Narcolepsy:: A Clinical Guide

Narcolepsy

Meeta Goswami  ·  S.R. Pandi-Perumal Michael J. Thorpy Editors

Narcolepsy A Clinical Guide

Editors Meeta Goswami, BDS, MPH, PhD Montefiore Medical Center Director Narcolepsy Institute Albert Einstein College of Medicine Bronx, NY, USA [email protected]

S. R. Pandi-Perumal, MSc President and Chief Executive Officer Somnogen Inc. New York, USA [email protected]

Michael J. Thorpy, MD Montefiore Medical Center The Saul R. Korey Department of Neurology Albert Einstein College of Medicine Bronx, NY, USA [email protected]

ISBN 978-1-4419-0853-7 e-ISBN 978-1-4419-0854-4 DOI 10.1007/978-1-4419-0854-4 Springer New York Dordrecht Heidelberg London Library of Congress Control Number: 2009938702 © Humana Press, a part of Springer Science + Business Media, LLC 2010 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Foreword

Narcolepsy serves as a prototype of how the interaction of high quality clinical research and groundbreaking basic science can collaborate to define the cause of a disease and change forever how we evaluate and treat it. There is scarcely a topic in this book that would have been covered in the same way 10 years ago as it is discussed today. We are also fortunate that many of the players in this dramatic turnaround have contributed to this volume, so that the result is a tapestry of the events that have transformed the field over the last decade that is both authentic and detailed. The first section of the book provides much of the basic science background. As described in the first two chapters, the dramatic convergence of lines of evidence from two different laboratories first demonstrated in 1999 that narcolepsy is a disease of loss of neurotransmission by lateral hypothalamic neurons making the peptides that have been called orexins or hypocretins. These findings did much to clarify and unify a field that had puzzled for decades over the fundamental nature of this puzzling disease, as reflected in the chapters that review its epidemiology and neuroanatomical and imaging findings. The second section of the book reviews systematically the clinical aspects of narcolepsy. These chapters thoroughly describe and discuss the clinical phenomenology of narcolepsy, and try to place it into context with the exploding basic science literature. This is followed by a section on the psychosocial aspects of narcolepsy which discusses in great detail aspects of psychological and emotional difficulties that patients with narcolepsy encounter. The final section on management of narcolepsy describes both traditional and newer pharmacological and nonpharmacological approaches to treating the patient with narcolepsy. It is here where we have perhaps made our greatest strides in recent years, with the introduction of two new classes of drugs, modafinil and sodium oxybate. The future of treatment, in the minds of many experts in the field, will depend upon the development of methods to replace the lost orexin/hypocretin signaling. In this regard, we enter the realm of approaches that are currently science fiction (gene therapy, cell transplants), but which are likely to become feasible in the next few years. Narcolepsy presents an exceedingly attractive target for these approaches, because the disorder appears to be due to the monophasic loss of a single class of cells, making a single critical neurotransmitter. Hence, replacement should be more straightforward than in many of the neurodegenerative disorders, which involve multiple systems and are progressive.

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Foreword

The last decade of research in narcolepsy has been one of the most intense and productive of any neurological disorder. The next decade promises to bring even more spectacular advances and modes of therapy. This volume sits at the threshold between an extraordinary past, and the future that it portends. It will serve as a platform for those who lead the exploration. Boston, MA

Clifford B. Saper, MD, PhD

Credits and Acknowledgments

Narcolepsy: A Clinical Guide provides scientific and clinical information on narcolepsy for all healthcare workers interested in disorders of sleep. It is our pleasure to acknowledge the contributions of those who were instrumental in the production of this book. Our sincere appreciation goes to Prof. Clifford Saper, James Jackson Putnam Professor of Neurology and Neuroscience, Harvard Medical School; and Chairman, Department of Neurology, Beth Israel Deaconess Medical Center, and Associate Director of Harvard Medical School Division of Sleep Medicine, who agreed to write the foreword. We wish to express our appreciation for his contribution. We would like to express our deep appreciation to all the contributors for their scholarly contributions that facilitated the development of this book. The expertise of contributors to Narcolepsy: A Clinical Guide reflects the broad diversity and knowledge concerning narcolepsy research, which has continued to grow over the last several decades. These authors represent the cutting edge of basic and applied narcolepsy research and provide the most recent information regarding how such knowledge can be used in clinical settings. Their informed opinions and insights have significantly contributed to our scientific understanding of narcolepsy and have provided important interpretations regarding future research directions. The highly talented people of Humana/Springer USA made this project an especially pleasurable one. We were delighted to have the professional and highly enthusiastic support of Mr. Richard Lansing, Executive Editor, Springer USA. Without Richard’s continuous and unstinting support this volume would not have been possible. We gratefully acknowledge his help and support. It was a pleasure to work with the entire production team of Springer. Their guidance, technical expertise, and commitment to excellence were invaluable. We wish to acknowledge the help of Amanda Quinn Thau, Production Editor, who supported us from the start to finish. Finally, and most importantly, we want to thank our spouses and families for their support and understanding during the development of this book. Meeta Goswami S.R. Pandi-Perumal Michael J. Thorpy

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Preface

During the last few decades, the ever increasing number of topics in sleep medicine has become the focus of intense medical and scientific interest. This interest has grown in tandem with the growing recognition that sleep disorders represent a major public health concern [1]. It also reflects the philosophy of the editors that mastery of the basic, translational, clinical and psychosocial, and quality of life aspects of narcolepsy is essential to the process of becoming a skilled sleep practitioner. The earliest reported description of narcolepsy was provided by Gelineau [2] in 1880 who used the term narcolepsie to denote a condition characterized by brief episodes of irresistible sleep and by falls (astasias) associated with emotional stimuli. Since then there have been numerous developments in the field. These developments have continually deepened our understanding of narcolepsy as a pathophysiological condition and have also drawn attention to its impact on the lives of those who have this condition. Narcolepsy is a severe, chronic, debilitating, and disabling neurological disorder, typically having an early age of onset. It usually involves excessive daytime sleepiness and cataplexy (a sudden and transient decrement of muscle tone and loss of deep tendon reflexes, leading to muscle weakness, paralysis, or postural collapse, usually in response to an external stimulus) [3]. As a lifelong neurodegenerative disorder, narcolepsy produces restrictions in almost all the personal, social, educational, and vocational activities of affected individuals [4]. Despite its prominent symptoms and impact on patients’ health-related quality of life (HRQoL), narcolepsy remains an under-recognized and under-appreciated disorder. Patients with narcolepsy often suffer from a constellation of other comorbid medical and/or psychiatric conditions [5], and additionally complain about problems with memory and cognition. In children and adolescents, the psychological and social complications of narcolepsy appear to be widespread and potentially severe [6]. Narcolepsy affects patients’ overall daily functioning, including their academic and vocational performance, and social and recreational activities. Accordingly, this volume addresses issues in the etiology, pathophysiology, and management of narcolepsy including psychosocial ramifications and effects on quality of life. In the last decade, significant advances in elucidating the pathophysiology of narcolepsy have been made. The use of recently introduced drugs has been shown to reduce the excessive daytime sleepiness of narcolepsy and to improve functional ability. It has been shown that some patients can benefit from medications such as modafinil and sodium oxybate [7] while others have benefited from behavioral interventions. Strategies for the management of excessive daytime sleepiness, such as the

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scheduling of naps, diet and exercise, and the planning of activities during times of optimal alertness, are discussed in this volume. The role of sleep hygiene and stimulus control in narcolepsy is also discussed. The nature and mechanisms of cataplexy remain important issues, and the latest research evidence from animal model studies are covered here. The volume also considers the significant contributions that have resulted from recent translational research into narcolepsy. The reader will find important discussions of the pharmacological strategies for dealing with narcolepsy’s classic symptoms of daytime sleepiness, cataplexy, sleep paralysis, hypnagogic, and hypnopompic hallucinations. Also provided in this volume is an overview of an Food and Drugs Administration (FDA)and European Medicines Agency (EMEA)-approved medications for use in the treatment of narcolepsy with cataplexy. The volume is broadly divided into four main sections: Section I: Etiology; Section II: Clinical Considerations; Section III: Psychosocial Considerations; and Section IV: Management. In its first section, the basic, translational, and clinical background of narcolepsy is reviewed. In this regard, the three introductory chapters cover the genetic predisposition and pathophysiology, animal models of narcolepsy along with neuroimaging of narcolepsy. In the second section of the book, the epidemiology of narcolepsy, its development and impact across the lifespan, its symptomatology, comorbidity, and neurochemical correlates are discussed in detail. Also covered are aspects of hypersomnias other than narcolepsy, narcolepsy’s particular effects on dream experience, and important considerations for its differential diagnosis. The third section deals with the psychosocial aspects of narcolepsy. Issues relating to the psychosocial impact of narcolepsy in children and adolescents, the impact of narcolepsy on patients’ experienced quality of life, intimacy and sexuality, and driving safety are covered here. Also dealt with are narcolepsy’s effects on cognition and memory and comorbid psychiatric conditions, as well as medico-legal aspects of the disabilities that are produced by the condition. The fourth and final section addresses the overall management of narcolepsy, modes of action of medications related to narcolepsy, as well as pharmacological and nonpharmacological treatment strategies. The reader will find that among the pluses of this volume are detailed discussions of important secondary issues including the importance of psychosocial support, education, counseling, and recognition of psychiatric and cognitive comorbidities. It has been the editors’ objective to provide a comprehensive and authoritative guide for clinicians that is presented in a manner which is both readable and easily understood. It is our hope that we have succeeded in accomplishing this goal. This volume is intended primarily for sleep disorders specialists and sleep researchers. However, it is suitable for psychiatrists, neurologists, and any professionals and researchers interested in the interdisciplinary field of sleep medicine. It will be of considerable interest to general practitioners and physicians who evaluate and treat sleep disorders. It will also be equally interesting to psychiatry and neurology residents and fellows, clinical psychologists, advanced graduate medical students, neuropsychologists, house officers, and other mental health and social workers who want to get an overall understanding of narcolepsy.

Preface

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Preface

Inasmuch as research findings in many areas are rapidly broadening our understanding of narcolepsy, it is anticipated that future edition of this volume Narcolepsy: A Clinical Guide will take these developments into account. Bronx, NY New York, NY Bronx, NY

Meeta Goswami S.R. Pandi-Perumal Michael J. Thorpy

References 1. Leger D, Pandi-Perumal SR (Eds.) Sleep Disorders: Their Impact on Public Health. London: Informa UK Ltd, p. 234. 2. Gelineau J (1880) De La Narcolepsie. Gazette de l’Hopital (Paris) 53: 626–8; 635–7. 3. Goswami M, Pandi-Perumal SR (2007) Narcolepsy: psychosocial, socioeconomic, and public health considerations. In: Pandi-Perumal SR, Ruoti RR, Kramer M (eds.). Sleep and Psychosomatic Medicine. London: Informa UK Ltd, pp. 191–205. 4. Goswami M (2008) Sleep and quality of life in narcolepsy. In: Verster JC, PandiPerumal SR, Streiner DL (eds.). Sleep and Quality of Life in Clinical Medicine. Totowa, New Jersey: Humana Press (Springer Science + Business Media, LLC), pp. 93–99. 5. Krahn LE (2007) Clinical features, diagnosis, and treatment of narcolepsy. In: Pagel JF, Pandi-Perumal SR (eds.). Primary Care Sleep Medicine: A Practical Guide, pp. 231–36. 6. Goswami M, Pollak CP, Cohen FL, Thorpy MJ, Kavey N, Kutscher AH (Eds.) (1992) Psychosocial Aspects of Narcolepsy, New York: Haworth Press, 203p. 7. Thorpy M (2007) Therapeutic advances in narcolepsy. Sleep Med. 8(4):427–40. Epub 2007 May 1.

Contents

Section I  Etiology   1  Narcolepsy: Genetic Predisposition and Pathophysiology...................... Emmanuel Mignot

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  2  Animal Models of Narcolepsy: Development, Findings and Perspectives.......................................................................... 23 Christopher M. Sinton   3  Neuroimaging of Narcolepsy...................................................................... 39 Eric A. Nofzinger Section II  Clinical Considerations   4  Epidemiology of Narcolepsy....................................................................... 47 Lauren Hale   5  Narcolepsy in Childhood............................................................................ 55 Suresh Kotagal and Shalini Paruthi   6  Narcolepsy in the Older Adult................................................................... 69 Hrayr Attarian   7  Diurnal and Nocturnal Sleep in Narcolepsy with Cataplexy.................. 77 Yves Dauvilliers and Giuseppe Plazzi   8  Hypnagogic Hallucinations and Sleep Paralysis...................................... 87 Armando D’Agostino and Ivan Limosani   9  REM Sleep Behavior Disorder in Narcolepsy with Cataplexy............... 99 Giuseppe Plazzi and Yves Dauvilliers 10  Narcolepsy and Other Comorbid Medical Illnesses................................ 105 Lori A. Panossian and Alon Y. Avidan 11  Humor Processing in Human Narcolepsy with Cataplexy...................... 115 Aurélie Ponz and Sophie Schwartz

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12  Dreams in Patients with Narcolepsy.......................................................... 125 Michael Schredl 13  Psychoanalysis and Narcolepsy................................................................. 129 J.F. Pagel and Lawrence Scrima 14  Symptomatic Narcolepsy or Hypersomnia, with and Without Hypocretin (Orexin) Deficiency.................................. 135 T. Kanbayashi, M. Nakamura, T. Shimizu, and S. Nishino 15  Hypersomnias Other than Narcolepsy: Differential Diagnosis.............. 167 Michel Billiard Section III  Psychosocial Considerations 16  Psychosocial Impact of Narcolepsy in Children and Adolescents.......... 181 Gregory Stores 17  Quality of Life and Psychosocial Issues in Narcolepsy............................ 189 Meeta Goswami 18  Narcolepsy, Intimacy and Sexuality.......................................................... 205 Gila Lindsley 19  Narcolepsy, Driving and Traffic Safety..................................................... 217 Claire EHM Donjacour, Monique AJ Mets, and Joris C Verster 20  Memory and Cognition in Narcolepsy...................................................... 223 Christian Bellebaum and Irene Daum 21  Medico-Legal Aspects of Disability in Narcolepsy................................... 231 Francesca Ingravallo and Giuseppe Plazzi 22  Narcolepsy and Mental Health.................................................................. 239 John Shneerson Section IV  Management 23  Overview of Management of Narcolepsy.................................................. 251 Seiji Nishino and Nozomu Kotorii 24  Modes of Action of Drugs Related to Narcolepsy: Pharmacology of Wake-Promoting Compounds and Anticataplectics.................................................................................... 267 Seiji Nishino 25  Modafinil/Armodafinil in the Treatment of Narcolepsy.......................... 287 Michael Thorpy 26  Sodium Oxybate in the Treatment of Narcolepsy.................................... 295 Geert Mayer

Contents

Contents

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27  Emerging Treatments for Narcolepsy....................................................... 301 Meredith Broderick and Christian Guilleminault 28  Non-pharmacologic Treatments of Narcolepsy........................................ 313 Renee Monderer, Shelby Freedman Harris, and Michael J. Thorpy Index..................................................................................................................... 323

Contributors

Hrayr Attarian, MD  Associate Professor of Neurology and Medicine, University of Vermont/Fletcher Allen Health Care, Director of the Vermont Regional Sleep Center, Patrick 5 CNL, 111 Colchester Ave, Burlington, VT 05401, USA, [email protected] Alon Avidan, MD, MPH  Associate Professor of Neurology, Neurology Residency Program Director, Director, UCLA Neurology Clinic, Associate Director, Sleep Disorders Center, UCLA, Department of Neurology, 710 Westwood Blvd., Room 1-169/RNRC, Los Angeles, CA 90095-1769, USA, [email protected] Christian Bellebaum, PhD  Post Doctoral Fellow, Institute of Cognitive Neuroscience, Department of Neuropsychology, Ruhr-University of Bochum, Universitätsstraße 150, D-44780 Bochum, Germany, [email protected] Michel Billiard, MD  Honorary Professor of Neurology, Department of Neurology, Gui de Chauliac Hospital, 80, Avenue Augustin Fliche, 34295, Montpellier cedex 5, France, [email protected] Meredith Broderick, MD  Fellow, Stanford University Sleep Medicine Program, 401 Quarry Rd suite 3301, Stanford, CA 94305, USA, [email protected] Armando D’Agostino, MD  Unità Operativa Psichiatria, 52, Azienda Ospedaliera San Paolo, Università degli Studi di Milano, Milan, Italy, [email protected] Irene Daum, PhD  Professor of Neuropsychology, Institute of Cognitive Neuroscience, Department of Neuropsychology, Ruhr-University of Bochum, Universitätsstraße 150, D-44780 Bochum, Germany, [email protected] Yves Dauvilliers, MD, PhD  Neurologie B, Neurology Department, CHU Montpellier, INSERM U888, National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia); and Service de Neurologie, Hôpital Gui-de-Chauliac, 80 avenue Augustin Fliche, 34295 Montpellier cedex 5, France, [email protected], [email protected] Claire E.H.M. Donjacour, MD  Leiden University Medical Centre, Department of Neurology, The Netherlands

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Meeta Goswami, BDS, MPH, PhD  Director, Narcolepsy Institute, Montefiore Medical Center, Assistant Professor, Albert Einstein College of Medicine, 111 East 210 Street, Bronx NY 10467, USA, [email protected] Christian Guilleminault, MD, BiolD  Professor of Psychiatry and Behavioral Science, Stanford University Sleep Disorders Clinic, 401 Quarry Rd suite 3301, Stanford, CA 94305, USA, [email protected] Lauren Hale, PhD  Graduate Program in Public Health, Assistant Professor of Preventive Medicine, State University of New York, Stony Brook, HSC Level 3, Room 071, Stony Brook, NY 11794, USA, [email protected] Shelby Freedman Harris, PsyD, CBSM  Assistant Professor, The Saul R. Korey Department of Neurology, Assistant Professor, Department of Psychiatry and Behavioral Sciences, Montefiore Medical Center, 3411 Wayne Avenue, Room 1st Flr., Bronx, NY 10467, USA, [email protected] Francesca Ingravallo, MD, PhD  Assistant Professor of Legal Medicine, Section of Legal Medicine, Department of Medicine and Public Health, University of Bologna, Bologna, Italy, [email protected], [email protected] Takashi Kanbayashi, MD, PhD  Department of Neuropsychiatry, Akita University School of Medicine, Akita, Japan, [email protected] Suresh Kotagal, MD  Professor of Neurology, Division of Child Neurology and the Center for Sleep Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA, [email protected] Nozomu Kotorii, MD, PhD  Visiting Assistant Professor, Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Sleep and Circadian Neurobiology Laboratory, Stanford University School of Medicine, 1201 Welch Road, MSLS, P224, Palo Alto CA 94304, USA Ivan Limosani, MD  Unità Operativa Psichiatria, 52, Azienda Ospedaliera San Paolo, Università degli Studi di Milano, Milan, Italy Gila Lindsley, PhD  Assistant Professor, Department of Psychiatry, Tufts School of Medicine, Boston, MA, USA; Sleepwell Lexington, 7 White Pine Lane, Lexington, MA 02421, USA, [email protected] Geert Mayer, MD  Professor of Neurology, Hephata Klinik, Schimmelpfengstr. 2, 34613 Schwalmstadt-Treysa, Germany, [email protected] Monique A.J. Mets  Utrecht University, Faculty of Science, Section Psychopharmacology, PO BOX 80082, 3508 TB, Utrecht, The Netherlands Emmanuel Mignot, MD, PhD  Craig Reynolds Professor of sleep Medicine, Director of the Center for Narcolepsy, Howard Hughes Medical Institute, Stanford University Center For Narcolepsy, Department of Psychiatry and Behavioral Sciences, 701-B Welch Road, basement, Room 145, Palo Alto, CA 94304-5742, USA, [email protected] Renee Monderer, MD  Assistant Professor, Montefiore Medical Center, 111 East 210th Street Room: Ground Fl, Bronx, NY 10467, USA, [email protected]

Contributors

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Contributors

Michikazu Nakamura, MD, PhD  Department of Neurology, Kyoto Medical Center, Kyoto, Japan Seiji Nishino, MD, PhD  Professor, Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Sleep and Circadian Neurobiology Laboratory & Center for Narcolepsy, Stanford University School of Medicine, 1201 Welch Road, MSLS P213, Palo Alto CA 94304, USA, [email protected] Eric A. Nofzinger, MD  Sleep Neuroimaging Research Program, University of Pittsburgh School of Medicine, 3811 O’Hara Street, Pittsburgh, PA 15213, USA, [email protected] James F. Pagel, MS, MD  Associate Clinical Professor, University of Colorado School of Medicine, Director Rocky Mountain, 1619 N. Greenwood Suite 206, Pueblo, CO 81003, USA, [email protected] S.R. Pandi-Perumal, MSc  President and CEO, Somnogen Inc, New York, NY 10021, USA, [email protected] Lori A. Panossian, MD  Resident, Department of Neurology, UCLA Medical Center, 710 Westwood Plaza 1241 RNRC, Los Angeles, CA 90095-1767, USA Shalini Paruthi, MD  Fellow Sleep Medicine, Michael S. Aldrich Sleep Disorders Laboratory, Med Inn Building 7th Floor, 1500 E. Medical Center Drive, Ann Arbor, MI 48103 USA, (official/personal): [email protected] Giuseppe Plazzi, MD, PhD  Dipartimento di Scienze Neurologiche, Alma Mater Studiorum, Università di Bologna, Via Ugo Foscolo 7; and Sleep Disorders Center, Dept. of Neurological Sciences, University of Bologna, Via Ugo Foscolo 7, 40123, Bologna, Italy, [email protected], [email protected], [email protected] Aurélie Ponz  PhD student, University Medical Center, Dept. Neurosciences, Michel-Servet 1, 1211 Geneva 4, c, [email protected] Clifford B. Saper, MD, PhD  James Jackson Putnam Professor of Neurology and Neuroscience, Harvard Medical School; and Chairman, Department of Neurology, Beth Israel Deaconess Medical Center, Associate Director, Harvard Medical School Division of Sleep Medicine, Beth Israel Deaconess Medical Center (BIDMC), 330 Brookline Avenue,77 Louis-Pasteur/HMI 8th floor (Saper lab), Boston, MA 02215, USA Michael Schredl, PhD  Prof. Dr. phil. Dipl. Psych. Dipl. Ing. Etec., Sleep laboratory, Central Institute of Mental Health, PO Box 12 21 20, 68072 Mannheim, Germany, [email protected] Sophie Schwartz, PhD  Laboratory for Neurology and Imaging of Cognition, Department of Neurosciences, University Medical Center (CMU), Building A, room 7028, 1 Michel-Servet - 1211 GENEVA – CH and Neurology Clinic, Geneva University Hospital, Micheli-Du-Crest 24, 1211 Geneva, Switzerland, [email protected] Lawrence Scrima, PhD  Sleep Alertness Disorders Center Consultants Inc., 1390 S. Potomac Street, Suite 110, Aurora, CO 80012, USA, [email protected] Tetsuo Shimizu, MD, PhD  Department of Neuropsychiatry, Akita University School of Medicine, Akita, Japan

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John Shneerson, MA, DM, MD, FRCP, FCCP  Consultant Chest and Sleep Physician, Fellow of the Royal College of Physicians, Fellow of the American College of Chest Physicians, Respiratory Support and Sleep Centre, Papworth Hospital, Papworth Everard, Cambridgeshire, CB3 8RE, UK, john.shneerson@ papworth.nhs.uk Christopher M. Sinton, PhD  Associate Professor, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390-8874, USA, [email protected] Gregory Stores, MA, MD, DPM, FRCPsych, FRCP  Emeritus Professor of Developmental Neuropsychiatry, University of Oxford, North Gate House, 55 High Street, Dorchester on Thames, Oxfordshire, OX10 7HN, UK, [email protected] Michael J. Thorpy, MD  Professor of Neurology, Albert Einstein College of Medicine; and Director, Sleep-Wake Disorders Center, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467, USA, [email protected] Joris C. Verster, PhD  Assistant Professor, Utrecht University, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Section Psychopharmacology, PO Box # 80082, 3508TB Utrecht, The Netherlands, [email protected] (Visiting Address: Went Building, W038A, Sorbonnelaan 16, Utrecht)

Contributors

Biographies

Dr. Meeta Goswami has been the director of the Narcolepsy Institute since its inception in 1985 and is Assistant Professor of Neurology, Albert Einstein College of Medicine. She graduated with a dental degree from Bombay, India and received a PhD in Sociomedical Sciences and a Master in Public Health from Columbia University in New York. Dr. Goswami is a member of the American Academy of Sleep Medicine, Sleep Research Society, and the National Sleep Foundation (USA); she is also a member of the medical advisory board of the Narcolepsy Network, the national association for people with narcolepsy. The narcolepsy Network awarded her a Life Time Achievement in 2008. Since its inception in 1985, the Narcolepsy Institute has been funded by New York State to provide information, referral, and psychosocial support services to individuals with narcolepsy and their families. Meeta Goswami, with Michael J Thorpy and others, edited the first book on Narcolepsy and Psychosocial Issues 1992; she has coauthored with Michael J. Thorpy, the Narcolepsy Primer 2006 Second Edition, developed a Video on Narcolepsy, and publishes a semiannual newsletter, Perspectives, on Narcolepsy. She has published several papers on Narcolepsy and has presented her papers nationally and internationally. Dr. Goswami is committed to integrating the social and medical sciences and applying this knowledge to enhance the quality of care provided to patients and improving the quality of life of those who have narcolepsy. The Narcolepsy Institute has a website: http://www.narcolepsyinstitute.org. As the director of the Narcolepsy Institute, Montefiore Medical Center for more than 20 years, Dr. Goswami learned that patients benefit most when their medical care for narcolepsy is integrated with comprehensive psychosocial support at the individual level and in group sessions. S.R. Pandi-Perumal is the President and Chief Executive Officer of Somnogen Inc, a New York Corporation. He is a well-recognized sleep researcher both nationally and internationally, and has authored many publications in the field of sleep and biological rhythms. His general area of research interest includes sleep and biological rhythms. He has edited several books related to sleep and biological rhythms research. He was quoted in the New York Times in 2004. Further details can be found at: http:// pandi-perumal.blogspot.com. Michael J. Thorpy, MD, board-certified in sleep disorders medicine, is director of the Sleep-Wake Disorders Center at Montefiore Medical Center, Bronx, New York. Both a clinician and a well-published researcher, Dr. Thorpy serves as Professor of neurology at Albert Einstein College of Medicine and is the past chairman of the Sleep Section of the American Academy of Neurology. In addition, Dr. Thorpy is the xxi

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past secretary of the National Sleep Foundation (NSF) and was founder and director of the NSF’s National Narcolepsy Registry, which was located at Montefiore. Dr. Thorpy was born in New Zealand and earned his medical degree from the University of Otago in 1973. He has published extensively on narcolepsy, insomnia, and sleep disorders. His numerous books include the Encyclopedia of Sleep and Sleep Disorders. His curriculum vitae list more than 50 articles, including peerreviewed publications in journals such as the New England Journal of Medicine. Dr. Thorpy’s Sleep Medicine Home Page is one of the major sleep Web sites on the Internet, and his comprehensive computerized textbook of sleep, SleepMultiMedia (on CD-ROM), is the only one of its kind. In 1993, he was awarded one of the sleep field’s highest honors: the Nathaniel Kleitman Award from the American Academy of Sleep Medicine (formerly the American Sleep Disorders Association). Dr. Thorpy is frequently quoted in the media, including The New York Times, The Washington Post, and Good Housekeeping. He has appeared on the Today Show, 20/20 and Donahue and given more than 100 television, radio, and print interviews.

Biographies

Section I

Etiology

Chapter 1

Narcolepsy: Genetic Predisposition and Pathophysiology Emmanuel Mignot

The definition of narcolepsy has been recently revised [1]. Recent studies indicate that in most narcolepsy cases with cataplexy and in fewer cases without cataplexy, a deficiency in the neuropeptide system hypocretin, with low CSF hypocretin-1, is involved [2–7]. As a result, in the most recent revision of the international classification of sleep disorders, narcolepsy with and without cataplexy have been separated [8]. In this chapter, we will primarily discuss the pathophysiology of narcolepsy/hypocretin deficiency, as there is a strong suggestion of etiological homogeneity based on the strong association with DQB1*0602 and low Cerebrospinal Fluid (CSF) hypocretin-1. References to narcolepsy without cataplexy (as defined by excessive daytime sleepiness and a positive MSLT) will also be made, when appropriate, keeping in mind that the condition is only clinically and polysomnographically defined, and thus likely represent a complex constellation of problems and pathologies [9, 10].

Prevalence Studies Population-based prevalence studies of narcolepsy– cataplexy have been performed in multiple countries and using multiple designs. These are made relatively straightforward by the fact that cataplexy is a pathognomonic symptom, and thus, to screen for this symptom allows for a rapid first screen. In a study performed in Finland, 11,354 individual twin subjects were asked to E. Mignot (*) Stanford University Center For Narcolepsy, Howard Hughes Medical Institute, 701-B Welch Road, Basement, Room 145, Palo Alto, CA, 94304-5742, USA e-mail: [email protected]

respond to a questionnaire. Subjects with answers suggestive of narcolepsy were contacted by phone and subjected to clinical interviews and polysomnographic recordings if indicated [11]. Three narcoleptic subjects with cataplexy and abnormal MSLT results were identified, leading to a prevalence of 0.026% [11]. Other studies have led to similar prevalence (0.013–0.067%) in Great Britain, France, Hong Kong, the Czech Republic, and in the United States [12–14]. A study performed in 1945 in African American Navy recruits also led to 0.02% in this ethnic group for narcolepsy–cataplexy, although this study concluded that narcolepsy was more frequent in this ethnic group because of so called “natural tendencies” [15]. Narcolepsy–cataplexy may be less frequent in Israel (0.002%) [16] and more frequent in Japan (0.16–0.18%) [17, 18], but these studies were less perfectly designed so a direct comparison is difficult. It is of interest to note that DQB1*0602 is rare in Israel (4–6%), Japan (8%), Korea (13%), but not in most Caucasian (25%), Chinese (25%) and African American (38%) population, thus a direct correlation between the prevalence of narcolepsy and DQB1*0602 is not evident. The prevalence of narcolepsy without cataplexy is largely unknown, as a proper population-based study would require MSLT testing of all subjects. In case series, narcolepsy without cataplexy represents 20–50% of cases [19]. Patients without cataplexy are, however, more likely to be underdiagnosed (e.g., narcolepsy plus sleep apnea), undiagnosed (no major complaints) or misdiagnosed (e.g, as depression or sleep apnea) [9] considering their milder phenotype. Some studies have suggested that ~2% of the adult population may have unexplained sleepiness and multiple SOREMPs during MSLT testing [20, 21]. Other studies have found even higher prevalence in adolescents or young adults, probably because voluntary chronic sleep deprivation is

M. Goswami et al. (eds.), Narcolepsy: A Clinical Guide, DOI 10.1007/978-1-4419-0854-4_1, © Humana Press, a part of Springer Science + Business Media, LLC 2010

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E. Mignot

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common in these populations [22, 23]. A recent study identified all diagnosed narcoleptic patients in the Olmsted County (MN, USA), using the medical records-linkage system of the Rochester Epidemiology project [24]. The study identified 0.036% of the population with narcolepsy–cataplexy and 0.021% with narcolepsy without cataplexy, suggesting a very significant prevalence of the variant narcolepsy without cataplexy [24]. In the King County (WA, USA), a similarly designed recent study found 0.031% of the population with narcolepsy, only 0.009% without cataplexy (27% of DQB1*0602 positive) [14]. As mentioned above, however, it is clear that registry-based estimations of diagnosed narcolepsy without cataplexy prevalence probably underestimate, while populationbased epidemiological studies that do not exclude other confounding factors, overestimate the true population prevalence. What percent of narcolepsy without cataplexy cases have hypocretin deficiency is also unknown. In some centers, when all other causes of daytime sleepiness have been excluded, it may reach 30% while in others it may be as low as 5% [5–7, 25, 26], with a mean of 15% overall and 31% in HLA positive subjects in a recent metanalysis of 162 samples tested in our center [27]. This is also reflected by the % DQB1*0602 positivity in such samples ranging from 27% (slightly above the 23% population frequency in Caucasian) to 40% in a large multi-center drug trial [19] and other samples [5, 27]. We have conducted systematic CSF

hypocretin-1 measurement in random samples of healthy individuals (approximately 250 subjects in total), and have been unable to detect a single subject with CSF hypocretin-1 below 110  pg/ml. Interestingly, testing 162 patients without cataplexy in our center since 2000, we found that a cut of 200  pg/ml improved the sensitivity for this test to 41% in the presence of HLA-DQB1*0602 and 9% in the absence of HLADQB1*0602 [27] (Table 1.1). It is, therefore, possible that some subjects without cataplexy have less pronounced hypocretin cell loss, as reflected by intermediary (110–200  pg/ml) or normal CSF hypocretin-1 [27]. The notion is also supported by the slightly increased HLA frequency observed in narcolepsy without cataplexy subjects with normal CSF hypocretin [28], although it is difficult in this case to exclude the patients diagnosed after HLA positivity was established, thus creating a bias.

Animal Models Narcolepsy was first reported in two dogs by Knecht [29] and Mitler [30] in 1973. These cases were sporadic, without any familial history. A non-simple genetic etiology was established through breeding experiments in most cases of canine narcolepsy. In 1975, narcoleptic Dobermans were reported in a single litter [31], a finding that led to the establishment of the

Table 1.1  Sensitivity (SE) and specificity (SP) of various diagnostic tests for narcolepsy/cataplexy and narcolepsy without cataplexy Narcolepsy with cataplexy HLA

Narcolepsy without cataplexy

Idiopathic hypersomnia

SE 89.3% (822/1,291) 45.4% (306/1,291) 17.7% (62/1,291) SP 76.0% (1,291) 76.0% (1,291) 76.0% (1,291) MSLT SE 87.9% (964/1,095) Not applicable Not applicable SP 96.9% (1,095) 96.9% (1,095) 96.9% (1,995) Hcrt £ 110 pg/ml SE 83.3% (233/182) 14.8% (162/182) 0.0% (49/182) SP 100% (182) 100% (182) 100% (182) Hcrt £ 200 pg/ml SE 85.0% (233/182) 22.8% (162/182) 6.1% (49/182) SP 98.9% (182) 98.9% (182) 98.9% (182) Not applicable: as part of the clinical definition. Number within parenthesis indicates the number of patients and corresponding number of controls used to calculate sensitivity (SE). For specificity (SP), only the number of controls is reported. Narcolepsy with atypical and no cataplexy are grouped as narcolepsy without cataplexy per ICSD2 [1]. Idiopathic hypersomnia includes both patients as defined by a positive MSLT or with prolonged sleep time independent of MSLT results. A positive MSLT is a mean sleep latency £8 min and ³2SOREMP for narcolepsy without cataplexy and mean sleep latency £8 min, 2, 56%) (Table 1.2). HLA typing data in these

Family structure

Clinical subgroups

DQB1*0602, n (%)

Sporadic cases

Narcolepsy–cataplexy 498/574 (87%)††† Narcolepsy without cataplexy 83/210 (40%)††† Unrelated controls 358/1416 (25%) Multiplex Narcolepsy–cataplexy 51/74 (70%)***,††† cases Narcolepsy without cataplexy 21/39 (54%) Narcolepsy–cataplexy in 36/47 (77%)*,††† families with £ 2 affected 15/27 (56%)#,*** Narcolepsy–cataplexy families with >2 affected in families Healthy relatives 78/164 (48%) Sporadic cases: Random cases without family history; Data reported for multiplex cases include multiple cases in each multiplex family. Results are identical when only one proband per family (n = 35 families) is included, data not shown. Typical cataplexy is defined as musle weakness trigerred at least sometimes by laughing or joking * P = 0.05 vs. sporadic cases *** p 200 pg/ml). Note that these pg/ ml values are largely artificial, and meant to represent approximately 30% of mean control value as tested in a given center using direct radioimmunoassay and a set of healthy controls [5]. Mean CSF hypocretin-1 concentration was not significantly different between HLA DQB1*0602 positive and negative controls. The percentage and number of subjects is specified for each group of subjects according to the two CSF hypocretin thresholds

Genetic Factors Other Than HLA

involvement of other genes. Linkage analysis in HLADQB1*0602 positive Japanese families have suggested the existence of a susceptibility gene on 4q13–23 [91]. A possible association with TNF-alpha gene polymorphism (independent of HLA) has been suggested [92–94]. Other results indicate that a polymorphism in the catechol-O-methyltransferase (COMT) gene, a key enzyme in the degradation of catecholoamine, may also modulate disease severity [95, 96]. Additional studies are needed to identify non-HLA genetic factors.

As mentioned above, genetic factors other than HLA-DQ and DR are likely to be involved in narcolepsy predisposition. The increased familial risk in first-degree relative (10-fold in Japanese, 20- to 40-fold in Caucasians) cannot be solely explained by the sharing of HLA subtypes, estimated to explain two- to threefold increased risk [13]. Additionally, the existence of HLA negative families suggests disease heterogeneity and the possible

12

The search for additional narcolepsy genetic factors is likely to accelerate, thanks to novel techniques, allowing for genome wide studies of single nucleotide polymorphisms. In a recent study, Miyagawa et  al. screened 222 narcolepsy and 289 Japanese controls [97] using a 500K SNP microarray platform, with replication of top hits in 159 narcolepsy and 190 controls, followed by the testing of 424 Koreans, 785 individuals of European descent and 184 African Americans. A SNP located between CPT1B and CHKB, rs5770917, was associated with narcolepsy in Japanese (rs5770917[C], odds ratio (OR) = 1.79, combined P = 4.4 × 10(−7)) and other ancestry groups (OR = 1.40, P = 0.02), although the association was primarily replicated in Korean and was not significant in Caucasians. Real-time quantitative PCR assays in white blood cells indicated decreased CPT1B and CHKB expression in subjects with the C allele, suggesting that a genetic variant regulating CPT1B or CHKB expression is associated with narcolepsy. Either of these genes is a plausible candidate, as CPT1B regulates beta-oxidation, a pathway involved in regulating theta frequency during REM sleep [25], and CHKB is an enzyme involved in the metabolism of choline, a precursor of the REM- and wake-regulating neurotransmitter acetylcholine.

CSF Hypocretin-1 as a Diagnostic Tool for Narcolepsy The observation that cerebrospinal fluid (CSF) hypocretin-1 levels are decreased in patients with narcolepsy provides a new test to diagnose this disorder [27]. Using a large sample of patients and controls, we recently conducted a quality receiver operating curve (QROC) analysis to determine the CSF hypocretin-1 values most specific and sensitive to diagnose narcolepsy [5]. A cut-off value of 110 pg/ml was the most predictive (30% of mean control values). A majority of samples had undetectable levels ( R) frontal, parietal, and thalamic activation. After SD, there was disproportionately greater activation of the left dorsolateral prefrontal cortex and bilateral thalamus when manipulation was required.

Narcolepsy Narcolepsy is a sleep disorder characterized by recurrent daytime sleep attacks and often cataplexy, sleep onset paralysis, and hypnagogic hallucinations. Recent advances have linked narcolepsy with altered function in the hypocretin system, a peptide produced in the posterior lateral hypothalamus that has activating properties and is functionally related to all known arousal systems in the central nervous system [25–27]. The role of functional neuroimaging studies in human narcoleptic patients is in further clarifying the mechanisms of the extra-hypothalamic manifestations of the illness, such as cataplexy, sleep attacks, and hypnogogic hallucinations. Few studies have been conducted to date. Hublin et  al. [28] performed 123I-iodobenzamide SPECT studies in narcoleptic patients and Parkinsonian controls. They found no differences in striatal/frontal D2 occupancy ratios between these two groups. Asenbaum et al. [29] assessed blood

3 Neuroimaging of Narcolepsy

flow during waking and sleep onset REM periods in six narcoleptic patients using the HMPAO SPECT method. They found evidence for right hemispheric increased flow and thalamic decreased flow in REM sleep. Given the small sample sizes, they suggested that a replication of the findings was needed. Sudo et al. [30] assessed muscarinic cholinergic receptors in narcoleptic subjects using [11C]N-methyl-4piperidylbenzilate ([11C]NMPB) both before and after pharmacotherapy. No differences were observed between patients and healthy subjects at baseline and minimal treatment effects were observed. Joo et  al. [31] assessed cerebral glucose metabolism in 24 narcoleptic patients and 24 normal controls. They found cerebral glucose hypometabolism in hypothalamus–thalamus–orbitofrontal pathways in narcoleptic patients. Joo et al. [32] assessed cerebral perfusion in 25 narcoleptic patients and 25 normal controls using 99 m Tc-ethylcysteinate dimmer single photon emission computed tomography (SPECT). They found reduced cerebral perfusion in bilateral anterior hypothalami, caudate nuclei, pulvinar nuclei of the thalamus, parts of the dorsolateral/ventromedial prefrontal cortices, parahippocampal gyri, and cingulated gyri in narcoleptic patients. These findings were interpreted to be consistent with deficits in neural networks related to the hypocretin arousal pathway. Brenneis et al. [33] assessed regional brain volumes between narcoleptic patients and healthy controls. They found significant gray matter loss in the right prefrontal and frontomesial cortex of patients with narcolepsy. The comparison of cerebrospinal fluid partition detected an enlargement of subarachnoidal space of controls close to the prefrontal cortex. The volume reduction of gray matter in narcoleptic patients could indicate a disease-related atrophy pattern, although they suggested that these findings require replication in an independent drug-naïve sample of patients. Eisensehr et  al. [34] assessed the striatal presynaptic dopamine transporter and postsynaptic D2-receptors in seven patients with narcolepsy and seven control subjects using [123I](N)-(3-iodopropene-2-yl)-2betacarbomethoxy-3beta-(4-chlorophenyl) tropane and [123I](S)-2-hydroxy-3-iodo-6-methoxy-([1-ethyl-2pyrrolidinyl]methyl) benzamide SPECT. D2-receptor binding was elevated in narcolepsy (p = 0.017) and correlated with the frequency of cataplectic and sleep attacks (R> or =0.844, p< or =0.017). They propose that the human striatal dopaminergic system is altered

41

in  vivo in narcolepsy/cataplexy. Hong et  al. [35] assessed cerebral perfusion using SPECT in narcoleptic patients during baseline wake states, REM sleep, and periods of cataplexy. They found activation of an amygdalo-cortico-basal ganglia brainstem circuit in cataplexy.

Narcolepsy Pharmacotherapy and Neuroimaging Neuroimaging studies may provide important information regarding pharmacotherapy of narcolepsy in several realms: drug development, assessment of mechanism of action of therapeutic compounds, and assessment of treatment response/nonresponse to pharmacologic agents. A variety of compounds have been discovered with mechanisms of action that may affect sleep/wake regulation and that may play some role in the pathophysio­ logy or treatment of narcolepsy. Testing in preclinical models suggests that these compounds may have novel mechanisms of action; however, the degree to which these mechanisms will translate into a clinical application is often unknown. Functional neuroimaging studies may identify the degree to which these compounds have beneficial mechanisms of action on brain structures that are known to regulate behavioral states in humans. One way of achieving this goal is to administer the compound to human subjects, then assess a functional neuroanatomic response to the compound within sleep in humans, such as a blood flow or metabolic response. Further, these studies may help to determine the optimum dose of the compound in humans that maximizes beneficial effects of the compound, yet does not lead to adverse effects. The use of receptor ligands may clarify whether one compound has a unique mechanism of action on a specific receptor subtype that may not be shared by other compounds in its class and may therefore hold a therapeutic advantage over other agents. Finally, once a compound has been identified and shown to have effects in the central nervous system in humans, functional neuroimaging studies can then be used to determine the degree to which the compound reverses distinct alterations in neural function in a clinical population. The review below reveals some of the early studies in these areas of relevance to narcolepsy.

E.A. Nofzinger

42

Receptor Ligand Studies Cholinergic receptor density and distributions have been studied in narcolepsy and sleep-related movement disorders. Sudo et al. [30] assessed muscarinic cholinergic receptors in narcoleptic subjects using [11C] N-methyl-4-piperidylbenzilate ([11C]NMPB) both before and after pharmacotherapy. No differences were observed between patients and healthy subjects at baseline and minimal treatment effects were observed. Modafinil has been shown clinically to improve daytime sleepiness in patients with narcolepsy. Neuroimaging studies could be useful in clarifying the brain mechanisms of this agent in reversing the biology of sleepiness and possibly in the sleep attacks associated with narcolepsy. Joo et al. [36] assessed cerebral blood flow in healthy volunteers using SPECT before and after modafinil administration, a wake promoting agent. They found increases in blood flow in bilateral thalami, dorsal pons, bilateral frontopolar, orbitofrontal, superior frontal, middle frontal gyri, short insular gyri, left cingulated gyrus, left middle/inferior temporal gyri, left parahippocampal gyrus, and left pons consistent with the effects of this medication on arousal, emotion, and executive function networks in the brain. Joo et al. [37] assessed the effects of modafinil on regional cerebral blood flow using SPECT in 43 narcoleptic patients. They found increased rCBF in the right dorsolateral and bilateral medial prefrontal cortices. Conversely, after modafinil administration, rCBF was decreased in bilateral precentral gyri, left hippocampus, left fusiform gyrus, bilateral lingual gyri, and cerebellum. There was no significant rCBF change after placebo administration. They concluded that by a chronic administration of modafinil in narcoleptic patients, rCBF increased in the bilateral prefrontal cortices, whereas it decreased in left mesio/basal, temporal, bilateral occipital areas, and cerebellum.

Summary While it is early to summarize these collected studies in narcolepsy, some neurobiological features start to emerge. First, the sleepiness and/or reduced arousal in narcoleptic patients may relate to generalized deficits in a neural arousal network related to the hypocretin

system. Second, early evidence implicates limbic/ paralimbic neural networks in the cataplectic attacks of narcolepsy patients, consistent with the role of these structures in emotional behavior and in REM sleep. Acknowledgments  Support for this work was provided by AG-020677; MH66227, MH61566, MH24652; and RR00056.

References   1. Maquet P, Dive D, Salmon E, Sadzot B, Franco G, Poirrier R, von Frenckell R, Franck G. Cerebral glucose utilization during sleep-wake cycle in man determined by positron emission tomography and [18F]2-fluoro-2- deoxy-Dglucose method. Brain Res 1990;513(1):136-43.   2. Madsen PL, Holm S, Vorstrup S, Friberg L, Lassen NA, Wildschiodtz G. Human regional cerebral blood flow during rapid-eye-movement sleep. J Cereb Blood Flow Metab 1991;11(3):502-7.   3. Maquet P, Peters J, Aerts J, Delfiore G, Degueldre C, Luxen A, Franck G. Functional neuroanatomy of human rapideye-movement sleep and dreaming. Nature 1996;383(6596): 163-6.   4. Meyer JS, Hayman LA, Amano T, Nakajima S, Shaw T, Lauzon P, Derman S, Karacan I, Harati Y. Mapping local blood flow of human brain by CT scanning during stable xenon inhalation. Stroke 1981;12(4):426-36.   5. Heiss WD, Pawlik G, Herholz K, Wagner R, Wienhard K. Regional cerebral glucose metabolism in man during wakefulness, sleep, and dreaming. Brain Res 1985;327(1-2): 362-6.   6. Buchsbaum MS, Gillin JC, Wu J, Hazlett E, Sicotte N, DuPont RM, Bunney WE. Regional cerebral glucose metabolic rate in human sleep assessed by positron emission tomography. Life Sci 1989;45(15):1349-56.   7. Maquet P, Dive D, Salmon E, Sadzot B, Franco G, Poirrier R, Franck G. Cerebral glucose utilization during stage 2 sleep in man. Brain Res 1992;571(1):149-53.   8. Hofle N, Paus T, Reutens D, Fiset P, Gotman J, Evans AC, Jones BE. Regional cerebral blood flow changes as a function of delta and spindle activity during slow wave sleep in humans. J Neurosci 1997;17(12):4800-8.   9. Braun AR, Balkin TJ, Wesenten NJ, Carson RE, Varga M, Baldwin P, Selbie S, Belenky G, Herscovitch P. Regional cerebral blood flow throughout the sleep-wake cycle. An H2(15)O PET study. Brain 1997;120(Pt 7):1173-97. 10. Maquet P. Positron emission tomography studies of sleep and sleep disorders. J Neurol 1997;244(4 suppl 1):S23-8. 11. Maquet P, Phillips C. Functional brain imaging of human sleep. J Sleep Res 1998;7(suppl 1):42-7. 12. Maquet P. Brain mechanisms of sleep: contribution of neuroimaging techniques. J Psychopharmcol 1999;13(4 suppl 1):S25-8. 13. Maquet P. Functional neuroimaging of normal human sleep by positron emission tomography. J Sleep Res 2000;9(3): 207-31.

3 Neuroimaging of Narcolepsy 14. Nofzinger EA, Mintun MA, Wiseman MB, Kupfer DJ, Moore RY. Forebrain activation in REM sleep: An FDG PET study. Brain Res 1997;770:192-201. 15. Nofzinger EA, Mintun MA, Price J, Meltzer CC, Townsend D, Buysse DJ, Reynolds CF, Dachille M, Matzzie J, Kupfer DJ, Moore RY. A method for the assessment of the functional neuroanatomy of human sleep using FDG PET. Brain Research Protocols 1998;2:191-8. 16. Nofzinger EA, Buysse DJ, Miewald JM, Meltzer CC, Price JC, Sembrat RC, Ombao H, Reynolds CF, Monk TH, Hall M, Kupfer DJ, Moore RY. Human regional cerebral glucose metabolism during non-rapid eye movement sleep in relation to waking. Brain 2002;125: 1105-15. 17. Kjaer TW, Law I, Wiltschiotz G, Paulson OB, Madsen PL. Regional cerebral blood flow during light sleep – a H (2) (15) O-PET study. Sleep Res 2002;11(3):201-7. 18. Wu JC, Gillin JC, Buchsbaum MS, Hershey T, Hazlett E, Sicotte N, Bunney WE. The effect of sleep deprivation on cerebral glucose metabolic rate in normal humans assessed with positron emission tomography. Sleep 1991;14(2): 155-62. 19. Thomas M, Sing H, Belenky G, Holcomb H, Mayberg H, Dannals R, Wagner H, Thorne D, Popp K, Rowland L, Welsh A, Balwinski S, Redmond D. Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity. J Sleep Res 2000;9(4): 335-52. 20. Thomas ML, Sing HC, Belenky G, Holcomb HH, Mayberg HS, Dannals RF, Wagner HN, Thorne DR, Popp KA, Rowland LM, Welsh AB, Balwinski SM, Redmond DP. Neural basis of alertness and cognitive performance impairments during sleepiness II. Effects of 48 and 72 h of sleep deprivation on waking human regional brain activity. Thalamus Relat Syst 2003;2:199–229. 21. Mu Q, Nahas Z, Johnson KA, Yamanaka K, Mishory A, Koola J, Hill S, Horner MD, Bohning DE, George MS. Decreased cortical response to verbal working memory following sleep deprivation. Sleep 2005;28(1):55-67. 22. Mu Q, Mishory A, Johnson KA, Nahas Z, Kozel FA, Yamanaka K, Bohning DE, George MS. Decreased brain activation during a working memory task at rested baseline is associated with vulnerability to sleep deprivation. Sleep 2005;28(4):433-46. 23. Drummond SP, Brown GG, Salamat JS, Gillin JC. Increasing task difficulty facilitates the cerebral compensatory response to total sleep deprivation. Sleep 2004;27(3):445-51.

43 24. Chee MW, Choo WC. Functional imaging of working memory after 24 h of total sleep deprivation. J Neurosci 2004; 24(19):4560-7. 25. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999;98(3):365-76. 26. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999;98(4):437-51. 27. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000;355(9197):39-40. 28. Hublin C, Launes J, Nikkinen P, Partinen M. Dopamine D2-receptors in human narcolepsy: a SPECT study with 123I-IBZM. Acta Neurol Scand 1994;90(3):186-9. 29. Asenbaum S, Zeithofer J, Saletu B, Frey R, Brucke T, Podreka I, Deecke L. Technetium-99 m-HMPAO SPECT imaging of cerebral blood flow during REM sleep in narcoleptics. J Nucl Med 1995;36(7):1150-5. 30. Sudo Y, Suhara T, Honda Y, Nakajima T, Okubo Y, Suzuki K, Nakashima Y, Yoshikawa K, Okauchi T, Sasaki Y, Matsushita M. Muscarinic Cholinergic receptors in human narcolepsy: a PET study. Neurology 1998;51(5):1297-302. 31. Joo EY, Tae WS, Kim JH, Kim BT, Hong SB. Glucose hypometabolism of hypothalamus and thalamus in narcolepsy. Ann Neurol 2004;56(3):437-40. 32. Joo JH, Solano FX, Mulsant BH, Reynolds CF, Lenze EJ. Predictors of adequacy of depression management in the primary care setting. Psychiatr Serv 2005;56(12):1524-8. 33. Brenneis C, Brandauer E, Frauscher B, Schocke M, Trieb T, Poewe W, Hogl B. Voxel-based morphometry in narcolepsy. Sleep Med 2005;6(6):531-6. 34. Eisensehr I, Linke R, Tatsch K, von Lindeiner H, Kharraz B, Gildehaus FJ, Eberle R, Pollmacher T, Schuld A, Noachtar S. Alteration of the striatal dopaminergic system in human narcolepsy. Neurology 2003;60(11):1817-9. 35. Hong SB, Tae WS, Joo EY. Cerebral perfusion changes during cataplexy in narcolepsy patients. Neurology 2006; 66(11):1747-9. 36. Joo EY, Tae WS, Jung KY, Hong.S.B. Cerebral blood flow changes in man by wake-promoting drug, modafinil: a randomized double blind study. J Sleep Res 2008;17(1):82-8. 37. Joo EY, Seo DW, Tae WS, Hong SB. Effect of modafinil on cerebral blood flow in narcolepsy patients. Sleep 2008; 31(6):868-73.

Section II

Clinical Considerations

Chapter 4

Epidemiology of Narcolepsy Lauren Hale

Introduction Narcolepsy Has a Variable Phenotype First described by Gelineau in 1880 and by Westphal in 1887, narcolepsy refers to a sleep disorder characterized by excessive daytime sleepiness and episodic weakness [1]. This episodic weakness later became known as cataplexy. In the 1950s, Yoss and Daly described the classic tetrad of narcolepsy symptoms: excessive daytime sleepiness, cataplexy, hypnagogic (at the onset of sleep) or hypnopompic (on awakening) hallucinations, and sleep paralysis [2]. Other symptoms of narcolepsy include disturbed nocturnal sleep and rapid eye movement (REM) sleep behavior disorder [3]. Excessive daytime sleepiness, or hypersomnia, refers to when patients suddenly feel overwhelmingly tired and become unaware of their environment during the day. This sleepiness occurs regardless of the amount or quality of nocturnal sleep [4], and tends to be heightened in sedentary or boring environments [5]. For narcolepsy patients, even short sleep is refreshing upon awakening. Cataplexy refers to episodic bilateral muscle weakness without loss of consciousness and occurs in 60–90% of patients diagnosed with narcolepsy [6, 7]. Cataplexy usually occurs after the onset of daytime sleepiness. However, in rare cases cataplexy may occur first or be the only symptom of narcolepsy. Attacks of cataplexy range from a slight slackening of the facial muscles to total collapse on the ground. Often attacks of cataplexy only affect certain muscle groups, such as those in the L. Hale (*) Department of Preventive Medicine, Stony Brook University, HSC Level 3, Room 071, Stony Brook, NY, 11794-8338, USA e-mail: [email protected]

neck or face [3]. A cataplexy attack can last up to a few minutes, during which the patient is unable to move, despite maintaining consciousness. If the attack is prolonged, sleep may occur. Positive emotions such as exhilaration and surprise tend to trigger these attacks [5]. Yet other emotions, including anger, embarrassment, or sexual arousal, can also prompt an attack though less frequently [8]. The frequency of cataplexy attacks ranges from 1 to 2 episodes per year to 12 or more per day [9, 10]. Generally, the frequency of cataplexy attacks remains stable as the patient ages [11], but some patients may adapt to their illness over time and avoid situations in which cataplexy attacks may occur [12]. Sleep paralysis refers to an inability to move one’s head or limbs during the transition to sleep or wakefulness. Sleep paralysis can accompany hypnogogic/ hypnopompic hallucinations, which are vivid auditory or visual experiences. These symptoms may be difficult to recognize, especially in children, where they may resemble nightmares. Narcoleptic patients tend to have dreams involving flying, being chased, and crawling into a tube more than non-narcoleptic patients do [5]. Additional symptoms include disrupted nighttime sleep and participating in automatic behavior while sleeping, but having no memory of doing things (e.g., talking, eating, putting things away) [5]. Abnormal REM sleep includes persistence of muscle tone, excessive twitching, and periodic leg movements while sleeping.

Difficulties with Diagnosis Complicate Epidemiological Estimates Given the variable phenotype for narcolepsy, there is no gold standard for diagnosis. Many of the symptoms overlap with non-narcoleptic patients. Generally, diagnosis

M. Goswami et al. (eds.), Narcolepsy: A Clinical Guide, DOI 10.1007/978-1-4419-0854-4_4, © Humana Press, a part of Springer Science + Business Media, LLC 2010

47

L. Hale

48

of narcolepsy with cataplexy requires the combina­ tion of the relatively common symptom of excessive daytime sleepiness with the uncommon symptom, cataplexy. There remains some controversy over whether cataplexy need be an essential feature of narcolepsy, however. Symptoms can vary in their nature and seve­ rity, which complicates diagnosis, and could lead to misdiagnosis. Indeed, both excessive daytime sleepiness and cataplexy-like symptoms can be reported in non-narcoleptic patients with other sleep disorders and even in healthy patients [5]. In addition, before diagnosing a patient, physicians need to rule out other potential causes for excessive daytime sleepiness, including inadequate sleep hygiene, use of medications or illicit drugs, sleep-disordered breathing, and delayed sleep phase syndrome. Further, hypersomnia can disguise other neuropsychiatric conditions, including autism and depression. Due to the potential for misdiagnosis and people not seeking or not knowing of treatment, it is estimated that less than 50% of patients with narcolepsy have been diagnosed [10]. And among those who are diagnosed with narcolepsy in the United Kingdom, the median interval between symptom onset and receiving a diagnosis of narcolepsy is 10.5 years, although it appears to be decreasing [13]. A sample among narcolepsy patients in southern China reveals a mean time to diagnoses of 16 years [14]. Diagnostic criteria have been updated to three categories of narcolepsy: narcolepsy with cataplexy, narcolepsy without cataplexy, and narcolepsy due to another underlying condition (see Table 4.1). Diag­ nosis is based on a clinical presentation along with both night and daytime polysomnographic (PSG) testing. In narcoleptic patients, sleep latency is low, and there is the presence of sleep onset REM periods or SOREMPs. Patients are usually diagnosed for narcolepsy using the multiple sleep latency test (MSLT), which assesses the degree of sleepiness and timing of REM sleep onset. The MSLT is performed by allowing five opportunities for the patient to nap at 2-h intervals throughout the day, as described elsewhere [15]. Sleep-onset REM sleep indicates that REM occurs within 15  min of sleep onset, while sleep latency refers to the time from lights out to stage I sleep, for each nap. The mean sleep latency (the arithmetic mean for all naps) provides an index of the severity of sleepiness. Patients with narcolepsy usually have an MSL of less than 8 min. However, low MSL

Table  4.1  Diagnostic criteria for narcolepsy (Adapted from Longstreth [1]; from the International Classification of Sleep Disorders: Diagnostic and Coding Manual. Westchester, IL: American Academy of Sleep Medicine, 2005) Narcolepsy with Cataplexy • Excessive daytime sleepiness • Definite history of cataplexy • MSLT optional but advised • Hypersomnia not better explained by another disorder Narcolepsy without Cataplexy • Excessive daytime sleepiness • Typical cataplexy is not present • Abnormal MSLT required • Hypersomnia not better explained by another disorder Narcolepsy due to medical condition • Excessive daytime sleepiness • Definite history of cataplexy, abnormal MSLT, or low CSF or hypocretin-1 levels • Underlying medical or neurological disorder accounts for daytime sleepiness • Hypersomnia not better explained by another disorder MSLT Multiple Sleep Latency Test; CSF cerebrospinal fluid

can occur in up to 15% of the population so this is not enough to diagnose narcolepsy. When a patient has a combination of sleep-onset REM and an MSL of less than 5 min, the MSLT has a sensitivity of 70% but a specificity of 97% for narcolepsy [16]. Laboratory tests for human leukocyte antigen (HLA) and cerebrospinal fluid (CSF) hypocretin-1 (110 pg/ mL or less) analysis also can be helpful diagnostic tools. The majority of narcolepsy patients with cataplexy are carriers of the HLA DQB1*602 gene [17, 18]. In addition, animal and human studies show a connection between a deficiency in the hypothalamic orexin/ hypocretin system and the pathogenesis of narcolepsy with cataplexy [19–22].

Prevalence and Incidence Estimates Vary by Methods and Populations Most of the early literature on narcolepsy was based on case reports. A series of case reports collected by physicians at the Mayo Clinic details many early experiences with the disorder [1]. Yet, while these studies were important, they did not provide any information on the prevalence of narcolepsy in the population. As with many rare diseases, prevalence varies depending on the study methods and population. Longstreth et al. [1]

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4 Epidemiology of Narcolepsy

provide a table (Table 2a in their article) summarizing narcolepsy prevalence estimates and other details from 30 studies around the world. Generally, for more intensive screening, the prevalence of narcolepsy with cataplexy falls between 25 and 50 per 100,000 people in the United States and Western Europe [2, 3, 6]. When prevalence rates are based on self-reported diagnosis or initial symptom screening but no follow-up testing, the prevalence rates are higher and some go up to 799 per 100,000 in the US Gallup poll in 1997. The Gallup study also reveals that only 53% of participants had heard of narcolepsy, and only 28% of those felt they knew what it was. Thus, basing prevalence data on self-reports of an unknown disorder is of questionable value. Of their review, Longstreth et al. identified a set of 12 studies in which patients are more intensively screened for narcolepsy [1]. For example, Ohayon et al. [2] conducted a representative population-based sample of nearly 19,000 Europeans from five countries (UK, Germany, Italy, Portugal, and Spain) and diagnosed narcolepsy according to the International Classification of Sleep Disorders (ICSD). Their results are within the range of other estimates at 26–47 per 100,000 people, for moderate to severe narcolepsy. Another analysis of the entire population of Olmsted County in Minnesota has a range of 36–56 per 100,000 people, depending on whether the definition requires the symptom of cataplexy or not [6]. The lowest prevalence estimate among the sample of more intensively screened epidemiological studies [1] is 1.08 per 100,000 people in a survey of providers and pharmacies in Singapore [23]. This number may be low due to under diagnosis or low reporting to the Singapore General Hospital. Prevalence of narcolepsy symptoms vary dramatically depending on the study design. In general, the symptoms of narcolepsy are much more common than the diagnosis with cataplexy. Studies show that daytime sleepiness is prevalent in approximately 8–15% of adults [2, 24]. Incidence of narcolepsy, which is less frequently studied, is estimated at 0.74 per 100,000 person-years for those with narcolepsy and cataplexy and 1.37 per 100,000 person-years for narcolepsy with or without cataplexy (1.72 per 100,000 person-years for men and 1.05 per 100,000 person-years for women) [6]. These incidence rates are similar to those of multiple sclerosis and motor neuron disease.

Age of Onset Generally Begins in the First Two Decades Age of onset for narcolepsy usually starts in the second decade of life. In Olmsted County, the age of onset had a median of 16 years with a full range between 4 and 56 years. In this sample, age of onset was unrelated to sex or HLA type [6]. Several studies reveal a bimodal distribution of age of onset, with the first peak at age 15 years, and the second peak at age 35 years [14, 25]. In Southern China, the bimodal patterns were observed even after separating the sample into males and females and cataplectic and non-cataplectic. The only difference was that the ages of the peaks in females came earlier than that for males, which may be related to puberty [14]. An analysis of 57 narcoleptic patients in Switzerland shows that only 5% of the sample started having symptoms of narcolepsy before age 10, and only 8% after the age of 40 [5]. In general, the pediatric literature has paid scant attention to the disorder, but is becoming recognized as an important key to understand the disease [26, 27]. Parents may not recognize excessive daytime sleepiness in a child under five, and not know to report it. Daytime sleepiness in school-aged children and adolescents is relatively common at 17–21% [28]. Once children start attending school, however, parents and teachers may become more aware of the frequent napping behaviors of narcoleptic children. Another reason it may be hard to diagnose among young children is that they may also experience the episodes of sleepiness differently than adults [26]. At the other end of the age spectrum, narcolepsy prevalence data in the elderly are not available [29]. Secondary forms of narcolepsy can occur at any age, and are typically due to intracerebral disease such as brain tumors or head trauma [30].

Narcolepsy Without Cataplexy Is More Common Among Men than Women Several studies that have looked at gender and narcolepsy do not see large differences by gender with regard to narcolepsy [3, 14]. Yet, in Olmsted County and in the Mayo Clinic case series, narcolepsy appears to be more common in men than in women [1, 6].

L. Hale

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Analyses from the Wisconsin Sleep Cohort Study show that the gender difference is larger in those without cataplexy [31].

excessive daytime sleepiness have up to four times the risk of a motor vehicle accident compared to controls [5, 36, 37].

Narcolepsy Has Few Links to Lifestyle Characteristics

Narcolepsy Overlaps with a Variety of Co-morbidities

Given the rarity and complications with diagnoses, it is difficult to compare estimates across studies to look for ethnic differences, but some comparisons suggest that there is as much as a 2,500-fold difference in ethnic predisposition to narcolepsy [32]. Japanese popu­ lations have much higher rates of narcolepsy than Israeli Jews [18]. But these dramatic differences may be in part due to differences in stringency of the definitions for narcolepsy. With regard to lifestyle, very few studies show a link between lifestyle and behavioral characteristics such as tobacco or illicit drug use or exercise are related to narcolepsy [1]. The Longstreth review refers to studies that show an association between narcolepsy and excessive alcohol consumption. Small studies during the 1970s revealed that narcoleptics ate more snacks throughout the day than controls, but in the end narcoleptic patients consumed fewer calories total. One investigation shows that there are no increased eating disorders among patients with narcolepsy [33]. Early studies showed that narcoleptic cases were more likely to be overweight, and were associated with non-insulin-dependent diabetes mellitus. Obesity appears to be present in the early stages of the disease, even when the disease begins in childhood. However, it is not clear whether the symptoms of narcolepsy precede the onset of the weight [34].

Given the associations with obesity, narcolepsy is correlated with higher risks of type 2 diabetes mellitus and cardiovascular disease. Initial case studies show that patients with narcolepsy are at a high risk of migraine or other headaches. These headaches may be due to either the disorder itself or the treatment. Narcolepsy may also be associated with other sleep disorders, such as sleep apnea (which is related to excess weight) and parasomnias [3, 5]. There is also a set of conditions that appear to have the same symptoms as narcolepsy, but it is unclear whether they are causally linked to narcolepsy. For example, narcolepsy and schizophrenia, which both usually begin in one’s teenage years or early twenties, have many of the same symptoms, although schizophrenia is more common than narcolepsy. These overlapping symptoms sometimes lead to misdiagnoses and mistreatment. Hallucination patterns may differ by narcolepsy and schizophrenics [38]. Auditory hallucinations are more common in schizophrenia whereas visual or kinetic may be more common in narcolepsy [38]. It is unknown whether having narcolepsy or schizophrenia might confer risk of getting the other [39], but it is likely that the similar symptoms among narcoleptics and schizophrenics are due to either just chance or medical treatments [40]. Similar questions are asked about the linkages between narcolepsy and bipolar disorder [41]. Patients with Parkinson’s Disease also have excessive daytime sleepiness, yet in general they do not suffer from cataplexy [42].

Narcolepsy Impairs Quality of Life and Increases Accident Risks Individuals with narcolepsy have greatly reduced outcomes with regard to quality of life (across a series of domains, bodily pain, social functioning, and general health), educational attainment, and memory, in addition to higher incidence of motor vehicle accidents [35–37]. In the classroom, narcolepsy is related to poor grades, interpersonal problems with teachers, and embar­ rassment [37]. In the workplace, narcoleptic patients are more likely to report reduced job performance, fear of job loss, and job dismissal [37]. Finally, patients with

Narcolepsy Has Both a Genetic and Environmental Link The genetics of narcolepsy is complex. In humans, narcolepsy is more common among first-degree relatives, but it is less common than one would expect based on normal inheritance patterns [43]. Concordance among monozygotic twins is only 25–31%, emphasizing

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4 Epidemiology of Narcolepsy

the importance of environmental factors [18]. As with many other conditions, there is likely a genetic susceptibility to an environmentally controlled event [17, 18]. Genetically, there are tight ties to multiple genes including HLA DQB1*602 (which is present in around 25% of the population), with other interacting alleles [17]. Over 85% of narcoleptic patients with cataplexy have this allele compared to no more than 38% in the general population, depending on the population. In Israel, for example, less than 7% of a sample of 252 healthy controls had HLA DQB1*602, which suggests this population has a lower percentage of genetic susceptibility to narcolepsy. This is consistent with large epidemiological studies showing a very low prevalence of narcolepsy Israel [44, 45]. Canine narcolepsy is genetically transmitted in Dobermans and Labradors [46, 47], but the links between canine narcolepsy and human narcolepsy are unknown.

Seasonality of Birth Gives Clues to Environmental Origins of Narcolepsy Narcolepsy is more common among patients who were born between March (with a peak odds ratio of 1.45), with the lowest prevalence of narcolepsy occurring for those born in September (with a trough odds ratio of 0.63) in a study using data from France, Canada, and the United States [48]. In Southern China, narcolepsy prevalence peaks for those patients with births in January (OR = 3.0 with 95% Confidence Interval = 1.4– 6.4) [14]. This seasonal pattern suggests that exposure in utero may have an increased risk of the disease, but this does not explain why concordance between monozygotic and dizygotic twins is not higher. Differences in environment could include in utero nutrition, sunlight, toxins, infectious agents, and temperatures. For example, children born in certain months may be more likely to get an infection after birth that may lead to a future risk of narcolepsy.

Treatment Options Are Developing Rapidly Narcolepsy is currently an incurable disease, but it is not a progressive disease. Treatment options for narcolepsy focus on behavioral and lifestyle changes in addition to medications.

Non-pharmacologic treatment of narcolepsy includes standard sleep hygiene advice: maintaining a regular sleep–wake schedule, scheduling afternoon naps, avoiding caffeine and nicotine, and engaging in regular exercise. Many of these behaviors would be recommended for any patient, and treatment can be highly individualized depending on severity of daytime sleepiness, cataplexy, and sleep disruption [29, 49]. It may also be appropriate to restrict driving, and report it as necessary by law for one’s jurisdiction [29]. Stimulants, such as methylphenidate or dextroamphetamine, or more recently the non-amphetamine wake-promoting modafinil, are used to increase alertness during the day [50]. At present, the leading treatment for most patients is modafinil, which has undergone extensive randomized clinical trials showing its safety and effectiveness [51]. Treating cataplexy, however, requires something different. Tricyclic anti-depressants (TCAs) have been used since the 1960s to address cataplexy; however, their efficacy has never been studied in large, controlled trials. Selective serotonin reuptake inhibitors (SSRIs) have also been used as treatment for cataplexy, although they are less efficacious than TCAs in treatment of cataplexy [7]. Gamma-hydroxybutyrate (GHB) or sodium oxybate is the first medication approved by the FDA in 2002 for the treatment of cataplexy, with large well-controlled studies to demonstrate its effectiveness for the long-term treatment of cataplexy, without tolerance [7, 52]. Although it is more expensive than other treatment options, sodium oxybate also results in improvements in daytime sleepiness and reduction in fragmented nighttime sleep [52]. To date, knowledge of hypocretin deficiency peptide is not well incorporated into the treatment, and this is an important area for future research. In general, effective pharmacologic treatments have been found empirically, but the modes of action are not well understood.

Looking Ahead: The Future of Epidemiology of Narcolepsy With the rapid development of sleep centers and improved ability to test and treat sleep disorders, awareness about the diagnosis and prevalence of narcolepsy has increased dramatically. Thus knowledge about the predictors and consequences of narcolepsy at the population level is growing. Understanding the

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epidemiology of the disease should help scientists focus on the social, behavioral, genetic, and environmental pathways and consequences of the disease. Even with the increased understanding, however, narcolepsy remains rare enough that many people do not know about the disorder nor know when or where to get tested. At the clinical level, individual concerns are primarily about quality of life and daily functioning. The public health implications of the disease relate to public safety, because patients with narcolepsy are at a heightened risk of falling asleep while driving. With regard to social disparities, to the best of the scientific knowledge, the disease does not target certain socially vulnerable populations more than others. However, due to high rates of non-diagnosis, misdiagnosis, or delayed diagnosis, there is a serious problem for people who do not have access to health care or are not receiving adequate treatment or diagnosis. In addition, due to the social and occupational difficulties with the disease, people with narcolepsy may be more prone to fall through the cracks. Disadvantaged populations, particularly the unemployed who do not have as much access to health care, should be considered at a higher risk for having undiagnosed cases of narcolepsy. Through better epidemiological research on narcolepsy, the scientific and medical community can improve awareness, early recognition, and treatment of the disease.

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L. Hale   8. Krahn LE, Lymp JF, Moore WR, Slocumb N, Silber MH. Characterizing the emotions that trigger cataplexy. J Neuro­ psychiatry Clin Neurosci 2005;17(1):45–50.   9. Wise MS. Narcolepsy and other disorders of excessive sleepiness. Med Clin North Am 2004;88(3):597–610, vii–viii. 10. Thorpy MJ. Narcolepsy. Continuum 2007;13(3):101–14. 11. Gelb M, Guilleminault C, Kraemer H, et al. Stability of cataplexy over several months – information for the design of therapeutic trials. Sleep 1994;17(3):265–73. 12. Broughton WA, Broughton RJ. Psychosocial impact of narcolepsy. Sleep 1994;17(8 Suppl):S45–9. 13. Morrish E, King MA, Smith IE, Shneerson JM. Factors associated with a delay in the diagnosis of narcolepsy. Sleep Med 2004;5(1):37–41. 14. Wing YK, Chen L, Fong SY, et al. Narcolepsy in Southern Chinese patients: clinical characteristics, HLA typing and seasonality of birth. J Neurol Neurosurg Psychiatry 2008; 79(11):1262–7. 15. Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 2005;28(1):113–21. 16. Arand D, Bonnet M, Hurwitz T, Mitler M, Rosa R, Sangal RB. The clinical use of the MSLT and MWT. Sleep 2005; 28(1):123–44. 17. Mignot E, Lin L, Rogers W, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet 2001;68(3):686–99. 18. Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998;50(2 Suppl 1):S16–22. 19. Chemelli RM, Willie JT, Sinton CM, et  al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999;98(4):437–51. 20. Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000;6(9):991–7. 21. Buskova J, Vaneckova M, Sonka K, Seidl Z, Nevsimalova S. Reduced hypothalamic gray matter in narcolepsy with cataplexy. Neuro Endocrinol Lett 2006;27(6):769–72. 22. Silber MH, Rye DB. Solving the mysteries of narcolepsy: the hypocretin story. Neurology 2001;56(12):1616–8. 23. Seneviratne U, Puvanendran K. Narcolepsy in Singapore: is it an elusive disease? Ann Acad Med Singapore 2005;34(1): 90–3. 24. Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry 1996;39(6): 411–8. 25. Dauvilliers Y, Montplaisir J, Molinari N, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 2001;57(11):2029–33. 26. Hood BM, Harbord MG. Paediatric narcolepsy: complexities of diagnosis. J Paediatr Child Health 2002;38(6):618–21. 27. Peterson PC, Husain AM. Pediatric narcolepsy. Brain Dev 2008;30(10):609–23. 28. Kothare SV, Kaleyias J. Narcolepsy and other hypersomnias in children. Curr Opin Pediatr 2008;20(6):666–75. 29. Chakravorty SS, Rye DB. Narcolepsy in the older adult: epidemiology, diagnosis and management. Drugs Aging 2003; 20(5):361–76.

4 Epidemiology of Narcolepsy 30. Nishino S, Kanbayashi T. Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypotha­lamic hypocretin/orexin system. Sleep Med Rev 2005;9(4):269–310. 31. Mignot E, Lin L, Finn L, et  al. Correlates of sleep-onset REM periods during the Multiple Sleep Latency Test in community adults. Brain 2006;129(Pt 6):1609–23. 32. Wing YK, Li RH, Lam CW, Ho CK, Fong SY, Leung T. The prevalence of narcolepsy among Chinese in Hong Kong. Ann Neurol 2002;51(5):578–84. 33. Dahmen N, Becht J, Engel A, Thommes M, Tonn P. Prevalence of eating disorders and eating attacks in narcolepsy. Neuropsychiatr Dis Treat 2008;4(1):257–61. 34. Muller HL, Muller-Stover S, Gebhardt U, Kolb R, Sorensen N, Handwerker G. Secondary narcolepsy may be a causative factor of increased daytime sleepiness in obese childhood craniopharyngioma patients. J Pediatr Endocrinol Metab 2006;19 Suppl 1:423–9. 35. Daniels E, King MA, Smith IE, Shneerson JM. Health-related quality of life in narcolepsy. J Sleep Res 2001;10(1):75–81. 36. Aldrich MS. Automobile accidents in patients with sleep disorders. Sleep 1989;12(6):487–94. 37. Broughton R, Ghanem Q, Hishikawa Y, Sugita Y, Nevsimalova S, Roth B. Life effects of narcolepsy in 180 patients from North America, Asia and Europe compared to matched controls. Can J Neurol Sci 1981;8(4):299–304. 38. Dahmen N, Kasten M, Mittag K, Muller MJ. Narcoleptic and schizophrenic hallucinations. Implications for differential diagnosis and pathophysiology. Eur J Health Econ 2002;3 Suppl 2:S94–8. 39. Kishi Y, Konishi S, Koizumi S, Kudo Y, Kurosawa H, Kathol RG. Schizophrenia and narcolepsy: a review with a case report. Psychiatry Clin Neurosci 2004;58(2):117–24. 40. Walterfang M, Upjohn E, Velakoulis D. Is schizophrenia associated with narcolepsy? Cogn Behav Neurol 2005; 18(2):113–8.

53 41. Douglass AB. Narcolepsy: differential diagnosis or etiology in some cases of bipolar disorder and schizophrenia? CNS Spectr 2003;8(2):120–6. 42. Arnulf I. Excessive daytime sleepiness in parkinsonism. Sleep Med Rev 2005;9(3):185–200. 43. Ohayon MM, Ferini-Strambi L, Plazzi G, Smirne S, Castronovo V. Frequency of narcolepsy symptoms and other sleep disorders in narcoleptic patients and their first-degree relatives. J Sleep Res 2005;14(4):437–45. 44. Peled N, Pillar G, Peled R, Lavie P. [Narcolepsy]. Harefuah 1997;133(1–2):43–7. 45. Lavie P, Peled R. Narcolepsy is a rare disease in Israel. Sleep 1987;10(6):608–9. 46. Hungs M, Fan J, Lin L, Lin X, Maki RA, Mignot E. Identification and functional analysis of mutations in the hypocretin (orexin) genes of narcoleptic canines. Genome Res 2001;11(4):531–9. 47. Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999;98(3):365–76. 48. Dauvilliers Y, Carlander B, Molinari N, et al. Month of birth as a risk factor for narcolepsy. Sleep 2003;26(6):663–5. 49. Zeman A, Britton T, Douglas N, et al. Narcolepsy and excessive daytime sleepiness. BMJ 2004;329(7468):724–8. 50. Black J, Guilleminault C. Medications for the treatment of narcolepsy. Expert Opin Emerg Drugs 2001;6(2): 239–47. 51. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy: US Modafinil in Narcolepsy Multicenter Study Group. Neurology 2000;54(5): 1166–75. 52. A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep 2002;25(1):42–9.

Chapter 5

Narcolepsy in Childhood Suresh Kotagal and Shalini Paruthi

Historical Notes

Introduction

Westphal published the first good description of the disease in 1877 as “strange attacks of falling to sleep” [1]. He used the term “epileptoid” to describe it. In 1880, Jean Baptiste Gélineau wrote of a patient who was experiencing as many as 200 sleep attacks per day, some probably cataplectic [2]. Gélineau believed that he was dealing with a disorder that was distinct from epilepsy, and hence proposed the term “narcolepsy.” He wrote of “a specific neurosis, characterized by the twofold criterion of drowsiness and falling or astasia” [2, 3]. In June 1930, Janota and Skala presented a paper at the Neurological Society of Prague which described the successful treatment of narcolepsy with ephedrine sulfate, but the work was not formally published [3]. A series of 147 patients with narcolepsy was published by Luman Daniels from the Mayo Clinic in 1934 [4]. A distinction was made between idiopathic and symptomatic forms of narcolepsy, but Daniels questioned the relevance of classifying them separately. The term “cataplexy” was first used by Adie [5]. It was defined by the Oxford Dictionary of the early twentieth century as a “temporary paralysis or hypnotic state in animals when shamming death.” Cataplessa in Greek means to strike down with fear or the like [5]. In the early 1930s, a neurologist at the Mayo Clinic, upon seeing a patient in an attack of cataplexy, made the following vivid observation “he looked like a patient with myasthenia gravis for 30 s, then normal [4].”

Narcolepsy is a lifelong neurologic disorder of rapid eye movement sleep. The International Classification of Sleep Disorders, Second Edition (ICSD-2), provides three classifications of narcolepsy, including narcolepsy with cataplexy, narcolepsy without cataplexy, and narcolepsy due to a medical condition, all of which apply to children [6]. The tetrad of narcolepsy is characterized by excessive daytime sleepiness for at least 3 months, hypnagogic or hypnopompic hallucinations, sleep paralysis, and cataplexy; the additional complaint of disrupted nocturnal sleep completes the pentad of narcolepsy. The diagnosis of narcolepsy is particularly challenging in children, given the variability in clinical presentation, limited descriptive ability of the child, and variations in reliability of the parents as historians.

S. Kotagal () Department of Neurology and the Center for Sleep Medicine, Mayo Clinic, Rochester, Minnesota, USA e-mail: [email protected] S. Paruthi Sleep Disorders Center, University of Michigan Medical Center, Ann Arbor, MI, 48109, USA e-mail: [email protected]

Prevalence The prevalence of narcolepsy is estimated to be 0.05% globally. Variation exists due to the inconsistency of clinical diagnostic criteria [7], such as requiring coexistence of cataplexy, and characterization by frequency and intensity of cataplexy. Some epidemiologic studies have exclusively evaluated children. For instance, Honda queried school children aged 12–16 years in Fujisawa, Japan, by using a questionnaire, and estimated a prevalence of 160/100,000 or 0.16% for narcolepsy with cataplexy [8]. In contrast, Han found a prevalence of 40/100,000 or 0.04% among 70,000 consecutive children evaluated in China in a pediatric neurology clinic using a screening questionnaire, polysomnogram (PSG), multiple sleep latency test (MSLT), and human leukocyte antigen (HLA) typing [9].

M. Goswami et al. (eds.), Narcolepsy: A Clinical Guide, DOI 10.1007/978-1-4419-0854-4_5, © Humana Press, a part of Springer Science + Business Media, LLC 2010

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Other epidemiologic studies include wider age ranges of adults and children. In the United States, prevalence and incidence were analyzed through the records-linkage system of the Rochester Epidemiology Project in Olmstead County, Minnesota. Silber et  al. found the overall prevalence of narcolepsy to be 0.056%, with an incidence of 1.37 per 100,000 persons per year (1.72 for men and 1.05 for women) [10]. Approximately 36% of prevalence cases did not have cataplexy. Further examination of data by age groups of 0–9 years and 10–19 years showed a prevalence rate of narcolepsy with cataplexy of 4/16,074 and 15/15,112, respectively. These figures were slightly higher for cases without cataplexy. Incidence was calculated as 1.01 for the 0–9  year age group and 3.84 for the 10–19 year age group [10]. It is well known that a lag often exists between symptom onset and diagnosis of narcolepsy in adults – this may apply to children as well. Guilleminault et  al. studied 410 patients, finding the mean age at onset of daytime hypersomnia was 23.7 ± 12.9  years (median age 20.9  years) [11], with the diagnosis of narcolepsy often made in the third or fourth decades. The typical age of onset of narcolepsy is also disputed [7, 12–14]. For example, Silber et al. found a median age at diagnosis of 16 years in the Olmstead county population, with a range of teens to early twenties [13]. On the other hand, Dauvilliers et  al. found a bimodal distribution in Canadian and French subjects, with peaks at ages of 14.7 and 35  years (n = 519) [14].

Clinical Presentation Pre-School-Age Children Narcolepsy is rare in pre-school-age children, with rates ranging from 4.6% (235 patients) [15] to 11.7% (85 patients) [16] diagnosed by age 5 years. Nevsimalova described a boy whom she has followed for years who was noted to have cataplexy at 6 months, found to be HLA DQB1*0602 negative, and subsequently diagnosed with hypocretin-deficient narcolepsy due to a mutation in the hypocretin-1 gene. He suffered severe bulimia in early childhood, predominantly at night. Post puberty he developed hypnagogic hallucinations,

sleep paralysis, disrupted night sleep, automatic behavior, and behavioral disorders. He was the only child to present with the full tetrad of narcolepsy in her case series of 23 children [17, 18]. Additionally, Sharp and D’Cruz described a 12-month-old with hypersomnia, which was later confirmed to be narcolepsy [19]. In general, diagnosing narcolepsy prior to age 4 or 5 years is difficult as physiologic napping still commonly occurs in this age group; besides, the ability to verbalize history of cataplexy, sleep paralysis, and hypnagogic hallucinations is limited. Judicious use of family history, sleep diaries, actigraphy, histocompatibility antigen (HLA) typing, and cerebrospinal fluid (CSF) hypocretin-1 measurement, and polysomnography can aid in early diagnosis of suspected narcolepsy in this age group.

School-Age Children Excessive daytime sleepiness is the most universal and disabling characteristic of narcolepsy. School-age children are likely to present with daytime sleepiness, including sleep attacks (an irresistible urge to nap). Sleep attacks most commonly occur during sedentary activities such as sitting in a classroom or reading. The consequences of sleepiness include impaired memory consolidation, decreased concentration, impaired executive functioning, and emotional disorders [20, 21]. Automatic behaviors (performing behaviors without recall) and mood swings have been described [20, 21]. Excessive daytime sleepiness can manifest as reemergence of napping in a child who had previously stopped napping. Most children stop napping between the ages of 5 and 6 years, thus the MSLT has not been validated in this younger population. Naps in children with narcolepsy are often longer than those seen in adults (30–90 min duration), and in contrast to adults, children do not uniformly experience a refreshed feeling after the nap [21, 22]. Parents may not recognize daytime sleepiness until it starts affecting the child’s mood, behavior, or academic performance. Moreover, daytime sleepiness can manifest as behavioral problems or poor performance in school. Teachers may mistake sleepiness for laziness. Sleepiness in children may mimic attention deficit hyperactivity disorder (ADHD) [23], oppositional behavior, or disruptive conduct disorder. It is important

5 Narcolepsy in Childhood

to recognize that young children may actually exhibit increased motor activity and disruptive behavior as a consequence of sleepiness [24]. Multiple researchers, including Teixeira et al., have investigated the psychosocial problems at school as recalled by adults with narcolepsy [24]. One-half of the 45 respondents recalled falling asleep in class. A third or more of respondents noted achieving less than capable performance, interpersonal conflicts with teachers, embarrassment due to symptoms, or inability to use their qualifications. Eleven percent recalled difficulty making friends and taking frequent days off [24]. Stores et al. assessed the psychosocial difficulties of 42 children with narcolepsy (mean age 12.4, range 7.3–17.9), 18 subjects with excessive daytime sleepiness unrelated to narcolepsy (EDS; mean age 14.2, range 5.1–18.8), and 23 unaffected controls (mean age 11.3, range 6–16.8) [25]. They found significantly higher scores on the Strengths and Difficulties Ques­ tionnaire in the narcolepsy and EDS groups. The domains of this questionnaire included prosocial, peer problems, hyperactivity, conduct problems, emotional problems, and adverse impact on the family. As compared to healthy controls, both the narcolepsy and EDS group scored higher on the Child Depression Inventory. Children with narcolepsy and EDS also had more absences from school (means 6.4 and 5.3 days, respectively) as compared to controls (mean 1.3) and showed more problems on a composite educational difficulties score, suggesting that sleepiness in general, rather than narcolepsy per se adversely influences the psychosocial and emotional health of the patients [25]. Cataplexy is the most specific feature, and the second most common manifestation of narcolepsy after excessive sleepiness. It was identified in 80.5% of idiopathic narcolepsy and in 95% of symptomatic narcoleptic patients by Challamel et al. [16]. It is characterized by brief episodes of symmetric muscle atonia in which consciousness is preserved (thus distinct from a state of sleep) that occurs in response to emotional triggers such as laughter, fright, anger, or surprise. The duration of each episode is generally less than 2–3 min, but sometimes a series of episodes may be clustered together in a sequence. Cataplexy can be subtle such as a head bob, jaw dropping open, minor buckling of the knees, or it can be more pronounced with the child falling to the floor. The child may not be able to laugh during the episode, but can resume laughing when muscle tone returns. The loss of muscle tone is especially

57

likely to affect the anti-gravity muscles such as the extensor muscles of the thighs, back, or neck. Children may develop defense mechanisms to minimize the impact of cataplexy on their lives – some may avoid attending fun-filled and exciting events like birthday parties, whereas others may attend a birthday party but try to avoid smiling or laughing. These behaviors may over time impact the development of peer relationships (authors’ opinion). Cataplexy results from intrusion of skeletal muscle atonia, characteristic of REM sleep onto wakefulness [26–29]. There is hyperpolarization of spinal alpha motor neurons that results in active inhibition of skeletal muscle tone and suppression of the monosynaptic H-reflex and tendon reflexes. Cardio­ vascular and respiratory functions remain intact. It is also difficult for children to provide a description of cataplexy, given its unusual nature and the embarrassment they may feel because of it. A trigger can often be identified and may be associated with usually positive, rarely negative, conversation, thoughts, or actions. For example, Kotagal describes a 6-yearold girl with proven narcolepsy who denied any episodes of weakness, yet she would repeatedly fall whenever she jumped on a trampoline [28]. Hypnagogic or hypnopompic hallucinations are noted in 50–60% of narcoleptic patients, and are described as vivid, sometimes frightening, dream-like images. They can be auditory or visual in nature. Sleep paralysis is described as an inability to move or speak when falling asleep or awakening from sleep. Both can be normal, but the child with narcolepsy is more likely to describe them as occurring regularly or on a daily basis. Children may also complain of disrupted nocturnal sleep. Sleep fragmentation is common in narcolepsy patients. This may be intrinsic to narcolepsy or due to periodic limb movements of sleep (PLMS) which are more frequently reported in narcolepsy patients. Sleep fragmentation may occur with or without electroencephalographic evidence of cortical arousal. (See earlier chapter for further discussion of PLMS in narcolepsy.) Particularly, Young and colleagues describe PLMS in five of eight children with narcolepsy [29]. The combination of symptoms of inattentiveness, trouble sleeping at night, sleepiness, and bizarre hallucinations can lead to a psychiatric misdiagnosis such as depression or schizophrenia. This clearly emphasizes the need to gather a complete psychiatric history including depression or mood changes to distinguish true psychopathology versus consequences of narcolepsy.

58

In a report of 51 children found to have narcolepsy, all children presented at least once during follow-up with depressive symptoms as a response to their disease [27]. Information is becoming available regarding beha­ vioral manifestations in childhood narcolepsy. An example of a well-validated tool is the Conners’ Rating Scale, primarily used to assist with a diagnosis of ADHD, but can also provide information on the consequences of sleepiness in children with suspected narcolepsy. Neuropsychological deficits are difficult to define in pediatric narcolepsy at this time due to the lack of valid and practical batteries of neuropsychological tests for sleepy children. Adults with narcolepsy demonstrate selective cognitive deficits in response latency and word recall [30].

Histocompatibility Antigens and Human Narcolepsy The association between narcolepsy and HLA DR2 was reported in 1984 by Juji and coworkers in Japan [31]. As in adults, HLA typing is a useful diagnostic tool in children. In 2001, Mignot demonstrated a strong association of narcolepsy with HLA DQ antigens, specifically DQB1*0602 and DQA1*0102, which are present in 95–100% of narcoleptic patients, as compared to a 12–38% prevalence in the general population [32]. Homozygosity of these two haplotypes is associated with a twofold to fourfold increase in the likelihood of developing narcolepsy over heterozygotes; however, the presence of the haplotypes does not predict severity [33]. HLA DQB1*0602 has a strong association with the prepubertal development of narcolepsy [27]. In contrast, it has also been suggested that DQB1*0601 and DQB1*0501 are protective alleles [32]. HLA typing is expensive and may not be covered by insurance carriers.

Hypocretin Deficiency Narcolepsy was shown to be tightly associated with hypocretin-1 deficiency in 2000. Nishino and others have shown that a CSF level less than 100 pg/mL carried a diagnostic sensitivity of 84.2% and was almost always found in patients who are HLA DQB1*0602

S. Kotagal and S. Paruthi

positive and had narcolepsy with cataplexy [34–36]. Thannickal found an 85–95% reduction of hypocretin producing neurons in the hypothalamic region [37]. The hypocretin-1 secreting neurons that are located in the dorso-lateral hypothalamus have widespread projections to alerting regions in the forebrain, and also to the brainstem. The “REM-off’ neurons of the locus ceruleus that are located in the midbrain have receptors for hypocretin-1 and are normally activated by hypocretin. It is possible therefore that hypocretin deficiency leads to imbalance between “REM off” and “REM on” neurons, whereby uninhibited “REM on” neurons faci­ litate the superimposition of REM sleep onto wakefulness in the form of cataplexy, hypnagogic hallucinations, and sleep paralysis. In the absence of cataplexy, the value of hypocretin-1 testing is not fully understood. Currently, CSF hypocretin-1 measurement is limited due to hesitancy of patients to undergo lumbar puncture and limited assay availability. To date, studies have not been able to elicit consistent results from blood testing for hypocretin-1 levels. The CSF hypocretin-1 assay should be considered in HLA DQB1*0602 positive cases when MSLT data will be difficult to interpret (such as pre-school age children), and when the patient is receiving REM-suppressant medications like selective serotonin reuptake inhibitors (SSRIs) or tricyclic agents (TCA) that cannot be stopped safely.

Two Threshold Hypothesis The development of narcolepsy is multifactorial; in addition to increased susceptibility with the presence of HLA antigens, it is felt that stresses such as bereavement, systemic illnesses, and injuries may play a role as trigger factors. A combination of the genetic predisposition and acquired stress seems to trigger most cases of narcolepsy [38]. Case series of monozygotic twins provide the strongest evidence for this with high discordant rates up to 13/20 (65%) in twins [39–42]. For example, Honda describes a pair of twins, with one child developing narcolepsy–cataplexy at age 12 years, and the other twin developing narcolepsy at age 45 years after suffering from emotional stress and sleep deprivation [41]. Major environmental events have been found to be present in up to 82% of narcolepsy patients, compared to 42% of controls (p  NC patients 5 4 3 2 1 0 −1 −2 −3 −4

b NC patients > Controls

Hypothalamus (12x, 3y, -18z) humor neutral

Controls

Patients

fMRI effect size

Amygdala (33x, 3y, -21z) humor

4 3 2 1 0 −1 −2

neutral

Controls

Patients

Fig. 11.2  Functional brain maps showing group differences in response to humor. (a) Right hypothalamus (plus medial prefrontal and cingulate cortex) activation for controls but not for NC patients. Parameter estimates derived from hypothalamic peak illustrate selective activation for humorous stimuli in the

controls. (b) Increased amygdala response to humor in NC patients compared to controls. Parameter estimate show increased fMRI signal to humorous sequences in the patients but not in the controls. Statistical maps are overlaid on an average T1-structural scan

would in turn suppress the amygdala response [77–79]. Thus, reduced hypothalamic and prefrontal activity, together with increased amygdala activation in NC patients found in the present study, could reflect a dysfunction of this Hcrt/DA-mediated pathway leading to an abnormal release of amygdala response to positive emotions in narcolepsy. The left NAcc also showed increased activity for humorous stimuli in the patients. The NAcc is a wellknown key component of the mesolimbic reward system that has strong interconnections with the amygdala, prefrontal cortex, and thalamus [70]. Increased activity in the nucleus accumbens could be secondary to increased amygdala activity, or might result from a disruption of direct Hcrt modulation of brain reward networks [13–16]. Effects of Hcrt depletion on the behavioral response to reward was found in Hcrt knockout mice that show attenuated withdrawal response to morphine [80]. Similarly, human NC patients who are often treated with highly addictive amphetamine-like drugs rarely become addicted to these drugs [1, 7, 28, 81]. Moreover, NC patients often

report that they experience muscle weakness (cataplexy) when they play exciting games or when they anticipate positive feelings (such as winning a game) [23]. Future neuroimaging studies may use dedicated reward paradigms to directly test whether Hcrt deficiency in humans selectively affects the activity in brain reward circuits. Preliminary fMRI results from our group suggest distinct effects of high motivational cues and/or reward delivery in NC patients compared to healthy controls, involving the ventral midbrain (VTA), the striatum, and the amygdala [82].

Implications for Models of Cataplexy Because of the similarity between cataplexy attacks and muscle atonia during rapid-eye-movement (REM) sleep, it was postulated that cataplexy represents an intrusion of REM sleep during wakefulness. Specifically, the H-reflex disappears during cataplexy, while REM sleep is presumed to be the only state in

A. Ponz and S. Schwartz

122

which the H-reflex is normally inhibited [25]. Yet, recent findings demonstrate that the H-reflex can also be suppressed during laughter in NC subjects as well as in healthy controls (see Section  11.2.1) [32, 33]. Instead of a REM-related phenomenon, Overeem et al. [83] suggested that cataplexy may be an atavism of tonic immobility or freezing, i.e., defense or fear response patterns involving a sudden immobilization of the animal and which typically rely on amygdala functioning [71, 84–87] . Tonic immobility shares some similarities with cataplexy, as both phenomena are induced by a strong emotion, and activate the amygdala. Moreover, a role of the Hcrt system in defense or fear response control is suggested by animal findings showing that the Hcrt system allows the maintainance of a high level of wakefulness in order to elaborate appropriate behavioral reactions to threats [11, 89] or to acute stress [90]. Corticotrophin-releasing factor (CRF) released during stress was found to mediate stress-induced activation of the Hcrt system, which then relays these signals to brainstem nuclei involved in the modulation of arousal, as well as to the extended amygdala involved in emotional response [91, 92]. Such a functional link between Hcrt and limbic systems supports the idea that cataplexy in Hcrt-deficient NC patients may involve a dysfunction in the hypothalamus-amygdala response to emotions. However, there are several limitations to the hypothesis that cataplexy-atonia is analogous to tonic immobility. First of all, negative emotions are not commonly involved in cataplexy; nor are they specific of clear-cut cataplexy [23, 88]. Moreover, no study to date has reported pure muscle atonia in humans in response to an intense emotion (either positive or negative). Instead, “tonic immobility” in humans usually refers to an “active resistance” to a physical threat in the context of traumatic situations (e.g., rape, life-threatening events) [93]. Functional MRI studies on humor processing in healthy volunteers as well as our own data from NC patients demonstrate that the amygdala is not only involved in reactions to danger but is also strongly activated during laughing and humor processing (see above) [42, 58, 63, 66]. While these data establish that the amygdala represents a crossroads for responses to threatening signals and positive emotions, more research is needed to better understand the multifaceted role of the amygdala in the regulation of emotions, motivational behaviors, and sleep [94].

Conclusions The data reviewed in this chapter provide evidence for an implication of hypothalamus-amygdala circuits in the pathophysiology of human narcolepsy. NC patients show an altered functional interaction between hypothalamus and amygdala regions during the processing of positive emotions, consistent with the clinical observation that positive emotions can trigger cataplexy in these patients. The human Hcrt system may thus regulate hypothalamus-limbic circuits involved in the integration of emotion, reward, and sleep processes. In this chapter, we also show that modern brain imaging methods offer unprecedented means to assess brain functions not only in healthy controls but also in patients with a complex sleep disorder such as narcolepsy–cataplexy. Acknowledgments  This work was supported by grants from the Swiss National Science Foundation (# 3200B0-104100, # 3100A0-102133), by the National Centre of Competence in Research (NCCR) Affective sciences financed by the Swiss National Science Foundation (# 51NF40-104897), and the Geneva Center for Neurosciences.

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Chapter 12

Dreams in Patients with Narcolepsy Michael Schredl

Although narcolepsy is a sleep disorder involving the REM sleep systems, systematic research of dream recall and dream content in these patients is scarce. Prior to the review of the studies, several introductory remarks will be presented. Dreaming is defined as mental activity which occurs during sleep [1]. In many ways subjective dream experiences are comparable with those in the waking state, e.g., regarding perception (visual, auditory, etc.), emotions, and being part of the ongoing action; while bizarre elements like flying or metamorphoses might also be part of the dream [2, 3]. It is important, though, to notice that dreaming itself cannot be directly assessed; the only source available is the dream report recalled by the person upon awakening. As early as the nineteenth century, Maury [4] raised the question as to whether dreams are really recollections of mental processes occurring during sleep or whether they unfold during the awakening process. Modern research combining physiological approaches with dream content analysis, however, has been able to demonstrate that dream reports are accounts of mental activity during sleep since physiological parameters, e.g., eye movements, heart rate, electromyographic records, measured while the person was in REM sleep, at least partially match the dream contents elicited upon awakening [5]. In addition, the incorporation of stimuli applied during sleep into dreams corroborates the assumption that dreaming is indeed a mental activity during the sleep state [2, 3]. After the discovery of REM sleep by Aserinsky and Kleitman [6], it was possible to study dreams M. Schredl (*) Sleep Laboratory, Central Institute of Mental Health, PO Box 12 21 20, 68072, Mannheim, Germany e-mail: [email protected]

systematically in the sleep laboratory. Nielsen [7] reviewed 35 studies in which persons have been awakened and asked for their mental activity prior to the awakening. Over 80% of the REM awakenings and almost 50% of the NREM awakenings yielded dream reports. Based on these high recall rates, several researchers (e.g. [8]) assume that dreaming is always present during sleep; the brain and the mind never sleep. Since dream recall frequency has been linked to sleep parameters, e.g., frequency of nocturnal awakenings, sleep duration and REM sleep physiology (overview: [9]), the question arises whether the presence of a sleep disorder like narcolepsy might affect dream recall. Secondly, since the dreaming process itself might be affected by the sleep disorder, it seems very promising to study dream content in patients with narcolepsy. The dreams of patients with narcolepsy have been described as vivid and often disturbing [10–13], although Vogel [14, 15] found equal proportions of negative and positive emotions in sleep onset dreams of narcoleptic patients. He also reported that the patients were aware more often of their state of consciousness during dreaming, i.e., they knew that the dream experience was not real. A small pilot study was conducted by Schredl [16] to investigate dream recall and dream content in narcoleptic patients more systematically. The sample of 23 patients showed higher dream recall frequency on a questionnaire measure and a tendency to report more negatively toned dreams upon awakening in the sleep laboratory in comparison to healthy controls. Dream content analysis of 14 dreams recorded by 8 patients during the diagnostic nights in the sleep laboratory clearly showed that the dreams of these patients were more bizarre than those of healthy controls. The following dream example will illustrate this:

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126 “I dreamt that I stepped out of the bright light of the lamp and slipped into another time period. I met my grandfather who I had never seen in my waking life and saw other persons from my hometown, much younger than today. With the help of friends I managed to travel back to the present time. I even brought some stuff from the past with me which my mother identified as her former belongings.” ([16], p. 106)

A REM awakening study [17, 18] in 15 patients with narcolepsy indicated that the percentage of recall after REM awakenings is very high in these patients (about 90%) and comparable to the figures obtained from matched controls. Overall, the late night dreams of the patient group were shorter than those obtained from the control group but correlations of sleep fragmentation (stage shifts, movements prior to awakening) to dream length or other dream characteristics were not found [17]. In the patient group, the sleep onset REM dreams (elicited during the day) are more vivid and more intense (fear/anxiety and joy/elation) than the patients’ nighttime dreams [18]. The patients with narcolepsy showed higher scores on a scale measuring reflective consciousness, i.e., they were aware more often that they were dreaming (in sleep onset REM dreams and night-time dreams) compared to healthy controls [17]. Despite the extensive methodology, some questions are not answered by Fosse’s study, e.g., effect of age on dream content (the sample included persons from 17 to 70), effect of coping with the disorder (the sample consisted mainly of welladjusted members of the Norwegian Narcolepsy Association) and the question as to whether dream content differs in drug-naïve patients (most patients had discontinued their treatment). To summarize, the deregulation of the REM sleep system underlying narcolepsy also manifests in dream changes like higher dream recall frequency, more negatively toned and bizarre dreams. Larger samples are necessary to replicate the findings of the reviewed pilot studies [16, 17]. It would be very interesting to study whether specific disorder-related symptoms (e.g., daytime sleepiness) or problems regarding the coping with the sleep disorder are reflected in dream content, as it would be predicted by the specific continuity hypothesis formulated by Schredl [19]. In this line of research, the sleep-onset REM periods of narcoleptic patients are of particular interest since one might find more incorporations of, for example, a presleep film elements than in REM periods occurring at least 90 min after the actual waking life experience.

Since simple methods for coping with bad dreams and nightmares are available (Imagery Rehearsal Therapy; [20]), narcoleptic patients should by asked about their dream experiences in the course of diagnosis, so that specific treatment procedures for nightmares can be included. Up to now, no systematic research on nightmare treatment in patients with narcolepsy has been carried out, not even a case report of a successful intervention has been reported. Lucid dreaming as a treatment for nightmares [21] might be well suited for these patients since they were often aware that they are dreaming within the dream.

References 1. Schredl, M. and Wittmann, L. (2005) Dreaming: A psychological view. Swiss Arch Neurol Psychiatr 156, 484–492. 2. Strauch, I. and Meier, B. (1996) In search of dreams: Results of experimental dream research. Albany: State University of New York Press. 3. Schredl, M. (2008) Traum. München: Reinhardt/UTB. 4. Maury, A. (1861) Le sommeil et les reves. Paris: Didier. 5. Erlacher, D. and Schredl, M. (2008) Do REM (lucid) dreamed and executed actions share the same neural substrate? Int J Dream Res 1, 7–14. 6. Aserinsky, E. and Kleitman, N. (1953) Regularly occurring periods of eye motility and concomitant phenomena during sleep Science 118, 273–274. 7. Nielsen, T. A. (2000) A review of mentation in REM and NREM sleep: “covert” REM sleep as a possible reconciliation of two opposing models. Behav Brain Sci 23, 851–866. 8. Wittmann, L. and Schredl, M. (2004) Does the mind sleep? An answer to “What is a dream generator?” Sleep Hypnosis 6, 177–178. 9. Schredl, M. (2007) Dream recall: models and empirical data. In: Barrett, D. and McNamara, P. (eds) The new science of dreaming – Volume 2: Content, recall, and personality correlates. Westport: Praeger, pp. 79–114. 10. Nixon, O. L., Pierce, C. M., Lester, B. K., and Matthis, J. L. (1964) Narcolepsy: nocturnal dream frequency in adolescents. J Neuropsychiatr 5, 150–152. 11. Passouant, P. and Cadilhac, J. (1967) Activite onirique et narcolepsie. J Psychol Norm Pathol 64, 171–187. 12. Roth, B. and Bruhova, S. (1969) Dreams in narcolepsy, hypersomnia and dissociated sleep disorders. Exp Med Surg 27, 187–209. 13. Lee, J. H., Bliwise, D. L., Labret-Bories, E., Guilleminault, C., and Dement, W. C. (1993) Dream-disturbed sleep in insomnia and narcolepsy. J Nerv Ment Dis 181, 320–324. 14. Vogel, G. W. (1960) Studies in psychophysiology of dreams: III. The dream of narcolepsy. Arch Gen Psychiat 3, 421–428. 15. Vogel, G. W. (1976) Mentation reported from naps of narcoleptics. Adv Sleep Res 3, 161–168.

12 Dreams in Patients with Narcolepsy 16. Schredl, M. (1998) Dream content in narcoleptic patients: preliminary findings. Dreaming 8, 103–107. 17. Fosse, R. (2000) REM mentation in narcoleptics and normals: an empirical test of two neurocognitive theories. Conscious Cogn 9, 488–509. 18. Fosse, R., Stickgold, R., and Hobson, J. A. (2002) Emotional experience during rapid-eye-movement sleep in narcolepsy. Sleep 25, 724–732.

127 19. Schredl, M. (2003) Continuity between waking and dreaming: A proposal for a mathematical model. Sleep Hypnosis 5, 38–52. 20. Krakow, B. and Zadra, A. (2006) Clinical management of chronic nightmares: imagery rehearsal therapy. Behav Sleep Med 4, 45–70. 21. Spoormaker, V. I. and Van den Bout, J. (2006) Lucid dreaming treatment for nightmares: a pilot study. Psychother Psychosom 75, 389–394.

Chapter 13

Psychoanalysis and Narcolepsy J. F. Pagel and Lawrence Scrima

Narcolepsy was first described as a diagnosis during the same era that Freud was developing his insights into psychodynamics. Freud’s first book on dreaming, published in 1900, startled and changed the fields of both neurology and psychiatry, and led to a psychoanalytic fascination with the dreamlike epiphenomena of narcolepsy. This association between narcolepsy and psychoanalysis has been bidirectional. There is a long history of both psychoanalytic techniques being utilized in the treatment of narcolepsy and the incorporation of physiologic insights of the basis for narcolepsy into psychoanalytic theory. The association of narcolepsy with REM sleep phenomena has been integrated and applied in forming the conceptual framework for some of the most widely accepted neuroscientific theories of consciousness.

Psychoanalytic Approaches to Narcolepsy Narcolepsy is an illness as strange as either epilepsy or schizophrenia with its symptoms of extreme sleepiness developing during the psychologically and sexually stormy years of adolescence. The diagnosis of narcolepsy was clearly associated with dream-like phenomena including bizarre hallucinations, sleep paralysis and cataplexy. To many, this illness seemed one clearly appropriate for treatment with the new psychoanalytic techniques of the early psychoanalysts. J.F. Pagel (*) University of Colorado School of Medicine Rocky Mt. Sleep, 1619 N. Greenwood Suite 107, Pueblo, Colorado, 81003, USA e-mail: [email protected]

Freud addressed sleep paralysis in The Interpretation of Dreams, postulating that the sensation of inhibited motor movement represented a “conflict of will” [1]. It is unclear whether Freud himself treated narcolepsy. Rumors of an unpublished and untranslated paper persist. Freud was not developing his theories in a vacuum. Gilineau (1880) in his initial presentation of narcolepsy had described it as a “neurosis,” placing it clearly within the purview of psychoanalysis [2]. Freud’s work contributed to the differentiation of neurology into separate fields of psychiatry and neurology. At the time diseases such as narcolepsy and epilepsy, now known to have clear neurological basis, were classified among the psychoses and neurosis. It is not surprising that psychoanalysis was used to treat narcolepsy, particularly during an era in which alternative treatment modalities for narcolepsy included electroshock therapy, insulin induced hypoglycemic coma, and psychosurgery [3–5]. Narcolepsy was often managed by psychological methods including analytic explorations into the background causes for the attacks of unwanted sleep [6]. Narcolepsy was viewed as one of the pathological states of sleep and consciousness disturbances, “basically…a form of neurosis to be treated by psychotherapeutic means.” [7]. Before the use of activating medications for narcolepsy became accepted in the 1930s, many narcoleptics underwent extensive psychoanalysis of their bizarre dreams and their dream-associated behaviors. During Freud’s era, sleep itself was viewed by some as “a nirvana state of the intrauterine life, while awakening symbolizes the painful birth” [8]. Such perspectives were incorporated into Freud’s insights into the association between sleep and dreaming: “all dreams

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are in a sense dreams of convenience: they are the purpose of prolonging sleep instead of waking up, because they are the guardians of sleep and not its disturbers [9].” “Thus the wish to sleep, must in every case be reckoned as one of the motives for the formation of dreams and a successful dream is the fulfillment of that wish [10].” From this psychoanalytic perspective, sleep was often described as an escape mechanism [11]. The view of sleep as a temporary escape from harsh reality into a memory of protected intrauterine nirvana would lead to a series of psychodynamic explanations for narcolepsy as a disease of psychological regression [12, 13]. The concept of sleep as “momentary suicide” was adopted by some schools of psychoanalytic thought [14]. Jones (1936) highlighted the potential role of psychological factors in the etiology of narcolepsy in a 22-year-old patient: “It seems logical to suppose that the sleep attacks have developed from the previous states of dissociation. The faints, the cataplexies, amnesias and sleeps may then be regarded much the same in function, in giving the patient a temporary escape from reality” [15]. Dream analysis is intrinsic to the therapeutic process of psychoanalysis. In a Freudian sense, dreams are the process by which we deal with or at least review within the shelter of our mostly unconscious dream state, repressed and suppressed experiences and emotions, as well as or in light of all our positive and negative experiences and memories. Freud posited that repressed feelings, especially of loss, may inspire sublimation, fostering higher cultural achievement [16]. For the Freudian psychoanalyst dreams include repressed memories and emotion that can be brought into waking consciousness through the techniques of free association and dream analysis. Once the dream is available for waking analysis, the dream provides useful insights into the patient’s and the therapist’s psychodynamics. Dreams were viewed somewhat differently by Carl Jung with emphasis on shared symbols and archetypes. In a Jungian sense, dreams may facilitate “transcendent” function by integration of opposing trends to work toward an ideal good “... the unconscious expression of a desire for wholeness is found in dreams ...” [17]. Psychoanalysts have focused on the symbolism and fascinating condensation of ideas to be found in dreams, using the content of impactful, significant dreams in the attempt to understand an individual’s personality and emotional conflicts [18].

J.F. Pagel and L. Scrima

The extraordinarily bizarre dreams of narcoleptic patients provided fertile ground to be utilized in psychoanalytic therapy for the illness. Psychoanalytic theoretic constructs based on repression, abuse, mythology, and transference served as a basis for attempts at intense interpersonal therapy for patients with the diagnosis. In case reports, narcolepsy was postulated to occur in particular patients with “difficulties in realistic adjustments in personal relationships with others” [19]; as well as a result of “the unconscious wish to return to an incestuous relationship with his sister during a somnolent state” [20]. Such perspectives have extended into the modern era, “The psychogenic fraction of narcolepsy is centered about unacceptable impulses and defenses they provoke. In cataplexy episodes, sexual and aggressive actions and fantasies are blocked on a neuromuscular level. A sleep attack is far more complicated and some aspects may be compared to a classical psychoneurosis because the symptom provides not only defense but simultaneous disguised gratification of a wish” [21]. More recent studies into the dreams of narcoleptic patients utilize the same rational: “Data obtained from a study of dreams of narcoleptic patients clearly demonstrates the force of sexual drive and aggressive instinct in these individuals. These drives are so strongly suppressed and guilt ridden during wakefulness that the representations and affects that could express these drives do not attain consciousness. In certain circumstances, however, that which is repressed and suppressed tends to reappear at the conscious level and it is this situation that the narcoleptic or cataplectic attack appears” [22]. It seems appropriate to point out that only a subset of narcolepsy patients were treated with psychoanalysis. There are major psychoanalytically based texts of psychiatry that do not even mention the diagnosis of narcolepsy or cataplexy [18, 23]. However, today, community and medical conceptions of narcolepsy continue to be affected by its psychogenic history. Patients may view the diagnosis as one based on suppressed, guilt-ridden, sexual drives. This conceptual association can contribute to social and medical handicaps for some narcolepsy patients [24]. Narcolepsy patients complain of physicians and cohorts demonstrating a lack of understanding and on occasions taking a moral stance in labeling them as “lazy, unable to work, or unable to face the vicissitudes” [25].

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Narcolepsy – The Rems Model In 1964, Rechtschaffen and Dement determined that in patients with narcolepsy associated with cataplexy, both sleep paralysis and hypnogogic hallucinations occurred in association with REMs periods. This finding led to their hypothesis that consciousness could best be described as occurring during three relatively independent neurophysiological states – wakefulness, sleep, and the paradoxical state of REMS [26] (Fig. 13.1). The dreams reported from narcoleptics during sleep onset REMS periods could be utilized as a model for the psychological and physiological characteristics of the dream state, as narcoleptics can go to sleep quickly during the day, and are accustomed to naps, and about 50% of their naps have REMS [27]. A research paradigm, called the narcolepsy approach paradigm (NAP) provided an efficient way to study REMS and NREMS dreams, psychological, and physiological functions. It has also been used to study what affects REMS, non-REMS, or dreams, more directly and what effect REMS, non-REMS and dreams have on various performance tests, etc. as well as providing some guidelines on how to better predict REMS vs. non-REMS naps in narcoleptics [28]. This approach was used in the attempt to determine how REMS and non-REMS might function as part of a CNS information processing system, providing the first direct evidence in humans (narcoleptics) that REMS significantly improved memory of complex associative information more so than non-REMS or an equal period of nonrehearsing wakefulness, and confirmed (replication of several earlier studies) that non-REMS significantly improved memory of complex associative information more so than an equal period of nonrehearsing wakefulness [29]. This research was inspired by the a

THE THREE STATES OF BEING

REMS WAKE

NREMS

Fig. 13.1  The hypothesized three states of consciousness

priori Neuronal Activity Correlates (NAC) theory of information processing [30]. Based on EEG correlates of information processing capacity, the NAC theory was proposed to predict differential effects of REMS and non-REMS on memory. This theory proposes that since there is limited data suggesting that complex mentations are associated with high amplitude slow wave EEG, or synchronous spindle EEG of nonREMS, NREM sleep could prevent retroactive interference and thereby provide some memory enhancement by preventing new information from interfering with recall of information acquired before non-REM sleep. Whereas complex mentation may be more likely to be associated with low-amplitude, mixed frequency EEG waves, alpha and theta EEG waves of wakefulness and REMS. Such EEG activity correlated with wakefulness and REMS may be necessary for information processing and learning, but should also promote retroactive interference during later recall tests. Studies have repeatedly demonstrated that recall after wakefulness is less than after sleep which has been explained by retroactive interference, which should also apply to REMS [31–33]. The data collected with the NAP method supports the theory that REMS is actively involved in information processing, since it did not interfere with recall of complex associative information like the awake condition. Moreover, the data supports the passive theory of preventing retroactive interference for improved recall after non-REMS, since it was significantly better than recall after the awake condition [29]. There is still much controversy on the role of sleep and REMS on memory, despite studies demonstrating that sleep improves memory, there is still contradictory data on the effect of REMS on memory, especially from REMS deprivation studies which have confounding stress factors, and the precise role of how sleep improves memory [34]. Other authors have used the sleep onset REMS phenomena of narcolepsy to derive information and theoretical models for dreaming. REM sleep theoretically came to be equated with the presence of dreaming. The symptoms of narcolepsy are postulated to be related to dreaming since they are associated with REMS [35]. Based on this concept that the REMS phenomena of narcolepsy are equivalent to dreaming, data based on narcolepsy have been applied to our understanding of dreaming in normal individuals. This association has contributed to narcolepsy being considered

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as a disorder of the reticular activating system, the system controlling REMS and the system considered to be the primary center for the control of sleep and wakefulness [36].

Narcolepsy and Neuroscientific Theory The association between narcolepsy and dreaming has altered the definition of dreaming. Psychoanalysts have stretched the definition of dreaming to include the REMS associated states of narcolepsy, defining dreams as bizarre, hallucinatory mental activity that can occur in either a sleep or a wake state [37]. This has become the most generally accepted psychoanalytic definition of dreaming. When “bizarre” is defined as “discontinuities and improbabilities unlikely to occur in waking life,” the dreams of narcoleptics associated with hypnagogic hallucinations and sleep paralysis are more “bizarre” than other dreams. [38]. Severe anxiety may accompany episodes of sleep paralysis occurring either at sleep onset (hypnagogic) or offset (hypnopompic), when the individual feels conscious but unable to move, speak and, at times, breathe properly and be further aggravated if disturbing hypnagogic hallucinations or dream sequences accompany the paralysis [39]. Some authors have proposed that other mentation occurring during sleep that does not meet such “bizarreness” criteria is not dreaming. It is suggested that this nonbizarre mentation be referred to as sleep associated thought rather than as dreaming [40]. Some authors have postulated that the occurrence of dreaming, defined as bizarre hallucinatory mentation, occurring outside REM sleep indicates that REM sleep must occur outside what is polysomnographically defined as REM sleep. This theory would account for the dream reports from other sleep stages and for dream-like mentation reported while awake [40]. The most commonly utilized definition of dream for a sleep medicine physician (mentation reported as occurring in sleep) contradicts this psychoanalytic definition for dream [37]. Some theorists have extended the postulate that dreams are bizarre, hallucinatory mental activity, to support the theory that dreams are a form of visual hallucination. Dreams seem to have some qualities of hallucinations, in that they feel like what is unfolding in a dream seems real and happening to us or to someone

J.F. Pagel and L. Scrima

else that we are observing. This perspective is based on formal characteristics of the dreaming process that can be considered hallucinatory: visual and motor hallucinations, the delusional acceptance of hallucinoid experience as real, extremely bizarre spatial and temporal distortion, strong emotion, and the failure to remember – findings far more characteristic of sleep paralysis and hypnagogic hallucinations than normal dreaming. These authors suggest that the dream is a hallucination because the dreamer has a “delusional” acceptance during dreaming of the dream experience as being real [41]. This view of dreaming as hallucinatory and delusional has contributed to the view of dreaming as a valid model for psychosis. The concept of dream as hallucination has been widely incorporated into modern dream theory. If dreaming is basically a perceptual hallucination, it is easier to consider dreaming as a simple meaningless, perceptual state based on primitive brain-stem activity (REM sleep) of the self-referenced mind [41]. Viewed as a process of perceptual hallucination, dreaming can be postulated to be one of the processes utilized by the CNS during sleep to detoxify the system of unwanted memories of potentially pathological nature such as obsessions, hallucinations and delusions. The hallucination theory of dreaming has been so utilized in supporting the “erasure” theory of Crick and Mitchinson (1983) [42]. Extending this view to its logical conclusions, sleep itself can be considered as a state independent of waking consciousness, a state of unconsciousness or coma, as well as a state of perceptual dislocation. In other words, sleep could also be considered a hallucinatory state in which actual perceptions (external objects) are negated by the CNS perceptual system [43]. Psychodynamically based interpretations of narcolepsy associated symptoms, particularly sleep paralysis, continue to be published [44, 45]. The dream associated phenomena of narcolepsy continue to be considered as representative of the dreaming state [38, 46]. The conception of REM dreaming as bizarre and REM sleep as a psychodynamically primitive state of CNS activation parodying the psychoanalytic “Id” persists in modern versions of Activation-Synthesis theory including AIM [41] (Fig.  13.2). Psychodynamic, neuroanatomical, and neurochemical postulates as to the pathophysiology of narcolepsy have been based on this theoretical construct. Such postulates have included:

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13 Psychoanalysis and Narcolepsy

A W

NREM

M

Direct entry into REM

Narcolepsy AIM theory box: Activation (A), Modulation (M), Input-Output gating (I), Wake (W).

REM

I Fig. 13.2  AIM theory – disorders related to input–output gating: narcolepsy – “Instead of traversing the NREM domain of the AIM conscious state space (dotted line) en route to REM sleep, patients with narcolepsy are pulled directly into it. They can thus experience all or part of REM sleep behavioral complex at the edge of waking. This is why they have sleep-onset REM periods.” Hobson A. [41] p. 201

1. In narcolepsy full blown REMS replaces waking consciousness. [41] 2. The emotionally based symptoms of narcolepsy, temporal lobe seizures, and normal dreaming result from unchecked paroxysmal discharges of limbic lobe neurons. [41] 3. Narcolepsy exaggerates the normally partial dissociations of waking and dream consciousness. While having hallucinatory experiences within dreams is analogus to psychosis, having them while awake is identical to psychosis. [41] 4. Narcolepsy involves a deficiency of dopamine. [41] The status of these postulates based on AIM theory can now be compared to actual data based on PET, and f-MRI scans as well as recent genetically based research into the neurochemistry and neural interconnections involved in the disease state of narcolepsy. This data demonstrates that the neurochemistry and neuroanatomy of narcolepsy and cataplexy vary markedly from postulates based on the AIM hypothesis.

Discussion The use of psychoanalysis as a treatment option for narcolepsy was based on theory. Psychoanalysis was also less likely to induce harm for the patient than the available treatment options in the early twentieth

century of psychosurgery and electroshock therapy. There is little evidence, even based on anecdotal case studies, that psychoanalysis led to an improvement in patient symptoms or affected the course of the illness for individual patients in a positive fashion. In the current era, narcolepsy is clearly a neurological illness with well defined genetic, electrophysiological, and neurotransmitter basis. Psychoanalysis based therapy is rarely used in its treatment, however, its psychoanalytic history continues to affect social and medical attitudes towards patients with the diagnosis. The effects of narcolepsy on psychoanalytic theory have been far more persistent. Integrated through psychoanalytic theory, the dream-like epiphenomena of narcolepsy have been incorporated into popular and theoretical conceptions of dreaming, sleep, and consciousness. Adapted versions of the NAP protocols continue to be used to study both physiological and psychological aspects of dreaming in REMS and NREMS sleep [47]. Psychoanalysis failed as a treatment and psycho-pathogenesis model when applied to narcolepsy, yet psychoanalytic theory has been preserved in modern cognitive state definitions and neuroscientific theories of consciousness such as AIM. Because these theories have been based on and applied in studies of narcolepsy, current scientifically based insights into the pathogenesis of the disease state of narcolepsy provide a useful measuring stick as to the predictive value of such hypotheses.

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134 8. Ferenczi S. (1913) Entwicklungsstufen des wirklichteirsinnes. Internat Zeitschr f artzl Psychoanalyse I, 124, cited by Notkin & Jelliffe 1934. 9. Freud S. (1900) The interpretation of dreams I, vol. 4, A dream is the fufillment of a wish, chap. 3, p. 233. In Strachey J (ed.), The complete Psychological Works of Sigmund Freud. London: Hogworth, 1953. 10. Freud S. (1900) The interpretation of dreams I, vol. 4, A dream is the fufillment of a wish, chap. 3, p. 234. In Strachey J (ed.), The complete Psychological Works of Sigmund Freud. London: Hogworth, 1953. 11. Wiley MM. (1924) Sleep as an escape mechanism. Psychoanal Rev II:181–3. 12. Wilson SAK. (1928) The Narcolepsies. Brain 51:63–109. 13. Wilson SAK (1928) The narcolepsies. Modern Problems in Neurology. Arnold, London 14. Wiley MM, Rice AR. (1924–1925) The psychic utility of sleep. J Abnorm Soc Psychol 19:174–178. 15. Jones MS. (1935–1936) A case of recurrent attacks of prolonged sleep. J Neurol Psychopatholl 16:130–139, p. 138. 16. Freud S. (1930) Civilization and its discontents. In Standard Edition, vol 21. London: Hogarth Press, 1961, First German Edition. 17. Jung CG. (1916) The transcendent function. In Collected Works, vol 8. Princeton, NJ: Princeton Press, Random House 1960, First German Edition. 18. Langworthy O, Betz BJ. (1944) Narcolepsy as a type of response to emotional conflicts. Psychosom Med 6:211–226, p. 226. 19. Gregory RL (ed.). (1987) Dreaming. In: The Oxford Companion to the Mind, Oxford: Oxford University Press, 201–203. 20. Coodley A. (1948) Psychodynamic factors in narcolepsy and cataplexy. Psychiatric Q 22:696–717. 21. Morgenstern AL. (1965) The neurotic component of narcolepsy. Am J Psychiatry. 122:306–12, p. 312. 22. Bourguignon A. (1976) Narcolepsy and psychoanalysis. In: Guilleminault C, Dement WC, Passouant P (eds.), Proceedings of the First International Symposium on Narcolepsy – Advances in Sleep Research, vol 3. New York, Spectrum, pp. 257–76, p. 259. 23. Menninger KA. (1945) The Human Mind – 3rd Edition. New York, Alfred Knopf. 24. Bladin PF, Wilson SJ, Saling MM, McIntosh PK, O’Shea MF. (1999) Outcome assessment in seizure surgery: the role of postoperative adjustment. J clin Neurosci 6(4):313–318. 25. Zarcone V. (1973) Narcolepsy N Engl J Med 288:1156–1168. 26. Rechtschaffen A, Dement WC. (1969) Narcolepsy and Hypersomnia. In: Kales A (ed.), Sleep: Physiology and Pathology. Philadelphia, PA: Lippincott. 27. Scrima L. (1981) An etiology of narcolepsy-cataplexy and a proposed cataplexy neuromechanism. Int J Neurosci 15:69–86. 28. Scrima L. (1982) The narcoleptic approach paradigm (NAP) for the direct study of dreams and dream sleep functions. Int J Neurosci 16:69–73.

J.F. Pagel and L. Scrima 29. Scrima L. (1982) Isolated REM sleep facilitates recall of complex associative information. Psychophysiology 19:252– 259, 1982; Dissertation Abstracts International 40(9):454B. 30. Scrima L. (1984) Dream sleep and memory: new findings with diverse implications. Integr Psychiatry 2:201–240. 31. Eskstrand B. (1967) Effects of sleep on memory. J Exp Psychol 75:64–72. 32. Lovatt D, Warr P. (1968) Recall after sleep. Am J Psychol 81:253–257. 33. Benson K, Feinberg I. (1975) Sleep and memory: retention 8 and 24 hours after intial learning. Psychophysiology 12:192–195. 34. Frank MG, Benington JH. (2006) The role of sleep in memory consolidation and brain plasticity: dream or reality. Neuroscientist 12(6):477–488. 35. Liddon SC. (1970) Sleep paralysis, psychosis and death. Am J Psychiat 126:1027–1031. 36. Liddon SC (1967) Sleep paralysis and hypnagogic hallucinations – Their relationship to the nightmare. Arch Gen Psychiat 17:88–96. 37. Pagel JF, Blagrove M, Levin R, States B, Stickgold B, White S. (2001) Definitions of dream: A paradigm for comparing field descriptive specific studies of dream. Dreaming 11(4):195–202. 38. Fosse R. (2000) REM mentation in narcoleptics and normals: An empirical test of two neurocognitive theories. Conscious Cogn 9:488–509. 39. Pagel JF, Nielsen T. (2005) Parasomnias: Recurrent Nightmares – The International Classification of Sleep Disorders – Diagnostic and Coding Manual (ICD-2). Westchester, IL: American Academy of Sleep Medicine. 40. Nielsen T. (2003) A review of mentation in REM and NREM sleep: “Covert” REM sleep as a reconciliation of two opposing models. In: Pace-Schott E, Solms M, Blagrove M, Harand S (eds.), Sleep and Dreaming: Scientific Advances and Reconsiderations. Cambridge, England: Cambridge University Press, pp. 59–74. 41. Hobson JA. (1999) Abnormal States of Consciousness: AIM as a Diagnostic Tool in Consciousness. New York: Scientific American Library, pp. 188–215. 42. Crick F, Mitchinson G. (1983) The function of dream sleep. Nature 304:111–114. 43. Pagel JF. (2008) The Limits of Dream – A Scientific Exploration of the Mind/Brain Interface. Oxford: Academic. 44. Cheyne JA, Rueffer SD, Newby-Clark IR. (1999) Hyponogogic and hyponopompic hallucinations during sleep paralysis: neurological and cultural construction of the night-mare, Conscious Cogn 8(3):319–337. 45. Cheyne JA, Girard TA. (2007) Paranoid delusions and threatening hallucinations: a prospective study of sleep paralysis experiences, Conscious Cogn 16(4):959–74. 46. Attarian HP, Schenck CH, Mahowald MW. (2000) Presumed REM sleep behavior disorder arising from cataplexy and wakeful dreaming. Sleep Med 1(2):131–133. 47. Pagel JF. (2008) Sleep stage associated changes in dream recall across the day on awakening from MSLT naps. Sleep 31:A373.

Chapter 14

Symptomatic Narcolepsy or Hypersomnia, with and Without Hypocretin (Orexin) Deficiency T. Kanbayashi, M. Nakamura, T. Shimizu, and S. Nishino

Introduction Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations (HH), and sleep paralysis (SP) (i.e., narcolepsy tetrad) [1, 2]. A major breakthrough in narcolepsy research was recently made through the identification of hypocretin deficiency in narcolepsy–cataplexy [2–9]. Hypocretins are hypothalamic neuropeptides involved in various fundamental hypothalamic functions including, sleep–wake control, energy homeostasis, autonomic and neuroendocrine functions [10–12]. Hypocretin containing neurons are located exclusively in the lateral hypothalamic area (LHA). Since hypocretin deficiency in narcolepsy is also tightly associated with human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602) positivity, an acquired cell loss of hypocretin containing neurons with autoimmune process are suggested in “so-called” idiopathic cases of narcolepsy [2, 6]. “Idiopathic narcolepsy” has been used for the cases with narcolepsy unassociated with apparent radiographical or clinical evidence of brain pathology apart from sleep-related abnormalities. Hypocretin deficiency in the brain can be determined clinically via cerebrospinal fluid (CSF) hypocretin-1 measures with CSF hypocretin-1 levels in healthy subjects above 200 pg/ml regardless of gender, age (from neonatal to 1970s), and time of the CSF collections [1, 4, 6]. Due to the specificity and sensitivity of low CSF

T. Kanbayashi (*) Department of Neuropsychiatry, Akita University School of Medicine, Akita, Japan e-mail: [email protected]

hypocretin-1 levels (less than 110 pg/ml or 30% of the mean normal levels) narcolepsy–cataplexy is high among various sleep disorders [2, 13, 14]; CSF hypocretin measures were in the diagnostic criteria for narcolepsy– cataplexy in the second edition of international classification of sleep disorders (ICSD-2) [15]. Impaired hypocretin systems may also be observed in some neurological disorders affecting the LHA (where hypocretin cell bodies locate) and/or hypocretin projection pathways. Indeed, an earlier study by Ripley et al. [13] had measured CSF hypocretin levels in 235 neurological patients and shown that a subset of subjects with acute or sub-acute neurological disorders (i.e., intracranial tumors, cerebrovascular events, craniocerebral trauma, central nervous system [CNS] infections, and Guillain-Barré Syndrome [GBS]) had decreased CSF hypocretin-1 level, although CSF hypocretin-1 levels in the majority of patients with chronic neurological conditions, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are not significantly reduced. Arii et  al. [16] also recently studied CSF hypocretin-1 levels in 132 pediatric neurological conditions. The results are consistent with Ripley’s study [13], and only a limited number of neurological conditions beside narcolepsy showed reduced CSF hypocretin-1 levels. These include intracranial tumors [16], craniocerebral trauma and autoimmune and post-infectious disease (GBS and acute disseminated encephalomyelitis [ADEM] [15]) and in some inherited disorders, such as Niemann-Pick disease, type C [NPC] and Prader-Willi syndrome [PWS] [16]. The findings by Ripley et  al. [13] and Arii et  al. [16] are particularly interesting since these neurological conditions are often associated with acutely disturbed consciousness, lethargy, sleepiness, and/or

M. Goswami et al. (eds.), Narcolepsy: A Clinical Guide, DOI 10.1007/978-1-4419-0854-4_14, © Humana Press, a part of Springer Science + Business Media, LLC 2010

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residual sleep disturbances. In rare cases, symptoms of narcolepsy can be seen during the course of a neurological disease process (i.e., symptomatic narcolepsy). Interestingly, involvements of the hypothalamic structures in symptomatic narcoleptic cases are emphasized repeatedly from several decades ago [17, 18], and impaired hypocretin system may also be involved in some symptomatic narcolepsy cases. Association with EDS/cataplexy in some inherited neurological diseases (such as NPC, PWS, or myotonic dystrophy [MYD]) is also known [19–21]. An impaired hypocretin system may thus also be involved in these sleep-related symptoms in conjunction with these neurological conditions. In this chapter, we first overview cases of symptomatic narcolepsy reported in literature. Since EDS without other narcolepsy symptoms can also occur with a variety of neurological disorders and are not usually an indication of narcolepsy, we will also extend our discussion on the roles of hypocretin system in EDS disorders associated with various neurological conditions. Since data of CSF hypoocretin-1 measures are available for some recent symptomatic narcolepsy and/ or EDS cases, we will focus on these cases and discuss the roles of hypocretin status in these disorders (Table 14.1). For this purpose, we categorized the cases as follows: (1) symptomatic narcolepsy–cataplexy associated with focal/generalized CNS invasion, such as cerebral tumors, vascular diseases and neurodegenerative disorders; (2) hypersomnia associated with focal/generalized CNS invasion, such as cerebral tumors, brain infections, vascular diseases, neurodegenerative disorders (AD and PD) and head trauma with CNS diseases mediated with neuroimmune mechanisms, such as inflammatory and demyelinating diseases (Sect.  4.2). Nonnarcoleptic hypersomnia categories include less defined EDS cases, and likely consist of heterogeneous conditions. This is partially due to the fact that applying standardized polygraphic assessments (all night polygraphic recordings followed by multiple sleep latency test [MSLT]) was often difficult in these neurological conditions. However, since prevalence of these hypersomnia cases appeared to be much higher than that of symptomatic narcolepsy, we believe that the discussion on the roles of the hypocretin system in less well-defined EDS cases also have valuable clinical implications.

T. Kanbayashi et al.

Definition of Symptomatic Narcolepsy and Its Overview Symptoms of narcolepsy can be sometime seen during the course of a neurological disease process. In such instances, the term “symptomatic narcolepsy” is used, implying that narcolepsy is a symptom of the underlying process rather than idiopathic. In this case, the signs and symptoms of narcolepsy should be temporally associated with underlying neurological process. Many authors use symptomatic narcolepsy and secondary narcolepsy indiscriminately, even though they have apparently different meanings. We suggest the use of symptomatic narcolepsy/EDS, since “secondary EDS” has also been used for EDS associated with sleep apnea and restless leg syndrome. Although several important original studies and extensive reviews for symptomatic narcolepsy are available [22–30], many older cases have no objective measures for sleepiness, and the diagnosis of these cases mostly based on the clinical criteria [31–39]. Furthermore, some of these reports did not provide the symptomatology and course of the assumed causal disease. The current diagnostic criteria for idiopathic narcolepsy include: (1) EDS occurring almost daily for at least 3  months or short sleep latency (SL) (less than 10 min [less than 8  min is used in second edition of ICSD]) [15] by MSLT together with (2a) cataplexy (sudden and transient episodes of loss of muscle tone triggered by emotions; narcolepsy with cataplexy in second edition of ICSD) or (2b) with abnormal REM sleep features documented by polygraphic measures (more than two sleep onset REM periods [SOREMPs] in MSLT; narcolepsy without cataplexy in second edition of ICSD) [15]. In our review, symptomatic narcolepsy is defined as the cases that met the criteria (if MSLT data were not available, equivalent polygraphic REM sleep abnormalities were also considered, and this is noted in each case). In addition, association with a significant underlying neurological disorder accounts for the EDS and temporal associations (narcolepsy onset should be within 3  years if the causative diseases are “acute” neurologic conditions) (see Ref. [40]). In contrast, if neither cataplexy nor polygraphic abnormal REM sleep features are associated with EDS (clinically “or” short sleep latency documented by polygraphic

Craniopharyngioma Hypothalamus

Germinoma

Arachnoid cyst

Choroid plexus carcinoma resection Adenoma

Tumor

E

E

E

N

NC

NC

Head trauma

E

Base of skull

15

M

M

Head trauma

E

+

+

+

M

21

+

M

Nonspecific

+

F

+

+

+

+

+

+

+

+

+

+

NM Craniopharyngioma Hypothalamus 11 by ICSD2 NM CNS lymphoma Left basal ganglia, 46 by thalamus, cerebral ICSD2 pedunculus, splenium of the corpus callosum, right internal temporal lobe Head trauma (n = 7) Head injury location E Head trauma Nonspecific 23

M

M = 2, F = 3 M = 2, F = 3 M = 2, F = 3 M = 2, F = 3 M = 2, F = 3 F

M

F

2 min/IEEG

3 min/MSLT

4.5 min/MSLT

?

1.4 min/MSLT

5 min/1EEG

6.4 min/MSLT

Mean:10.3 min/ MSLT Mean:10.3 min/ MSLT Mean:10.3 min/ MSLT Mean:10.3 min/ MSLT Mean:10.3 min/ MSLT 7.5 min/MSLT

?

1.7 min/MSLT

Gender EDS Sleep latency

F

60

Mean 15 Mean 15 Mean 15 Mean 15 Mean 15 28

11

16

Age

65

Pituitary, hypothalamus Hypothalamus

Pineal gland, thalamus

Thalamus

Hypothalamus

Craniopharyngioma Hypothalamus

E

E

N

Tumors (n = 12)

Location

Astrocytoma Hypothalamus resection Astrocytoma Suprasellar resection Craniopharyngioma Hypothalamus

E

Lesion

Narcoleptic symptoms

Table 14.1  Symptomatic narcolepsy or EDS with hypocretin measurements

−

−

−

?

+

+

+

+

?

?

?

?

?

+

−

−

−

−

−

−

+

+

−

−

−

−

−

−

−

−

?

+

−

−

−

?

−

−

?

?

?

?

?

−

−

DR2/ DQB1*0602 (DQw1)

SOREMP CA HLA