors the prepared mind.” Stay vigilant, carry a smartphone in your office and on rounds, and be prepared to request written consent before recording any patient images. Be alert not only for the unusual and bizarre, but for archetypal images of common diseases and exemplary physical exam findings. Make creative use of videos and real-time monitoring devices in addition to photographs and standard imaging studies. Use more than one modality to increase the power and persuasiveness of your images; for instance, in the case of a patient with a classic paradoxical S2 split caused by a left bundle branch block, include a phonocardiogram with respiratory tracings along with the standard 12-lead ECG. Above all, stay curious; the best reason to photograph an unexpected lesion is to preserve it, study it, and finally diagnose it. If the diagnosis is elusive, find the pathologist or dermatologist or whoever else can help you to nail it down. Like case reports, clinical images are almost never publishable without a diagnosis. Your helpful colleague will be happy to sign on as a co-author.

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The “Clinical Quiz” or “Mystery Image” Another common way to present an image is in the form of a clinical quiz, where a brief history is given in the image caption, followed by one or more questions (usually multiple choice) to test the reader’s knowledge. Answers with explanations are given separately. One of my best medical students published the following clinical image article based on a patient she cared for on the wards during her internal medicine clerkship (see Fig. 8.2 and accompanying text). Note the paradoxical title: “When Asthma is Not Asthma.” If this were a simple “clinical images” article without the quiz, a straightforward title such as “Post-intubation tracheal stenosis” would be most appropriate (see my comments on case report titles in Chap. 7). However, this title is apt because a clinical quiz or mystery image works better with an ironic, mysterious, or humorous title to preserve uncertainty and entice the reader to solve the mystery. When Asthma is Not Asthma A 52-year-old woman with a five-pack-year smoking history was admitted to the hospital with persistent shortness of breath, wheezing, and dry cough of 2 weeks’ duration following an upper respiratory infection. Her medical history was notable for a 72-hour intubation for hypoxic respiratory failure secondary to a drug overdose months prior. She had never been hospitalized for shortness of breath in the past. She was prescribed an albuterol inhaler for seasonal allergies. She is now using her albuterol inhaler four times a day with minimal relief of her symptoms. During her admission to the hospital, she was given albuterol and ipratropium nebulizers and discharged to home to complete a 5-day course of prednisone for a presumed asthma exacerbation. She returned to the emergency department 5 days later when her symptoms persisted. Lung auscultation revealed mild bilateral expiratory wheezes and stridorous breath sounds on exertion. The rest of her physical exam was unremarkable. Her chest radiograph was normal. On spirometry, her flow-volume loop demonstrated marked limitation of the inspiratory and expiratory flow, consistent with fixed obstruction. Flexible laryngoscopy revealed 80 % tracheal stenosis at the third tracheal ring. Computer tomography (CT) of the chest and neck with contrast confirmed the presence of a stenosis in the mid-trachea with an area of 6 mm by 3 mm (Fig. 8.2).

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Figure 8.2 Sagittal CT view of the chest and neck revealing severe mid-tracheal stenosis (Reproduced with permission from Strohl and Packer [38])

What is the most significant risk factor for the development of post-intubation tracheal stenosis? • • • • •

Cuff pressure and volume History of GERD Female sex Concurrent use of corticosteroids No previous intubations

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Since this is an online journal, the reader is prompted to click on the best answer. Once a selection is made, the percentage of readers who selected each answer appears: • • • • •

Cuff pressure and volume (72.31 %) History of GERD (15.38 %) Concurrent use of corticosteroids (7.69 %) No previous intubations (3.08 %) Female sex (1.54 %)

The reader is then directed to view the answer and explanation: Answer: A. Cuff pressure and volume MCQ Explanation: The diagnosis of tracheal stenosis should be considered in patients with a recent history of intubation who are presenting with new or worsening respiratory symptoms. It is commonly misdiagnosed as an asthma or COPD exacerbation, which results in delayed diagnosis and treatment. Cuff pressure and volume are the most significant predictors of the development of post endotracheal intubation tracheal stenosis. When stenosis develops, it most often occurs at the level of the endotracheal tube cuff. The cuff exerts pressure on the tracheal wall, leading to mucosal ischemia and ulceration, and eventual development of chondritis and fibrosis. Fortunately, the development of large-volume, low-pressure cuffs has markedly reduced the occurrence of tracheal stenosis. Other factors contributing to the development of stenosis include length of intubation, traumatic intubation, history of previous intubations, excessive corticosteroid use, advanced age, female gender, severe respiratory failure, severe reflux disease, autoimmune diseases, obstructive sleep apnea, and previous radiation therapy to the neck or chest. After diagnosis, this patient was continued on albuterol and ipratropium nebulizers and restarted prednisone with mild improvement of her symptoms. She later underwent tracheal resection with no complications [38].

Note that the typical clinical scenario, pathophysiology, risk factors, and treatment for post-intubation tracheal stenosis are all briefly discussed, and the important teaching point – that tracheal stenosis is commonly misdiagnosed as

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an asthma or COPD exacerbation, which delays diagnosis and treatment – is clearly stated. The multiple-choice question is neither too difficult nor too easy, but at the appropriate level for a trainee or generalist physician reading a general medicine journal. Subspecialty-level questions, on the other hand, should be reserved for subspecialty journals. Here is an example of a challenging multiple-choice question aimed at infectious disease specialists, which refers to a case of a pregnant woman with a multidrug-resistant KPC-producing Klebsiella pneumoniae pyelonephritis [39]: Which antimicrobial(s) would be appropriate for the patient presented in the case? A. B. C. D. E. F.

Colistin (i.v.) Oral fosfomycin Oral fosfomycin and extended-infusion meropenem Oral fosfomycin and extended-infusion cefepime Ceftazidime-avibactam (i.v.) Meropenem and ertapenem (i.v.)

The clinical image associated with this case is the genetic typing of the KPC-producing Klebsiella cultured from this patient, as compared with two more prevalent KPC-producing Klebsiella isolates. A table with antimicrobial susceptibility testing is also included. This case-based quiz provides a formidable challenge even for an infectious disease specialist, and is intended to improve care for patients with these devastating infections [40]. Similarly, the tracheal stenosis case has an important educational message for the generalist. Clinical quizzes and images help to make these teaching points more memorable, and the learning process more challenging and enjoyable. Table 8.3 compares the features of clinical images and mystery image/clinical quiz articles. Regardless of the article type, a clear and compelling image with a strong teaching point has the best chance for publication.

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Table 8.3 Comparison of clinical images and mystery image/clinical quiz articles Mystery image/clinical Article type Clinical images quiz Title • Straightforward, • Mysterious, ironic, descriptive paradoxical Image Selection

• Archetypal images of common diseases/ exam findings • Rare or atypical presentations of common conditions • Classic presentations of rare conditions • Rare adverse effects • High educational value • Combine different media to enhance education (e.g., ECG and video of jugular vein pulsations) • High-quality images with appropriate legends and arrows • Avoid: foreign bodies, gross trauma, extreme rarity, poor-quality images, implied criticism of physician or patient

• In general, same as for “clinical images” articles • Diagnosable by many or most generalist physicians and some trainees • Neither too obvious nor too obscure • High educational value • High clinical relevance • Avoid: obscure and clinically irrelevant cases, trivia without clear practical value, excessive technical complexity (e.g., blots and gels, subtle radiologic variants, electrophysiologic studies) unless aimed at subspecialists

(continued)

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Mystery image/clinical quiz

Article type

Clinical images

Caption

• Generally 100–450 words • Includes brief case history, discussion of pathophysiology, differential diagnosis, treatment, clinical course, implications

• Generally 300–1500 words • Brief case history only; discussion of pathophysiology, differential diagnosis, etc., given separately, following answers to multiple-choice questions

Multiplechoice questions and answers, with explanations

• N/A

• Accessible to most generalists • Subspecialty level questions only if subspecialty journal • Incorrect answers explained • Clear justification of correct answer(s), followed by full discussion

Teaching point

• Essential

• Essential

References 1. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998;279:1200–5. 2. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356:1255–9. 3. Choe M, Packer CD. Severe romiplostim-induced rebound thrombocytopenia after splenectomy for refractory ITP. Ann Pharmacother. 2015;49(1):140–4. 4. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–45.

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5. The use of the WHO-UMC system for standardized case causality assessment. http://who-umc.org/Graphics/24734.pdf. Accessed 7 Feb 2016. 6. Gallagher RM, Kirkham JJ, Mason JR, et al. Development and inter-rater reliability of the Liverpool adverse drug reaction causality assessment tool. PLoS One. 2011;6:e28096. 7. Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother. 2007;41(4):674–80. 8. Mookherjee S, Narayanan M, Uchiyama T, Wentworth KL. Three hospital admissions in 9 days to diagnose azathioprine hypersensitivity in a patient with Crohn's disease. Am J Ther. 2015;22(2):e28–32. 9. Frankel JK, Packer CD. Cushing’s Syndrome due to antiretroviralbudesonide interaction. Ann Pharmacother. 2011;45(6):823–4. 10. Kelly WN, Arellano FM, Barnes J, et al. Guidelines for submitting adverse event reports for publication. Drug Saf. 2007;30(5):367–73. 11. Kelly WN. The quality of published adverse drug event reports. Ann Pharmacother. 2003;37(12):1774–8. 12. Impicciatore P, Mucci M. Completeness of published case reports on suspected adverse drug reactions. Drug Saf. 2010;33(9):765–73. 13. Kane-Gill SL, Smithburger PL, Williams EA, Felton MA, Wang N, Seybert AL. Published cases of adverse drug reactions: has the quality of reporting improved over time? Ther Adv Drug Saf. 2015;6(2):38–44. 14. Lillie EO, Patay B, Diamant J, Issell B, Topol EJ, Schork NJ. The n-of-1 clinical trial: the ultimate strategy for individualizing medicine? Per Med. 2011;8(2):161–73. 15. Schork NJ. Personalized medicine: Time for one-person trials. Nature. 2015;520(7549):609–11. 16. Exceptional responders initiative: questions and answers. http:// w w w. c a n c e r . g o v / n e w s - e v e n t s / p r e s s - r e l e a s e s / 2 0 1 4 / ExceptionalRespondersQandA. Accessed 7 Feb 2016. 17. Brannon AR, Sawyers CL. “N of 1” case reports in the era of whole genome sequencing. J Clin Invest. 2013;123(11):4568–70. 18. Topol EJ. Pharmacy benefit managers, pharmacies, and pharmacogenomics testing: prescription for progress? Sci Transl Med. 2010;2(44):44cm22. 19. Hamburg MA, Collins FS. The path to personalized medicine. N Engl J Med. 2010;363(4):301–4.

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20. Kung S, Espinel Z, Lapid MI. Treatment of nightmares with prazosin: a systemic review. Mayo Clin Proc. 2012;87(9):890–900. 21. Dekkers OM, Egger M, Altman DG, Vandenbroucke JP. Distinguishing case series from cohort studies. Ann Intern Med. 2012;156:37–40. 22. Abu-Zidan FM, Abbas AK, Hefny AF. Clinical “case series”: a concept analysis. Afr Health Sci. 2012;12(4):557–62. 23. Vandenbroucke JP. In defense of case reports and case series. Ann Intern Med. 2001;134:330–4. 24. Johnson LL. Observational studies. In: Gallin JI, Ognibene FP, editors. Principles and practice of clinical research. 3rd ed. Amsterdam: Academic Press; 2012. p. 209–10. 25. Jenicek M. Clinical case reporting in evidence-based medicine. Oxford: Butterworth-Heinemann; 1999. p. 101. 26. Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo J, Taieb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649–51. 27. Hess DR. Retrospective studies and chart reviews. Respir Care. 2004;49(10):1171–4. 28. Martyn C. Case reports, case series, and systemic reviews. QJM. 2002;95(4):197–8. 29. Wakefield AJ, Murch SH, Anthony A, et al. RETRACTED: Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 1998;351(9103):637–41. 30. Carvalho SM, Dalben I, Corrente JE, Magalhaes CS. Rheumatic fever presentation and outcome: a case-series report. Rev Bras Reumatol. 2012;52(2):236–46. 31. Hymes KB, Greene JB, Marcus A, William DC, Cheung T, Prose NS, et al. Kaposi’s sarcoma in homosexual men – a report of eight cases. Lancet. 1981;2(8247):598–600. 32. Sampathkumar K, Muralidharan U, Kannan A, Ramakrishnan M, Ajeshkumar R. Childhood Bartter’s syndrome: an Indian case series. Indian J Nephrol. 2010;20(4):207–10. 33. NEJM Author Center: images in clinical medicine. http://www. nejm.org/page/author-center/images-in-clinical-medicine. Accessed 28 Feb 2016. 34. BMJ Minerva Pictures. http://www.bmj.com/about-bmj/ resources-authors/article-types. Accessed 28 Feb 2016. 35. Clinical Pictures. Lancet. Information for authors. http://www. thelancet.com/pb/assets/raw/Lancet/authors/lancet-informationfor-authors.pdf. Accessed 28 Feb 2016.

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36. CMAJ Submission guidelines: clinical images. http://www.cmaj. ca/site/authors/preparing.xhtml#practiceImages. Accessed 28 Feb 2016. 37. Tung MKY, Healy S. Cannon A waves. N Engl J Med. 2016;374:e4. 38. Strohl M, Packer C. When asthma is not asthma. JGIM clinical images. 2015. http://www.sgim.org/web-only/clinical-images/ when-asthma-is-not-asthma. Accessed 23 Feb 2016. 39. Khatri A, Naeger Murphy N, Wiest P, Osborn M, Garber K, Hecker M, et al. Community-acquired pyelonephritis in pregnancy caused by KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2015;59:4375–8. 40. Arias CA, Rice LB. A new AAC section: translating resistance to the bedside. Antimicrob Agents Chemother. 2015;59:4365.

Chapter 9 How to Write a Clinical Vignette Abstract Jeffrey Wiese and Somnath Mookherjee

Introduction Many professional medical conferences invite authors to submit clinical vignette abstracts: brief case reports formatted as structured abstracts. These abstracts have strict word limits that require efficient and precise prose. Submissions are peer reviewed based on established criteria (Table 9.1). The authors of accepted abstracts are invited to present posters or give short oral presentations. This chapter presents 20 tips for writing an excellent clinical vignette abstract for submission to a conference. “Before and after” examples are used throughout to illustrate key points.

© Springer International Publishing Switzerland 2017 C.D. Packer et al., Writing Case Reports, DOI 10.1007/978-3-319-41899-5_9

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•

•

•

Teaching value: Offers an important diagnosis, physical examination, or management pearl Relevance to general internal medicine: Describes impact on clinical practice in internal medicine, teaching/education, or future research, places case in context Overall assessment: Overall evidence of scholarship, potential for publication

Significance: How significant or relevant are the abstract's conclusions in increasing understanding of a disease process or in improving the diagnosis or treatment of a disease state? How relevant is it to the field of internal medicine? • Presentation: How logical are the ideas presented in the abstract? How interesting is the manner of presentation? How clearly is the content written and free of significant grammatical errors? • Methods: If applicable, how suitable is the design for the stated objectives, and how appropriate are any analysis techniques applied?

•

• • • •

Originality Organization Writing ability Relevance to hospital medicine

Table 9.1 Examples of criteria used for peer review of clinical vignette abstracts for three major internal medicine conferences Society of General Internal Medicine American College of Physicians Society of Hospital Medicine (SGIM) [1] (ACP) [2] (SHM) [3]

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Step 1: Just Tell the Story! Then Revise Using These Tips …. First draft of the “case description” section of a clinical vignette A 34 y/o male with hemophilia A with a history of IV drug use and hepatitis C was admitted from clinic with fevers, shortness of breath, dyspnea on exertion, and abdominal distension that had been worsening for the past 2 months. The patient had been crushing Dilaudid and injecting it every 6 h for the past 2 years. On physical exam, he had a new 4/6 murmur consistent with TR, JVD, a remarkably tense and distended abdomen that was moderately tender, hepatosplenomegaly, and bilateral tender lower extremity edema with a petechial rash from mid shin distal. Lungs were clear, and no lymphadenopathy was appreciated. Chemistry panel showed Na 139, K 4.7, Cl 100, Bicarb 25, BUN 8, Cr 0.98, and glucose 107. AST was 20 U/L, ALT was 32 U/L. CBC showed WBC count of 10, HCT of 32, and platelets of 165. INR, albumin, and bilirubin were normal. ESR was elevated at 24. An abdominal ultrasound showed an 18.7 cm liver, a 22.8 cm spleen, and minimal ascites around the liver, and portal vein flow was hepatopedal. The TTE and TEE showed no valvular masses or vegetations, severely depressed RV systolic function and RV dilatation, severe tricuspid regurg, and severe pulmonary hypertension.

The biggest barrier to writing a clinical vignette abstract is getting the project started. Overcome this obstacle by imagining that you are telling a colleague about an interesting case, and simply put the words on paper. Determine the abstract headings for the conference to which you will be submitting (Table 9.2), but do not yet worry about word limits or style – simply tell the story. The box above shows an excellent first draft of the “case description” section of a typically structured clinical vignette abstract. By following these tips, this draft can be transformed into an excellent submission.

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Tip 1 Write a great opening sentence: concisely introduce the patient and the chief complaint. Include only the chief complaint, but if there are two equally important symptoms, then it is acceptable to include them both. The remaining symptoms can be listed with the associated symptoms, which should follow in the next sentence. Do not include the past medical history in the opening sentence. Original A 34 y/o male with hemophilia A with a history of IV drug use and hepatitis C was admitted from clinic with fevers, shortness of breath, dyspnea on exertion, and abdominal distension that had been worsening for the past 2 months. Revised A 34-year-old man presented with 2 months of progressively worsening shortness of breath and fever. He also noted abdominal distension and dyspnea on exertion. His past medical history included hemophilia A, intravenous drug use, and hepatitis C.

Tip 2 Use an academic style of writing: pay attention to grammar, syntax, and avoid the use of informal prose. Use man or woman as a noun; use male or female (i.e., a female carpenter) Table 9.2 Examples of clinical vignette abstract formats for three major internal medicine conferences Society of General American College Society of Hospital Internal Medicine of Physicians Medicine (SHM) – (SGIM) – 500 words (ACP) – 450 words 3,000 characters Title Title Title Learning objectives

Introduction

Case presentation

Case presentation

Case presentation

Discussion

Discussion

Discussion Conclusions

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as adjectives. Do not use any informal abbreviations (y/o), and write out all standard abbreviations on the first usage. Do not use the brand names of drugs: for example, use “hydromorphone” rather than “Dilaudid.” Tip 3 When possible, include the duration of the chief complaint as a descriptor of the complaint (rather than adding to the end of the sentence). Tip 4 Omit the site of care unless it is unusual or important to the case. For example, it is unnecessary to report that this patient was “admitted from clinic.” On the other hand, include the site of care when it is integral to the patient’s story: resuscitated in the field, presented to a rural hospital in Botswana, etc. Original The patient had been crushing Dilaudid and injecting it every 6 h for the past 2 years. Revised Moved to the end of the case presentation: On further questioning, he revealed that he had been crushing hydromorphone (Dilaudid) and injecting it intravenously for the past 2 years.

Tip 5 Do not release the highlight of the vignette too soon. It may sometimes seem disingenuous not to present critical information at the beginning of the vignette, especially if this information was revealed relatively early during the actual clinical encounter. However, as long as you are not altering the case history, it is desirable to preserve some of the mystery for later in the abstract. Delaying the punch-line makes the case much more educational and engaging; so, the reader can ponder the case much like the providers did when caring for the patient.

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Original On physical exam, he had a new 4/6 murmur consistent with TR, JVD, a remarkably tense and distended abdomen that was moderately tender, hepatosplenomegaly, and bilateral tender lower extremity edema with a petechial rash from mid shin distal. Lungs were clear, and no lymphadenopathy was appreciated. Revised He had a four out of six murmur located at the apex that increased in intensity with inspiration; neck veins were not elevated. The abdomen was distended, and the liver and spleen were enlarged. There was lower extremity edema and a petechial rash on his shins.

Tip 6 Unlike in clinical documentation or oral case presentations, not all section headings need to be announced. Save some space by not stating the obvious. For example, it is unnecessary to state “on physical exam.” Rather, directly report the key findings without introduction. Tip 7 Report physical examination findings, NOT your interpretation of the findings. Rather than “new 4/6 murmur consistent with TR,” describe what was actually observed, such as “holosystolic murmur that increased with inspiration.” Tip 8 Avoid lengthy, run-on sentences. In the face of strict word limitations, writers will often try to pack as much information as possible into a single sentence, hoping that this will somehow decrease the word count. In actuality, this strategy usually results in long, run-on sentences that are difficult to parse. A much better strategy is to write short sentences that directly convey one or two concepts, and omit all information that is not truly important to the story. In the example above, the first draft has 46

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words (253 characters), and the rewritten version also has 46 words (but only 214 characters). When it does make sense to group multiple concepts in a single paragraph, separate them using semicolons, for example, the heart examination findings. Tip 9 Include only the most relevant examination findings: determine the relevance by considering the likely differential diagnosis that is emerging from the story thus far. Include pertinent negative findings. Consider including a set of vital signs – but this is not always necessary if they were unremarkable. Tip 10 Report the physical examination as objective data: qualifiers such as “remarkably” or “essentially” are uninterpretable to the reader. What is remarkable to you may not be as remarkable to others. Furthermore, using such adverbs adds an unnecessarily dramatic element in a clinical case report. Original Chemistry panel showed Na 139, K 4.7, Cl 100, Bicarb 25, BUN 8, Cr 0.98, and glucose 107. AST was 20 U/L, ALT was 32 U/L. CBC showed WBC count of 10, HCT of 32, and platelets of 165. INR, albumin, and bilirubin were normal. ESR was elevated at 24. Revised Basic metabolic panel, complete blood count, prothrombin time, albumin, and bilirubin were normal.

Tip 11 This is not morning report. It is not necessary to provide the initial laboratory panel unless the findings are relevant to the case. If they are normal, that information may be briefly stated. If lab values do need to be provided, be sure to write out all abbreviations and provide units for all measurements. Doing so typically adds significantly to the

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word count; so, authors must be parsimonious in determining which labs are salient for the case. Original An abdominal ultrasound showed an 18.7 cm liver, a 22.8 cm spleen, and minimal ascites around the liver, and portal vein flow was hepato-pedal. The TTE and TEE showed no valvular masses or vegetations, severely depressed RV systolic function and RV dilatation, severe tricuspid regurg, and severe pulmonary hypertension. Revised The liver was 19 centimeters (cm) and the spleen was 23 cm by ultrasound. There were no valvular vegetations on the transesophageal echocardiogram; the right ventricular ejection fraction was depressed, and the right ventricle was dilated. There was severe tricuspid regurgitation; the estimated pulmonary pressure was _____. On further questioning, he revealed that he had been crushing hydromorphone (Dilaudid) and injecting it intravenously for the past 2 years.

Tip 12 We are accustomed to stating that a test “showed” a certain result; however, tests do not actually “show” things. It is better to state the finding followed by the modality that revealed the finding. Tip 13 Do not include unnecessary information: it is tempting to be comprehensive when reporting results, especially when there are abnormal findings that may or may not have had significance at the time the study was originally done. In a clinical vignette abstract, however, it is necessary to discard findings from lab or radiographic reports that ultimately prove to be irrelevant or unimportant. For example, “minimal ascites around the liver” could be omitted. Similarly, reporting measurements or lab values to the greatest degree of accuracy possible is seldom necessary. Round numbers that can be

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rounded without changing the meaning of the number: “18.7” is no more or less significant than “19,” and the result Tip 14 Report data that is important to the theme of the case. If information that most clinicians would expect to have been provided is clearly missing, then briefly explain why it was not available. In this example, the estimated pulmonary pressure would be important to report, if available.

Step 2: Write Good Learning Objectives Even if the conference abstract format does not require the submission of learning objectives alongside the abstract, it is critical to determine the key points that were learned from the case. These points will form the anchor for the discussion and should be prominently featured in an oral or poster presentation. Tip 15 Consider the most important lessons that you learned from the case: think about what a clinician should do when faced with a similar clinical situation. Use this information to construct the learning objectives. Tip 16 Write the learning objectives as actions the reader will be able to perform as a result of reading the case. Formulate them as completing the sentence, “After reading this case report (or visiting this poster, or hearing this presentation) the reader will be able to….” Avoid the temptation to use words such as “know” or “understand” when formulating learning objectives. Objectives that begin with passive verbs are weak and uninteresting compared to objectives that start with more active verbs. Table 9.3 provides examples of strong and weak learning objectives for this case.

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Table 9.3 Examples of strong and weak learning objectives Strong Weak 1. Recognize the clinical 1. Review the clinical presentation of impurity-induced presentation of impuritypulmonary hypertension induced pulmonary hypertension 2. Describe the pathophysiology of impurity-induced pulmonary hypertension

2. Understand the pathophysiology of impurity-induced pulmonary hypertension

3. Determine the etiology of fluid accumulation by mentally tracing the flow of blood backward from the aortic root

3. Know the differential diagnosis of edema and ascites

Step 3: Write a Focused Discussion Original discussion Cardiac complications of IV drug abuse are well known, especially endocarditis. Less stressed in medical education are the pulmonary complications from IV drugs use. Many of these complications present as nonspecific complaints consistent with interstitial lung disease. In IV drug users, the microvasculature of the lung is particularly susceptible to embolization by filtration of injected particulate matter. This may occur when granular particles of drug or impurities such as talc or starch are injected with the drug, acting as foci for chronic granulomatous inflammatory lesions. Subsequent fibrotic obliteration of the parenchymal microvasculature results in angiothrombotic pulmonary hypertension, and ultimately cor pulmonale with right heart failure. The degree of disease is directly related to the amount of material injected. Typical findings upon imaging are diffuse symmetric pattern of interstitial fibrosis either alone or with evidence of cor pulmonale. Superimposed bacterial infections frequently complicate the diagnosis. Shortness of breath in an IV drug user should always prompt the clinician to look for pulmonary complications, such as fibrosis, regardless of the presence of infection.

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Revised discussion Edema and ascites are problems commonly encountered by the internist. A methodical approach to determining the cause of the fluid accumulation is important in identifying less common causes of this problem. One method is to trace the flow of blood backward from the aortic root to the site of the fluid accumulation. The point where fluid is no longer accumulating is the site of the pathology. In our patient with ascites, pulmonary hypertension and pulmonary fibrosis were present with normal left heart findings. The point of pathology was therefore the fibrosis in the lung with precapillary obstruction causing pulmonary hypertension. The microvasculature of the lung is the primary filter for large particles from intravenous drugs. Embolic occlusions of these vessels by injected drugs and foreign materials like starch and talc act as foci for chronic granulomatous inflammatory lesions. Progressive obliteration of the microvasculature of the lung by fibrosis results in angiothrombotic pulmonary hypertension and ultimately right heart failure. The degree of disease is directly related to the amount of material injected. The pathology predominates in the middle and upper lung zones. With the incidence of drug use on the rise, physicians should be adept in identifying impurity-induced pulmonary hypertension as a cause of right heart failure.

Tip 17 Establish the relevance of the case for the audience from the very beginning. Case report authors already have a strong sense that their case is important and should be shared – ask yourself why that is and explicitly state the answer at the beginning of the discussion. Abstract reviewers are looking for the most relevant cases (Table 9.1), and conference participants will be most engaged by cases that are important in their clinical practice. Tip 18 Address each of the teaching points that were previously determined. Discussions of esoteric pathophysiology and

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in-depth literature reviews are not only prohibitively lengthy, but will not be engaging to most time-limited readers and reviewers. Tip 19 Explain important concepts simply and without digression. Imagine having a 1-minute window to explain the key points from the case to a colleague. Rather than saying, “In IV drug users, the microvasculature of the lung is particularly susceptible to embolization by filtration of injected particulate matter,” it is more efficient and more likely to be remembered if you say, “The microvasculature of the lung is the primary filter for large particles from intravenous drugs.” Tip 20 End with a “moral of the story” that highlights the relevance of the case and reinforces one of the major teaching points.

Conclusion Submitting a clinical vignette can be a valuable experience. It is an ideal opportunity for trainees and faculty to work closely together on a scholarly project. Many conferences offer competitive awards for the best clinical vignettes’ oral or poster presentations, providing an avenue for recognition by peers and leaders. For those in academic medicine, presenting an abstract may allow access to travel funds and bolster a curriculum vitae. Finally, writing and submitting a clinical vignette abstract is a great first step to publishing a full case report. Follow the tips listed above to start the writing project with a concise, brief report of the case, setting the stage for a subsequent manuscript. Chapters 7, 8, and 10 provide further guidance on writing full case reports for publication.

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References 1. Newsom J, Estrada CA, Panisko D, Willett L. Selecting the best clinical vignettes for academic meetings: should the scoring tool criteria be modified? J Gen Intern Med. 2012;27(2):202–6. 2. Guidelines for Submissions of Abstracts [Website]. American College of Physicians. Available from: https://www.acponline.org/ membership/residents/competitions-awards/acp-nationalabstract-competition. Accessed 2 May 2016. 3. Guidelines for Submissions of Abstracts [Website]. Society of Hospital Medicine. Available from: http://www.hospitalmedicine. org/Web/Education/Academic___Research/Academic_ Research_Community/Abstract_Submission.aspx. Accessed 2 May 2016.

Chapter 10 How to Write a Clinical Problem Solving Manuscript Gurpreet Dhaliwal and Gabrielle N. Berger

Introduction A clinical problem solving (CPS) exercise highlights the process by which an experienced clinician approaches a diagnostic puzzle. It is constructed in a manner that emphasizes thought process and reasoning as the case unfolds. A CPS manuscript is a variation on the traditional case report which allows the authors to explore a clinical dilemma in greater detail and present a broader set of teaching points. Writing a CPS manuscript requires a larger investment of time and energy than a traditional case report or clinical image. A CPS project will enhance the author’s understanding of clinical reasoning while advancing their medical knowledge. CPS manuscripts are often published in high-impact journals. This chapter is a step-by-step guide to writing a successful CPS manuscript.

Selecting the Case Characteristics of a suitable case for a CPS manuscript can be summarized by the TEACH acronym (courtesy of Sanjay Saint MD MPH): • Teaching points can be made • Enigma – the diagnosis must be a challenge © Springer International Publishing Switzerland 2017 C.D. Packer et al., Writing Case Reports, DOI 10.1007/978-3-319-41899-5_10

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• Answer must be established by a gold standard test • Cool (interesting) case – readers should say “wow” at the end • Honest – authors cannot change the facts of the case Among these, the most important criterion is that the expert discussant must be able to make meaningful teaching points that are relevant to a generalist audience; no other aspect of the case can overcome a deficit in this area.

The Planning Stage Once the primary author identifies a clinical case, it is important to invite a faculty mentor who has coauthored a CPS case previously to participate in the project. This person will often become an active collaborator and coauthor, although neither is assumed. This mentor is rarely the faculty member on the primary team or the consulting service; rather, the primary author should look for someone who understands the process of writing a clinical problem solving case, not the details of the case itself. The authors should contemplate the discussion section of the paper before focusing on the presentation of the case. How will you engage the audience after they have read the case? What topic will you highlight in addition to the final diagnosis? This may include a theme about clinical reasoning, changes in the practice of medicine, or reaffirmation of a principle (e.g., the importance of the social history). Without a narrative to engage the reader, the commentary section is likely to fall flat. Esoteric teaching points about rare diseases are of limited interest to most readers. Authors should determine whether the case has already been published in any format, or if other providers (e.g., a specialty service) intend to do so. Prior dissemination as a poster, abstract, or oral presentation at a medical conference does not preclude publication in most journals, but such presentation should be noted in the acknowledgment section. If the case has been disseminated in any other print or elec-

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tronic format, it may be difficult to publish as a CPS manuscript on account of duplicate publication policies. These issues are best discussed with the target journal series editor before embarking on the project. Journals encourage the inclusion of images that enhance the reader’s experience and the visual appearance of the article. Think about what images capture the key data the treating physicians contended with. Common images are rashes, surgical specimens, histopathology, radiology, or an EKG. These visual representations of the case substantially enhance the manuscript by engaging the audience and bringing the case to life. Although procuring or interpreting images may require assistance from a colleague, beware when this assistance is provided only on the condition of authorship. Such assistance is grounds for acknowledgment, not authorship. Choose a target journal and review author instructions early. Journals that regularly publish CPS manuscripts include the New England Journal of Medicine (NEJM), Journal of General Internal Medicine (JGIM), and Journal of Hospital Medicine (JHM). Journal-specific instructions provide valuable information on authorship guidelines, formatting, and word limits. Authors should send a pre-submission inquiry to the series editor of the target journal that includes a brief summary of the case, the diagnosis, and anticipated teaching points. The editor may encourage submission or advise that the case is not suitable (e.g., insufficient clinical dilemma or similar case already in progress). This inquiry can save valuable time and allow the authors to redirect their efforts toward a different journal where publication is more likely. Finally, do not invite coauthors (other than the faculty mentor) in the planning phase. The primary author will eventually invite coauthors, but after one or two people are involved, there is rarely enough work to go around in the early stages. It is not fair to invite colleagues when there are no available tasks that qualify them for authorship. A useful rule of thumb is the likelihood of completion is inversely related to the number of early authors. See authorship guide below for more details.

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Constructing the Case Protocol After selecting a faculty mentor, clarifying the key teaching points and themes, identifying a target journal, and collecting images, the primary author should start constructing the case protocol. The case protocol (see Table 10.1 for definitions) is the text and images that will be presented to the discussant. Once Table 10.1 Glossary of terms used in this chapter Terminology Definition Case The complete narrative of the case that will be protocol presented to the discussant. Aliquot

A section of the case protocol. After the case protocol is written, it is divided into aliquots, each of which is presented sequentially to the discussant. A case protocol is typically divided into 6–8 aliquots.

Discussant response

The discussant’s analysis of the information presented in the preceding aliquot.

Case discussion

The entire exchange between author and discussant. The case discussion consists of the aliquots with interspersed sequential discussant responses.

Commentary

The section of the manuscript that summarizes the case, explores the clinical dilemmas, and reviews relevant diseases or clinical reasoning principles.

Clinical reasoning analysis

A section required by some journals (e.g., Journal of General Internal Medicine) that is integrated into the case discussion and follows most discussant responses. The clinical reasoning analysis section provides commentary on the diagnostic reasoning process.

Teaching points

A section at the end of the manuscript required by some journals (e.g., Journal of Hospital Medicine) consisting of 3–5 bulleted clinical teaching points.

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completed, the protocol should be divided into six to eight sections (aliquots). Each aliquot should provide the discussant with enough information to modify their differential diagnosis from the section before. The first aliquot usually starts with the chief complaint and history of present illness (HPI). The second aliquot often reveals the past medical history (PMH) and medications with relevant health-related behaviors. Sequential aliquots outline the physical examination, then labs and imaging, then clinical course, then more clinical course, then final clinical event, and then gold standard test result. The primary author should review and edit the protocol with the faculty mentor for clarity and accuracy before sending it to the discussant. The medical details of the case must be accurate as the case will become part of the scientific record.

Constructing the Case Discussion After finalizing the case protocol, the first author and faculty mentor should identify a clinical discussant to invite as a coauthor. This person should not know the case in advance. Such knowledge makes the case discussion less authentic and violates the spirit of the exercise, which is predicated on extemporaneous thinking. Select a clinician who can discuss a broad range of medical topics, not an expert in the final diagnosis. It is the journey to the final diagnosis – not the diagnosis itself – that makes for an educational discussion. The invited discussant should have a reputation for timeliness and a track record of following through on projects. The first author may even consider including a timeline in the invitation such as the period of time (e.g., within 2 weeks) in which a response from the discussant would be appreciated for each aliquot. Send the first aliquot to the discussant. The discussant response should be two to four paragraphs. Following the discussant response, paste aliquot 2 (but no additional aliquots) into the same document and return the updated document

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to the discussant. Repeat this process for all subsequent aliquots. With each new aliquot the primary author may direct the discussant to address specific issues, such as “please elaborate on the initial differential diagnosis here,” or “what conditions are you most concerned about?” but should not provide hints. Give the discussant a warning when the next-to-last aliquot is being presented so he/she will commit to a leading diagnosis in their response. A discussant response to the final aliquot (where the diagnosis is disclosed) is optional. The resulting document is the first draft of the case discussion.

Writing the Manuscript The primary author (often assisted by a coauthor) should edit the first draft of the case discussion to generate a concise narrative that flows easily from one aliquot to the next while highlighting the discussant’s clinical problem solving skills. The editing author may decide to merge two aliquots and their respective discussant responses if this helps achieve a succinct case presentation with clear teaching points. (See the example below for excerpts from a case discussion in a CPS manuscript published in the New England Journal of Medicine) [1]. Once the case discussion has been edited, the first author should draft the commentary section (typically 500–700 words). It should briefly summarize the case, review the relevant diseases and dilemmas, and highlight general themes and takeaway points. After review by the faculty mentor, it is often helpful to invite a disease or domain expert who can review the clinical discussion and commentary and add teaching points. This person, typically a middle author, will be a valuable resource when specialty-level inquiries come from the editors and reviewers.

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Excerpts from a Case Discussion This is the first aliquot of a CPS, followed by the discussant’s response. The aliquot is brief, providing enough information for the discussant to formulate an initial approach to the patient without overwhelming the reader or discussant with too much data. A 22-year-old woman presented to the emergency department with a 4-week history of cough, progressive shortness of breath, subjective fevers, and malaise. On the day of admission, she was unable to walk farther than one city block without stopping to rest. She also noted new swelling in both legs. This patient’s progressive dyspnea may be due to volume overload, primary pulmonary processes, or anemia. The combination of dyspnea and lower-extremity edema suggests volume overload, typically explained by cardiac, hepatic, or renal failure. The duration of the reported problems and the association with systemic symptoms suggest an inflammatory, infectious, or malignant cause. This is the second aliquot followed by the discussant’s response. This aliquot provides more information about the patient’s presenting symptoms and history. The discussant now formulates a more detailed differential diagnosis, supporting his clinical reasoning with brief statements about the patient’s risk factors and clinical associations.

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The patient reported having arthralgias in her hands and knees that had begun 3 months before admission and were worse in the morning. Her medical history included migraine headaches since she was 10 years of age and subclinical herpes simplex virus type 2 infection. Three years earlier, she had undergone an uncomplicated delivery of a healthy baby at 40 weeks’ gestation; she reported no other pregnancies. She was taking no prescription medications. Originally from El Salvador, she had immigrated to the United States 5 years earlier but had not traveled recently. She worked in food services. She did not smoke cigarettes or use illicit drugs and rarely consumed alcohol. A sister in El Salvador had received a diagnosis of kidney disease of uncertain cause. The patient did not have patchy alopecia, aphthous ulcerations, dry eyes, dry mouth, rashes, or Raynaud’s phenomenon. Rheumatoid arthritis could explain subacute symmetric arthralgias in a young woman, but severe pulmonary or cardiac manifestations early in the disease course would be unusual. Systemic lupus erythematosus (SLE) with renal involvement could account for the arthralgias and volume overload. Sarcoidosis can cause arthralgias with pulmonary or cardiac involvement. Patients with dermatomyositis or polymyositis may present with early interstitial lung disease and concomitant arthritis. Subacute bacterial endocarditis could also explain this constellation of symptoms.The patient’s Central American origin raises the possibility of Chagas’ cardiomyopathy. Other infectious causes to consider include tuberculosis and infection with endemic fungi, such as histoplasmosis or paracoccidioidomycosis. The history of kidney disease in her sister raises the question of hereditary renal conditions, such as Alport’s disease or polycystic kidney disease, although they do not cause arthralgias; there could also be a shared predisposition to multisystem disease that affects the kidney (e.g., SLE). Thyroid disease (hyperfunction or hypofunction) should also be considered as a cause of at least some of her presenting symptoms.

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c

Figure 10.1 Findings on Transthoracic Echocardiography at the Time of Presentation. The parasternal long-axis view in Panel A shows a complex mass of soft tissue infiltrating the posterior wall of the left ventricle and encasing the posterior mitralvalve leaflet (arrow). The apical four-chamber view in Panel B shows encasement of the posterior mitral-valve leaflet by the soft-tissue mass (arrow) and involvement of the anterior mitralvalve leaflet. The mean diastolic mitral-valve pressure gradient of 16 mm Hg, shown on continuous-wave Doppler imaging in Panel C (arrow), is consistent with severe mitral stenosis

This is the eighth aliquot followed by the discussant’s response and accompanied by an image. At this point, the discussant is evaluating very specific hypotheses in detail. A transthoracic echocardiogram showed a large, irregular mass encasing the posterior leaflet of the mitral valve and resulting in severely reduced leaflet mobility (Fig. 10.1;

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Figure 10.2 Findings on magnetic resonance imaging at presentation. A transverse cardiac image obtained without the administration of gadolinium shows a mass extending into the left atrium and left ventricle (arrow)

and available with the full text of this article at NEJM. org). There was severe leaflet thickening, with a mean diastolic transmitral gradient of 16 mm Hg. The pulmonary artery systolic pressure was 67 mm Hg. The mass extended into the basal posterior and inferior walls of the left ventricle and the posterior wall of the left atrium. Left ventricular function and right ventricular function were normal. Transesophageal echocardiography and cardiac magnetic resonance imaging (Fig. 10.2) confirmed these findings and showed involvement of the anterior leaflet and chordae tendineae, along with extensive spread into the atrioventricular groove. This large, infiltrative mass may be causing heart failure due to valvular involvement, hemodynamic obstruction, or both. In addition, it is probably the source of the embolic phenomena (e.g., splinter hemorrhages). The encasement of the mitral valve is causing severe mitral stenosis and accounts for both the apical diastolic murmur and the dyspnea on exertion.

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The most common intracardiac tumor is atrial myxoma, which frequently causes emboli and striking immunologic phenomena. However, myxomas are typically pedunculated and mobile. In this case, the degree of invasiveness and adherence is more characteristic of a primary cardiac tumor, such as rhabdomyosarcoma or angiomyosarcoma, or a metastasis. The patient’s presentation is otherwise suggestive of SLE, but the large size of the mass is not typical for Libman–Sacks endocarditis. It is plausible that her employment in food services may put her at risk for a culture-negative endocarditis (e.g., brucellosis or Q fever), but signs of infection, such as fever, are absent. Although bland thrombus due to the antiphospholipid syndrome or the nephrotic syndrome is a consideration, invasiveness and valvular encasement are not characteristic of thrombus.

Journals with Additional Emphasis on Clinical Reasoning There are two requirements that are specific to the Journal of General Internal Medicine “Exercises in Clinical Reasoning” series (JGIM ECR). This format requires a clinical reasoning analysis section that follows most of the discussant responses, so that the case discussion is a repeating series of case aliquot‒ case discussion‒clinical reasoning analysis segments. A third author with expertise in clinical reasoning is often required for this analysis and will usually be a middle author on the paper. This section is typically constructed after the case discussion is completed, because it allows the clinical reasoning author to observe the arc of the case and discussant comments to determine which theme(s) warrant emphasis. JGIM ECR also differs from other journals in that the commentary section is focused entirely on additional clinical reasoning analysis of the case; didactic medical facts are deferred to bulleted teaching points, which conclude the manuscript (see the example below for excerpts from an Exercises in Clinical Reasoning article published by Journal of General Internal Medicine) [2]:

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This is the first aliquot of an Exercise in Clinical Reasoning article from Journal of General Internal Medicine, followed by the discussant’s response and a clinical reasoning analysis section. Similar to the NEJM format, the initial aliquot allows the discussant to formulate an initial approach to the patient. The diagnostic reasoning section provides additional commentary to describe the discussant’s thought process and teach clinical reasoning concepts.

Clinical Information: A 43-year-old Mexican woman presented to the emergency department with abdominal pain. Her illness had begun 1 week earlier with fevers to 38.9 °F and intermittent frontal headache without photophobia or other neurological symptoms. Two days prior to presentation, she began having left upper quadrant (LUQ) abdominal pain described as sharp, unremitting, and radiating to the midepigastrium, right upper quadrant, and left flank. The pain did not change with eating, but she did report episodic nausea and vomiting. She denied hematemesis, dysuria, or diarrhea. Her last menstrual period had begun 3 weeks earlier, and she denied recent sexual activity. One day prior she had been diagnosed with gallstones at another emergency department and treated with oral metoclopramide and hydrocodone-acetaminophen. Clinician. Left upper quadrant pain commonly results from gastritis, colitis (splenic flexure), pancreatitis, pyelonephritis, nephrolithiasis, splenic enlargement or infarction, or left lower lobe pneumonia. Intermittent headaches frequently accompany systemic illness, so the challenge is determining if the associated fever signals

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an intracranial infectious process such as meningitis, encephalitis, or brain abscess. The severity and duration of headache, lack of previous headache history, presence of meningeal signs, and neurological deficits are common indications for imaging the central nervous system and analyzing the CSF. Diagnostic Reasoning. The problem representation is an abstract one-sentence summary that elaborates the key features of the case. It triggers plausible diagnostic hypotheses and directs exploration of further historical elements, physical examination features and diagnostic testing. In complex cases it is often necessary to consider more than one problem representation. Here the competing versions might be: (1) a 43-year-old woman of reproductive age with a subacute febrile illness and headaches associated with LUQ abdominal pain, nausea, and vomiting; or (2) a 43-year-old woman of reproductive age with acute onset of sharp, unremitting LUQ pain, nausea, and vomiting. Using the first problem representation, the clinician would likely consider serious intracranial infections and mass lesions. In the second problem representation, the LUQ pain is the focal point that directs further data gathering. It is often useful to explore competing problem representations to avoid “premature closure.” Premature closure is the failure to consider other plausible diagnoses after an initial working diagnosis is reached. It is one of the most common clinical reasoning errors made by clinicians. A clinical teaching points section concludes the article, summarizing the key take-home points from the case. It includes teaching points on the specific disease process (brucellosis), the differential diagnosis (granulomatous hepatitis), and the importance of the social history.

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Clinical Teaching Points 1. Human brucellosis is a very common illness worldwide. Four brucella species ‒ melitensis, suis, abortus, and canis ‒ cause the majority of human illness, with B. melitensis being the most common.6 2. Brucellosis is generally transmitted by direct contact with infected animals (cattle, sheep, goats, or pigs) or by consuming unpasteurized dairy products. The incubation period is days to months. 3. Though brucellosis can involve any organ system, it usually presents with nonspecific symptoms, including undulating fevers, night sweats, malaise, weight loss, and arthralgias. It can also present with focal brucellosis syndromes, including meningitis, arthritis, endocarditis, or epididymo-orchitis. 4. Granulomatous hepatitis is caused by infections (e.g., tuberculosis, histoplasmosis, coccidioidomycosis, Q fever, brucellosis, syphilis, cryptococcosis, leprosy), drugs, malignancy (e.g., lymphomas, renal cell carcinoma), or autoimmune diseases (e.g., sarcoidosis, polymyalgia rheumatica, primary biliary cirrhosis). Up to 20 percent of cases are idiopathic.7 5. The social history is often a key discriminating feature in febrile illnesses, particularly for patients who travel outside of industrialized areas. They are often exposed to infections that are not routinely considered.

Final Steps There are a number of final steps in preparing the manuscript for publication including: • Formatting images (e.g., adding arrows if necessary) • Drafting image legends • Drafting the teaching points section

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• Adding references • Determining a title The best title makes a clever but obtuse reference to the teaching points, the manner in which the case unfolds, or the final diagnosis. For instance, “The Right Angle” was chosen as a title for a case of constrictive pericarditis that evaded detection because the extreme elevation in jugular venous pressure was difficult to appreciate when the patient was at the typical 45° of recumbency; the “right angle” of 90° (seated position) would have facilitated detection. Involve the entire authorship group in multiple rounds of editing to produce a succinct and engaging manuscript. Before submitting the manuscript, carefully check the author instructions again. Failure to follow author instructions is a common reason for immediate manuscript rejection.

Guide to Authorship The maximum number of authors on a CPS manuscript is typically five or six. While there is no standard approach to authorship, consider the following framework as a guide: First author: this is the person who initiated the project and remains the leader throughout. The first author drafts most of the case protocol and parts of the commentary, coordinates the contributions of other coauthors, leads the submission process, and serves as the corresponding author with the journal. Middle authors: these collaborators should be listed in descending order according to the amount of work contributed and stage of involvement in the project. Middle authors typically include the discussant, the clinical reasoning expert (if one is involved), and a disease/ domain expert. Final author: this person is often the coordinating faculty advisor for the project who made multiple contributions through the project such as helping the first author

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identify other collaborators, editing the case discussion and commentary, and providing substantial input into the final editing and submission process. It is equally important to understand what types of contributions do not qualify for authorship: • • • • • • •

“I made the diagnosis” “I took care of the patient” “I was on the team” “I was the consultant” “I was the attending” “I am the primary care provider” “I interpreted the image”

The guiding principle is that caring for the patient does not equal scholarship. Rather, authorship is reserved for people who contribute substantially to the creation of the manuscript.

Conclusion Taking a case from the medical record to a CPS manuscript requires tenacity, leadership, and collaboration. This process is rewarding because it offers the opportunity to simultaneously enhance medical knowledge and clinical reasoning, just like we strive for in our daily practice and teaching.

References 1. Tarter L, Yazdany J, Moyers B, Barnett C, Dhaliwal G. The Heart of the Matter. N Engl J Med. 2013;368(10):944–50. doi:10.1056/ NEJMcps1114207. 2. Keenan CR, Dhaliwal G, Henderson MC, Bowen JL. A 43-yearold woman with abdominal pain and fever. J Gen Intern Med. 2010;25(8):874–7. doi:10.1007/s11606-010-1372-3.

Chapter 11 Submitting a Case Report Manuscript Gabrielle N. Berger and Somnath Mookherjee

Introduction Publishing a case report requires thoughtful selection of an appropriate journal. Historically, case reports were fixtures of many prominent journals. However, this practice has declined significantly over the last several decades as the rise of evidence-based medicine led journals to focus more closely on their impact factor, a measure of the journal’s competitiveness and relevance to the field [1]. In this competitive environment, most traditional journal editors publish only the case reports they feel will resonate most strongly with their audience. In this chapter, we present guidance to help authors successfully navigate the submission process.

Defining the Target Audience The most important first step in selecting a journal for a case report submission is to identify the target audience. Some case reports may be of interest to a generalist audience while others may be more suited for subspecialists or even nonphysician health professionals such as pharmacists and nurses.

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When deciding on the target audience, consider the following: • What are the take-home points of the case report? Who is most likely to incorporate these take-home points into their daily practice? • If the case report focuses on an unusual presentation, who is most likely to see the patient – a primary care physician, an emergency department physician, a surgeon, a hospitalist, a subspecialist? • If the case report focuses on treatment, who is most likely to be administering that therapy? Narrow the search for the most appropriate journals by taking time to define the anticipated audience as clearly as possible. Consider targeting subspecialty audiences even if you have a generalist practice, such as internal medicine, pediatrics, or general surgery. Subspecialty journals may be particularly interested in publishing case reports of rare presentations or unexpected side effects of a treatment that affect their specific patient populations. Furthermore, some specialty journals publish many more case reports than generalist journals. For example, a recent issue of the Annals of Thoracic Surgery published no less than 21 case reports [3]. While the majority of the authors were cardiothoracic surgeons or cardiologists, other specialties represented among the authorship included anesthesiology, radiology, radiation oncology, pulmonary medicine, intensive care medicine, neurosurgery, maternal fetal medicine, obstetrics and gynecology, pathology, hematology, and oncology. When considering submission to a subspecialty journal, it is helpful to request that a colleague in that subspecialty review the case to ensure it will be a good fit for the journal under consideration. If so, you may wish to invite them to be a coauthor to review the submission for clarity, focus, relevance, and accuracy. This co-author may prove particularly helpful in fielding inquiries that come from the editors and other readers.

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Selecting a Journal and Format After considering the target audience, identify the journals in that field with a track record of publishing case reports. Some journals publish case reports in every issue, while others have a recurring (e.g., quarterly) segment devoted to case reports. Before submitting, review recent case reports published by the target journal to ensure the submission resonates with the topics, tone, and format of cases previously published in that journal. If there is any doubt about the appropriateness of the submission, send an inquiry to the journal’s editor prior to submitting. A journal that does not regularly publish case reports may be more likely to do so if the clinical conundrum or syndrome being reported piques the editor’s interest. When submitting a research manuscript, authors commonly aim for journals with a high-impact factor to augment their CV and enhance opportunities for career promotion. While it is valuable to be aware of a journal’s impact factor when submitting a case report, it is more important to identify journals that have a history of publishing this type of work. Submitting to journals that do not accept case reports or only publish case reports from major institutions (such as the Centers for Disease Control or the National Institutes of Health) is unlikely to result in a satisfying outcome for the authors and will delay eventual publication. Many journals have developed unique variations of the traditional case reports in order to be more interesting and relevant to their readership. Clinical challenge cases, mystery cases, novel therapeutic strategies, images in clinical medicine, clinical reasoning papers, and clinical vignettes can all be considered to fall under the general description of “case reports,” but have varying formats. Review the various casereporting options in the journals under consideration to determine the best fit for your case. At the same time, consider the amount of time that you can invest in putting the

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manuscript together. Clinical problem-solving papers require the most time (see Chap. 10). Clinical images take much less time and may better highlight the teaching point of your case.

Predatory Publishers Avoid falling prey to predatory publishers. These are companies and individuals that charge authors large sums to publish their work, often in non-peer-reviewed journals or online forums [4]. In the era of open access information, there has been a proliferation of these types of publications; they are rarely subjected to quality control processes, often are not recognized by academic promotions committees, and publications are rarely listed in reputable databases. Charges for publication can range from as little as $25.00 to as high as a staggering $3,000.00. Authors eager for publication should resist the temptation to engage with these groups and focus instead on respected, peer-reviewed outlets. An increasing number of journals are devoted entirely to publishing case reports. While some of these journals adhere to the accepted peer-review process, many do not. Before submitting to a case report journal, verify whether it is indexed on PubMed and whether it is affiliated with an established subspecialty publication.

Submitting a Case Report Manuscript After choosing the target journal and determining the format for your case, closely review the journal’s guidelines for submission [5]. This can be done by visiting the journal’s website and reading the information listed under author instructions. Verify that your case meets the journal’s criteria for consideration: some journals will only accept submissions that report novel syndromes or disease processes being reported for the first time. Other journals have more liberal criteria, publishing case reports as long as they are educational in some way. Pay

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particular attention to the journal’s requirements on patient consent and permission for use of images. There is usually a limit to the number of authors allowed on a case report; note that a submission may be rejected simply because there are too many authors. When submitting, clearly identify the corresponding author. This is the person whom the journal editors will contact for additional information and clarification on the manuscript. It is not uncommon for a journal’s editorial board to engage in multiple rounds of editing with the corresponding author prior to accepting the manuscript (See Chap. 12 for strategies for responding to peer review). Be sure to strictly adhere to the journal’s guidelines regarding word count and formatting. A manuscript that is not formatted correctly, has spelling or other grammatical errors, or is too long is likely to be rejected without further consideration. Some case report manuscripts may need to be reformatted to fit the section requirements for a particular journal; this work should be done thoughtfully and prior to submission to increase the likelihood of acceptance. Finally, note whether the journal requires inclusion of an abstract.

Conclusion Selecting an appropriate journal for submission is a critical step toward having a case report published in the medical literature. Cast a wide net when considering what types of journals and audiences would be most interested in the clinical question addressed in the case report. Have an open mind when considering the most appropriate format for your submission, balancing what best fits your case and the time you have to invest in the project. Additionally, consider inviting a subspecialty collaborator to make the submission more appealing to subspecialty audiences. Approach the submission process thoughtfully and with a plan for adapting the manuscript as needed to help lay the groundwork for a successful outcome.

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References 1. Thompson PJ, Bs M. How to choose the right journal for your manuscript*. Chest. 2007;132:1073–6. doi:10.1378/chest.07-1340. 2. Warner JO. Case reports–what is their value? Pediatr Allergy Immunol. 2005;16(2):93–4. doi:10.1111/j.1399-3038.2005.00266.x. 3. Oliemy A, Mahesh B, Pathi V. Acute traumatic right to left cardiac shunt. Ann Thorac Surg. 2016. doi:10.1016/j. athoracsur.2016.02.080. 4. Beall J. Best practices for scholarly authors in the age of predatory journals. Ann R Coll Surg Engl. 2016;98(2):77–9. doi:10.1308/ rcsann.2016.0056. 5. McCarthy LH, Reilly KEH. How to write a case report. Fam Med. 2000. doi:10.1136/bmj.327.7424.s153-a.

Chapter 12 The View from the Journal Somnath Mookherjee and Brian J. Harte

Introduction Writing a manuscript is a long, arduous process. At some point, the lead author must decide that the work is finished, and prepare to submit it. The first part of this chapter provides a final checklist to review before proceeding with submission. Even if the guidance offered in Chaps. 7, 8, and 10 is closely followed while writing the case report, the “final” version of the manuscript could almost certainly use a little more polish to maximize the chances of acceptance. While it may feel like the end of a lengthy process, submitting a case report to a journal is usually the beginning of another long journey. Peer review can take months, and responding to peer review can be equally time consuming. Papers often go back and forth between the journal and the authors several times before finally being accepted for publication. The second part of this chapter provides practical guidance to make this process as smooth as possible.

Presubmission Checklist 1. Read the submission guidelines from the journal – again! Make sure that the submission is in compliance with all the journal’s requirements. Even though this was presumably

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done prior to creating the manuscript, there are several reasons to verify the guidelines prior to submitting: • Guidelines may have changed from when the paper was started – many months have passed…. • Double-check the word limits and word counts in the final draft. Otherwise, the automated submission system may reject the paper due to length, requiring lastminute edits and deletions to permit the paper to be submitted. • Trying to shoehorn in a submission NEVER works. For example, if the journal guidelines say that case reports can only be submitted as letters to the editor, trying to sneak it into the journal as a full report will not be successful. 2. Re-read the manuscript from the perspective of the journal’s readership. Case reports may be submitted to several journals before finally being accepted. Verify that the content and teaching points are targeted to the appropriate audience with the original submission and with any resubmission. Editors and reviewers greatly appreciate it when authors have made the effort to create a case report that is relevant and informative for their readers. As discussed in Chap. 11, it is often fruitful to submit case reports to subspecialty journals. A specialized audience is much different than a generalist audience, and unless the manuscript is adjusted accordingly, it will almost certainly be immediately rejected, no matter how interesting the case. 3. Sweep the manuscript for any (accidental) plagiarism. Plagiarism is surprisingly common: a recent systematic review showed that 1.7 % of scientists admitted to having committed plagiarism at least once, and 30 % reported that they knew of at least one colleague committing plagiarismrelated behaviors [1]. One journal reported that 12 % of their medical case report submissions were rejected due to plagiarism [2]. Revisit the manuscript and make sure that all of the prose is original. A common inadvertent source of

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plagiarism is initially “outlining” parts of a manuscript with elements cut and pasted from other sources. Authors plan on rewriting and citing sources later, but with successive drafts, these elements may unintentionally become integrated into the manuscript. If unsure whether a particular turn of phrase was original or copied, try searching for it by pasting into a standard Internet search engine. Limited online plagiarism-check services are also freely available. Journals use more sophisticated plagiarism screeners to detect previously published material. It is critical to eliminate any “borrowed” material before submitting the article. Plagiarism, even if inadvertent, is a major publishing and academic offense. If the journal’s editorial team discovers evidence of plagiarism, the consequences can be severe. 4. Re-read for clarity and flow. “Poor writing” repeatedly emerges as a major reason why journal editors reject papers [3]. This is a disconcerting fact. After all, an immense amount of effort is expended on putting the manuscript together. By the time it is submitted, the manuscript has survived ruthless editing, wordsmithing, and rearranging of sentences and paragraphs. Every change has been tracked, accepted or rejected, and commented upon. As a consequence, the manuscript probably has a certain logic and organization to the authors, but consider how it would read to someone who picks it up for the first time. What may look like a perfectly crafted, albeit lengthy, sentence to an author, with three semicolons and five commas, is more likely an unintelligible quagmire to a reader who has not had 3 months to parse it. Upon this final re-reading, if sections emerge that might benefit from revision – do not submit the paper. It is much preferred to take the time to give a final polish for clarity and flow rather than submitting something that still does not read well. Here are four quick tips to optimize the paper for clarity and flow: • Examine the structure of each paragraph, especially in the discussion. The majority of paragraphs should be in a traditional format: topic sentence, body sentences

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(3-4) supporting the topic sentence, and concluding sentence. • Eliminate unnecessary qualifiers. Look for areas where phrases such as “may want to consider” or “could be indicated” are used in an effort to “hedge your bets.” Wherever possible, rewrite to definitive phrases such as “should consider” and “is indicated.” • Eliminate tangents. Cut out entire paragraphs that are full of well-researched, interesting information, but are not 100 % relevant to the main teaching points of the case. • Have a nonmedical friend or relative read the article – ask them to point out places that are difficult to understand. 5. Revise for active voice. Optimize the “voice” of the manuscript to markedly increase the quality. Take the time to carefully remove examples of passive voice whenever possible; reviewers and editors will be able to tell the difference. Examples: Passive A basic metabolic panel was ordered by the admitting team.

Active The admitting team ordered a basic metabolic panel.

A lumbar puncture was performed by the emergency department provider.

The emergency department provider performed a lumbar puncture.

Magnetic resonance imaging was considered by the neurology consultants.

The neurology consultants considered magnetic resonance imaging.

By then, the patient would have been re-evaluated by the neurologists.

By then, the neurologists would have re-evaluated the patient.

6. Double-check the tenses. Write the case presentation entirely in the past tense. The discussion can include past and present tense as appropriate. Examples:

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Past Case presentation: “The patient presented with 5 days of upper extremity weakness.”

Present Case presentation: “Figure 1 shows the patient’s left foot.” Discussion: “Our case demonstrates the importance of taking a complete review of systems.”

Future Discussion: “The patient will require yearly CT scans for the rest of his life.”

Discussion: “Our case demonstrated the importance of taking a full review of systems.”

Case presentation: “The patient then shows the rash to the physician.” Case presentation: “A CT scan is performed.”

Case presentation: “Figure 1 will show the patient’s left foot.”

7. Eliminate use of the first or second person. Third person is the preferred style in academic writing. In some instances, journals allow the use of first or second person (such as if a discussant is responding to a case presentation in a clinical reasoning manuscript), but this is rare. Examples: First person

Second person Third person

I, me, my, mine, we, us, our, ours

You, your, yours

He, she, it, him, her, his, her, hers, its, they, them, their, theirs

8. Double-check the images. Images can greatly enhance case reports, but poorly presented images can be distracting.

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Take a final look at any included images and verify the following: • The image should be appropriately cropped. For example, if the area of interest is the hand, is it necessary to include the patient’s arm and torso? • Clearly identify the finding of interest. Your readers may not be skilled at interpreting pathology slides or radiology images. Any arrows should be clearly visible and unmistakably indicate the area of interest. • The image resolution should be appropriate. If the image is grainy, it may be best to leave it out.

Responding to Peer Review Most authors enjoy the respite gained by having a manuscript out of their grasp and finally under review by a journal. During this time, it feels like anything is possible. Perhaps, there will be an e-mail waiting in your inbox from the editor stating “Your submission was magnificent! The reviewers were astounded by both the fascinating case and the quality of your writing. We would like to immediately publish it without further revision.” More likely, the message will either be, “Thank you for your submission. Unfortunately, your manuscript is not a good fit for our journal at this time,” or “We would be interested in considering a revised manuscript. The reviewers have made a number of critiques and suggestions. If you would like to revise and resubmit your manuscript, please respond to each of the reviewers’ comments and note all modifications made to your manuscript.” It may not feel like it in the moment, but this second message is actually great news. This means that there is a path to publication, provided a revision is assiduously pursued. The remainder of this chapter describes the steps to effectively respond to a journal’s request for revisions.

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Step 1. Break Down the Critique into Manageable Segments This ensures that every reviewer comment is addressed, which is a critical requirement with the submission of a revised manuscript. Start by creating a chart like the one shown here: Reviewer #, Comment #

Reviewer/editor comments

Authors’ response

Changes made in the manuscript

Sequentially copy segments directly from the review, independently listing distinct issues. Do not edit the reviewers’ phrasing or omit any of the text in the review – this demonstrates that all of the feedback was taken into consideration. Depending on the clarity of the review, in many cases, it is best to keep an entire paragraph intact if it clearly describes a discrete problem with the manuscript. In other cases, multiple concepts may be introduced simultaneously, even in the same sentence. In this case, it is important to dissect the content to individually define the issues and allow for an organized response. For example, a comment from a hypothetical reviewer 1: “Overall, this is an interesting case. However, the case presentation is disorganized, includes too much irrelevant information (the CBC is not necessary), and presents information nonlinearly.” This feedback is best organized as follows: Reviewer #, Comment # R1C1

Reviewer/editor comments “Overall, this is an interesting case.”

R1C2

“However, the case presentation is disorganized …

Authors’ response

Changes made in the manuscript

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Reviewer #, Comment #

Reviewer/editor comments

R1C3

… includes too much irrelevant information (the CBC is not necessary)

R1C4

… and presents information nonlinearly.”

Authors’ response

Changes made in the manuscript

Step 2. Examine the reviewer and editor comments in totality. After the table is populated with all the reviewer and editor comments, look for common issues or themes. If multiple reviewers mention the same issue, it is important to comprehensively address this in your response. A repeatedly mentioned issue almost certainly represents an area of significant weakness in the work. Simultaneously, look for areas of contradiction or disagreement between reviewers. For these issues, the authors must come to consensus on how to respond appropriately.

Step 3. Draft responses and revisions to the manuscripts. Follow these principles to draft your response: A. Never be offended – if the critique was particularly harsh, take a few days to re-establish comportment before beginning the response. B. Recognize the difference between a “request” and a “suggestion.” Revision’s “requests” should almost always be completed if the manuscript is to be resubmitted to the same journal. Most suggestions should also be implemented, but there is more leeway to make and explain a different tack. See below for some examples:

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Requests – almost always implement requested changes

Suggestions – if it is important to the authorship team, it is OK to make a reasoned argument against making suggested changes

Example “requests”

Example “suggestions”

•

The editor specifically requests that a certain change is made. “Please remove all use of the first person.” “Please write out all abbreviations.” “The final diagnosis remains unclear; please revise so that there is no uncertainty regarding the diagnosis.”

•

Editor asks that authors consider a reviewer’s comment but does not state full agreement with the reviewer’s position. “Please note reviewer 2’s concern regarding the accuracy of the diagnosis. Consider providing the lab values that were queried.”

•

Editor highlights a reviewer’s comments and requests that attention is paid to the issue. “Please attend to reviewer 2’s concern regarding the suitability of this case for the journal’s audience.”

•

Reviewer or editor asks authors to consider a revision. “Consider dividing the first paragraph into two separate paragraphs – the first with the ED presentation and the second with the initial work-up.”

• Reviewer or editor highlights a comment as a “major comment” and emphasizes the importance of a revision to strengthen the manuscript. “I strongly suggest revising the manuscript to reflect the actual clinical course of the patient. This is a major issue and will require considerable revision.”

•

Reviewer or editor highlights a comment as a “minor comment” and states “I suggest mentioning the hospital day during the patient’s hospital course; this is a style preference and is at the discretion of the authors.”

C. Resist the temptation to “score points” on the editor or reviewer. It is not difficult to identify inconsistencies and

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errors in reviews and comments from editors. Pointing these out or making subtle slights will not be beneficial to you. For example, instead of saying, “Two reviewers hated the title (and much of the rest of the manuscript) and one reviewer loved it – we decided to keep it as is,” consider something like, “We appreciate that the title elicited strong reactions from the reviewers. After much consideration of other possibilities, we ultimately agreed with reviewer 1 and elected to keep the title unchanged; we felt that the current title best reflected the crux of this case.” D. Use professional and courteous language in phrasing all responses. Be sure to thank the commenter for any positive comments. Acknowledge all concerns, repeating the concern in your response. If reviewer comments have already been previously addressed in an earlier response, simply refer to the comment. See below for examples: Reviewer/ Reviewer #, editor comment # comments R1C1 “Overall, this is an interesting case.” R1C2

“However, the case presentation is disorganized …

Authors’ response We thank the reviewer for the positive comment.

Changes made in the manuscript

We appreciate the reviewer’s concern regarding the overall organization of the case presentation. We have rewritten the case presentation to accurately depict the sequence of events in the order that they occurred.

Case presentation paragraph 1: Removed reference to the CT scan and labs that were obtained later in the hospital stay. Added physical exam and admission labs. Case presentation paragraph 2: Added CT scan and later lab results. Removed physical exam and admission labs.

Responding to Peer Review Reviewer/ Reviewer #, editor comment # comments

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Authors’ response

Changes made in the manuscript

R1C3

… includes too much irrelevant information (the CBC is not necessary)

We appreciate that some of the included labs may be perceived as being irrelevant to the case. We suggest that the admission CBC is quite germane to the case, given the occult bleeding which occurred later in the hospital course. Therefore, we have kept the admission CBC in the case presentation, but moved it to the first paragraph (see R 1 C 2).

No changes.

R1C4

… and presents information nonlinearly.”

Please see response to R 1 C 2.

Please see response to R 1 C 2.

Depending on the journal requirements, the “changes made in the manuscript” column may or may not need to be included in the response. In all cases, some sort of tracking is required to demonstrate changes from the original submission. This can range from using the “track changes” function in Microsoft Word © or bolding all changes in the revision.

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Step 4. Compose a response letter. The key components of the response letter are shown below. Address the letter to the corresponding editor and thank them for considering the manuscript. Explain how the comments are being addressed – either using a table or by sequential listing. Journal of Extraordinary Cases Sophie Snozzcumber, MD, MPH Deputy Editor Re: MS # 1217, Major Revision Dear Dr. Snozzcumber, We thank you for your review of our manuscript entitled “Macrotia in Micronesia.” This manuscript has been substantially revised for your re-consideration. In this letter we respond to the concerns raised by yourself and the reviewers. The first column lists the reviewers’ comments in their entirety, divided by issue addressed. We have attached a revision with changes tracked as well as a clean version. Comments

Response

Reviewer 1, Comment 1 Reviewer 1, Comment 2

We would like to thank the Editor and reviewers for their thoughtful evaluation of our work and insightful comments. We believe that the consequent changes inthe manuscript have made this a stronger work, and we look forward to your review of this revised manuscript. Best regards, Dr. Mary Clonkers, MD

Conclusion Every interesting case report has a home somewhere in the literature. Previous chapters have provided guidance on picking the right case to report, how to write case reports, and where to submit them. Follow the tips in this chapter to complete the process of case reporting and bring your case report home.

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References 1. Pupovac V, Fanelli D. Scientists admitting to plagiarism: a metaanalysis of surveys. Sci Eng Ethics. 2015;21(5):1331–52. 2. Garg A, Das S, Jain H. Why we say no! A look through the editor’s eye. J Clin Diagn Res. 2015;9(10):JB01–5. 3. Pierson DJ. The top 10 reasons why manuscripts are not accepted for publication. Respir Care. 2004;49(10):1246–52.

Chapter 13 It’s Published! Clifford D. Packer

Fifteen Minutes of Fame In 1968, Andy Warhol said: “In the future, everyone will be world-famous for fifteen minutes.” Warhol seems to have anticipated the Internet age, where news blips, video clips, fads, and ideas can go viral in minutes and then disappear from view just as quickly. In May of 2009, I had my 15 minutes of fame when an obscure editorial I had written for a second-tier English medical journal became part of the worldwide medical scare of the week. It started in 2008, when I published a case report about one of my patients with a puzzling case of chronic hypokalemia that I eventually discovered was caused by long-term excessive cola consumption [1].The next year, the International Journal of Clinical Practice (IJCP) contacted me to referee a review article by three Greek doctors that summarized all the known cases of cola-induced hypokalemia, and hypothesized on the pathophysiology of the condition [2]. They also asked me to write an editorial on the subject, which was published a few months later along with the review article [3]. Soon afterward, a London PR firm representing IJCP put out a press release that summarized the review article, and also quoted my editorial comments on the subject. And then, well, things happened very fast. The story spread like wildfire to newspapers, wire services, and health news © Springer International Publishing Switzerland 2017 C.D. Packer et al., Writing Case Reports, DOI 10.1007/978-3-319-41899-5_13

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websites the world over. “Too Much Cola Zaps Muscle Power,” warned the BBC News headline [4]. “Drinking Large Amounts of Cola Can Cause Paralysis, Doctors Warn,” cried the Daily Telegraph [5]. “Mediziner-Warnung: Kola klaut dem Korper Kraft,” trumpeted Der Spiegel [6]. USA Today, ABC News, Reuters, UPI, and newspapers from New York to Glasgow, Myanmar to Melbourne picked up the story and ran with it. “Cola Drinks Up Paralysis Risk,” according to the Fars News Agency of Tehran. In fact, the story was picked up – and I was quoted – in newspapers of Iran, Iraq, and even North Korea! During my VA clinic that afternoon, while I was examining a patient, my office phone rang. It was the press agent working for IJCP, calling from London. She sounded excited, almost frenzied: “Dr. Packer! Your article on cola-induced hypokalemia is white-hot right now! Everybody is picking it up. I just had a call from ABC News in New York – they want to interview you right now.” She gave me the name and phone number of the reporter, and begged me to call them immediately. Perversely, though, I finished seeing my patients and dictating my notes (first things first!), and it was 5 o’clock before I nervously dialed the 212 area code and left a message on the reporter’s voice mail. Alas, the story had already peaked by then, and was on the wane. The half-life of a medical scare like this is measured in hours, not days. She never called me back. Over the next week or two I received one request for an online interview, and several e-mails from people who described their own experiences with cola and low potassium, some of which were dramatic – severe muscle weakness and pain was the common thread. I also received a few e-mails from medical academics, some of whom thanked me for corroborating their nutritional theories, a couple of which were a bit on the wacky side. My editorial also found its way into the Wikipedia article on hypokalemia (see under “other” causes) [7]. Interestingly, the review article and editorial also brought this earnest but somewhat disingenuous press release from the Coca-Cola company (obviously, they consulted an

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expert who knew something about the limitations of case reports): The safety and quality of all our products is paramount and is something we would never compromise. This has been the case since we first began making Coca-Cola more than 120 years ago. The examples used in a paper by the International Journal of Clinical Practice are all extreme cases of chronic consumption (3–9 liters per day). Moderate consumption of cola drinks is safe and people can continue to enjoy such drinks as part of a sensible, balanced diet and active lifestyle. The foundation of good nutrition is balance, variety and moderation. This paper is a review – it is not scientific research (ie, clinical study) and is an insufficient basis to claim cola consumption causes hypokalaemia. The reported cases of hypokalaemia were associated with persistent consumption of unusually large quantities of cola drinks, which does not represent typical cola soft drink consumption pattern among consumers. Furthermore, the authors speculate that moderate quantities of caffeine (180–360 mg) may result in hypokalaemia. The observation is not supported by any well-designed clinical study. We market our products in a responsible manner and have taken a leading role to provide fact-based nutrition and health information for all our products. We believe providing fact-based nutrition and health information for all our products, supported by effective consumer messaging and education programs, will help empower people to select sensible, balanced diets and become more physically active [8].

It turns out that heavy cola consumption is not rare. An analysis of data from the National Health and Nutrition Examination Survey (NHANES) shows that about 5–10 % of US teenagers and adults consume at least 2 l of cola or other sugary drinks per day [9]. Also, I have yet to see how CocaCola is empowering people to “select sensible, balanced diets and become more physically active.” I am happy to report, however, that real progress has been made in removing their products from US schools in an effort to reduce childhood obesity. In 2010, a New Zealand woman died from cola-induced hypokalemia after years of heavy consumption, and there was another brief tabloid storm, which soon blew over. However, there has been a steady trickle of case reports of

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profound hypokalemia and myopathy from excessive cola consumption, some of which I have been asked to referee. The case report and review published by Sharma and Guber in 2013 is particularly interesting and well-written, and makes a strong case that excessive cola consumption should be considered in the differential diagnosis of hypokalemia [10]. This awareness could reduce morbidity and perhaps even save some lives. I am more than happy to have retreated back into well-deserved and comfortable anonymity, but it is gratifying to see that cola-induced hypokalemia is becoming a “known” condition, and that this knowledge is permanent and will not go away. This story shows how a case report can lead to a peer review request, an invited editorial, a press release, a worldwide media frenzy, corporate damage control, and new awareness among physicians of a potential problem. This may not be the typical course for a case report, but it does happen.

Peer Review Opportunities When your case report is published, you may be contacted by a journal editor and asked to serve as a referee. If the case report you review is especially interesting or controversial, and you write a thoughtful appraisal, you may also be invited to write an editorial or commentary on the case. At that point, even if the case report and editorial do not go viral, you will have demonstrated expert knowledge in the field. This can lead to more requests for reviews and more editorializing. Peer review can thus be a way to expand one’s range of expertise and influence. As a direct result of my own published case reports, I have been invited to referee case reports and research articles for a broad range of journals, on topics including nutrition, pharmacology, toxicology, oncology, diabetes research, rheumatology, and hematology. Polymaths excepted, very few authors are called upon to referee in so many disciplines.

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I am certainly no polymath; I see myself simply as a generalist who likes to write case reports and investigate new and interesting topics. The impulse to write case reports arises from a love of variety, which is what motivates many of us to become generalists in the first place. For authors of case reports, participation in peer review stimulates academic growth and sharpens critical insight, while at the same time helping to uphold the validity and integrity of the editorial process and improve the quality of published papers. Other benefits, in addition to invitations to write commentaries or editorials, may include CME credit (offered by some journals) and increased consideration for academic promotion. Several authors have commented on the peer review process and how to referee a scientific paper [11, 12, 13]; for case reports, as opposed to research articles, the referee should consider these five specific questions: 1. Is the case description clear and concise, and does it include all essential clinical and clinimetric data? 2. Is there a satisfactory literature review? 3. Is the case placed in context – does the author compare it with other similar cases and convey what is rare, interesting, or unique about it? 4. Is there a plausible and convincing hypothesis to explain the clinical event? 5. Is there some discussion of the clinical implications of the case? When I refereed case reports of cola-induced hypokalemia, metformin-associated lactic acidosis, and vertebral sarcoidosis, I was able to suggest changes in one or more of the above areas that led to significant improvements in the manuscripts and, in some cases, to publication. I also discovered many things – such as little-known references, alternative mechanisms of disease, and previously unconsidered hypotheses and speculations – in the process of reviewing each paper. Peer review, it seems, can be a compelling scholarly experience, and well worth the (uncompensated) effort.

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For medical students, residents, and practicing physicians who do not participate in formal research, publishing case reports can allow access to the unique responsibilities and enrichments of peer review.

Editorial Writing Opportunities There are three main pathways to writing editorials for medical journals. The first is by direct invitation from the journal editor, which is generally reserved for top experts in the field. The second is to contact the editor and ask about submitting an unsolicited editorial; this approach is seldom successful. The third pathway, as discussed above, is through peer review. Some journals ask peer reviewers directly: “Would you be willing to write an editorial on this subject?” Other journals may not solicit editorials openly, but a thoughtful referee who brings out the interesting implications of a paper may very well be invited to write more about it. When I reviewed the cola-induced hypokalemia article by Tsimihodimos et al. [2], I commented on the possible adverse effects of low potassium in a population of heavy cola consumers with cardiovascular disease. This point was then taken up by the authors in the final version of their paper, and I raised it again in my invited editorial [3]. Journal editors like this sort of speculation, provided that it has some basis in fact and passes the plausibility test. An editorial on the findings of a case report or case series should be both provocative and circumspect. While the potential implications of the case can be explored, the author should avoid unsupported speculations and conclusions. In my editorial, I summarize the points in favor of the argument that chronic, heavy cola consumption can cause hypokalemia: In their review of cola-induced hypokalaemia, Tsimihodimos et al. make a compelling argument that potassium depletion should be added to the long list of soft drink-related health problems. In the cases they describe, chronic consumption of 3–10

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liters of sugar-sweetened cola per day led to severe hypokalaemia, hypokalaemic myopathy, and in some cases, hypokalaemic paralysis. One patient developed hypokalaemic nephropathy and subsequent nephrogenic diabetes insipidus. In all cases, the patients’ symptoms improved, and the hypokalaemia resolved with potassium repletion and reduction or cessation of cola drinking. [3]

Another useful function of an editorial is to discuss pathophysiology and evaluate the proposed mechanisms of the disease: The proposed mechanisms of cola-induced hypokalaemia run practically the whole gamut of electrolyte physiology. First, the large glucose load can cause both an osmotic diuresis, with increased renal potassium wasting, and hyperinsulinaemia, causing intracellular redistribution of potassium. Second, drinks containing large amounts of high-fructose corn syrup send boluses of largely indigestible fructose into the GI tract, which causes potassium wasting via an osmotic diarrhea. Third, caffeine has been shown to cause beta adrenergic stimulation, increase Na+/K + -ATPase via cellular phosphodiesterase inhibition, and produce metabolic alkalosis, diuresis, and increased renin levels, all of which may contribute to hypokalaemia…Soft drinks that combine large amounts of high-fructose corn syrup with caffeine, such as regular colas, might deplete potassium stores more effectively because of concurrent osmotic and caffeine-mediated potassium wasting. With his 4 liter per day Pepsi-Cola habit, my patient was ingesting 396 g of fructose, enough to cause a chronic low-grade osmotic diarrhea, and 400 mg of caffeine, the equivalent of about 7 cups of coffee. [3]

Finally, the editorialist should avoid, in the words of Samuel Johnson, “the conclusion, in which nothing is concluded” [14]. Make the points that can reasonably be made, touch on the broader implications, and end with an aphorism: In addition to the usual questions about alcohol, tobacco, and illicit drug use, internists need to start asking their adult patients about soft drink consumption. Cola drinks need to be added to the physician’s checklist of drugs and substances…that can cause hypokalaemia. More work is needed on the epidemiology of cola consumption, hypokalaemia, and cardiovascular disease. Finally, the soft drink industry needs to promote safe and moderate use

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of its products for all age groups, reduce serving sizes and pay heed to the rising call for healthier drinks. The tale of the thirsty kangaroo hunter reminds us of the wisdom of Aristotle: “In all things, moderation.” [3]

Article Indexing Those of us who are old enough to remember searching through the old Index Medicus (a gigantic tome that was hard to lift and continually out of date) have a great appreciation for PubMed and Google Scholar. PubMed is a service of the US National Library of Medicine that provides free online access to the MEDLINE database of indexed citations and abstracts to medical, nursing, dental, veterinary, health care, and preclinical science journal articles. Google Scholar is an online, freely accessible search engine that allows users to search the scholarly literature in all fields. Most PubMedindexed articles are peer-reviewed, and PubMed-indexed journals must pass a rigorous review for scope and coverage, quality of content, quality of editorial work, production quality, and intended audience [15]. As compared with PubMed, Google Scholar searches tend to be broader and less specific; they contain more “gray literature” such as conference proceedings, theses, book chapters, and other non-peer-reviewed articles. Although Google Scholar searches may return twice as many relevant articles [16], PubMed searches appear to be more practical for evidence-based patient-care protocols, for guiding the care of individual patients and for educational purposes [17]. Most authors prefer to publish in PubMed-indexed journals, in the belief that their articles will receive more citations and the prestige of PubMed indexing will help with academic promotion. Case reports can be more difficult than other article types to publish in indexed journals, especially with editorial concerns about the negative effects of case reports on the all-important impact factor. However, with careful journal selection and judicious use of indexed case report

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journals, such as the Journal of Medical Case Reports, Case Reports in Medicine, and BMJ Case Reports, the increased exposure and prestige of PubMed indexing should be possible for most case reports. Fifteen of the 18 case reports I have authored or co-authored since 2005 are published in PubMedindexed journals.

Publication Analytics and Social Media Publication analytics can include citations, views, downloads, web analytics, and multisource metrics such as Altmetric and ResearchGate scores. Publication analytics measure attention, not quality; articles can receive attention for many reasons, not all of which are positive. Self-citation may also swell citation counts and popularity scores. However, analytics can tell us a number of useful things: who is citing our articles, how many are reading and discussing them, and what part of the world they are from. Case reports are cited less than other types of medical studies. Patsopoulos et al. reviewed the citation rates of various study designs in 2001 and found that <1% of case reports had ≥10 citations within 2 years of publication, as opposed to 43.6% of meta-analyses, 29.5% of randomized controlled trials, and a range of 10–25% for other study designs [18]. Bhandari et al. had similar results in a study of citations in the orthopedic literature over a 3-year period, with meta-analyses, randomized trials, basic science articles, and case reports receiving 15.5, 9.3, 7.6, and 1.5 citations, respectively [19]. The low early citation rate for most case reports probably reflects a fundamental difference in the evidence function of case reports as opposed to randomized controlled trials and meta-analyses. While some case reports of unexpected therapeutic success (such as dramatic responses to cancer treatment) may receive much attention and many citations early on [20], most case reports describe rare or solitary events which may or may not recur in future patients. They serve as a permanent record of the unusual, and only sometimes –

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when clusters of similar cases begin to appear – as harbingers of a new disease, syndrome, or significant adverse drug reaction. Thus, it is not surprising that many case reports are hardly cited at all, or pick up citations gradually over the years as events unfold. Meta-analyses and randomized controlled trials, on the other hand, tend to make a splash early as they report significant findings or trends with immediate implications. This explains their high initial citation rates. In my own case reports, citations tend to accumulate gradually over time. Of the 18 case reports published since 2005, 13 have been cited, with a total of 77 citations (range 1–20, average 5.9 citations per case report). Three of the 18 case reports (17%) now have ≥10 citations, and one, published in 2005, has 20. In general, at least 70–80 % of the citations have come more than 2 years after publication, and citations have continued to accrue steadily – over 5–9 years in several cases. I strongly suspect, based on an unscientific sampling of other case reports in addition to my own, that this slow and gradual pattern of citation is the norm for case reports. In comparing case reports with other types of research articles, then, it might be more reasonable to use 10-year rather than 2–3 year citation rates. Be patient, case report authors! In addition to citation rates, other metrics such as “accesses,” “views,” “reads,” and “downloads” are commonly available on both journal websites and research scoring sites such as Altmetric and ResearchGate. Several authors have found a strong positive correlation between early Internet “hits” or downloads and subsequent citation rates [21, 22]. Perneger hypothesizes that scientific value explains the association between hits and citations, and concludes that “the number of early hits is a potentially useful measure of the scientific value of published medical research papers” [22]. For case reports, considering that they deal with practical patient management in the real world of medicine, hits may be more important than citations as a measure of impact. The high ratio of hits to citations for case reports seems to support this premise. Consider the numbers for

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three of my own open-access case reports: 6484 accesses/10 citations [1], 8337 accesses/9 citations [23], and 2080 accesses/4 citations [24]. This comes to 500–900 accesses for every citation, which suggests not only that people like reading case reports, but that many must be reading them (we hope!) for practical reasons such as education and better clinical care. Altmetric is a system that tracks, collects, and collates the attention that scholarly articles receive online, and presents the data on a single web page. It gathers data from three main sources: social media (Twitter, Facebook, Google+, Pinterest, and blogs), traditional media (both mainstream and sciencespecific), and online reference managers such as Mendelay and CiteULike. The data are organized by category, and an Altmetric score is generated that purports to measure both the quantity and quality of the online response [25]. ResearchGate is a similar service that tracks reads and downloads, and generates an “RG Score” based on both the publications in an author’s profile, and how other researchers interact with that author’s content [26]. For case report authors, these systems can give insight into the ongoing response to one’s work, irrespective of citations. For example, over the past week, I know from my ResearchGate page that seven of my case reports have been read or downloaded a total of 19 times; eight of the readers were from Brazil, five from the United States, four from Russia, and one each from China and the Philippines [27]. While the practical utility of this information is unclear in terms of promotion or career advancement, it is certainly good for morale to know that people around the world are reading one’s case reports.

References 1. Packer CD. Chronic hypokalemia due to excessive cola consumption: a case report. Cases J. 2008;1(1):32. 2. Tsimihodimos V, Kakaidi V, Elisaf M. Cola-induced hypokalaemia: pathophysiological mechanisms and clinical implications. Int J Clin Pract. 2009;63(6):900–2.

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3. Packer CD. Cola-induced hypokalemia: a super-sized problem. Int J Clin Pract. 2009;63(6):833–5. 4. BBC News. Too much cola zaps muscle power. http://news.bbc. co.uk/2/hi/health/8056028.stm. Accessed 5 Mar 2016. 5. The Telegraph. Drinking large amounts of cola can cause paralysis, doctors warn. http://www.telegraph.co.uk/news/science/ science- news/5350530/Drinking-large-amounts-of-cola-cancause-paralysis-doctors-warn.html. Accessed 5 Mar 2016. 6. Spiegel On Line. Mediziner-Warnung: Cola klaut dem Körper Kraft http://www.spiegel.de/wissenschaft/mensch/medizinerwarnung-cola-klaut-dem-koerper-kraft-a-625807.html. Accessed 5 Mar 2016. 7. Wikipedia. Hypokalemia. https://en.wikipedia.org/wiki/ Hypokalemia. Accessed 5 Mar 2016. 8. Coca-Cola Company Statements. Statement on cola-induced hypokalemia. http://www.coca-colacompany.com/press-center/ company-statements/statement-on-cola-induced-hypokaleaemia/. Accessed 5 Mar 2016. 9. Packer CD. Letter to the editor: reply. Int J Clin Pract. 2009;63(10):1545–6. 10. Sharma R, Guber HA. Cola-induced hypokalemia – a case report and review of the literature. Endocr Pract. 2013;19(1): e21–3. 11. Pyke DA. Writing and speaking in medicine. How I referee. Br Med J. 1976;2(6044):1117–8. 12. Neill US. How to write an effective referee report. J Clin Invest. 2009;119(5):1058–60. 13. Ajao OG. Peer review and refereeing in medicine and medical sciences. Saudi J Gastroenterol. 1997;3:107–12. 14. Johnson S. The Works of Samuel Johnson, vol. 7. Troy: Pafraets Press; 1903. p. 156. 15. US National Library of Medicine Fact Sheet. MEDLINE Journal Selection. https://www.nlm.nih.gov/pubs/factsheets/jsel. html#. Accessed 20 Mar 2016. 16. Shariff SZ, Bejaimal SA, Sontrop JM, et al. Retrieving clinical evidence: a comparison of PubMed and Google Scholar for quick clinical searches. J Med Internet Res. 2013;15(8):e164. 17. Anders ME, Evans DP. Comparison of PubMed and Google Scholar literature searches. Respir Care. 2010;55(5):578–83. 18. Patsopoulos NA, Analatos AA, Ioannidis JP. Relative citation impact of various study designs in the health sciences. JAMA. 2005;293(19):2362–6.

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19. Bhandari M, Busse J, Devereaux PJ, et al. Factors associated with citation rates in the orthopedic literature. Can J Surg. 2007;50(2):119–23. 20. Nieder C, Pawinski A, Dalhaug A. Contribution of case reports to brain metastases research: systematic review and analysis of pattern of citation. PLoS One. 2012;7(3):e34300. 21. Deciphering citation statistics. Nat Neurosci. 2008;11(6):619. 22. Perneger TV. Relation between online “hit counts” and subsequent citations: prospective study of research papers in the BMJ. BMJ. 2004;329(7465):546–7. 23. Packer CD, Hornick TR, Augustine SA. Fatal hemolytic anemia associated with metformin: a case report. J Med Case Rep. 2008;2:300. 24. Chiang E, Packer CD. Concurrent reactive arthritis, Graves’ disease, and warm autoimmune hemolytic anemia: a case report. Cases J. 2009;2:6988. 25. Altimetric score. https://help.altmetric.com/support/solutions/ articles/6000059309-about-altmetric-and-the-altmetric-score. Accessed 25 Mar 2016. 26. RG Score. A new way to measure scientific reputation. https:// www.researchgate.net/publicprofile.RGScoreFAQ.html . Accessed 25 Mar 2016. 27. ResearchGate Stats. https://www.researchgate.net/profile/ Clifford_Packer/stats. Accessed 25 Mar 2016.

Chapter 14 The Future of the Case Report Clifford D. Packer

When evidence-based medicine purists raise the argument that case reports are a weak form of evidence, I recall an old joke from one of my college philosophy courses. A logical positivist bought his fiancée a ring. When he presented it to her, she broke into tears. “It’s not engraved, dear – can’t you have it engraved?” “Certainly,” he replied and rushed back to the jeweler, had the ring engraved, and raced back to give it to her. On looking at it, to the astonishment of the logical positivist, she again began to sob inconsolably. “What on earth is wrong?” asked the logical positivist. “I had it engraved exactly as you asked.” Of course, as you may have guessed, it was engraved with the word: “Ring.” Now think of the logical positivist as evidence-based medicine; his fiancée is the individual patient, and the ring is the proposed treatment. The ring was engraved correctly based on strong empiric evidence that it was indeed a ring; the personal touch, however, was sorely lacking. In a future where the demand for personalized medicine will almost certainly increase, the case report – or aggregations of case reports – will play an increasingly important role in delivering care that fits the characteristics of the individual patient. In this book, we have discussed how the case report can be used in hypothesis-generation, identification of new syndromes, pharmacovigilance, and as evidence for patient care decisions when randomized trials are unavailable. We have © Springer International Publishing Switzerland 2017 C.D. Packer et al., Writing Case Reports, DOI 10.1007/978-3-319-41899-5_14

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touched on ways in which case reports can serve in personalized medicine, such as n-of-1 trials and genomic studies of outlier cancer survivors. These trends will undoubtedly continue. In addition, we will see increasingly broad and innovative uses of aggregated case reports, patient registries, and other clinical databases. It has been estimated that our current databases collect only about 20 % of the data contained in medical texts[1]; case reports “represent an enormous potential reservoir of knowledge that is largely untapped at the present time” [2]. As our data-mining and biometric technologies improve, case reporting will begin to merge with population medicine and population health. Aggregation of case reports will help us to collect usable evidence in patients with multiple chronic conditions, such as diabetes, hypertension, COPD, heart failure, and cancer, where the interplay of disease and treatment variables is too complex to be studied with randomized controlled trials. As Jonathan Teich has said: The sweet spot is where there are variations and unknowns. While we know how to treat COPD patients, there may be answers contained in populations about how the disease affects certain demographics. Using a large population lets you mine for that information. You can ask a lot of questions of that data and find something you weren't looking for. [1]

Potential roles for case report databases could include investigating the interdependence of sequential events; assessing the efficacy of various treatment schedules, doses, and regimens; evaluating concomitant or causal comorbidities; and improving our contingency decision-making in complex patients, using real-life examples [3]. Eventually, as electronic data collection grows more and more pervasive, I expect that every patient encounter will become a de facto case report, in the sense that every encounter will contribute real-time data to a massive database. At the same time, information will flow from the database back to the physician to support clinical decision-making at the point of contact. More cases, more data; more data, better care. Because they capture novelty and innovation, case reports tend to flourish at the cutting edge of new technologies.

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Consider a recently published case report by Rudner et al. in Annals of Emergency Medicine, “Interrogation of patient smartphone activity tracker to assist arrhythmia management”[4]. In this case, it was determined that a patient with new atrial fibrillation was safe for immediate cardioversion when examination of his wrist activity tracker revealed that the arrhythmia had occurred within the past 3 hours. The patient was safely and successfully cardioverted in the emergency room. This was the first reported use of the information in a smartphone activity-tracking system to assist in specific medical decision-making. The case report received extensive media coverage, including a story on National Public Radio [5]. Another exciting new technology is the “liquid biopsy,” where blood testing for circulating tumor DNA (ctDNA) shows great promise as a tool for diagnosing cancer, identifying mutations to guide treatment, detecting relapses, and exploring mechanisms of tumor resistance, while allowing cancer patients to avoid painful and invasive biopsies [6]. Case reports and case series will play an important role in developing clinical applications for ctDNA testing. For example, a recent case report describes the use of ctDNA multiplex genotyping in a patient with metastatic non-small cell lung cancer and rapidly progressive liver metastases. The test identified a novel ALK translocation as the mechanism of tumor resistance, without the need for a risky liver biopsy [7]. The patient then had excellent clinical responses to two different ALK inhibitors. We should expect to see many more such case reports highlighting new technologies in the coming decades. What will case reports look like in the year 2050? Will Cherenkov radiation and nanoparticle imaging be the standard of care? Will 3D holograms replace the routine chest X-ray? And will genomic profiling be as easy and accessible as ordering a CBC? Whatever technologies evolve, case reports will be there at the forefront, and I hope – and expect – that the basic form and function of the case report will not change. However compelling the image, however powerful the technology, we must put the case in context, explain it, and find out what it has to teach us.

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References 1. Healthcare IT News: populations hold key to future medicine. http://www.healthcareitnews.com/news/populations-hold-keyfuture-medicine. Accessed 29 Apr 2016. 2. Jackson D, Daly J, Saltman DC. Aggregating case reports: a way for the future of evidence-based health care? Clin Case Rep. 2014;2(2):23–4. 3. Kidd MR, Saltman DC. Case reports at the vanguard of 21st Century medicine. J Med Case Rep. 2012;6:156. 4. Rudner J, McDougall C, Sailam V, Smith M, Sacchetti A. Interrogation of patient smartphone activity to assist arrhythmia management.Ann Emerg Med.2016.pii:S0196-0644(16)00143-148. [Epub ahead of print]. 5. A Fitbit Saved His Life? Well, Maybe. http://www.npr.org/ sections/health-shots/2016/04/11/473393761/a-fitbit-saved-hislife-well-maybe. Accessed 30 Apr 2016. 6. Chi KR. The tumour trail left in blood. Nature. 2016;532:269–71. 7. Liang W, He Q, Chen Y, Chuai S, Yin W, Wang W, et al. Metastatic EML4-ALK fusion detected by circulating DNA genotyping in an EGFR-mutated NSCLC patient and successful management by adding ALK inhibitors: a case report. BMC Cancer. 2016;16:62.

Index

A ACP. See American College of Physicians (ACP) Acquired immune deficiency syndrome (AIDS), 5, 16, 35, 45, 91, 106 Acquired immunity, 11 Adverse drug reaction (ADR) case report azathioprine hypersensitivity, 101 dose related/augmented type, 97 drug interaction case reports, 99 iatrogenic Cushing’s syndrome, 101 mechanism of reaction, 101 Naranjo scale, 98, 100 patient’s platelet counts, 99 pharmacovigilance, 97 postmarketing surveillance, 98 quality and clinical usefulness, 102 ritonavir and oral budesonide, 101–102 timeline, 98 Adverse events, 45 Aequanimitas, 15 AIDS. See Acquired immune deficiency syndrome (AIDS)

Airway obstruction, 23–24 Altmetric score site, 179–181 American College of Physicians (ACP), 28, 122, 124 Annals of Thoracic Surgery, 152 Antimicrobial therapy, 25, 26 Aphorisms, 10 Atenolol, 2, 3 Authorship responsibilities, 59–61 Automated submission system, 158 Autopsy, 13, 14

B Bartter’s syndrome, 108 Behcet’s syndrome, 29 British Medical Journal (BMJ), 54, 56, 57, 179

C Canadian Medical Association Journal (CMAJ), 110 Cannabinoid hyperemesis syndrome, 28, 66 Career enhancement, 39–40 Case presentation, 67, 68, 72, 163 CAse REport (CARE) guidelines, 18–19, 36, 93

© Springer International Publishing Switzerland 2017 C.D. Packer et al., Writing Case Reports, DOI 10.1007/978-3-319-41899-5

189

190

Index

Case reports abstract, 67–69 aggregations of, 185 in ancient and medieval times Chinese case reports, 12 diabetes mellitus, ancient Hindu text on, 9 Egyptian medicine, 9–10 European case reports, 12 Galen’s On the Affected Parts, 11 Hippocratic case histories, 10 Rhazes, case histories of, 11–12 authorship responsibilities, 59–61 brevity, 70 CARE checklist, 93 career enhancement, 39–40 CARE guidelines, 18–19, 93 case description clinimetrics, 71 diagnostic assessment, 75 Duke criteria score, 72 essential elements, 72 laboratory test results, 74 physical examination, 74 prescribed medications, 73 serum potassium values, 73 clinical decision-making, 186 clinical presentation, 69 cola-induced hypokalemia, 3 context of acute obstructive suppurative pancreatic ductitis, 82–83 advanced search tool, 80 clinical presentation and bacteriology, 84 clinical setting, 80 direct Coombs test, 80 literature review, 80 metformin-induced hemolytic anemia, 81 ctDNA testing, 187 data-mining and biometric technologies, 186

discussion, 77, 79, 80 effective and succinct introductions, 70–71 electronic case report journals, 18 evidence-based medicine, 185 evidence value of, 4–5 form and function, in twenty first century, 6–7 future case reports, 18 hypothesis development aggressive gastric carcinoma, 89 hemangiomas, 85 lithium toxicity, 87 plausibility (and publishability), 88 propranolol, 85 steps in, 86 supposition/proposed explanation, 84 TCMA, 87, 88 TIA mimics, 87 Warburg effect, 89 watershed zones, 88 images and data collection, 58–59 impact of, 5–6 informed consent to publication BMJ Case Reports, 54, 56, 57 ICMJE, protection of privacy, 55–56 just write something, 61–62 liquid biopsy, 187 medical literature, 34–36 medical students and residents, 38–39 modern case report, origins of Charcot’s case report, 14 heart disease, distressing effects of, 14 Osler’s interspecies case report, 14–16 Parkinson’s Essay on the Shaking Palsy, 13–14

Index Pomata’s Observationes, 12–13 syphilitic abdominal aortic aneurysm, 15 Warren’s Remarks on Angina Pectoris, 13 patient care, 37–38 personalized medicine, 185, 186 population medicine and health, 186 as “reports from the frontline,” 5 speculation, 90–91 teaching point, 91–92 timeline, 75–77, 79 title, 65–66 in twentieth century, 16–17 vibrato, atenolol effects on, 2–3 Case Reports in Medicine, 179 Case series case-control studies, 105 childhood Bartter’s syndrome, 108 comparison table, 107 cross-sectional studies, 106 disadvantages, 106 immune suppression hypothesis, 106 limitations of, 109 MMR vaccination, 106 “Patients and Methods” section, 107 pneumonia and Kaposi’s sarcoma, 106 statistical analysis, 105 teaching points, 108 Cellulitis, 10 Centers for Disease Control (CDC), 35, 45, 153 Chen Hue, 12 Chinese case reports, 12 Circulating tumor DNA (ctDNA), 187 CiteULike, 181 Claudication, 14–15

191

“Clinical images” article, 109–111 Clinical problem solving (CPS) manuscript case discussion construction, 139–144 aliquots, 139–140 antiphospholipid syndrome, 143 arthralgias, 141 commentary section, 144 embolic phenomena, 142 extemporaneous thinking, 139 invasiveness and adherence, 143 magnetic resonance imaging, 142, 144 nephrotic syndrome, 143 next-to-last aliquot, 140 patient’s progressive dyspnea, 140 reported problems duration, 140 specialty-level inquiries, 144 symptoms and history, 142 teaching points, 144 transesophageal echocardiography, 142 case protocol construction, 138–139 case selection, 135–136 clinical reasoning clinical information, 145 clinician, 146 diagnostic reasoning, 146 JGIM ECR, 145 problem representation, 147 clinical teaching points authorship, 150 final author, 150 final steps, 148–149 first author, 149 middle authors, 149 manuscript writing, 140 planning stage, 136–137

192

Index

Clinical quiz/mystery image antimicrobial susceptibility testing, 115 vs.clinical images, 116–117 post-intubation tracheal stenosis, 112, 113 subspecialty journals, 115 teaching points, 114 tracheal stenosis case, 115 “When Asthma is Not Asthma,” 112 Clinical vignette abstracts academic style of writing, 124–125 case description, 123 chief complaint, 125 clinical encounter, 125–126 focused discussion case report authors, 131 key points, 132 teaching points, 131–132 lab values, 127–128 learning objectives as actions, 129–130 important lessons, 129 lengthy and run-on sentences, avoiding, 126–127 objective data, 127 opening sentence, 123–124 peer review of, 122 physical examination findings, 126 relevant examination findings, inclusion of, 127 reporting data, 129 section headings, 126 site of care, 125 tests, 128 unnecessary information, avoiding, 128–129 word limits/style, 123 Cola-induced hypokalemia, 3, 86, 90, 171–177 Collaborative writing, 27 CONSORT guidelines, 35 Coombs test, 68, 71

D Data Protection Act, 57 Diabetes mellitus, 9, 68, 70 Drug Interaction Probability Scale (DIPS), 99 Duke criteria score, 72

E Early warning system, 90 Ebers papyrus, 9 Ebola virus, 5, 25, 26 Ebstein’s anomaly, 29 Editorial writing, 176–178 Educational benefits of reading case reports Ebola virus infection, 25, 26 infectious mononucleosis, 23–25 prostate cancer, metastatic, 26–27 “recognition patterns,” 26 of writing case reports for medical students and residents, 27–29 for practicing physicians, 30 Egyptian medicine, 9–10 Egyptian papyrus, 9–10 Electronic case report journals, 18 Epidemics, 7, 10 Essay on the Shaking Palsy, 13–14, 45 European case reports, 12 Evidence-based medicine, 17, 34–37, 185 Exceptional Responders Initiative, 104

F Fetal microcephaly, 5 Foot infection, 10

G Galen, 11 Genomic sequencing, 6–7

Index Glasgow Coma Scale, 72 Google Scholar, 178

H Heart disease, 14, 90, 98 Hippocrates, 10, 11, 91 History of present illness (HPI), 139 Hypertension, 2, 3, 66, 73, 92, 101 Hypokalemia, 3, 65, 70, 73–75, 86, 90, 92, 101, 108, 171–176

I ICMJE. See International Committee of Medical Journal Editors (ICMJE) IJCP. See International Journal of Clinical Practice (IJCP) Index Medicus, 178 Infectious mononucleosis, 23–25 Informed consent BMJ Case Reports, 54, 56, 57 ICMJE, protection of privacy, 55–56 Intermittent claudication, 14, 15 International Committee of Medical Journal Editors (ICMJE), 55–56, 60 International Journal of Clinical Practice (IJCP), 171, 173 Interspecies case report, 14–16 Islamic medicine, 11–12

J Journal of General Internal Medicine (JGIM), 47, 137, 145 Journal of General Internal Medicine “Exercises in

193

Clinical Reasoning” series (JGIM ECR), 145 Journal of Hospital Medicine (JHM), 137 Journal of Medical Case Reports, 179 Journal of Paediatrics and Child Health, 54

K Kissing tonsils, 23, 24 Klebsiella pneumoniae, 115

L Lectures on Literature, 3 Left upper quadrant (LUQ) abdominal pain, 145, 146 Leg claudication, 15 Liquid biopsy technology, 187 Lusitanus, Amatus, 12

M Manuscript review presubmission checklist active voice, revise for, 160 clarity and flow, re-reading for, 159–160 double-checking images, 161–162 double-checking tenses, 160–161 first/second person usage, elimination of, 161 plagiarism, 158–159 re-reading manuscript, 158 submission guidelines, 157–158 revised manuscript critical requirement, 163–164 draft responses and revisions, 164–168

194

Index

Manuscript review (cont.) reviewer and editor comments, 164 Manuscript submission process abstract, 155 journal and format selection, 153–154 journal’s guidelines, 154 predatory publishers, 154 section requirements, 155 target audience, 151–152 word count and formatting, 155 Measles, 11, 106 Measles, mumps and rubella (MMR) vaccination, 106 Medical literature CARE guidelines, 36 CONSORT guidelines, 35 evidence-based medicine, 34–36 PRISMA, 35 Medical students, case reports for, 27–29, 38–39 Mendelay, 181 MeSH database, 80 Metformin-associated lactic acidosis, 175 Morbidity and Mortality Weekly Report (MMWR), 35, 45

N Naranjo Adverse Drug Reaction Probability Scale, 72 National Health and Nutrition Examination Survey (NHANES), 173 National Institutes of Health, 153 New England Journal of Medicine (NEJM), 109–110, 137, 140 N-of-1 trials anecdotal cases, 103 clinical decision-making, 105 “imprecision medicine,” 103 individual patients, 102

phenotypic monitoring devices, 104 prazosin, 104 RCTs, 103

O Observationes, 12 Onchocerca lupi infection, 35 Online case report journals, 18 Online reference managers, 181 On the Affected Parts, 11 Open-access electronic case report journals, 18 Osler, William, 14–16, 30

P Parasite-derived cancer cells, 16 Parkinson, James, 13–14, 45 Past medical history (PMH), 139 Patient care, 37–38, 45, 67, 185 Peer review process, 1, 2, 18, 27, 122, 154, 162–168, 174–176 Pharyngeal airway obstruction, 23, 25 “Phenotypic” monitoring devices, 7, 104 Pneumocystis pneumonia, 35, 45 Pomata, Gianna, 12–13 Presubmission checklist active voice, revise for, 160 clarity and flow, re-reading for, 159–160 double-checking images, 161–162 tenses, 160–161 first/second person usage, elimination of, 161 plagiarism, 158–159 re-reading manuscript, 158 submission guidelines, 157–158 PRISMA, 35 Prostate cancer, 26, 28 Publication analytics, 179–181

Index Publication criteria, case reports adverse events, 45 categories of, 46 characteristics, 44–45 medical science, contribution to, 46 modified five-question algorithm, 47–49 reflection/perspective pieces, 45–46 treatment, 47 Published case reports article indexing, 178–179 chronic hypokalemia, 171 editorial comments, 171 editorial writing opportunities, 176–178 heavy cola consumption, 173 IJCP, 171 limitations of, 173 peer review opportunities, 174–176 publication analytics and social media, 179–181 review article, 171 PubMed, 80, 105, 154, 178, 179

R Randomized controlled trials (RCTs), 4–5, 17, 103 Recognition patterns, 26 Remarks on Angina Pectoris, 13 ResearchGate score site, 179–181 Response letter, 168 Revised manuscript critical requirement, 163–164 draft responses and revisions, 164–168 reviewer and editor comments, 164 Rhazes, 11–12

S Self-citation, 179 Sepsis, 10

195

Septicemia, 25, 26 SHM. See Society of Hospital Medicine (SHM) Smallpox, 11 Social media, 179–181 Society of General Internal Medicine (SGIM), 28, 122, 124 Society of Hospital Medicine (SHM), 122, 124 Stone Mountain Medical Case Histories of Wang Ji, 12 Students, case reports for, 27–29, 38–39 Subspecialty journals, 115, 152, 158 Syphilitic abdominal aortic aneurysm, 15

T Take-home points, 148, 152 TCMA. See Transcortical motor aphasia (TCMA) TEACH, 135–136 TNM cancer staging, 72 Tonsillar hypertrophy, 23 Traditional media, 181 Transcortical motor aphasia (TCMA), 87, 88 Two cheers for case reports, 43

V Verminous aneurysms, 14 Vertebral sarcoidosis, 66–68, 92, 175 Veterinary medicine, 14, 15 Vibrato, 2–3, 66

W Warren, John, 13

Z Zika virus infection, 5