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, <2SOREMP in Idiopathic Hypersomnia per ICSD2. Hcrt : CSF hypocretin-1. HLA data from the Stanford Center for Narcolepsy Research database and ethnically matched controls [65]. MSLT data from the Stanford Center for Narcolepsy Research database, and 1,095 random controls from Mignot et al. [20] and Singh et al. [21]. CSF hypocretin-1 from the Stanford Center for Narcolepsy Research database and 182 CSF from healthy control subjects (volunteers or subjects undergoing spinal surgery for back pain)

1 Narcolepsy: Genetic Predisposition and Pathophysiology

Stanford canine colony. Familial autosomal recessive canine narcolepsy was also reported in Labrador Retri­evers and in a family of Dachshunds [31, 32]. Interes­tingly, experiments indicate that animals heterozygous for the canine narcolepsy gene (now known to be the hypocretin receptor 2) have subclinical abnormalities such as increased daytime sleepiness. In heterozygous animals, administration of drugs increasing the cholinergic and reducing the monoaminergic transmissions (manipulations known to promote REM sleep) can even induce cataplexy at specific developmental times [33]. The parallel between human and canine narcolepsy is striking. In MSLT-like procedures, narcoleptic canines have short sleep latency and faster REM onset [34]. Sleep fragmentation and proportionally more daytime sleep is observed during 24 h recordings [35]. Finally, as in human narcolepsy, sudden episodes of muscle weakness akin to cataplexy can be observed in association with strong positive emotions, most typically during the presentation of appetizing food or while at play (Fig.  1.1). These episodes usually last a few seconds and preferentially affect the hind legs, neck or face. Cataplexy may also escalate into complete muscle paralysis with abolition of tendon reflexes. During these episodes, the animal is conscious (for video, see: http:// www.med.stanford.edu/school/Psychiatry/narcolepsy/).

Fig.  1.1  Narcoleptic Doberman Pinschers in the middle of a cataplectic attack. Note eyes are open. Autosomal recessive forms of canine narcolepsy are due to mutations in the hypocretin receptor-2 gene [37]

5

Polygraphic recording indicates a desynchronized, wake-like EEG pattern at the onset of cataplexy, followed by increased theta activity and genuine REM sleep in long lasting episodes [36]. In 1999, after a long positional cloning project, mutations in a receptor for the newly identified neuropeptide system hypocretin (hcrtr2) were found to cause familial canine narcolepsy. Three different mutations causing a complete dysfunction of the receptor were identified in Doberman, Labrador and Dachshund pedigrees [32, 37]. Sporadic cases of canine narcolepsy were later shown to be associated with low CSF and almost absent brain hypocretin peptide content [38], as found in human narcolepsy [3, 4] (Fig. 1.2). Several rodent models of narcolepsy are also now available. In one model, Chemelli et al. [39] knocked out the preprohypocretin gene and found that the resulting mice had fragmented sleep, and rapid transitions from wakefulness into REM sleep. A reversible state of physical paralysis, akin to cataplexy or sleep paralysis, was also observed in these animals [39]. In another model, a toxic transgene derived from an ataxin-3 human gene mutation, was driven by the hypocretin promoter, resulting in narcoleptic mice lacking hypocretin-containing cells [40]. Rodents lacking either of the two hypocretin receptors, hcrtr1 and hcrtr2, are also now available [41, 42]. In these models, only hcrtr2 receptor knockout animals experience behavioral arrest episodes similar to cataplexy. Interestingly, however, hcrtr1 knockout animals have fragmented sleep patterns but no behavioral arrest episodes [42]. It is also suggested that hcrtr2 receptor knockout animals are less affected than hypocretin peptide knockout animals, suggesting a role for hcrtr1 in increasing the severity of the phenotype [41]. Interestingly, where it is clear that rodent hypocretin models have a narcolepsy-like phenotype, it is difficult to differentiate cataplexy from REM sleep transitions or sleep paralysis at sleep onset. The link between behavioral arrest and positive emotions is unclear and pharmacological characterization has not been performed. Further, whereas REM sleep bout length is clearly much shorter in rodents versus dogs or humans, the mean duration of cataplexy is not obviously shorter. This, together with the fact that cataplexy does not display any obvious circadian variation (as REM sleep) [43, 44], or has a different sensitivity to dopaminergic antagonists in animal models [45], suggests that cataplexy may not be simply equivalent to REM sleep atonia.

E. Mignot

6 mRNA in situ Hybridization

b

Hypocretin

a

1 cm

1 cm

d

MCH

c

Narcoleptic

Control

Fig. 1.2  Hypocretin (hcrt) and Melanin-Concentrating Hormone (MCH) expression studies in the hypothalamus of control and narcoleptic subjects. Hypocretin and MCH neurons are intermingled in this region of the hypothalamus. Staining of adjacent brain sections for MCH is showed for comparison as a control.

Prepro-Hcrt mRNA molecules are detected in the hypothalamus of control (b) but not in narcoleptic (a) subjects. MCH mRNA molecules are detected in the same region in both control (d) and narcoleptic (c) sections. f fornix. Scale bar in (a–d) represents 10 mm. Derived from Peyron et al. [3], with modification

Twin Studies and Environmental Factors in Narcolepsy

birth but rather in adolescence [12, 49], suggesting the existence of triggering factors. The nature of the environmental factor involved is still unknown. Frequently cited factors are head trauma [50–52], sudden change in sleep/wake habits [47, 53] or various infections [54, 55]. These factors may be involved but studies have used a retrospective design, limiting the value of any reported difference. Inte­ restingly, a recent paper has suggested increased incidence for narcolepsy in March and decreased frequency in September, suggesting the influence of perinatal factors [56]. Finally, a study has found increased passive smoking as a risk factor for the development of narcolepsy in a well designed epidemiological cohort study [57].

The only systematic twin study available was performed by Hublin et al. in Caucasian Finns [11], but the three twin individuals identified with narcolepsy were dizogotic so uninformative to establish concordance in monozygotic twins. Appro­ximately, 20 monozygotic twin reports are available in literature (see [13] for review). Five to seven are discordant for narcolepsy, depending on how strictly concordance is determined clinically [13, 46–48]. Most cases of human narcolepsy, therefore, require the influence of environmental factors for the pathology to develop. This is also substantiated by the fact that onset is not at

7

1 Narcolepsy: Genetic Predisposition and Pathophysiology

Familial Aspects of Human Narcolepsy

Table 1.2  HLA-DQB1*0602 in sporadic and familial Caucasian cases

The familial occurrence of narcolepsy–cataplexy was first reported in 1877 by Westphal [58]. Since then, numerous case reports have appeared in the literature. Until recently, narcolepsy was considered a familial disorder. More recent studies have shown that earlier reports were often confounded by unrecognized obst­ructive sleep apnea. One frequently cited publication by Krabbe and Magnussen [59] reports that “narcole­ptic” (obese) relatives of a narcoleptic proband would frequently fall asleep while playing cards, falling forward on the table, and snoring loudly. In more recent studies, the risk of a firstdegree relative to develop narcolepsy–cataplexy has been shown to be only 1–2% (see [13] for review). A larger portion of relatives (4–5%) may have isolated daytime sleepiness, when other causes of daytime sleepiness have been excluded [13]. These figures are important as they are helpful in reassuring patients regarding the risk to their children and relatives. A 1–2% risk is 10- to 40-fold higher than in the general population, but remains manageable. A 4–5% risk for daytime sleepiness is not negligible but similar values have been reported for excessive daytime sleepiness in the general population independent of narcolepsy [11, 60, 61]. As mentioned above, narcolepsy is not a purely genetic disorder as out of 20 reported monozygotic twin pairs, only 7 (35%) are concordant [1, 26–29]. Also somewhat surprisingly, only three of five concordant twin pairs tested (60%) are HLA-DQB1*0602 positive [28]. This suggests that some non-HLADQB1*0602 cases may have a particularly high genetic predisposition. In support of this hypothesis, studies in multiplex families have also reported lower DQB1*0602 positivity in selected multiplex families [1, 17, 30, 31]. We analyzed data from our own database and report findings in 31 Caucasian multiplex families (two members with narcolepsy and definite cataplexy) in Table 1.2. These results are compared to HLA typing data gathered from sporadic Caucasian narcoleptic subjects, who do not have a family history. As shown in Table 1.2, HLA DQB1*0602 positivity was indeed significantly lower in familial cases (70%) than in random narcolepsy cases (87%), especially in families with a large number of affected individ­ uals (>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 < 0.001 vs. sporadic cases # p = 0.05 vs. narcolepsy in £2 affected per family ††† p < 0.001 vs. unrelated controls or healthy relatives when appro­ priate

non-DQB1*0602 families did not support the concept of linkage to other HLA subtypes [1]. This strongly suggests that non-HLA genetic factors may be involved in a subset of non-HLA-DQB1*0602 cases. The pattern of extended HLA haplotype segregation was also examined in DQB1*0602 positive multiplex families. We found that, in general, these families had a smaller number of affected members, most often only two cases (Table 1.2). Interestingly, in some cases, the extended HLA-DQB1*0602 haplotype was not linked with narcolepsy and may have come from different branches of the family [1]. This suggests that in these cases, multiple DQB1*0602 haplotypes (if not all DQB1*0602 alleles in the general population) in the family were equally predisposing to narcolepsy. Also, note that as for sporadic cases, homozygocity for DQB1*0602 was quite common in multiplex families with less than three affected [28]. These results are generally consistent with the notion that in many cases, these families have narcolepsy cases of similar etiologies as random sporadic cases. As can be seen later, the result is also consistent with the observation of hypocretin deficiency in these HLA positive multiplex family cases.

E. Mignot

8

Hypocretin (Orexin) Deficiency and Human Narcolepsy–Cataplexy As expected from the observation that most cases of human narcolepsy are sporadic and not fully genetic like dogs or mice, an extensive screening study did not identify numerous preprohypocretin, Hcrtr1, Hcrtr2 mutations in human narcolepsy cases [3, 62, 63]. Surprisingly, even familial cases of narcolepsy (some of which were HLA-DQB1*0602 negative) did not have any hypocretin mutations, suggesting further heterogeneity in genetic cases [3]. Rather, only a single case with a signal peptide mutation of the preprohypocretin gene was identified. This case has an early onset (6 months), severe narcolepsy–cataplexy, DQB1*0602 negativity and undetectable hypocretin-1 cerebrospinal fluid (CSF) levels [3]. This important observation indicates that hypocretin system gene mutations can cause narcolepsy-like symptoms in animal models. Following the cloning of the canine narcolepsy gene, we have also found that most sporadic, HLA-DQB1 *0602 positive, narcoleptic patients with cataplexy have undetectable hypocretin-1 levels in the CSF [2– 7, 64]. Follow-up neuropathological studies in 10 narcoleptic patients also indicated dramatic loss of hypocretin-1, hypocretin-2 and preprohypocretin mRNA in the brain and hypothalamic of narcoleptic patients [3, 4]. Figure 1.3 displays hypocretin cell loss in narcolepsy, as detected using in situ hybridization for hypocretin mRNA. As mentioned above, these subjects have no hypocretin gene mutations and a peri- or postpubertal disease onset [49] as opposed to a 6-month onset in the subject with a preprohypocretin mutation [3]. Together with the tight HLA association [19, 65], a likely pathophysiological mechanism in most narcolepsy cases could thus involve an autoimmune alteration of hypocretin containing cells in the CNS.

HLA-DR2, Narcolepsy and Autoimmunity The observation that narcolepsy is associated with Human Leukocyte Antigen (HLA) DR2 was first reported in Japan in 1983 [66, 67]. It was quickly confirmed in Europe and North America with 90–100% of all patients with cataplexy carrying the HLA DR2 subtype [19, 65, 68–73]. Because many HLA (also called Major Histocom­ patibility Complex or MHC) associated diseases are

DQB1

DQA1

DRB1

12kb

85kb

Serological DQ1 typing DQ6

DNAbased typing

DR2 DQ5

DR15

Other DQB1*06 and DQA1*01 subtypes

DQB1*0602 DQA1*0102

DR5 DR16

DR11 DR12

DRB1*1502 (Asians)

DRB1*1501 (Caucasians, Asians) DRB1*1503 (African Americans)

DRB1*1101 (African Americans)

Fig. 1.3  Human Leukocyte Antigens (HLA) DR and HLA DQ alleles typically observed in narcolepsy (bold). The DR and DQ genes are located very close to each other onto chromosome 6p21. These genes encode heterodimeric HLA proteins composed of an a and a b chain. In the DQ locus, both the DQa and DQb chains have numerous polymorphic residues and are encoded by two polymorphic genes, DQA1 and DQB1, respectively. Polymorphism at the DR(ab) level is mostly encoded by the DRB1 gene; hence, only this locus is depicted in this figure. DQB1*0602, a molecular subtype of the serologically defined DQ1 antigen is the most specific marker for narcolepsy across all ethnic groups. It is always associated with the DQA1 subtype, DQA1*0102. In Caucasians and Asians, the associated DR2 subtype DRB1*1501 is typically observed with DQB1*0602 (and DQA1*0102) in narcoleptic patients. In African Americans, either DRB1*1503, a DNA-based subtype of DR2, or DRB1*1101, a DNA-based subtype of DR5, are most frequently observed together with DQB1*0602. Other DRB1 alleles (DRB1*0301, DRB1*0806, DRB1*08del, DRB1*12022 and DRB1*1602) have been observed together with DQB1*0602 in much rarer cases

known to be autoimmune, this discovery led to the hypothesis that narcolepsy may result from an autoimmune insult within the Central Nervous System (CNS). The finding of hypocretin cell loss in human narcolepsy [3, 4] suggests that the autoimmune process could target this small population of hypothalamic neurons. Attempts at verifying an autoimmune mediation have generally been disappointing [74–77]. Human narcolepsy is not associated with any striking patholo­gical changes in the CNS and/or increased frequency in the occurrence of oligoclonal bands in the CSF [74–77]. Gliosis in human narcolepsy brains has been reported [3, 4, 78] but remains controversial, as are imaging findings suggesting macroscopic hypothalamic changes [79–81]. Similarly, peripheral immunity does not seem to be altered even around disease onset [74, 75]. Lymphocyte

1 Narcolepsy: Genetic Predisposition and Pathophysiology

CD4/CD8 populations, various auto­antibody levels, erythrocyte sedimentation rate and C-reactive protein are within the normal range and were found not to change up to a year after disease onset. These studies do not exclude the possibility that an autoimmune mechanism will be discovered in the future, and in fact, evidence for and against this hypothesis are debated [82]. Rather, tissue destruction may be difficult to detect because of the small anatomical area involved. Additionally, tissue destruction may be short-lasting around the time of disease onset.

DQB1*0602 and DQA1*0102 Are the Main HLA Narcolepsy Susceptibility Genes The observation that narcolepsy is HLA associated but may not be a classical autoimmune disorder led to the hypothesis that HLA DR2 was only a marker for narcolepsy. To explore this hypothesis, investigators have isolated and tested novel markers in the HLA DR region and have studied neighboring HLA genes (e.g., HLA DQ). HLA testing techniques have also changed from serological, antibody-based technology to molecular typing at the DNA level, thus resulting in a further layer of complexity for the clinician. In order to facilitate the review of this nomenclature, the results are summarized in Fig. 1.3. At the DR level, DR2 was first split into two subtypes, DR15 and DR16, using serological typing techniques. DR15 was then identified in DR2 narcoleptic subjects. Molecular subtypes of DR15 were further identified at the DRB1 level using DNA sequencing and/or oligotyping. The DR molecule is a heterodimer consisting of a polymorphic DR beta chain (encoded by the DRB genes) and a monomorphic DR alpha chain (encoded by the DRA gene) so all the diversity at the DR level can be obtained by molecular typing of the DRB genes. DR15 subtypes recognized at the DNA level were identified as DRB1*1501 to DRB1*1514 [83]; note that most subtypes besides 1501–1503 are extremely rare). In Caucasians and Japanese, patients were found to carry the DRB1*1501 whereas most African American narcoleptic patients with the DR2 antigens were observed to be DRB1*1503 [19, 65, 84, 85]. A significant number of African American patients were also found to be negative for DR2 and to generally carry the DR11 subtype DRB1*1101 [19, 65, 84, 85].

9

DQ, another HLA antigen encoded by genes located 85 kb centromeric to DRB1 was also studied. Serolo­ gically, all patients were initially found to be DQ1, a very frequent DQ antigen. DQ1 was then serologically split into DQ5 and DQ6, and all patients found to be DQ6. At the molecular level, the DQA1 and DQB1 genes encoding the DQ molecule are both polymorphic so typing both the DQA1 and DQB1 is theoretically required to identify the biologically active DQ antigen. DQB1 is, however, the most polymorphic of the two genes and usually determines the DQ serological specificity. Molecular subtypes of DQ6 are thus identified at the DQB1 level as DQB1*0601 to DQB1*0618 (most subtypes beside DQB1*0601; 0602; 0603; 0604 and 0609 are very rare). The DQ6 subtype identified in patients with narcolepsy was found to be DQB1*0602 [19, 65, 84, 85]. Studies across ethnic groups have shown that DQB1*0602 is a better marker for narcolepsy. This is especially important in African-American where many patients are DQB1*0602 positive but DR2 negative [19, 65, 84, 85]. Subjects were also found to be DQA1*0102 positive [19, 65, 84, 85]. Novel DNA markers developed in the HLA DQ region have been tested to further map the narcolepsy susceptibility region within the DQA1–DQB1 interval [86, 87]. This segment was entirely sequenced and shown to contain no new genes [87]. It is also worth noting that in all narcolepsy susceptibility DR-DQ haplotypes identified, both DQA1*0102 and DQB1*0602 are present [84], thus suggesting that the active DQA1*0102/ DQB1*0602 heterodimer is necessary for disease predisposition. A number of other DR-DQ haplotypes in the population carry DQA1*0102 without DQB1*0602 and those do not predispose to narcolepsy [85]. Conversely, although DQB1*0602 subjects are almost always DQA1*0102 positive, rare haplotypes with DQB1*0602 but without DQA1*0102 are observed in the control population, but not in narcoleptic patients [85]. Both DQA1*0102 and DQB1*0602 alleles might thus be needed for disease predisposition [85]. Recent findings in families and in unrelated cases also suggest that most, if not all, the DQB1*0602/ DQA1*0102 alleles present in the population predispose equally to narcolepsy. One such finding comes from multiplex families where several patients are DQB1*0602 positive. In many cases, DQB1*0602 has been inherited from different branches of the family (for example, in one case from the father and the other

E. Mignot

10 Table 1.3  Odds Ratios (OR) of various heterozygotes across various ethnic groups Odds Ratio (OR) DQA1–DQB1

DQA1–DQB1

USA Cauc

0102–0602 0102–0602 Reference 0102–0602 06–0301 Rare 0102–0602 05–0301 0.6 0102–0602 03–0301 0.8 0102–0602 0103–0603 0.3 0102–0602 Others 0.17 0102–0602 0101–0501 0.17 0102–0602 0103–0601 Rare Data compiled from Mignot et al. [65] and Hong et al. [88]

from the mother) and are thus not “identical by descent” (ibd) [13]. It was also recently shown that subjects homozygous for DQB1*0602 are at two to four times increased risk for developing narcolepsy when compared to DQB1*0602 heterozygotes [65, 87]. Finally, risk in DQB1*0602 heterozygotic individuals is modulated by the other DQB1 allele. Most notably, risk is increased in DQB1*0602/DQB1*0301 heterozygotes and reduced in DQB1*0602/DQB1*0601 and DQB1*0602/DQB1*0501 heterozygotes [65]. These associations are remarkable as they are incredibly consistent across ethnic groups [88] (Table 1.3), again illustrating the likely etiological homogeneity of narcolepsy. Overall, the data accumulated to date strongly suggest that the HLA-DQ alleles themselves (most notably, DQB1*0602 and DQA1*0102), and not a yet unknown genetic factor in the region, predispose to narcolepsy.

HLA Typing in Clinical Practice The usefulness of HLA typing in clinical practice is limited by several factors. First, the HLA association is very high (>90%) only in narcoleptic patients with clear-cut cataplexy [19]. Clear-cut cataplexy is defined as episodes of muscle weakness triggered by laughter, joking or anger. Muscle weakness episodes triggered by anger, stress, other negative emotions or physical or sexual activity may not be cataplexy if joking or laughing is not mentioned as a triggering factor [89]. In patients without cataplexy or with doubtful cataplexy, HLA DQB1*0602 frequency is also increased (40–60%) but many patients are DQB1*0602 negative [19].

(Asians)

(Asians)

USA Blacks

Reference 1.2 0.7 Rare Rare 0.06 0.06 0.07

Reference 1.0 0.9 Rare Rare 0.08 0.08 0.05

Reference Rare 0.5 Rare 0.8 0.09 0.09 Rare

Secondly, a large number of control individuals (Tables 1.1 and 1.2, Fig. 1.4) have the HLA DQB1*0602 marker without having narcolepsy. Finally, a few rare patients with clear-cut cataplexy do not have the HLA DQB1*0602 marker [90]. Despite these limitations, HLA typing is probably most useful in atypical cases and/or in narcolepsy without definite cataplexy. A negative result should lead the clinician to be more cautious in excluding other possible causes of daytime sleepiness such as abnormal breathing during sleep or insufficient/ disturbed nocturnal sleep. Practically, it is always more useful to request HLA DQ high resolution typing rather than DR2 or DR15 typing to confirm the diagnosis of narcolepsy. HLA DQB1*0602 negative subjects with typical and severe cataplexy have been reported but these subjects are exceptionally rare [90]. An increase in DQB1*0301 has been suggested in these cases but needs further substantiation [65]. Most (but not all) of these patients have normal CSF hypocretin-1, suggesting a different pathophysiology [5] (Fig.  1.4). Interestingly, two partially concordant monozygotic twins reported in the literature were DQB1*0602 negative [13]. A number of DQB1*0602 negative families (with normal CSF hypocretin-1) have been reported where narcolepsy and cataplexy seem to be transmitted as a highly penetrant autosomal dominant trait, with many patients experiencing narcolepsy–cataplexy while other family members have sleepiness and documented REM abnormalities during the MSLT [5, 13]. These results emphasize the fact that HLA typing and CSF Hypocretin-1 results should be interpreted in conjunction with a careful family history.

11

1 Narcolepsy: Genetic Predisposition and Pathophysiology 700

600

Lumbar CSF Hypocretin-1 (pg/ mL)

500

In

so

m

ni

S

a

(2

(9 )

0)

6) (3 S SA

O

RL

) (8 S KL

(H L

IH

LA −) (H

w/

IH

A+ )

31% (22)

8% (3)

100% (9)

92% (37)

59% (41) 10% (7)

91% (84) 7% (6)

A+ ) HL t(

Ca o

Ca Na

rc

o

w/

Na

rc

o

o rc Na

t(

HL t(

o

Ca w

w o rc Na

A+ )

A− ) HL t(

Ca

l( ro nt Co

Co

nt

ro

l(

18

56

HL

HL

A−

A+ )

)

0

A− )

7% (2)

100

2% (2)

93% (192) 1% (1)

11% (3)

200

HL

300

6% (13)

81% (22)

400

Fig. 1.4  Lumbar CSF hypocretin-1 concentrations in controls versus subjects with narcolepsy and other sleep disorders (from an update of the Stanford Center for Narcolepsy Research database). Each point represents the concentration of hypocretin-1 as measured in unextracted lumbar CSF of a single individual, derived from references [5, 26, 28, 159]. Subjects are differentiated according to HLA DQB1*0602 status and include controls (samples taken during both night and day). Patients are classified according to the International Classification of Sleep Disorders [1], but cases without cataplexy are subdivided into cases with atypical (triangle) and no cataplexy (squares). Clinical subgroups include narcoleptics (Narco) with (w) and without (w/o) cataplexy, idiopathic hypersomnia (IH), periodic

hypersomnia (KLS: Kleine Levin Syndrome), obstructive sleep apnea syndrome (OSAS), restless legs syndrome (RLS), insomnia. Secondary narcolepsy/hypersomnia cases are not included. In the text, levels are described as low (£110 pg/ml), intermediate (111–200 pg/ml) or normal (>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 (<40  pg/ml in most assays), while a few samples had detectable but very diminished levels. None of the patients with idiopathic hypersomnia, sleep apnea, restless leg syndrome or insomnia had abnormal hypocretin levels. This study has now been updated to include a significantly larger sample (Fig. 1.4). The fact that the distribution is largely bimodal, with either very low or normal CSF hypocretin-1, suggests that a significant

E. Mignot

damage to hypocretin cells and profound hypocretin deficiency is needed before symptoms can occur (especially with cataplexy). Using the 110 pg/ml cut-off (or 30% of mean control values), the measurement was especially predictive in cases with definite cataplexy (99% specificity, 87% sensitivity). Sensitivity and specificity are higher for this test than for the MSLT. In most case series, approximately 15% of narcolepsy cases with cataplexy or hypocretin deficiency do not have a positive MSLT. For the patient, the diagnostic value of CSF Hcrt-1 measurements needs to be weighed against the trauma associated with obtaining cerebrospinal fluid. Lumbar punctures (LPs) are well known to be safe, but post-LP headaches are often observed [98]. Such headaches are positional, possibly severe and may last several days. They are always self-limited and rarely require a blood patch. In our experience, headaches are manageable if patients are clearly warned of such risks, and told that lying down almost always relieves symptoms, at least temporarily. Using a double-needle atraumatic technique, which facilitates dural puncture with a 24- to 25-gauge blunt needle, also decreases the likelihood that such post-LP headaches will occur to 2% cases. We do not advocate testing CSF Hcrt-1 levels in all patients in a systematic fashion. Even in cases with cataplexy where the CSF test is most predictive, the MSLT is still advised for most patients. The MSLT should follow nocturnal polysomnography, allowing for the identification of concurrent sleep disorders such as sleep-related breathing disorders (SRBD) and periodic limb movement disorder (PLMD), both of which can be associated with narcolepsy and may contribute to daytime sleepiness independently. SRBD is not uncommon in this population which has a modestly higher mean body-mass index than controls, and must be identified and treated to reduce known complications. A rational argument can be made that neither MSLT nor CSF Hypocretin-1 testing results will affect treatment plans in patients with straightforward sleepiness and clear-cut cataplexy, and therefore, such testing may be extraneous in such cases. In fact, the MSLT is not required for the diagnosis of narcolepsy if clear, definite cataplexy is present. However, in many patients presenting with cataplexy, objective data is still recommended. In these cases, CSF Hypocretin-1 testing may be most helpful when the MSLT is difficult to conduct or interpret. The trauma associated with the lumbar puncture must be balanced against the risk

13

1 Narcolepsy: Genetic Predisposition and Pathophysiology

of incorrectly labeling a patient with narcolepsy and possibly introducing life-long treatment. CSF Hypocretin-1 measurements have a more limited predictive power in cases with atypical or absent cataplexy. It is clear from HLA typing studies, and especially from CSF hypocretin-1 measurement studies (Fig.  1.4), that atypical cataplexy has no diagnostic value, thus the need to call cataplexy only with typical presentations. Atypical presentations include highly infrequent episodes, less than 1 per several months in untreated cases, or only long lasting episodes, for example more than 10 min, and most importantly, episodes that are never triggered by laughing or joking, for example episodes only occurring with stress or only during sex (suggesting a psychogenic origin). A possible exception is when very close to disease onset where episodes can be atypical (tongue thrusting, ill defined weakness) [99]. Specificity of the CSF hypocretin-1 measurement is still extremely high (99%) but sensitivity is low (16%) in cases with a typical or no cataplexy (see [5] Table 1.1 and Fig. 1.4), with most cases having normal levels [5–7]. This is clearly a dilemma for the clinician as there is more often a need for a definitive diagnosis in these atypical cases. The MSLT is generally a more useful first step as it is determinant for the diagnosis and possible treatment strategies. If a lumbar puncture is still required, HLAtyping could be useful as a first step, as almost all cases of narcolepsy with low CSF hypocretin-1 levels £110 pg/ml are also HLA-DQB1*0602 subtype positive [5–7, 100]; only three exceptions have been reported (over several hundred patients with low hypocretin), including one case where cataplexy was very mild and atypical [3, 5, 100]. We estimate the probability of observing low levels in HLA negative cases without cataplexy to be far less than 2%. Most (but not all) cases without any cataplexy and low CSF hypocretin-1 levels have been observed in children who develop cataplexy later in the course of the disease [5, 101, 102]. Therefore, we generally advise that young children with excessive daytime sleepiness but without cataplexy, undergo CSF hypocretin-1 testing, as well as cases in which there is a suspicion that cataplexy is present, but not clearly reported. While the diagnostic value of low CSF hypocretin-1 (£110 pg/ml) has been established, it is interesting to note that healthy control values have been shown to be above 200 pg/ml ([5], Fig. 1.4). In rare cases of narcolepsy and hypersomnia, we have found hypocretin-1

levels between these two values, raising the possibility of partial hypocretin deficiency in these cases [5]. Similarly, in a recent metanalysis, we found that 200  pg/ml was a better diagnostic cut off for cases without cataplexy, suggesting milder deficiency in at least a portion of cases [27]. Such values should, however, be cautiously interpreted, as a large series of individuals with various neurological disorders, we found that up to 15% had CSF hypocretin-1 values within this intermediate range; most of these cases represented severe brain pathology, most notably head trauma, encephalitis and subarachnoid hemorrhage [64]. Decreased hypocretin-1 levels in these cases may reflect damage to hypocretin-1 transmission, or may be related to changes in CSF flow, as discussed below. Other authors have shown that CSF hypocretin-1 increases with locomotor activity and decreases with treatment, with serotonin reuptake inhibitors (but never to near-undetectable, narcolepsy-like levels) [103]. Therefore, the finding of hypocretin-1 levels in this intermediate range should alert the clinician of the possibility of underlying brain patho­logy, which may require additional clinical evaluation, laboratory testing or imaging.

Secondary Narcolepsy Cases Another potential application for CSF hypocretin-1 testing lies in the complex field of narcolepsy and hypersomnia related to neurological disorders associated with trauma, tumors, infections, degenerative diseases, as well as genetic disorders. As discussed above, however, this area is complex and the CSF test is likely to be meaningless when conducted in the context of an acutely ill patient, for example immediately after a post-head trauma, when comatose or in the midst of an acute encephalitis [27]. Indeed, in many such cases, low to undetectable CSF hypocretin can be observed, and has been shown to recover with time, suggesting acute suppression of hypocretin release (for example, through the action of inflammatory factors or changes in internal milieu), or dynamic changes of CSF flow. In such cases, low CSF hypocretin-1 is thus less likely to genuinely reflect decreased hypocretin cell count than in chronic, progressive neurological conditions. Conversely, some pathologies have been reported to be associated with up to 50% hypocretin

14

cell counts, most notably Parkinson’s disease [104, 105] and Huntington Chorea [106], yet CSF hypocretin-1 have been reported to be generally in the normal range [27, 106, 107]. A meaningful finding of low CSF hypocretin as reflecting severe hypocretin cell damage, consistent with a narcolepsy impact, is more likely in the presence of cataplexy, a more pathognomonic symptom, providing the observation is not coincidental, or in pathologies where there is no acute inflation or trauma. Von Economo was the first to suggest that narcolepsy may have its origins in the posterior hypothalamus and in some cases a secondary etiology [108, 109]. The cause of idiopathic narcolepsy that had been described some 50 years earlier [58] was also speculated to involve this general area [109]. This hypothesis was further refined by many authors who noted that tumors or other lesions located close to the third ventricle were also associated with secondary narcolepsy and hypothesized that the posterior hypothalamic region may be the culprit [50, 110]. A postulated hypothalamic cause of narcolepsy was widespread until the 1940s but was then ignored during the psychoanalytic boom and was replaced by brainstem hypothesis [111]. Reports of third ventricle lesions (hypothalamus and upper midbrain) in association with narcolepsy (such as tumors) have been described for over 80 years [108–114], thus it is clear that these tumors can cause or precipitate narcolepsy. Interestingly, when with cataplexy, a number of these cases have been shown to be HLA-DR2 or DQB1*0602 positive, suggesting that the association could be partially coincidental. In these cases, the emergence of the tumor induced blood–brain barrier damage or an inflammatory response in the region that could have favored the development of hypocretin cell loss through an autoimmune attack are also possible. In some of these cases, CSF hypocretin may be low or intermediate (110–200 pg/ml), although often the data are difficult to interpret as cataplexy is not clearly present, and in some cases measurements have been made in very ill patients. Such intermediate levels may nonetheless reflect damage to nearby hypocretin projection sites, with sufficient preservation of cell bodies to maintain detectable levels of hypocretin-1. Alternatively (or additionally), other regions in the upper-midbrain may also contribute to the symptomatology, especially sleepiness, as initially proposed by Von Economo. The complex area of genetic or congenital disorders associated with primary central hypersomnolence

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is also of great interest. Specific familial syndromes combining HLA negative narcolepsy–cataplexy with ataxia and deafness on one hand [115, 116], and obesity-type 1 diabetes in another [117] are especially interesting, as both cataplexy and low to undetectable CSF hypocretin-1 have been documented. Genetic disorders such as Coffin–Lowry Syndrome [118], Moebius syndrome [119], Norrie’s Disease [119], Pradder–Willi syndrome [5], Neimann–Pick Type C [5, 120, 121] and Myotonic Dystrophy [122] have been reported to be associated with daytime sleepiness and/or cataplexy-like symptoms. CSF Hcrt-1 has been measured in cases of Neimann–Pick Type C, a condition where occulomotor symptoms are frequent, and intermediate levels have been found in some cases with cataplexy [5, 120, 121]. This condition is remarkable as cataplexy is often triggered by typical emotions (laughing) and is partially responsive to anticataplectic treatment. Some diseases are associated with the development of both narcolepsy and sleep disordered breathing, such as myotonic dystrophy [122] and Prader–Willi Syndrome [5]; in such cases, primary hypersomnia should only be diagnosed if excessive daytime sleepiness does not improve after adequate treatment of sleep-disordered breathing. We have explored CSF hypocretin-1 levels in such cases, and have found that some but not all of these patients have very low CSF Hcrt-1 levels (< 110  pg/ml), suggesting hypocretin deficiency [5, 120]. Similarly, in one case of late-onset Congenital Hypoventilation Syndrome, a disorder with reported hypothalamic abnormalities [123], we found very low CSF Hypocretin-1 levels in an individual with otherwise unexplained sleepiness and cataplexylike episodes [5]. Excellent response to anti-cataplectic therapy was observed in this case.

Pharmacological Studies: Monoaminergic and Cholinergic Interactions in Hypocretin Deficiency In the past, the most commonly prescribed anticataplectic agents were tricyclic antidepressants. These compounds had a complex pharmacological profile that includes monoamine (serotonin, norepinephrine, epinephrine and dopamine) uptake inhibition, and for older tricyclic antidepressants cholinergic, histaminic and alpha-adrenergic blocking effects [34, 124, 125]. Using

1 Narcolepsy: Genetic Predisposition and Pathophysiology

narcoleptic canines, we found that inhibition of adrenergic but not dopaminergic or serotoninergic uptake or other properties is critical to explain anticataplectic efficacy for antidepressant compounds [124, 125]. This observation fits well with available human pharmacological data [34] as protriptyline, desipramine, viloxazine and atomoxetine, four adre­nergic-specific uptake blockers with no effect on serotonin transmission, are effective and potent anticataplectic agents. In contrast, fluoxetine and other serotonin-specific uptake inhibitors (SSRI) are only active on cataplexy at relatively high doses, (low potency) an effect likely to be mediated by the weak adrenergic uptake effects of these compounds and their metabolites [124]. A typical and very effective anticataplectic compound, now commonly used is venlafaxine, a dual serotonin and norepinephrine reuptake blocker. Commonly prescribed stimulants include amphetamine-like drugs, such as dextroamphetamine, methamphetamine, methylphenidate, pemoline and modafinil. Like tricyclic antidepressant compounds, amphetaminelike drugs are very non-specific pharmacologically. Their main effect is to globally increase the monoaminergic transmission by stimulating the monoamine release and blocking the monoamine reuptake. Abuse and dose escalation can occur with amphetamine, especially in cases without cataplexy and when using short-lasting formulations. Less abuse is reported with methylphenidate and modafinil is not believed to be addictive. Recent studies have demonstrated that the wake-promoting effect of these compounds is secondary to dopamine release stimulation and reuptake inhibition [126, 127]. The mode of action of modafinil is debated but this compound also selectively inhibits dopamine uptake [128]. All these compounds are ineffective in dopamine transporter knockout mice, suggesting a primary mediation of wake promotion via dopaminergic systems [127]. Interestingly, compounds selective for dopaminergic transmission have no effect on cataplexy whereas amphetamine-like compounds with combined dopaminergic and adrenergic effects have some anticataplectic properties at high doses [124, 129]. Adrenergic effects of amphetamine-like stimulants also correlate with the respective effects of these compounds on normal REM sleep [34, 129]. Dopaminergic-specific uptake blockers have little effect on REM sleep when compared to adrenergic or serotoninergic compounds [34]. The most important effects of dopaminergic uptake blockers are to reduce the total sleep time and slow the wave sleep [18]. This preferential effect of dopaminergic

15

uptake blockers on non-REM sleep correlates with electrophysiological data. As opposed to adrenergic or serotoninergic neurons, the firing rate of dopaminergic neurons is known to remain relatively constant during REM sleep [130, 131]. Gammahydroxybutyric (GHB) acid, also called sodium oxybate, is a sedative anesthetic compound known to increase slow wave sleep, and to a lesser extent REM sleep [34]. Occasional abuse in the context of rave parties has been reported and the prescription of the compound is highly supervised. Because slow wave sleep is associated with growth hormone (GH) release, GHB also induces GH release and has been abused by athletes. When administered at night, it consolidates sleep and improves daytime functioning. Because of its short half-life, it must be administered twice a night. Interestingly, cataplexy and daytime alertness also improve over time, sometimes producing a full therapeutic effect only after several months of treatment and dose adjustments (see [132]). The mode of action of GHB on sleep and narcolepsy is unclear. GHB has a major effect on dopamine transmission, reducing firing rate and raising brain content of dopamine [34, 133]. Other effects on opioid, glutamatergic and acetylcholine transmission have been reported [133]. Specific GHB receptors have been identified but the compound is also a GABA-B agonist [133]. Most studies to date suggest that the sedative hypnotic effect is mediated via GABA-B agonist activity [133, 134]. Whether this effect also mediates the anticataplectic effects after long term administration is unknown. Human or animal studies using other GABA-B agonist, for example high dose baclofen (another GABA-B agonist), would be needed to answer these questions. The effects of more than 200 compounds with various modes of action have been examined in human patients and narcoleptic canines (see [34] for review). Almost all the effects have been reported for monoaminergic and cholinergic compounds. These systems have been studied more intensively than others because selective pharmacological probes for these systems are generally available. With cataplexy being easier to study than sleep in canines, most studies have also focused on cataplexy rather than sleepiness. For cataplexy, the findings were generally consistent with pharmacological studies of REM sleep. As is the case for REM sleep, the regulation of cataplexy is modulated positively by cholinergic systems and negatively

E. Mignot

16

by monoaminergic tone [34]. Muscarinic M2 or M3 receptors mediate the cholinergic effects, while monoaminergic effects are mostly modulated by post-synaptic adrenergic alpha-1 receptors and pre-synaptic D2/D3 autoreceptors [34]. A number of studies have shown abnormal cholinergic and monoaminergic receptor density and neuro­ transmitter levels in human or canine narcolepsy brain and CSF samples [34, 135–147]. Local injection studies in selected brain areas of narcoleptic canines (basal forebrain and brainstem) have also shown functional relevance for some of these abnormalities [148–150]. As a result, cholinergic hypersensitivity, dopaminergic abnormalities and decreased histaminergic tone are likely to be critical downstream mediators of the expr­ ession of the narcolepsy symptomatology [147–150]. The cholinergic/monoaminergic imbalances observed in narcolepsy are best illustrated by the finding that in asymptomatic animal heterozygotes for the hypocretin receptor-2 mutation, a combination of cholinergic agonists with an alpha-1 blocker or a D2/D3 agonist can trigger cataplexy [33].

Hypocretin Compounds as Therapeutic Targets Experiments aimed at studying the effects of hypocretins on sleep after systemic and central (e.g., intracerebroventricular injection and/or local perfusion in selected brain areas) administration have been conducted [151, 152]. Central administration of hypocretin-1, for example in the ventricle of wild type rodents or normal canines, is strongly wake-promoting [152]. This is likely mediated by the hcrtr2 as intracerebroventricular hypocretin-1 at the same dose (10–30 nmole), and has no effect on hcrtr-2 mutated narcoleptic canines [153]. Interestingly, hypocretin-2 administration has few if any central effects even in normal animals, most probably not because it is inactive, but because it is biologically unstable and rapidly degraded. The instability may also explain why hypocretin-1 and not hypocretin-2 is detectable in native CSF [153]. Experiments conducted after intravenous administration of hypocretin-1 have been performed in hcrtr2mutated canines and in two hypocretin deficient narcoleptic dogs. In spite of a previous report [151], we were unable to detect any significant effect even at extremely high doses in hypocretin receptor-2 mutated

animals [152]. This last result had been surprising to us considering the lack of effects after central administration of the same dose in these animals lacking hcrtr2 (see above). More interestingly, a possible very slight and short-lasting suppression of cataplexy was observed in a single hypocretin deficient narcoleptic animal at extre­mely high doses [154]. Similarly, we also attempted intranasal administration in animal models, but the results were not encouraging (S. Taheri, unpublished results). We also examined the possibility of intrathecal administration by implanting a Medtronic pump with catheterization of the cisterna magna in a single hypocretin-deficient narcoleptic canine [155]. It was assumed that at high dose, some reverse flow would occur into deeper brain structure, providing therapeutic relief. A positive result would have had a therapeutic application, as these pumps are frequently used in humans for the treatment of pain or spasticity using intrathecal administration. Disappointingly, however, we did not observe any significant effect on cataplexy [155], probably because the hypocretin did not diffuse in upper ventricular compartments. Additional studies using intraventricular rather than intracisternal injections will be needed to verify that hypocretin deficient narcoleptic canines are responsive to supplementation.

Conclusion and Perspectives Narcolepsy–cataplexy is most commonly caused by a loss of hypocretin-producing cells in the hypothalamus. Low CSF hypocretin-1 can be used to diagnose this condition. The disorder is tightly associated with HLADQB1*0602, suggesting that the cause of most of these cases may be an autoimmune destruction of these cells. The hypocretin system sends strong excitatory projections onto monoaminergic cells. The loss of hypocretin is likely to create a cholinergic monoaminergic imbalance in narcolepsy. Abnormally sensitive cholinergic transmission in the forebrain and brainstem, together with depressed dopaminergic and histaminergic transmission are believed to underlie the abnormal REM sleep and daytime sleepiness in canine narcolepsy. Whereas most cases with narcolepsy–cataplexy are caused by a ~95% hypocretin cell loss, some cases with cataplexy and most cases without cataplexy have normal CSF hypocretin-1 levels. This may either reflect disease heterogeneity or a partial loss of hypocretin neurons without significant CSF hypocretin-1 decrements.

1 Narcolepsy: Genetic Predisposition and Pathophysiology

A critical area in need of further inquiry is the role of CSF hypocretin-1 testing in predicting the therapeutic response to medications already in use to treat the symptoms of narcolepsy [156]. Developing an assay that could measure reliably hypocretin-1 in plasma may be possible and would also be extremely useful if low levels are observed in narcolepsy [156]. Measuring hypocretin-1 levels may someday facilitate development of therapies which may interrupt or delay the development of disease. Experience suggests that a subset of patients without cataplexy (including those with idiopathic hypersomnia), or with an unclear clinical diagnosis of narcolepsy, may be more resistant to stimulant treatment, leading to management difficulties. Whether or not narcolepsy is an autoimmune disorder is still unclear, but strongly suspected. Genome wide association studies, which are currently ongoing, are likely to reveal additional narcolepsy genetic factors. If immune related polymorphism are found like in other autoimmune disorders, it would re-enforce the autoimmune hypothesis. Other possible explanations could involve an infectious agent, with participation of the immune system. Explaining the link between the HLA association and the hypocretin deficiency must be a high priority, as is the need to explore more carefully environmental triggers [157]. It may be possible to use CSF hypocretin-1 testing to evaluate the extent of hypocretin cell loss in early stages of the disease (e.g., in children), thus facilitating the development of treatments that may be able to arrest or at least delay disease progression. Similar strategies using immunosuppression have been used in other autoimmune diseases, such as Type I Diabetes Mellitus. In one case, 2 months after an abrupt onset, we tried high-dose prednisone but did not observe significant effects on symptoms and CSF Hcrt-1 levels [101]; however, in this case, very low hypocretin-1 levels were already observed, suggesting the possibility that irreversible damage to cells had already occurred. In another case with recent onset, intravenous immunoglobulin administration was reported to have positive effects, suggesting the need for further studies [158].

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21 involved in canine cataplexy. Abstract Book: Soc Neurosci 1992;18:880. 149. Reid MS, Nishino S, Tafti M, Siegel JM, Dement WC, Mignot E. Neuropharmacological characterization of basal forebrain cholinergic stimulated cataplexy in narcoleptic canines. Exp Neurol 1998;151(1):89–104. 150. Reid MS, Tafti M, Nishino S, Sampathkumaran R, Siegel JM, Mignot E. Local administration of dopaminergic drugs into the ventral tegmental area modulates cataplexy in the narcoleptic canine. Brain Res 1996;733(1):83–100. 151. John J, Wu MF, Siegel JM. Systemic administration of hypocretin-1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs. Sleep Res Online 2000;3(1):23–8. 152. Nishino S, Fujiki N, Yoshida Y, Mignot E. The effects of hypocretin-1 in hypocretin receptor-2 mutated and hypocretin deficient narcoleptic dogs. Sleep 2003;26(Suppl):A287. 153. Yoshida Y, Fujiki N, Maki RA, Schwarz D, Nishino S. Differential kinetics of hypocretins in the cerebrospinal fluid after intracerebroventricular administration in rats. Neurosci Lett 2003;346(3):182–6. 154. Scammell TE, Nishino S, Mignot E, Saper CB. Narcolepsy and low CSF orexin (hypocretin) concentration after a diencephalic stroke. Neurology 2001;56(12):1751–3. 155. Schatzberg SJ, Barrett J, Cutter K, et al. The effect of hypocretin replacement therapy in a 3-year-old weimaraner with narcolepsy. J Vet Intern Med 2004;18(4):586–8. 156. Mignot E, Chen W, Black J. On the value of measuring CSF hypocretin-1 in diagnosing narcolepsy. Sleep 2003; 26(6):646–9. 157. Longstreth WT, Jr., Koepsell TD, Ton TG, Hendrickson AF, van Belle G. The epidemiology of narcolepsy. Sleep 2007;30(1):13–26. 158. Lecendreux M, Maret S, Bassetti C, Mouren MC, Tafti M. Clinical efficacy of high-dose intravenous immunoglobulins near the onset of narcolepsy in a 10-year-old boy. J Sleep Res 2003;12:1–2. 159. Bassetti C, Gugger M, Bischof M, et  al. The narcoleptic borderland: a multimodal diagnostic approach including cerebrospinal fluid levels of hypocretin-1 (orexin A). Sleep Med 2003;4(1):7–12.

Chapter 2

Animal Models of Narcolepsy: Development, Findings and Perspectives Christopher M. Sinton

Abbreviations 5-HT A11 ACh BF CNS CSF DA EEG EMG FECT HLA icv MHC MSLT NE NREM PECT PRF REM VTA

Serotonin Periventricular gray Acetylcholine Basal forebrain Central nervous system Cerebrospinal fluid Dopamine Electroencephalogram Electromyogram Food-elicited cataplexy test Human leukocyte antigen Intracerebroventricular Major histocompatibility complex Multiple sleep latency test Norepinephrine Nonrapid eye movement sleep Play-elicited cataplexy test Pontine reticular formation Rapid eye movement sleep Ventral tegmental area

Introduction First identified as a nosological entity by Gélineau in 1880 [1], idiopathic narcolepsy is a debilitating, lifelong neurological disorder primarily characterized by excessive daytime sleepiness and cataplexy [2].

C.M. Sinton (*) Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-8874, USA e-mail: [email protected]

Narcoleptic patients experience sleepiness that is constant and severe, often complaining of involuntary or irresistible daytime “sleep attacks” that can occur while talking, standing, walking, eating, or driving. Cataplexy consists of episodes of sudden bilateral skeletal muscle weakness, often provoked by strong emotions, frequently without the impairment of consciousness or memory, and lasting no more than a few minutes [3]. Since it was first identified, improved knowledge and understanding of the disorder have led to its conceptualization as primarily a dysregulation of sleep state transition, especially with inappropriate and pathological intrusions of REM (rapid eye movement) sleep, and the components of REM sleep, into normal wakefulness [4]. These pathological state transitions are believed to be the cause of the symptomatology. Narcolepsy is not confined to humans, and this chapter focuses on the development of animal models of the disorder. These models have proved exceptionally useful for understanding the underlying pathology and are likely to continue to aid this process as well as providing a basis for the development of treatments. This chapter reviews the development and history of the canine and rodent models and highlights the important insights into the disorder. The current status of these models and outstanding issues in narcolepsy research which these models can address are also summarized. Despite the data provided by the convergence of rodent and canine models in recent years, the precise etiology of narcolepsy is still poorly defined. Many puzzling results thus remain relevant. For example, studies of monozygotic twins and familial cases have led to the conclusion that undefined environmental factors act on a susceptible genetic background to produce the disorder, most often in early adulthood [5]. Neuro­ pharmacology studies, largely in the canine model, have

M. Goswami et al. (eds.), Narcolepsy: A Clinical Guide, DOI 10.1007/978-1-4419-0854-4_2, © Humana Press, a part of Springer Science + Business Media, LLC 2010

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suggested that imbalances in brain neurotransmitter systems are also involved; importantly these results have been used to support the thesis that cataplexy is separable from the muscle atonia component of REM sleep [6]. In addition, an autoimmune etiology cannot be ignored because of an association between the disorder and certain HLA haplotypes, even though convincing evidence of any systemic or localized CNS inflammatory process has not been found [7]. Other chapters in this volume also address these and related issues.

Narcolepsy for the Veterinarian An interested reader can search the Internet for several short videos of animals that are purported to be narcoleptic. Without complete pharmacological, behavioral, and polysomnographic analysis, including a recording of the electroencephalogram/electromyogram (EEG/EMG), none of these cases can be confirmed as having the disorder. Nevertheless, some of the animals in these videos clearly exhibit behaviors that are very similar to those expressed by animals that have been monitored under carefully controlled conditions. Several large animal species are now included in the latter group and have been confirmed as exhibiting narcolepsy, such as the horse [8, 9], with a familial occurrence also described in the miniature horse [10], the sheep [11], and the bull [12]. However, narcoleptic dogs are more frequently seen by veterinarians. Indeed the canine was the first animal species in which the disorder was formally identified, and because of the incidental veterinarian observation, it also became the first animal model to be studied in the laboratory.

Canine Narcolepsy By 1973, the clinical condition had been well characterized, and the authors of the initial publication describing a case of canine narcolepsy could reference the disorder in humans and refer in their patient to notable sleepiness and apparent cataplexy that could be elicited when food was presented [13]. At that time, Dement and his collaborators were establishing a narcolepsy clinic at Stanford. Realizing the

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importance of an animal model of narcolepsy to advance the management and treatment of the disorder, Mitler and Dement attempted the experimental induction of narcoleptic symptoms in a cat but with only limited success [14]. The existence of canine narcolepsy was, therefore, highly significant to these researchers when at least two cases were brought to their attention by a veterinarian who attended a presentation of their clinical findings. One of these dogs, evaluated at the School of Veterinary Medicine at UC Davis, had already been euthanized and only film records of its behavior remained. These films were then added to the presentation of the clinical work, with the result that the Stanford clinicians were soon informed of another case. This dog, a female toy poodle, was being observed at the Saskatchewan Veterinary Clinic where a tentative diagnosis of narcolepsy was made. The dog was then transferred to Stanford in 1974 where behavioral, EEG/EMG recordings, and pharmacology confirmed the diagnosis [15]. Press reports of these findings quickly led the owners of other canine narcoleptics to contact the Stanford clinic. Several dogs were then transferred to Stanford to begin a colony in 1975, and the first puppies were born in 1976. This breeding resulted in two strains of dog with inherited narcolepsy, Doberman pinschers and Labrador retrievers. In other breeds such as the toy poodle and the beagle, in which breeding was also begun, the disorder appeared to be only sporadic [16]. As the population in the colony increased, the inherited form of the disorder was found to be autosomal recessive and could be further characterized as early onset, gradual in development, and relatively moderate in symptomatology [17]. Labrador and Doberman cross-breeding showed, furthermore, that both breeds were carrying the same affected gene [17]. In contrast, the sporadic form had a later, more rapid onset with variable symptoms. By any measure, the breeding program was a scientific success. A review of the program in 1998 summarized birth data and outcome measures from the almost 500 dogs that had been born in the colony during the previous 22 years and had survived for at least 1 week [18]. Importantly, the presence of the narcolepsy phenotype had no influence on mortality at birth or on survival rate. Many of these dogs became the subjects in a series of significant pharmacological and genetic studies on canine narcolepsy.

2 Animal Models of Narcolepsy: Development, Findings and Perspectives

The Canine Narcoleptic Phenotype Cataplexy is evident in affected canines and appears to be more severe than in the human disorder [17]. However, like humans in whom cataplexy is frequently expressed as a corollary of strong emotions such as laughter, cataplexy in dogs was also found to be associated with an emotional component, including feeding, playing, or appetitive behavior such as attempting to open a package containing food [19]. This strong association with emotion enabled the development of the food-elicited cataplexy test (FECT) to quantify variations in severity and incidence of canine cataplexy. In this test, the dog, trained to eat 10 food pieces that were linearly spaced at equal intervals (a subsequent test comprised 12 food pieces equally spaced in a circular pattern), was timed at this task by an observer who also counted the number of cataplectic attacks during this process [19]. The test was sensitive: control dogs ate all the food pieces quickly in less than a minute whereas affected dogs could take up to 30 min to complete the task. A later similar test, the play-elicited cataplexy test (PECT), involved bringing two dogs into a testing room and allowing them to play freely with each other and with the toys provided [20]. During the PECT, the incidence and duration of cataplectic events were timed by an observer during a 2 h period. Narcoleptic dogs were also found to be excessively sleepy and a measure of sleepiness was developed, resembling the multiple sleep latency test (MSLT) used in humans [21]. In the initial version of this test, latency to fall asleep was measured every 60 min [19]. If the dog slept, it was not aroused for 30  min, but wakefulness was enforced between successive measures. Typically, narcoleptic dogs exhibited a sleep latency of less than 5  min on each trial, but normal dogs took much longer to sleep. A subsequent variant of the test comprised a 30 min period of lights-on, during which the dog was not allowed to sleep followed by 30  min of lights-off when the animal could sleep [22]. This schedule was repeated for 5 h while the dog was continuously monitored polygraphically so that the latency to the different sleep stages could be recorded for each lights-off sleep trial. Results were similar to those found in the earlier studies, with a reduction in sleep latency evident for all stages except deep sleep, though in this study with polygraphic monitoring [22], the significant incidence of REM sleep

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periods occurring within 15 min of sleep onset could also be identified in the narcoleptic animals. During the first EEG/EMG evaluation of the canine narcoleptic, the difficulty of distinguishing cataplexy from a direct transition from wakefulness to REM sleep became evident [23]. The authors noted, for example, that the eyes could be open in both REM sleep and cataplexy so that even close behavioral observation could not aid classification. As a result, any REM sleep episode that was immediately preceded by wakefulness was classified as cataplexy. Analyzed in this way, there was no significant difference over a 24 h period between normal and narcoleptic canines in terms of the total time spent in each state except that REM sleep in a normal subject (11%) was less than REM sleep plus cataplexy in the narcoleptics (16%). The major difference between the groups was in terms of the fragmentation of wakefulness (duration of mean wakefulness episode was 4 min in normal canines, but 1.8 min in narcoleptics). Interestingly, little difference in mean episode duration for nonrapid eye movement (NREM) sleep was noted and REM sleep mean episode duration exhibited a nonsignificant increase. These initial data thus supported the hypothesis that narcolepsy was a disruption of the normal cycle of sleep and wakefulness. A second polygraphic analysis of canine narcolepsy reported similar results though no significant difference in mean wakefulness episode duration was noted (3.7 min in normal canines, 2.2 min in narcoleptics) [24]. In a third study, EEG spectral analysis of the cataplectic episodes provided the first objective evidence of a differentiation between cataplexy and REM sleep in the dog [25]. This analysis revealed a progression in terms of the EEG spectral density function from wakefulness with atonia to REM sleep, suggesting that cataplexy began as muscle atonia but later developed into a state that was indistinguishable from REM sleep. A more recent report of polygraphic investigations in the canines [22] analyzed sleep data collected over several years from narcoleptic and control dogs, and came to essentially the same conclusions regarding the vigilance state fragmentation that had been highlighted in the first study [15]. The total time spent in each state, except cataplexy/REM sleep, was also found to be unchanged. For this report, polygraphic records were analyzed for a 6  h period during the light phase and were combined with concurrent behavioral observation. Results showed decreased mean episode durations

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for drowsy sleep, deep sleep, and wakefulness, but like in earlier studies, REM sleep episode duration was not changed in the narcoleptic canines. A discriminatory index of REM sleep phasic events (i.e., eye movements) was also introduced to separate REM sleep from cataplexy: REM sleep was reported to have more than 2 rapid eye movements/30  s, whereas cataplexy exhibited less than 2 rapid eye movements/30 s.

Neurotransmitter Differences and Imbalances in the Canine Narcoleptic The canine model demonstrated its utility by providing pharmacological data and indications of changes in central neurotransmitter levels associated with the disorder. These studies began soon after the colony was established at Stanford, and before the inheritable form of the disorder was discovered. Tricyclic antidepressants were used for the treatment of cataplexy in the clinic and were one of the first series of drugs to be tested in dogs using the FECT [26]. Imipramine and fluoxetine were found to be approximately equally effective anticataplectic agents in the model, but chlorimipramine was relatively less effective. These results suggested that increasing the level of central norepinephrine (NE) might be a more important variable than increasing the central serotonin (5-HT) levels. Hence, a continuing series of antidepressants were tested, including protriptyline, a compound without serotonergic uptake blocking action, which was found to be effective [27]. Conversely, compounds that exacerbated cataplexy were also discovered, notably physostigmine, a cholinesterase inhibitor [28]. In fact, the action of physostigmine was found to be so reproducible that a challenge with this drug became a routine test for canine narcolepsy [19]. An overall conclusion from these studies, therefore, was that cataplexy, which might result from an imbalance between cholinergic and noradrenergic systems, could be treated most effectively by drugs that act to counter such an imbalance. Importantly, it was also noted that muscarinic receptor blockers could reverse the effect of physostigmine, thereby emphasizing a central muscarinic action in the cholinergic effects [28]. This link with monoamine and cholinergic differences was followed by subsequent studies which attempted to uncover more details about the brain pathology in

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the disorder. Thus, cerebrospinal fluid (CSF) measures of circulating monoamine metabolites demonstrated that central serotonin (5-HT) and dopamine (DA) turnover was less and that NE neuronal activity was also lower in canine narcolepsy [29]. These results were then confirmed in postmortem studies which evaluated monoamines in discrete brain areas in narcoleptic dogs [30]. Serotonin turnover was decreased in the nucleus accumbens and locus coeruleus, DA turnover decreased in many brain areas, and the reduced turnover was associated with higher DA and NE levels. Figure 2.1 is a schematic that shows the location of the brain sites deemed as important in animal models of narcolepsy. Muscarinic receptor binding was also increased in most of the brain areas examined, especially in pontine regions associated with REM sleep generation, centered on the pontine reticular formation (PRF) [31]. These results again underlined a catecholaminergic deficit rather than serotoninergic, but the deficit was caused by a probable decreased impulse flow in these neurons. Baker and Dement in reviewing these data and the possible causes for this pattern of results, postulated a decreased excitatory input to catecholamine neurons in narcolepsy, a prescient suggestion that was not confirmed until 15 years later [19]. The muscarinic cholinergic hypersensitivity was also hypothesized as being secondary to the monoaminergic changes. However, the cholinergic effect seemed likely to be related to the REM sleep differences associated with the disorder since pontine injections of cholinergic

Fig. 2.1  A sagittal section from a mammalian brain to display the locations of the brain sites mentioned in the text. LC locus coeruleus; PRF pontine reticular formation; A11 dopaminergic cell body region of the periventricular gray; SN substantia nigra; VTA ventral tegmental area; LH lateral and perifornical hypothalamus; BF basal forebrain; nAcc nucleus accumbens

2 Animal Models of Narcolepsy: Development, Findings and Perspectives

agonists were known at that time to induce a state that closely resembled REM sleep [32]. The likelihood of decreased impulse flow in dopaminergic neurons was further supported by subsequent findings that showed increased postsynaptic D2 receptor binding, in association with decreased DA release [33]. The potential involvement of DA in central mechanisms of the disorder became evident when dopaminergic-acting compounds were tested in dogs. This important series of studies showed that D2/3 agonists, in particular quinpirole, could markedly aggravate cataplexy while also sedating the narcoleptic canine, but that these compounds had negligible effects in the control animals at the same doses [34, 35]. Conversely, D2/3 antagonists were effective in reducing cataplectic attacks. Furthermore, local injections of a D2/3 agonist into DA cell body regions, including the ventral tegmental area (VTA), substantia nigra and periventricular gray (A11) areas potentiated cataplexy, but sedation was also present only when injections targeted the VTA [36–38]. These data suggested that the reduction in DA neuron discharge rates resulting from cell body region autoreceptor activation is involved in the cataplexy-aggravating action of these compounds. However, local injections of these compounds into the caudate/putamen, though not other projection regions for DA neurons, also enhanced cataplexy, but the effect was not as marked as that resulting from local administration in the VTA [37]. In contrast to the effects of the D2/3 agonists, increasing the availability of the neuro­transmitter with DA uptake inhibitors increased arousal but had no influence on cataplexy [39]. The cataplexy-enhancing effect was also shown to be limited to the D2/3 receptor since D1 agonists and antagonists were without effect [37]. Similar pharmacological studies examined the effects of modulating noradrenergic receptors, based on the importance of the NE uptake inhibitory action of the tricyclic antidepressants in suppressing cataplexy. Prazosin, a a1 antagonist, for example, was found to aggravate cataplexy in one of the earlier studies [40]. Conversely, agonist action at the a1 receptor ameliorated cataplexy [41]. Alpha-2 antagonists, however, significantly reduced the number of cataplectic attacks, an effect that was typically associated with the established actions of these compounds, namely increasing arousal and blood pressure; conversely, a2 agonists enhanced cataplexy [42]. These data were explicable in terms of a postsynaptic noradrenergic effect at the

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a1 site, but a presynaptic action at the a2 site. In summary, any pharmacological action that potentiated NE postsynaptically was predicted to reduce the incidence of cataplexy. The initial results with physostigmine were also followed by studies that examined cholinergic mechanisms in narcolepsy. Local injections of carbachol, a cholinergic agonist, in the PRF elicited a dose dependent increase in cataplexy, whereas in control canines muscle atonia was only observed at the highest dose used [43]. These data thus confirmed cholinergic hypersensitivity in the canine narcoleptic and the functional relevance of the increased muscarinic binding in the PRF that was observed in these animals [31]. Further­ more, microdialysis measurements showed that ACh release was increased in the PRF in narcoleptics during cataplectic episodes [44], and local injection in the PRF of compounds targeted at different cholinergic receptors confirmed the importance of the M2 muscarinic subtype in these actions [45]. Interestingly, very similar results were obtained when the cholinergic area of the basal forebrain (BF) was targeted [6]. Thus, either carbachol or physostigmine locally injected in the BF elicited an increase in cataplexy whereas atropine, a muscarinic cholinergic antagonist, reduced cataplectic episodes. Since only higher doses of carbachol in the BF could induce muscle atonia in normal canines, these data indicated that a cholinergic hypersensitivity associated with narcolepsy was not limited to the PRF. However, unlike the PRF where the muscarinic effect is mediated by cholinoceptive neurons, cholinergic cell bodies are intermingled with cholinoceptive neurons in the BF. This made interpretation of the local injection studies in the BF more difficult.

The Genetics of Canine Narcolepsy The discovery of the autosomal recessive inherited form of narcolepsy in the canine colony at Stanford ensured that a genetic investigation could also be undertaken on these dogs in parallel with the pharmacological studies. This occurred at a time when the techniques of molecular genetics were being rapidly developed and enhanced. Nevertheless, the amount of work that this entailed in positional cloning over a decade can only be described as monumental.

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As breeding continued at Stanford, the pedigree in dogs and the evident inheritance of narcolepsy in this species was considered a critical finding in view of the known familial incidence of the disorder in humans. However, there was no reason to believe that the mode of transmission of the disorder was the same in both species [16]. Indeed, it seemed likely that the canine model would not be an acceptable genetic model of human narcolepsy, and the investigation in the canines proceeded on that basis. But it was hoped that understanding the canine mutation might provide some information relevant to the human disorder. In this regard, the first results were not encouraging. In the human disorder, a genetic linkage had been found indicating that narcolepsy was associated with a major histocompatibility complex (MHC) human leukocyte antigen (HLA) class II allele, HLA-DR2 [46]. This suggested an autoimmune disorder, and studies therefore examined the pattern of inheritance of MHC haplotypes in the canines and the possibility of a unique canine MHC class II antigen being present in the Stanford population. Results were negative in both experiments: the pattern of inheritance of MHC haplotypes did not correspond with the inheritance of narcolepsy [47], and several different antigens were present in the canine narcoleptics studied [48]. While work continued in humans to extend and refine the HLA association and to search for other potential narcolepsy genes in the MHC region of the genome, genetic studies in dogs focused on positional cloning. The existence of an autosomal recessive trait at least made positional cloning a theoretical possibi­lity in this species, and a candidate gene approach was adopted. Assuming that they were investigating a single unidentified gene which they labeled canarc-1, Mignot and collaborators reported that a linkage was identified when they used a human m-switch immunoglobulin probe [49]. The Sm-like gene, located outside the canine MHC region of the genome, co-segregated with canarc-1 to a high degree of probability in backcrossed animals. Although it was later shown to be of no functional significance [50], this m-switch like marker provided the first indication of a link that would eventually be used to locate canarc-1 in the dog genome. But the population of animals used was relatively small and canarc-1 could still be located at some distance from the marker. Fluorescence in situ hybridization was established and used to identify the chromosome containing the marker [51]. However, only following the establishment of a genomic library with control and narcoleptic haplo-

types in separate clones, did chromosome walking become a feasible proposition, though it remained a difficult process in view of the likely distance from the m switch-like sequence, and the lack of a map of the dog genome [51]. Markers were then developed from sequences in the library and tested in the backcrosses to confirm linkage [52]. Gradually, known genes were checked as each library-developed sequence was tested. Eventually, this process led to the identification of the chromosome region when a mapped gene was finally recognized with a known position on the human and mouse maps. Comparing the human map provided probes from the library which in turn were used to refine the canine sequence containing canarc-1 until a small flanking region was identified by March 1999. A single known gene was contained within this sequence, that of OX2R (also known as Hctr2), at that time a recently discovered G-protein coupled receptor for two hypothalamically expressed neuropeptides, orexin-A and orexin-B (also known as hypocretin-1 and hypocretin-2) [53, 54]. The orexins were being investigated as feeding-related neurotransmitters because of their expression in the lateral and perifornical hypothalamus, an area known to be important in the control of feeding. At first, therefore, OX2R seemed an unlikely candidate for canarc-1 and the search for other putative but unknown genes in the flanking region continued. But sequence analysis revealed that defective exon splicing produced a nonfunctional receptor in the narcoleptic canines, though remarkably by different mutations in the Doberman pinschers and Labrador retrievers. If any further confirmation was needed that canarc-1 and OX2R were identical, it came a few weeks later in June 1999 with the knowledge that the orexin knockout mouse appeared to exhibit a phenotype remarkably similar to narcolepsy. On July 1, the landmark manuscript that described the decade long successful search for the mutation causing the inherited form of canine narcolepsy was submitted for publication [52].

Rodent Narcolepsy Orexin-A and orexin-B are derived from a single precursor, prepro-orexin [53, 54]. The initial studies with these neuropeptides had demonstrated that food consu­ mption was increased in rats after intracerebroventricular (icv) injection of orexin-A and that prepro-orexin mRNA was upregulated during fasting [54]. Hence,

2 Animal Models of Narcolepsy: Development, Findings and Perspectives

when orexin null (i.e., orexin−/−) mice were generated by targeted disruption of the mouse prepro-orexin gene [55], the expectation was that orexin−/− mice would show differences in energy homeostasis and thus provide information on the role of the orexins in feeding. As part of the work to determine the phenotype, the activity of the mice, aged about 14–15 weeks, was recorded in an open field over a 24  h period. Unexpectedly, the orexin−/− mice exhibited periods of reduced activity during the dark phase when the animals would normally be most active. To observe what might be happening during these periods of low activity in the open field, the mice were then videotaped from overhead under infrared light. These video recordings of the knockout mice, together with similar videotapes of their wild-type littermates for comparison, demonstrated a curious pattern of activity occurring only in the knockout mice. This change in activity appeared as a sudden arrest of movement which lasted about a minute followed by an equally sudden return to normal activity. Seizures seemed a possible explanation, and additional video was therefore recorded during the dark phase from the side of a normal cage that housed a knockout mouse. Some of these video recordings gave a relatively clear indication of the behavior of the orexin−/− mice during these episodes of sudden arrest. The twitching vibrissae and slight jerking of the body during an arrest were characteristic of a mouse in REM sleep, but these movements did not resemble the more vigorous activity which is typical of a seizure in this species. Thus, the mouse had been awake and engaged in normal activity, and then had apparently suddenly begun an episode of REM sleep. More importantly, at the end of each episode, the mouse abruptly resumed the normal purposeful behavior (usually feeding or grooming) that it had been engaged in when the episode began. Overall, these behavioral characteristics made seizures an unlikely explanation for the arrests. Furthermore, the apparent occurrence of an episode of REM sleep interrupting normal ongoing wakefulness was indicative of narcolepsy. Within a few weeks of this discovery in March 1999, 24 h continuous EEG/EMG monitoring of the knockout mice, with their wild-type littermates for comparison, confirmed that direct transitions from wakefulness to REM sleep occurred only in the orexin−/− mice during the dark phase. By June, sufficient evidence was available to advise the Stanford researchers of the existence of the narcoleptic phenotype in the mouse, and submission of the manuscript describing

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the sleep and behavioral differences in the orexin−/− mouse followed on July 27 [55]. The combined findings from the canine and murine models had unquestionably linked narcolepsy with pathology of orexin signaling [56]. This was soon confirmed in human narcoleptic patients who were shown to exhibit the near or total absence of orexin-A in CSF when compared with normal controls [57].

Vigilance State Characterization of Orexin- and Orexin-Receptor Deficient Rodents (Table 2.1) The Orexin−/− Mouse The vigilance state characterization of the orexin−/− mice from EEG/EMG recordings exhibited sleep and wakefulness fragmentation, together with a reduced mean latency to REM sleep, including the direct transitions to REM sleep from wakefulness that had first identified the phenotype, as well as increased REM sleep time during the dark phase [55]. Following this initial description, the abrupt behavioral arrests of the orexin−/− mouse were subsequently shown to fulfill criteria that are comparable to the cataplectic episodes in the canines, as well as those used clinically to define cataplexy, including muscle atonia, an association with emotional arousal, and amelioration by clomipramine (Fig. 2.2) [58, 59]. A recent study reported that quinpirole markedly potentiates these arrests in the narcoleptic mouse, providing an additional parallel with cataplexy in the canine model [60]. Preserved awareness at the onset of these arrests was also demonstrated in the mouse though it occurred briefly and only occasionally [58]. Despite the limited expression of conscious awareness in the murine model during abrupt arrests, this is an important and relevant finding because it suggests that cataplexy develops rapidly into REM sleep in this species. Furthermore, this indicates that cataplexy is most probably the manifestation of REM sleep atonia and not a separable state in the mouse; by extension this should also be true in other species even if the duration of cataplexy is longer and the progression to REM sleep occurs less frequently [4]. Interestingly, additional observational studies of orexin−/− mice revealed a second type of behavioral arrest with a gradual loss of head and neck posture, similar to the excessive sleepiness of narcoleptic canines and humans

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Fig. 2.2  Panels a and b show the progression of an abrupt arrest as a narcoleptic mouse collapses suddenly, within 2  s, during ongo-ing grooming behavior. In contrast, panels c and d display a gradual arrest, as the mouse first shows a nodding or sleepy behavior followed by a collapse of the head and neck. Concurrent

EEG/EMG monitoring identified the first type of arrest as being associated with a change from wakefulness to REM sleep in terms of the polygraphic characteristics, whereas the second reflects a transition from wakefulness to NREM sleep

Table 2.1  Summary of the vigilance state characteristics of the rodent models of narcolepsy Genotype

Pathophysiology

Phenotype

Prepro-orexin gene knockout (orexin−/−)

Loss of orexin-A and -B function throughout development

Orexin receptor type 1 gene knockout (OX1R−/−) Orexin receptor type 2 gene knockout (OX2R−/−) Double receptor gene knockout (OX1R−/−;OX2R−/−)

Loss of OX1R function throughout development Loss of OX2R function throughout development Loss of OX1R and OX2R function throughout development

Orexin/ataxin-3 transgenic mouse (expression of neurotoxic gene fragment driven by orexin gene promoter)

Selective postnatal degeneration of orexin neurons completed by early adulthood

Orexin/ataxin-3 transgenic rat

Selective postnatal degeneration of orexin neurons completed by early adulthood

Severe sleepiness and sleep attacks. Frequent cataplexy Significant sleep/wake fragmentation Mild sleep/wake fragmentation. Absence of cataplexy and sleep attacks Severe sleepiness and sleep attacks. Rare cataplexy Significant sleep/wake fragmentation Severe sleepiness and sleep attacks. Frequent cataplexy Significant sleep/wake fragmentation Severe sleepiness and sleep attacks. Frequent cataplexy Significant sleep/wake fragmentation Phenotype reversed by icv administration of orexin-A Severe sleepiness and sleep attacks. Frequent cataplexy Significant sleep/wake fragmentation

(Fig. 2.2) [58]. This type of arrest appeared distinct from cataplexy, not only because of the gradual onset, but also because it began from quiet wakefulness rather than from an active state, it was correlated with the onset of NREM sleep and preservation of some muscle tone, and it was specifically suppressed by caffeine but not by clomipramine. These arrests could also be clearly distinguished

from normal sleep onset, as they were not preceded by stereotypical rest-associated behaviors such as nesting or sleep posturing. Importantly, wild-type mice did not exhibit these attacks under the same experimental conditions. It was, therefore, concluded that these gradual arrests most closely correspond to the sleep attacks observed in narcoleptic patients.

2 Animal Models of Narcolepsy: Development, Findings and Perspectives

Orexin/Ataxin-3 Transgenic Mice and Rats A human ataxin-3 gene fragment, containing an expa­ nded polyglutamine repeat, is neurotoxic. Expression of the fragment by neuron-selective promoters can therefore be targeted for neurodegeneration studies. Driven by the orexin gene promoter, the fragment caused specific postnatal degeneration of orexin neurons in orexin/ataxin-3 transgenic mice [61] and rats [62]. These models are significant because they mimic more closely the timing and specificity of the putative neuronal loss as it is believed to occur in most cases of human narcolepsy. Orexin/ataxin-3 transgenic mice exhibit essentially the same sleep phenotype as orexin−/− mice though this developed later, at about 6 weeks of age [61]. Similarly, by 17 weeks of age, orexin/ataxin-3 rats [62] exhibited postnatal loss of orexin neurons, and orexin-containing projections were essentially undetectable at this age. This loss of orexin in the rat resulted in a sleep phenotype during the dark phase that paralleled what was seen in the mouse, including abrupt arrests, some of which corresponded to direct transitions from wakefulness to REM sleep (Fig. 2.3), a decreased latency to REM sleep, and increased REM sleep time. Although the typical posture and behavior in rats made visual differentiation of gradual arrests

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more difficult than in the mouse, concurrent video and EEG/EMG monitoring revealed episodes in which the onset of NREM sleep occurred rapidly during ongoing motivated behaviors and which were frequently followed by a progression to REM sleep (Fig. 2.4) [62]. Such episodes, therefore, have the characteristics of

Fig. 2.3  Dark phase infrared video monitoring of the narcoleptic rat during concurrent EEG/EMG recording showed the sudden loss of muscle tonus and associated collapse of the head during normal ongoing behavior at the start of episodes of behavioral arrest. In this example, the rat was drinking when the episode began. The EEG/EMG recordings enabled differentiation of abrupt and gradual arrests in this species

Fig. 2.4  In the narcoleptic rat, EEG/EMG monitoring revealed (a) direct transitions from wakefulness to REM sleep, in terms of the polygraphic characteristics; and (b) transitions from normal wakefulness to periods of muscle atonia without any change to the EEG. Spectral analysis showed that the EEG continued unchanged when atonia began in (b) though this is also visually evident from this example. Compare the notable presence in the EEG of waves in the theta frequency band (6–9 Hz) during REM sleep (a). Some of the episodes of wakefulness plus atonia progressed to REM sleep; others, as in this example, progressed back to normal wakefulness

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gradual arrests as seen in the orexin−/− mice [58], and are proposed to be the rat model analogs of the sleep attacks seen in the narcoleptic human. Orexin/ataxin-3 rats also exhibited less wakefulness during the dark phase as well as vigilance state fragmentation. Importantly, studies in the orexin/ataxin-3 rats provided additional insight into the abrupt arrests and the relationship between cataplexy and REM sleep in the rodent models. For each episode of abrupt arrest, as expected, the EMG in the rat showed complete muscle atonia (Fig.  2.3). However, spectral analysis of the EEG during these arrests revealed several episodes that began, in terms of the spectral profile of the EEG, with wakefulness but which later progressed, again in terms of the EEG spectrum, to REM sleep [62]. These differences in EEG spectra were thus very similar to those previously reported in the canine narcoleptics [25], but were only observed in the narcoleptic mice with difficulty. In the latter species, this was presumably because of the rapid nature of state change, even when the mouse was briefly awake from behaviorally observable criteria [58]. These data thus suggested a significant species difference in abrupt arrests based on the length of time that awareness is maintained at the onset of an episode. In the narcoleptic mouse, maintenance of conscious awareness prior to the onset of REM sleep occurs rarely and is very brief, but in the rat, apparent wakefulness during muscle atonia is more frequently seen and continues typically for 20–30  s before the EEG becomes indistinguishable from that recorded during REM sleep. This issue is addressed in more detail below (cf. Current Research Issues, Cataplexy). When orexin-A was administered icv to orexin/ ataxin-3 mice, it resulted in increased wakefulness and reduced REM sleep, combined with a suppression of cataplectic episodes. This pharmacological reversal of the phenotype has significant therapeutic implications since the finding indicates that orexin receptors remain functional in the absence of orexin neurons [63].

The Orexin Receptor Null Mice: OX1R−/−, OX2R −/− and OX1R −/−; OX2R−/− Characterization of the receptor knockout mice (OX1R−/− and OX2R−/−) provided further information about the roles of each of the two receptors in both vigilance state control and the abrupt and gradual arrests of the narcoleptic phenotype [58, 64]. In contrast to the direct

transitions from wakefulness to REM sleep and abrupt behavioral arrests that characterized the orexin−/− mice, OX1R−/− mice exhibited no direct transitions to REM sleep and only a modest decrease in REM sleep latency [64]. OX1R−/− mice also showed some fragmentation of vigilance states when compared to the wild-type control animals. Furthermore, OX1R−/− mice exhibited possible sleep attacks so infrequently that detailed characterization was not possible. In contrast to the severe phenotype of the inherited form of canine narcolepsy which is also due to disrupted signaling at the OX2R receptor, OX2R−/− mice showed a relatively mild phenotype, considerably less severe than the orexin-deficient mice [58]. In addition to fewer REM sleep abnormalities, a comparison of videotaped behavioral arrests in OX2R−/− and orexin−/− mice, combined with concurrent EEG/EMG recording and EEG spectral analysis, demonstrated that abrupt arrests, though displaying similar features, were approximately 30 times less frequent in OX2R−/− mice than in the orexin null animals. However, like orexin−/− mice, OX2R−/− mice also exhibited gradual arrests. In both these mutant strains, gradual arrests occurred with similar frequency, and caffeine was similarly effective in suppressing them. The equivalent frequency of sleep attacks and comparable levels of vigilance state fragmentation recorded in orexin−/− and OX2R−/− mice indicated that these genotypes were approximately equivalent in their level of sleepiness. Hence, an important conclusion that could be drawn from these data is that the much higher incidence of direct transitions to REM sleep and reduced REM sleep latency in the orexin null mice are not the cause per se of sleepiness in narcolepsy [59]. The clinical management of narcolepsy with different classes of drugs (i.e., stimulants and antidepressants to treat sleepiness and REM sleep-associated symptoms, respectively) is concordant with this conclusion [65]. The series of receptor knockout mice was completed with the double receptor null mouse (OX1R−/− ; OX2R−/−), which was phenotypically indistinguishable from orexin−/− mice [66].

Summary Results from the different rodent models showed that the absence of orexin signaling at both receptors is required to produce the most severe phenotype and the

2 Animal Models of Narcolepsy: Development, Findings and Perspectives

profound dysregulation of REM sleep in this species [58, 64, 66]. Thus, in the absence of OX2R, some functional control for REM sleep must be provided by OX1R, i.e., the normal gating of REM sleep apparently depends on both OX1R and OX2R signaling. In contrast, OX2R signaling appears to be critical for regulating the transition from wakefulness to NREM sleep, so that the hypersomnolence, as well as the sleep attacks in the human disorder, are likely to be more closely linked to a lack of signal at the OX2R receptor. These conclusions were supported by studies in which orexin-A was administered icv to the knockout murine models [67]. Administration of orexin-A to wild-type mice increased wakefulness and decreased both NREM and REM sleep, and these results were essentially unchanged in the OX1R−/− mice over the dose range tested. In contrast, OX2R deficiency resulted in a significant reduction of the wakefulness-promoting action of orexin-A, though the effect of orexin-A was still observable. Thus, although OX2R mediates most of the arousing effects of orexin-A, the orexin signal at OX1R is still effective in the absence of OX2R. With respect to the changes in REM sleep induced by orexin-A, however, no significant differences between wild-type, OX1R−/−, and OX2R−/− mice were noted. These results are thus consistent with the hypothesis that both receptors function in a complementary manner to gate REM sleep, at least under these conditions.

Current Research Issues With the link between narcolepsy and the absence of orexin signaling now established, important research issues remain in the study of narcolepsy. Some are likely to be amenable to research with the animal models and two of these issues are addressed here.

Etiology The exact cause of narcolepsy in the vast majority of patients remains unknown, since the human disorder only very rarely involves highly-penetrant orexin-gene mutations [68]. Nevertheless, nearly all human cases of narcolepsy are now known to result from a selective loss of the orexin signal, probably reflecting a loss of

33

the population of hypothalamic neurons that contain orexin [68, 69]. Significantly, however, the reason for orexin-containing cell loss in typical narcolepsy remains a mystery. The HLA association continues to be intriguing because it suggests autoimmunity as a potential causative factor [70], but the weak genetic linkage in the human studies of monozygotic twins also implies unknown environmental factors acting on a susceptible genetic background [5]. The sporadic canine model might, therefore, eventually be relevant in the research on these aspects of the disorder, though species differences in the incidence of narcolepsy could also provide data to supplement epidemiological studies in patients. The inherent difficulty of determining both the genetic and environmental factors, neither of which is currently known, but that interact and result in the loss of orexincontaining neurons, is evident.

Cataplexy Cataplexy is a significant, pathognomonic and highly disabling core symptom of narcolepsy. It is also challenging to understand cataplexy at a mechanistic level despite the data that the canine and rodent models have provided. For example, no consensus has yet been reached on whether cataplexy is an entirely separable and unique symptom or, alternatively, the intrusion of REM sleep muscle atonia into wakefulness. An important future research direction for the animal models of narcolepsy will be to address this issue. Both the canine and rodent models, at least initially, have supported the conclusion that a cataplectic attack reflects the partial breakdown of the barrier between wakefulness and REM sleep. The first EEG/EMG recordings of the canine narcoleptics, for example, had revealed that it was difficult, if not impossible, from both the polygraphic records and behavioral observation, to separate cataplexy from a typical episode of REM sleep without knowledge of the preceding state [23]. Hence, any episode that would be classified as REM sleep from the EEG/EMG, but that followed directly from wakefulness was defined as cataplexy. This provided an understandable and repeatable scoring matrix for the vigilance states in dogs. The same classification method has been proposed and is equally valid for narcoleptic mice [71]. However, the alternative in the mouse is to classify all episodes of electrophysiologically-

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34

defined REM sleep as that state whether these episodes follow wakefulness or NREM sleep [55]. This classification is equally valid in the mouse because, as noted above, apart from occasional and very brief intervals at the onset of cataplexy, these episodes are in fact indistinguishable from REM sleep [58]. It is also remarkable that the initial classification difficulty in the canines led at that time to a reinvestigation of the clinical state. Narcoleptic patients, it was reported, did not believe that cataplexy was simply “paralyzed wakefulness” because the experience of an episode frequently included elements of unreality merging with conscious awareness [23]. Other clinical observations subsequently supported this conclusion. Hishikawa and Shimizu [4], for example, argued that cataplexy reflected a fragmentary manifestation of REM sleep muscle atonia, or alternatively, a transitional state between wakefulness and REM sleep. These authors noted that during prolonged episodes of cataplexy in humans, the awake EEG can transition through an EEG more closely resembling that of REM sleep, but with continued awareness, to unambiguous REM sleep [4]. The animal models evidently cannot be used to distinguish subtle differences in conscious state that depend on introspection. The incidence of cataplexy is high in the narcoleptic canine, however, making it apparently a useful model for mechanistic investigation. Recently authors have argued that their results with these dogs support the thesis that cataplexy is a unique state not directly related to REM sleep [22, 72, 73]. Briefly, these data can be summarized as showing that the brain sites and mechanisms for triggering cataplexy may be distinct from those that trigger REM sleep. These results remain unconvincing, however, until the neuronal substrates are known that support other significant state differences between REM sleep and wakefulness. Without such knowledge, it remains possible that a brain site or mechanism being investigated supports conscious awareness, for example, rather than muscle atonia. Indeed it is arguable that the cataplectic state in the canine narcoleptic could be a useful model for investigating the neuronal substrate of awareness. In contrast, the results from the rodent models suggest important species differences in terms of the nature and temporal characteristics of the progression from wakefulness through cataplexy to REM sleep [58, 62]. These data are thus concordant with the earlier EEG spectral studies in the canines [25]. But, because of the

evident brevity of any state that can be likened to cataplexy, especially in the mice, these species differences make the rodent models less useful for studying the inherent neuronal substrates of cataplexy per se. However, the rodent models are likely to remain important for understanding the triggering mechanisms responsible for the different vigilant states. In particular, why orexin should be so critical at the boundary between wakefulness and sleep. Apparently the absence of orexin triggers both the inappropriate transitions from wakefulness to NREM sleep (i.e., the sleep attack) and those from wakefulness to REM sleep (i.e., cataplexy) [74, 75]. Until our understanding of the mechanisms and pathophysiology of narcolepsy is improved, it is probably less fruitful to force each animal model to reflect the same characteristics because of the inherent species differences. In other words, each model has differences that can be used as strengths to continue our investigation into different aspects of the disorder.

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C.M. Sinton 56. Siegel, J.M. (1999) Narcolepsy: a key role for hypocretins (orexins). Cell, 98, 409–12. 57. Nishino, S., Ripley, B., Overeem, S., Lammers, G.J. and Mignot, E. (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet, 355, 39–40. 58. Willie, J.T., Chemelli, R.M., Sinton, C.M., Tokita, S., Williams, S.C., Kisanuki, Y.Y., Marcus, J.N., Lee, C., Elmquist, J.K., Kohlmeier, K.A., Leonard, C.S., Richardson, J.A., Hammer, R.E., and Yanagisawa, M. (2003) Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron, 38, 715–30. 59. Willie, J.T. and Yanagisawa, M. (2007) Lessons from Sleepy Mice: Narcolepsy-Cataplexy and the Orexin Neuropeptide System. In Bassetti, C., Billiard, M. and Mignot, E. (eds.), Narcolepsy and Hypersomnia. Informa Healthcare, New York, pp. 257–78. 60. Burgess, C., Tse, G. and Peever, J. (2008) Dopaminergic modulation of cataplexy in hypocretin-null mice. Sleep, 31(Suppl), A5. 61. Hara, J., Beuckmann, C.T., Nambu, T., Willie, J.T., Chemelli, R.M., Sinton, C.M., Sugiyama, F., Yagami, K., Goto, K., Yanagisawa, M., and Sakurai, T. (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron, 30, 345–54. 62. Beuckmann, C.T., Sinton, C.M., Williams, S.C., Richardson, J.A., Hammer, R.E., Sakurai, T. and Yanagisawa, M. (2004) Expression of a poly-glutamine-ataxin-3 transgene in orexin neurons induces narcolepsy-cataplexy in the rat. J Neurosci, 24, 4469–77. 63. Mieda, M., Willie, J.T., Hara, J., Sinton, C.M., Sakurai, T. and Yanagisawa, M. (2004) Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci USA, 101, 4649–54. 64. Kisanuki, Y.Y., Chemelli, R.M., Sinton, C.M., Williams, S.C., Richardson, J.A., Hammer, R.E. and Yanagisawa, M. (2000) The role of orexin receptor type-1 (OX1R) in the regulation of sleep. Sleep, 23(Suppl 2), A91. 65. Aldrich, M.S. (1998) Diagnostic aspects of narcolepsy. Neurology, 50, S2–7. 66. Kisanuki, Y.Y., Chemelli, R.M., Tokita, S., Willie, J.T., Sinton, C.M. and Yanagisawa, M. (2001) Behavioral and polysomnographic characterization of orexin-1 receptor and orexin-2 receptor double knockout mice. Sleep, 24(Suppl), A22. 67. Mieda, M. and Yanagisawa, M. (2006) Rodent models of narcolepsy-cataplexy. In Nishino, S. and Sakurai, T. (eds.), The orexin/hypocretin system: physiology and pathophysiology. Humana, Totowa, NJ, pp. 255–66. 68. Peyron, C., Faraco, J., Rogers, W., Ripley, B., Overeem, S., Charnay, Y., Nevsimalova, S., Aldrich, M., Reynolds, D., Albin, R., Li, R., Hungs, M., Pedrazzoli, M., Padigaru, M., Kucherlapati, M., Fan, J., Maki, R., Lammers, G.J., Bouras, C., Kucherlapati, R., Nishino, S., and Mignot, E. (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med, 6, 991–7. 69. Thannickal, T.C., Moore, R.Y., Nienhuis, R., Ramanathan, L., Gulyani, S., Aldrich, M., Cornford, M. and Siegel, J.M. (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron, 27, 469–74.

2 Animal Models of Narcolepsy: Development, Findings and Perspectives 70. Lin, L., Hungs, M. and Mignot, E. (2001) Narcolepsy and the HLA region. J Neuroimmunol, 117, 9–20. 71. Mochizuki, T., Crocker, A., McCormack, S., Yanagisawa, M., Sakurai, T. and Scammell, T.E. (2004) Behavioral state instability in orexin knock-out mice. J Neurosci, 24, 6291–300. 72. Wu, M.F., John, J., Boehmer, L.N., Yau, D., Nguyen, G.B. and Siegel, J.M. (2004) Activity of dorsal raphe cells across the sleep-waking cycle and during cataplexy in narcoleptic dogs. J Physiol, 554, 202–15.

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73. John, J., Wu, M.F., Boehmer, L.N. and Siegel, J.M. (2004) Cataplexy-active neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior. Neuron, 42, 619–34. 74. Saper, C.B., Chou, T.C. and Scammell, T.E. (2001) The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci, 24, 726–31. 75. Lu, J., Sherman, D., Devor, M. and Saper, C.B. (2006) A putative flip-flop switch for control of REM sleep. Nature, 441, 589–94.

Chapter 3

Neuroimaging of Narcolepsy Eric A. Nofzinger

Introduction In the past few decades, neuroimaging methods have emerged as a new way to assess brain function in health and in pathology. These methods allow for the quan­ tification of a variety of aspects of brain function including brain structure, metabolism, blood flow, and receptor binding. Given that sleep is regulated by the brain and may ultimately serve brain function, these tools may provide important information regarding brain function during healthy and pathological sleep, such as in narcolepsy patients. This chapter will review the use of neuroimaging studies in narcolepsy.

Functional Neuroimaging Studies of Healthy Human Sleep Functional neuroimaging studies have revealed reliable broad changes in cerebral activity across the sleep–wake cycle. Globally, brain activity decreases from waking to NREM sleep, then increases to waking levels again during REM sleep [1–17]. Preclinical studies support a deafferentation of the cortex at the level of the thalamus and the occurrence of intrinsic thalamocortical electrical oscillations in NREM sleep. Studies across several laboratories and using various imaging methods have demonstrated that from waking to NREM sleep there are relative regional reductions

E.A. Nofzinger (*) Sleep Neuroimaging Research Program, University of Pittsburgh School of Medicine, 3811 O’Hara Street, Pittsburgh, PA, 15213, USA e-mail: [email protected]

in activity in heteromodal association cortex in the frontal, parietal, and temporal lobes as well as in the thalamus. Preclinical work shows that REM sleep is associated with an electrophysiologically active cortex, with selective activation of cholinergic networks that originate in the brainstem and basal forebrain and that densely innervate limbic and paralimbic cortex. Consis­ tent with this, in relation to waking and NREM sleep, REM sleep is associated with increased relative activity in the pontine reticular formation, as well as limbic (e.g., amygdala and hypothalamus) and paralimbic cortex (e.g., ventral striatum, anterior cingulate, and medial prefrontal cortex). This suggests that REM sleep may play an important role in emotional behavior, given the important involvement of these structures in the regulation of affect and in motivated behavior. An important clinical feature of narcolepsy is daytime sleep attacks. While clinically distinct from the generalized daytime sleepiness found in healthy individuals who are sleep-deprived, it is possible that there may be some overlaps in terms of the brain mechanisms of healthy sleepiness and the disorder narcolepsy. Therefore, a brief review of the known brain mechanisms of sleep deprivation may provide some insights into the brain mechanisms of narcolepsy. Wu et  al. [18] assessed regional cerebral metabolism using the [18F]FDG method in healthy subjects before and after 32 h of sleep deprivation. They noted prominent decreases in metabolism in the thalamus, basal ganglia, temporal lobes, and cerebellum with increases in the visual cortex. Whole brain absolute metabolic rate was not different. Thomas et al. [19, 20] described the effects of 24, 48, and 72  h of sleep deprivation on waking regional cerebral metabolism assessed via [18F]FDG positron emission tomography (PET), as well as alertness and cognitive performance. Sleep deprivation was associated with global declines

M. Goswami et al. (eds.), Narcolepsy: A Clinical Guide, DOI 10.1007/978-1-4419-0854-4_3, © Humana Press, a part of Springer Science + Business Media, LLC 2010

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in absolute cerebral metabolism. Regionally, these declines were most notable in frontoparietal cortex and in the thalamus. This is consistent with studies showing that the effects of sleep deprivation on slow wave sleep are greatest in frontal EEG leads. Alertness and cognitive performance on a sleep-deprivation sensitive serial addition/subtraction test declined in association with the sleep-deprivation associated regional deactivations. These findings support the role for sleep in restoration of brain function in thalamocortical networks associated with higher order cognition. In terms of narcolepsy, the severity of this disorder on waking brain function may be measured by the degree to which there is a reduction in activity in the thalamus and frontoparietal cortex. Treatment response in narcolepsy may be measured by the ability of an intervention to reverse these alterations in thalamocortical function. More recent reports focus on defining how the brain behaves in a sleep-deprived state. For example, Mu et  al. [21] investigated the cerebral hemodynamic response to verbal working memory following sleep deprivation. Neuroimaging data revealed that, in the screening and rested states, the brain regions activated by the Sternberg working memory task were found in the left dorsolateral prefrontal cortex, Broca’s area, supplementary motor area, right ventrolateral prefrontal cortex, and the bilateral posterior parietal cortexes. After 30 h of sleep deprivation, the activations in these brain regions significantly decreased, especially in the bilateral posterior parietal cortices. Neuroimaging studies have been used to determine the neurobiological basis of individual differences in vulnerability to sleep deprivation. For example, Mu et al. [22] divided their sleep deprivation subjects into resilient and vulnerable subgroups based on subsequent performance following sleep deprivation. While both groups showed significant decreases in global brain activation compared to their rested group baseline, the sleep deprivation-resilient group had significantly more brain activation than did the sleep deprivationvulnerable group at both the rested baseline and in the sleep-deprived states. Investigators have also assessed the degree to which the brain is able to overcome the effects of sleep deprivation in order to perform more demanding tasks. These studies could have relevance for the clinical management of patients with narcolepsy. Drummond, for example [23], had subjects perform a modified version of Baddeley’s logical reasoning task while undergoing

functional magnetic resonance imaging before and after 35  h of total sleep deprivation (TSD). The task was modified to parametrically manipulate task difficulty. Subjects performed the same before and after TSD. Neuroimaging data revealed a linear increase in cerebral response with a linear increase in task demands in several brain regions after normal sleep. Even stronger linear responses were found after TSD in several brain regions, including bilateral inferior parietal lobes, bilateral temporal cortex, and left inferior and dorsolateral prefrontal cortex. Also, Chee and Choo [24] assessed the neurobehavioral effects of 24 h of total sleep deprivation (SD) on working memory in young healthy adults using functional magnetic resonance imaging. Two tasks, one testing maintenance and the other manipulation and maintenance, were used. After SD, response times for both tasks were significantly slower. Performance was better preserved in the more complex task. Both tasks activated a bilateral, left hemisphere-dominant frontal-parietal network of brain regions reflecting the engagement of verbal working memory. In both states, manipulation elicited more extensive and bilateral (L > 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

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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

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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.

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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

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L. Hale

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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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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].

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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

52

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.

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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 < 0.001) [43]. Of a group of 360 adults with narcolepsy–cataplexy

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5 Narcolepsy in Childhood

seen in Montpellier, France, 34% of patients could not identify a particular circumstance preceding onset of their excessive daytime sleepiness and cataplexy [44]. However, in this group, seven respondents identified boarding school as the environmental factor preceding their disease. Narcolepsy with cataplexy has a familial component. Guilleminault studied family members of 334 patients with narcolepsy–cataplexy, calculating the frequency of narcolepsy among first-degree relatives to be 0.9% [45]. It is extremely rare to find families with more than two relatives diagnosed with narcolepsy with cataplexy [38].

Secondary Narcolepsy While the majority of narcolepsy is idiopathic, structural lesions of the diencephalon and rostral brainstem can precipitate secondary narcolepsy in those who are biologically predisposed. Case reports have documented the development of secondary narcolepsy in cerebellar hemangioblastomas, temporal lobe B cell lymphoma, pituitary adenoma, third ventricular gliomas, craniopharyngioma, head trauma, viral encephalitis, ischemic brainstem disturbances, sarcoidosis, and multiple sclerosis [46–53]. Mild overlap can exist between narcolepsy and conditions which also feature cataplexy, such as Niemann-Pick type C, Coffin Lowry syndrome, and Norrie disease, but in general, children with these three conditions show evidence of severe brain dysfunction (see differential diagnosis).

Physical Examination Most children with narcolepsy will have a normal physical examination. There have been case series linking obesity with narcolepsy in children [54, 55]. In addition, if observing a child during an episode of cataplexy, deep tendon reflexes should be absent or diminished. Determination of Tanner staging is useful when interpreting MSLT results [56]. This can be done by questionnaire or visual inspection. Mental status examination may reveal impairments in digit span (indicative of a short attention span) and in recall of information.

Diagnosis The diagnosis of narcolepsy is established on the basis of history and corroborated by testing, principally with the gold standard of a nocturnal PSG immediately followed by the MSLT [57]. Consideration is also given to other tools such as sleep diaries, actigraphy, HLA typing, and CSF hypocretin-1 measurement.

Evaluating Sleepiness Many tools are available to evaluate excessive daytime sleepiness including the MSLT, the maintenance of wakefulness test, Epworth Sleepiness Scale, Stanford Sleepiness Scale, reaction time testing, performance testing, and pupillography [57]. In addition, in children, a picture scale has been validated in 345 children aged 4–7 years by Maldonado [58]. Other questionnaires also exist, such as the Cleveland Adolescent Sleepiness Questionnaire (CASQ), The School Sleep Habits Survey, and The Pediatric Daytime Sleepiness Scale (PDSS) [59–61]. The CASQ and PDSS have, however, been validated only in children with sleep disordered breathing, and not primary hypersomnias like narcolepsy. Nevertheless, they are easy to use and provide some quantitative measure.

Sleep Laboratory Testing Prior to sleep studies, patients should discontinue central nervous system acting medications, hypnotics, antidepressants, or other psychotropic drugs when medically safe, for approximately 2 weeks before the studies in order to minimize drug-induced changes in sleep architecture. The exact timing of medication discontinuation will depend on individual situations, given the varying half-lives of medications and the patient’s clinical setting. With some medications such as fluoxetine that have a very long half-life, a 3–4 week medication-free interval would be appropriate. The patient should attempt to maintain a regular wake– sleep schedule; this can be verified by sleep diaries or actigraphy when indicated. During nocturnal polysomnography, the following parameters are recorded: EEG (typically frontal, central,

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and occipital), eye movements, chin and leg electromyogram (EMG), nasal pressure, nasal-oral flow, thoracic and abdominal respiratory effort, and oxygen saturation simultaneously. Additionally, end-tidal carbon dioxide (EtCO2) monitoring is often routinely performed [62]. The overnight PSG is used to screen for other potential sleep disorders such as obstructive sleep apnea (OSA) or PLMS, and to ensure that the child obtained adequate sleep the night before the MSLT. Most often the PSG will be normal. However, additional findings on the overnight sleep study may include sleep onset REM period (SOREMP) within 15 min of sleep onset, increased stage N1 sleep, and increased PLMS. A shortened REM latency (not sufficient to be classified as a SOREMP) may also be a clue to narcolepsy in adolescents. In one small series, the REM latency was less than 67 min [63]. SOREMPs can also occasionally be seen on overnight PSGs [29]. The MSLT provides quantitative and qualitative information on the degree of sleepiness and nature of the transition between wake and sleep stages, such as wakefulness directly to REM sleep, which is characteristic of narcolepsy. It should be started 2 h after the final morning awakening. The MSLT consists of four to five 20 min nap opportunities, provided at 2 h intervals in a dark, quiet room [64]. Eye movements, EEG, chin EMG, and heart rate are recorded. A urine drug screen can be obtained between naps if the patient is falling asleep very quickly or if there is suspicion for drug use. Measures should be taken to keep the patient from accidentally falling asleep between nap opportunities, such as playing a board game with the parent. It is important to explain the MSLT nap times and enlist the parent’s assistance in keeping the child awake during idle times between naps to ensure an accurate study. See Table 5.1 for normal values on the MSLT. The MSLT has been validated for narcolepsy in adults when the mean sleep latency is less than 8 min and there Table  5.1  Normal values for the multiple sleep latency test (Adapted from Ref. [56])

Tanner stage

General corres­ ponding age range (in years)

Mean sleep latency

SD

Stage I Stage II Stage III Stage IV Stage V Older adolescents

10 and under 10–12 11.5–13 13–14 14+ 14+

18.8 18.3 16.5 15.5 16.2 15.8

1.8 2.1 2.8 3.3 1.5 3.5

are two or more SOREMPs [65]. Similar validation does not exist for the pediatric population. Generally accepted values in children with narcolepsy include a mean sleep latency of 5–8 min, with the presence of two SOREMPs. Chronic sleep deprivation and delayed sleep phase syndrome may masquerade as narcolepsy as patients may show short sleep latencies and multiple SOREMPs. Serial MSLTs can be used to objectively follow patients with hypersomnia in whom the diagnosis of narcolepsy is uncertain initially, but becomes gradually more apparent over time [66]. HLA DQB1*0602 association poses an increased susceptibility for narcolepsy–cataplexy. If HLA typing is positive, this lends greater support for obtaining a lumbar puncture for measuring CSF for hypocretin-1 levels. Patients who are negative for HLA DQB1*0602 are unlikely to exhibit low CSF hypocretin-1 levels. Correlation of narcolepsy with and without cataplexy and spinal fluid hypocretin-1 levels indicates that low levels of hypocretin are seen in those having narcolepsy with cataplexy [67, 68]. CSF hypocretin-1 evaluation may be beneficial when the patient is on medications that are difficult to discontinue safely, but will possibly affect MSLT values, such as SSRIs. Other circumstances include suspicion of insufficient sleep or other confounding sleep disorders. CSF hypocretin evaluation is limited to a few select centers nationwide. Additional testing includes blood work to rule out metabolic causes of daytime sleepiness, such as thyroid disorders and to ensure adequate blood counts. Imaging by CT or MRI evaluates for the presence of brain tumors or structural abnormalities as narcolepsy is especially rare in pre-school or early school aged children.

Differential Diagnoses Narcolepsy and its consequences can be mimicked by multiple other sleep disorders including insufficient sleep, idiopathic hypersomnia, circadian rhythm disturbance, PLMD, OSA, inadequate sleep hygiene, periodic hypersomnia, and medication or drug use [69, 70, 72]. Insufficient nocturnal sleep is by far the most common cause of daytime sleepiness in the adolescent [69]. Sleep length is often influenced by circadian factors such as the physiologic delay in dim light melatonin release in teenagers and the resulting post­ ponement in sleep onset time to 10:30–11:00 p.m. [70]. On most school days when the child has to awaken by

5 Narcolepsy in Childhood

5:30–6:30 a.m., this leads to sleep deprivation and daytime sleepiness [70]. Carksadon and colleagues have documented SOREMPs during MSLTs in 12 of 25 healthy adolescents [70]. Interestingly, Pollack found that the circadian rhythm in patients diagnosed with narcolepsy remained fairly intact [71]. Patients were found to sleep more often, but not necessarily longer than those without narcolepsy. He found the major sleep period remains about 6 h duration, occurring once every 24 h, indicating a normally functioning circadian rhythm. Whether this stability persists in children diagnosed with narcolepsy has not been systematically evaluated. Inadequate sleep hygiene, such as cell phone use, text messaging, playing video games, and watching television, leading to shifted bedtimes and wake times can worsen sleepiness. In addition, the use of illicit drugs, stimulants, prescription medications, over the counter hypnotics, and sedating antihistamines should also be considered when evaluating sleepiness. Idiopathic hypersomnia is characterized by daytime sleepiness, with a tendency to take long, unrefreshing naps (monosymptomatic form). Some patients also exhibit hypersomnia in association with prolonged night sleep and sleep drunkenness (polysymptomatic form; [72]). Onset of the symptoms may be during the later part of the first decade through the third or fourth decade of life. A family history is common. The nocturnal PSG shows a short sleep latency, increased slow wave sleep, and high sleep efficiency that is generally over 90%. The MSLT shows shortening of the mean sleep latency, though not to the degree seen with narcolepsy. Typically the sleep latencies are in the 5-10  min range, and SOREMPs are less than two. There may be spontaneous improvement in sleepiness over time in close to one-seventh of patients [72]. Patients with Kleine Levin syndrome or periodic hypersomnia are usually teenagers. There is a male predominance. The patients abruptly develop periods of extreme sleepiness that may last for 10–14 days during which they may sleep for 16–18 h per day. There may be a prodrome of fatigue or headache. There is extreme emotional lability when the patient is awakened. Hyperphagia with binge eating and tendency to gain weight as well as hypersexual beha-vior may accompany the sleepiness. If obtained during the symptomatic period, nocturnal polysomnography shows reduced sleep efficiency and increased time spent awake after sleep onset. The MSLT may show shortened sleep

61

latency but no SOREMPs. In between the periods of extreme sleepiness, which may occur one to three times a year, the patient remains normal. There might be an increased frequency of the allele HLA DQB1*0201 in patients with Kleine Levin syndrome [73]. In narcolepsy, patients frequently experience concurrent weight gain and increasing BMI with a higher likelihood of developing diabetes and OSA. The spectrum of non-apneic tonically increased upper airway resistance, upper airway resistance syndrome, and obstructive hypoventilation are additional sources of sleepiness to be considered. Cataplexy can also be mistaken for other similarly presenting clinical diagnoses, including epilepsy, vaso­ vagal syncope, or arrhythmia triggered syncope. When cataplexy is noted, clinical conditions that should be considered include Niemann–Pick disease type C, Norrie disease, Prader–Willi syndrome, or Coffin– Lowry syndrome. Niemann–Pick disease type C is a neurovisceral storage disorder which presents with dystonic gait abnormality, motor incoordination, downward gaze paresis, and cataplexy [74]. There may be foamy cells in the liver and bone marrow, the latter generally being manifest as “sea blue histiocytes.” There is slow progressive involvement of the cerebral cortex, thalamus, and midbrain. The disorder is due to defective esterification of cholesterol. The excessive, unesterified intracellular cholesterol shows up as increased staining with filipin. It can also be detected on electron microscopic examination of the skin or conjunctiva in the form of polymorphic lysosomal inclusion bodies [74]. Norrie disease is an X-linked recessive disorder characterized by retinal atrophy, microphthalmia, blindness, and severe mental retardation [75]. Cataplexy is a minor manifestation of the disorder, which is due to almost complete absence of monoamine oxidase. Coffin Lowry syndrome is associated with X-linked mental retardation, hearing loss, pugilistic nose, large ears, tapered fingers, hypertelo­ rism, and anteverted nares [76]. In most children with narcolepsy, cataplexy is more frequently observed close to disease onset. Since cataplexy is a defining hallmark of narcolepsy, when interviewing the child and parent, it is most important to ask open ended questions to elicit a complete description of the first episode of cataplexy. This helps to distinguish true cataplexy from “weakness” or other vague answers to yes/no type questions regarding weakness or cataplexy.

62

Management Given that narcolepsy is a lifelong disorder that often requires multiple medications, it is imperative that the diagnosis be accurate. It is important to individualize therapy by targeting the symptom(s) most bothersome to the patient. The key features of the disorder are shown in Table 5.2. Behavioral strategies include regularizing sleep– wake schedules, taking planned daytime naps when sleepiness peaks, exercising regularly, and remaining engaged in after school sports. One or two 25–30 min planned naps per day may help to offset sleepiness [77], but are rarely sufficient to completely treat sleepiness. Parents should monitor their child closely for signs/ symptoms of depression. Provision of emotional support through counseling is suggested for most patients given the rarity and complexity of the disease, and its lifelong nature. Driving should be discussed with Table 5.2  Key features of childhood narcolepsy Difficult diagnosis • Accuracy of the history is limited by expressive ability of the child in describing cataplexy, sleep paralysis, or hypnagogic hallucinations • Daytime napping is physiologic in pre-school age children • The multiple sleep latency is not applicable below the age of 6 or 7 years Daytime sleepiness • Re-emergence of napping in middle of first decade • Naps can be of variable length and not necessarily refreshing • Sleepiness may lead to behavioral and cognitive dysfunction and impair academic function Differential diagnosis • Inadequate sleep hygiene • Delayed sleep phase syndrome • Depression • Structural brain lesions leading to hypersomnolence • Idiopathic hypersomnia • Obstructive hypoventilation Management strategies • Assist the child in developing coping strategies • Provide emotional support • Encourage a regular sleep–wake schedule • Use exercise to counter sleepiness • Medications to enhance alertness • Medications to treat cataplexy • Medications to treat coexisting depression • Avoid driving • Avoid alcohol • Vocational guidance to assist in choice of a profession

S. Kotagal and S. Paruthi

adolescent patients. In general it should be discouraged, but limited driving may be allowed on a strict, case-by-case basis. In the series by Broughton et  al. [78] and Leon-Munoz et  al. [79], 66–72% of adults reported falling asleep when driving. An additional 16–28% of those surveyed reported experiencing cataplexy when driving. SSRIs such as fluoxetine or sertraline may be indicated when emotional and behavioral problems are superimposed on cataplexy. Caution should be used with SSRIs in children, given the “black box” warning for increased suicidal thinking and behavior during short-term treatment of children and adolescents with major depressive disorder and other psychiatric disorders [80]. Pharmacotherapy of daytime sleepiness: The objective is to enhance alertness to the point of effective daytime functioning in the classroom, home, and the social setting with a minimum of side effects. Currently there is no Food and Drug Administration (FDA) approved medications to treat the hypersomnolence of children with narcolepsy. In adults, there have been three level 2 studies and four level 5 studies that support the efficacy of traditional stimulants in the treatment of narcolepsy [81]. Drugs commonly used on an “off-label” basis are shown in Table  5.3. Modafanil, stimulants like methylphenidate, various preparations of amphetamines [80–84], and sodium oxybate (Xyrem) [85] are most commonly used to enhance alertness. Modafanil has not been systematically studied in the pediatric setting. Small case series of children with narcolepsy or other conditions causing hypersomnia show that children tolerate modafanil well, with improvement of daytime sleepiness [86–88]. The half-life is about 15 h; it can be given in a single dose upon awakening or divided among two doses. Common side effects include headache and nausea. On rare occasions, Stevens-Johnson syndrome may also develop. The open label study of Ivanenko et al. [86] provides Level 4 evidence about the effectiveness of modafinil in childhood narcolepsy/idiopathic hypersomnia. In 13 children, treatment with modafinil led to subjective improvement in sleepiness as reported by the parents. There was also objective improvement on the MSLT, with the mean sleep latency rising from a baseline of 6.6 ± 3.7 min to 10.2 ± 4.8 min on treatment with modafinil. There have been no head-to-head studies comparing the efficacy of modafinil to the traditional

5 Narcolepsy in Childhood

63

Table 5.3  Medications commonly used to treat narcolepsy in childhood (Adapted from Ref. [28, p. 178]) Symptom

Drug (Trade name)

Dosage

Daytime sleepiness

Modafanil (Provigil) Methylphenidate hydrochloride Ritalin Ritalin SR Concerta

up to 200 mg/day 5 mg bid to a maximum of 60 mg/day 5 mg bid to a maximum of 60 mg/day 20 mg qd to a maximum of 60 mg/day 18 mg qd to a maximum of 54 mg/day (to age 12) and up to 72 mg/day (to age 18) 20 mg qd to a maximum of 60 mg/day 10–30 mg skin patch 5 mg qd to a maximum of 40 mg/day, Dextrostat up to 60 mg/day 5–25 mg/day, in two divided doses 10–40 mg/day

Metadate Daytrana Dextroamphetamine (Dexedrine, Dextrostat)

Cataplexy and emotional problems

Periodic leg movements

Methamphetamine hydrochloride (Desoxyn) Amphetamine/dextroamphetamine Mixture (Adderall) Lisdexamfetamine (Vyvanse) Sodium oxybate (Xyrem) Venlafaxine (Effexor) Fluoxetine (Prozac) Sertraline (Zoloft)a Clomipramine (Anafranil) Imipramine (Tofranil) Protriptyline (Vivactil) Sodium oxybate (Xyrem) Elemental iron Gabapentin (Neurontin) Clonazepam (Klonopin) Levodopa-carbidopa (Sinemet) Pramipexole (Mirapex) Ropinorole (Requip)

psychostimulants, which are salts of methylphenidate or dextroamphetamine [80]. Some degree of tolerance may develop over months to years to the effect of methylphenidate and dextroamphetamine, necessita­ ting gradual dose escalation. The general side effects of stimulants range from loss of appetite, poor weight gain, nervousness, tics, and headache to insomnia. In general, stimulants are not recommended in children less than age 3. Safety below age 6 has not been established in amphetamine preparations of DEXEDRINE®, DEXTROSTAT®, ADDERALL®, or VYVANSE®. These amphetamine derivations are also not recommended in children with known structural cardiac defects. The half-life varies depending on age, 9 h in children aged 6–12  years and 11  h in children aged 12–17 years, which will affect dosing [80]. Methylphe­ nidate preparations including RITALIN®, CONCERTA®, METADATE®, and DAYTRANA® wcarry similar warn­ ings, with additional data suggesting slowing of growth rate. The half-life is typically 2–4  h. DAYTRANA®

30 mg qd to a maximum of 70 mg/day 3–9 g in two divided doses at night No trials in pediatrics; recommend start 12.5–25 mg, titrate to effect 10–30 mg/day every morning 25–200 mg/day every morning 25–100 mg/day 25–75 mg/day 15 mg/day in three divided doses 3–9 g in two divided doses at night 1–2 mg/kg in one to two divided doses 100–300 mg at bedtime 0.5–1.0 mg at bedtime 25/100 or 50/200 mg at bedtime 0.125–0.25 mg at bedtime 0.25–0.5 mg at bedtime

comes with a potential advantage as it is a skin patch formulation. Pharmacotherapy of cataplexy: Mild cataplexy that is not leading to falls or socially embarrassing situations may not need therapy. Cataplexy that is bothersome to the patient can be treated with SSRI agents, selective noradrenergic reuptake inhibitors (SNRI), and TCAs [80]. However, no antidepressant has an FDA indication for treatment of cataplexy. These agents might also ameliorate hypnagogic hallucinations and sleep paralysis. The side effects of TCA drugs include daytime sleepiness, orthostatic hypotension, weight gain, anorexia, dry mouth, and diarrhea. In adults, sodium oxybate has also been found effective for treating cataplexy, daytime sleepiness, and disrupted nocturnal sleep. Black et al. showed that modafanil and sodium oxybate have a synergistic relationship in controlling sleepiness and cataplexy when compared to placebo or each medication individually [89]. Sodium oxybate is known to increase slow wave sleep

S. Kotagal and S. Paruthi

64

and overall consolidate sleep, with many patients reporting refreshed sleep upon awakening. The safety and effectiveness have not been established in patients below 16 years of age. Caution is warranted with the use of sodium oxybate owing to its abuse potential. It is tightly regulated with only one central pharmacy across the United States. Exacerbation of concurrent sleep apnea, depression, enuresis, constipation, and tremor are potential adverse effects. Due to the short half-life of 0.5–1 h, the preparation of sodium oxybate must be given in two doses, the first one immediately before bedtime, with typically an alarm set to awaken the patient to take the second dose 2.5–3 h later [89]. Sodium oxybate has been successfully used in children in small series [90]. In children sodium oxybate has been reserved for extreme cases, and only used when strong family/parental support is readily available.

Immunotherapy Owing to possible underlying dysregulation of the immune system, narcolepsy–cataplexy subjects have been treated with intravenous immunoglobulin G soon after the diagnosis has been established. Lecendreaux et al. treated a 10-year-old boy [91] while Hecht et al. treated an 8-year-old boy [92]. In the four subjects treated by Dauvilliers et al. [93], there was significant and sustained improvement in cataplexy which minimized the need for medications. The limitations of the immunotherapy studies include the small sample size, open label design, and lack of adequate information about the natural history of cataplexy. With treatment and over time, it is likely that the signs/symptoms of narcolepsy will improve. For example, Honda and colleagues followed 329 patients up to 40 years, observing spontaneous improvement with a little over half of 133 patients noting no further cataplexy [94]. Similar percentages were provided for hypnagogic hallucinations and sleep paralysis. Finally, education is a tool which can help patients learn to manage their disease with the least amount of disruption to their daily lives. For example, The Narcolepsy Network (http://www.narcolepsynetwork. org) is a private, nonprofit resource for patients, families, and health professionals. There is also the National Narcolepsy Registry. More information can be found at http://www.ninds.nih.gov/disorders/narcolepsy.

Conclusions While many aspects of childhood narcolepsy resemble those of adults, some differences that stand out include the subtle and somewhat non-specific initial manifestations of fatigue, mood swings, inattentiveness, weight gain, and the limited reliability of the history. Why some children show significant SOREMPs right at the onset while others manifest a gradual, progression of intrusion of REM sleep phenomena onto wakefulness over months remains unknown. Also not known is the long-term difference, if any, between the outcome of those who are HLA DQB1*0602 positive versus those who are negative for this haplotype. The same goes for symptomatic versus idiopathic narcolepsy. Molecular mechanisms underlying the loss of hypocretin secreting neurons from the hypothalamus need elucidation. The utility, if any, of early intervention with intravenous immunoglobulin G infusions needs systematic study. Hopefully, spinal fluid hypocretin-1 assays will become more easily available. Pharmacokinetic, safety, and efficacy studies of drugs used to treat sleepiness and cataplexy are needed.

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S. Kotagal and S. Paruthi 73. Dauvilliers Y, Mayer G, Lecendreux M, et al. Kleine Levin syndrome: an autoimmune hypothesis based on clinical and genetic analyses. Neurology 2002; 59: 1739–1745 74. Patterson MC. (2003) A riddle wrapped in a mystery: understanding Niemann-Pick disease, type C. Neurologist 9 (6): 301–10. 75. Vossler DG, Wyler AR, Wilkus RJ, Gardner-Walker G, Vlcek BW. (1996) Cataplexy and monoamine oxidase deficiency in Norrie disease. Neurology 46(5): 1258–1261 76. Fryns JP. (1998) “Cataplexy” in Coffin Lowry syndrome. J Med Genet 35: 702. 77. Garma L, Marchand F. (1994) Non-pharmacological approaches to the treatment of narcolepsy. Sleep 17(Suppl 1): 97–102. 78. Broughton R, Ghanem Q, Hishikawa Y, et  al. (1981) Life effects of narcolepsy in 180 patients from North-America, Asia, and Europe compared to matched controls. Can J of Neurol Sci 8(4): 299–304. 79. Leon-Munoz L, de la Calzada MD, Guitart M. (2000) Accident prevalence in a group of patients with the narcolepsy-cataplexy syndrome. Rev Neurol 30(6): 596–598. 80. Wise MS, Arand DL, Auger RR, et al. (2007) Treatment of narcolepsy and other hypersomnias of central origin. Sleep 30: 1712–1727. 81. Littner M, Johnson SF, McCall VW, et al. (2001) Practice parameters for treatment of narcolepsy: An update for 2000. Sleep 24: 451–466. 82. Stahl SM. (2002) Awakening to the psychopharmacology of sleep and arousal: novel neurotransmitters and wake-promoting drugs. J Clin Psychiatr 63: 467–468. 83. Mitler MM. (1994) Evaluation of treatment with stimulants in narcolepsy. Sleep 17 (Suppl 1): 103–106. 84. Billiard M, Besset A, Montplasier F, et al. (1994) Modafanil: a double blind multicentric study. Sleep 17 (Suppl 1): 107–112. 85. The US Xyrem Multicenter Study Group (2002) 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 25: 42–49. 86. Ivanenko A, Tauman R, Gozal D. (2003) Modafanil in the treatment of excessive daytime sleepiness in children. Sleep Med 4: 579–582. 87. Dauvilliers Y, Nevsimalova S, Lecendreux M, et al. (2007) Modafinil reduces symptoms of excessive sleepiness in children and adolescents with obstructive sleep apnea or narcolepsy following 6 months of open-label therapy. Sleep 30(Suppl): A218. 88. Owens J, Bogan R, Lankford A, et al. (2007) Modafinil is well tolerated in children and adolescents with excessive sleepiness and obstructive sleep apnea: A 6-week doubleblind study. Sleep 30: (Suppl) A88–A89. 89. Black J, Houghton WC. (2006) Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep 29: 939–946. 90. Murali H, Kotagal S. (2006) Off-label treatment of severe childhood narcolepsy-cataplexy with sodium oxybate. Sleep 29(8): 1025–1029. 91. Lecendreaux M, Maret S, Bassetti C, et al. (2003) Clinical efficacy of high-dose intravenous immunoglobulins near the onset of narcolepsy in a 10-year-old boy. J Sleep Res 12(4): 347–348.

5 Narcolepsy in Childhood 92. Hecht M, Lin L, Kushida CA, et al. (2003) Report of a case of immunosuppression with prednisone in an 8-year-old boy with an acute onset of hypocretin-deficiency narcolepsy. Sleep 26(7): 809–810. 93. Dauvilliers Y, Carlander B, Rivier F, et  al. (2004) Successful management of cataplexy with intravenous

67 immunoglobulins at narcolepsy onset. Ann Neurol 56(6): 905–908. 94. Honda Y. (1997) A 10–40 year follow-up study of narcolepsy. Conference Information: Japanese/German International Symposium on Sleep-Wake Disorders, Date: OCT 09–10, 1996 Erfurt, Germany. Sleep-wake Disorders, pp 105–114.

Chapter 6

Narcolepsy in the Older Adult Hrayr Attarian

Introduction Narcolepsy is generally considered an illness of youth because of its incidence peaks around the second to third decade of life. In an Olmsted County-based epidemiological study, the median age of onset was found to be 16 years, with a range from 4 to 56 and a 90th percentile of 33.4 years [1]. Another study comparing two large populations in Quebec and France found the mean age of onset at approximately 24 years with a bimodal distribution of incidence. The first peak was at age 14 and the second peak at age 35 [2]. There have been a handful of cases that reported onset after age 35 and well into the seventies. Narcolepsy is still not as well recognized a syndrome as it should be, given its incidence (0.05% in Western Europe [3] compared to 0.03% for Multiple Sclerosis (MS), a much better known entity [4]). There is a significant delay in diagnosis of an average of 16–22 years from the onset of symptoms with a range of 1–60 years [5, 6]. Not all cases, therefore, diagnosed with narcolepsy after age 35 are due to late onset of symptoms; some are also due to delay in diagnosis. A third, smaller group of late onset narcolepsy consists of cases referred to as secondary narcolepsy or narcolepsy-like symptoms due to other neurological conditions. As narcolepsy is a chronic illness and we are an aging population, more and more people over the age of 40 have been living with this condition. According to a multi-nation European study, 43.4–48.7% of subjects

H. Attarian (*) Loyola University Chicago Stritch School of Medicine 2160 S. 1st Avenue Bldg. 105, Room 2700 Maywood, IL 60153 e-mail: [email protected]

with narcolepsy were over the age of 45 [3]. It is, therefore, important to recognize the clinical challenges age confers on this diagnostic entity. The remainder of this chapter presents narcolepsy cases with onset after age 40, those diagnosed after this age despite an earlier onset of symptoms, as well as some of the reasons behind this delay, and the different neurological problems that have caused narcolepsy and treatment challenges facing older adults with this condition and their physicians.

Narcolepsy Onset After Age 35 Rye et al. reported seven patients, as part of a series of 41 diagnosed later in life, whose symptoms started after age 40. All seven had narcolepsy without cataplexy [7]. Unfortunately, the above paper does not mention the total number of narcolepsy patients diagnosed at their center over the same 3-year period during which these 41 patients were presented. Population studies from different areas show extremely rare incidence of narcolepsy starting after age 40. In the Olmsted County study by Silber et al. there was only one patient with narcolepsy and cataplexy out of 72 (1.4%) who had onset of symptoms after age 40; this patient was in his mid-fifties [1]. In a study comparing two populations in Montpelier, France, and Montreal, Canada, only a few cases out of a total of 519 had their symptoms start after age 35 and none after age 40 [2]. Other population studies concur with the above finding, showing that the incidence of narcolepsy with or without cataplexy after age 40 is about 2–6% [8–10]. There are also sporadic case reports of narcolepsy with the onset of symptoms after age 40. The earliest

M. Goswami et al. (eds.), Narcolepsy: A Clinical Guide, DOI 10.1007/978-1-4419-0854-4_6, © Humana Press, a part of Springer Science + Business Media, LLC 2010

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such case was reported in 1987 in the UK by Kelly et al. They reported two cases: one who had narcolepsy with cataplexy starting at age 72 and the other had narcolepsy without cataplexy starting at age 85 [11]. Both cases were initially misdiagnosed as having complex partial seizures and treated with anti-epileptic medications (AEDs). In both the cases, obstructive sleep apnea (OSA) was also suspected because of their age despite the classic presentation of sleep attacks and cataplexy. In 2005, Chen et al. published another case of narcolepsy with cataplexy with the onset of symptoms at age 60, in which the patient was also misdiagnosed as having temporal lobe epilepsy and treated with AEDs [12]. In 2006, we reported the oldest case of new onset narcolepsy with cataplexy with symptoms starting at age 74 [13]. The patient was also treated with AEDs and underwent testing to rule out OSA, and was even given a therapeutic trial of empiric CPAP. Interesting parallels can be seen among all four cases. All four were treated with AEDs and three out of four were thought to have OSA, in addition to possible seizures. Interestingly, children under 10 presenting with narcolepsy are also often misdiagnosed as having seizures [14]. Despite the difference of almost 20 years and two different countries, these parallels highlight the fact that narcolepsy in the older individual is still not considered a possible diagnosis despite clear, text book description of cataplexy in two of the cases and clear description of sleep attacks in three [11–13]. A very interesting paper from Japan published in 2001 described a pair of monozygotic twin sisters, one of whom presented with symptoms in her early teens while the other did not develop any symptoms till age 45. She was addicted to methamphetamine as a drug of abuse since her early twenties, so she may have been masking the symptom of daytime sleepiness. She did have episodes of sleep paralysis early on in life and had auditory hallucinations when she was in an abusive marriage so the psychiatric overlay as well may have masked an earlier onset of the syndrome [15]. The above discussed cases highlight the importance of keeping an open mind when evaluating older patients (and children under 10) with new onset daytime sleepiness with or without “unusual spells” because it still could be narcolepsy.

Delayed Diagnosis One of the major reasons a good proportion of narcolepsy sufferers present later in life is because of delayed diagnosis. The mean number of years from onset to diagnosis has been reported in one UK study to be 15 with a range of 1–61 [5], 17 years in a Canadian study [16] and a few US papers have sited 10–14 years as the mean [6, 17]. About half of narcolepsy patients present for a correct diagnosis after age 40 [7, 18] and a majority probably go undiagnosed. According to a landmark paper published in 1994, approximately 85% of narcolepsy patients go through life undiagnosed [19]. Factors that influence the delay are: (1) the year of presentation to a medical professional with the initial complaint; since the 1980s there has been more awareness about the condition among physicians, leading to a more timely diagnosis, (2) the onset of symptoms, those presenting before teens and after age 30 are less likely to be diagnosed in a timely fashion and (3) lack of cataplexy or ancillary symptoms [5, 18]. The severity of symptoms may also hasten proper diagnosis and some patients with long-standing mild daytime sleepiness may seek medical attention after developing a comorbid disorder that increases the severity of the daytime sleepiness [18]. Cultural variables also play a role in shaping the presentation of the syndrome, especially when it comes to daytime sleepiness. Depending on the cultural background, different people may complain more of fatigue or malaise than sleepiness [20]. Surprisingly gender was not a factor in delayed diagnosis as it is known to be in OSA [21]. Another important variable is the impact of age on the results of objective testing which may make the diagnosis of an older individual more difficult. The Multiple Sleep Latency Test (MSLT) is the gold standard for the diagnoses of narcolepsy, and generally a mean sleep latency of less than 8 min with two or more sleep onset rem periods (SOREMPs) is considered diagnostic of it [22]. These numbers are based on studies that primarily included narcolepsy patients in the typical age group of late teens to early 30s. Dauvilliers et al. showed that there was a significant progressive decrease in the number of SOREMP with age and a progressive increase in the mean sleep latency on the MSLT as a function of age (Fig. 6.1). The former, however, was not associated with changes in REM latency at night, in contrast with the classic decrease of REM

6 Narcolepsy in the Older Adult

Fig. 6.1  Age groups vs. MSLT latency in minutes and number of SOREMPs (Adapted from Dauvilliers et al. (2004) [23])

latency in the non-narcoleptic aging population [23]. In general, there also is a progressive decrease in cataplexy attacks with age [23, 24] and a decrease in the severity of sleep paralysis and hypnagogic hallucinations [24]. Subjectively, however, there is no real difference in the degree of excessive daytime sleepiness (EDS) across the age spectrum [10, 24]. Nor is there any difference in the cognitive problems primarily related to attention or in the sleep disruptions at night [10]. Another symptom of narcolepsy that often goes undiagnosed is dream enacting behavior or Rem Sleep Behavior Disorder (RBD). RBD tends to occur in about one-third of narcoleptic and has a higher incidence in the 40 plus age group [25]. These “atypical” diagnostic features may be yet another reason why older adults with narcolepsy are less likely to receive a proper diagnosis.

Secondary or Symptomatic Narcolepsy Over the years there have been several case reports of narcolepsy or narcolepsy-like syndromes occurring in a variety of neurological illnesses. Some of these are in people of age 40 and above. The most well recognized association is with head trauma. A recent study found a narcolepsy prevalence of 6% in a group of traumatic brain injury patients. The mean age of those with sleep problems was 43.05 years. There was no correlation between the presence of a sleep problem and the severity of the trauma [26]. All other cases of post-head trauma narcolepsy were in younger individuals [27].

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Another reported association is with Parkinson disease (PD) and other neurodegenerative disorders. PD and other synucleinopathies are well-known causes of EDS and RBD, two entities commonly seen in narcolepsy. There is no common pathophysiology, however, between the sleep disorders of PD and other synucleinopathies and those of narcolepsy [28]. One exception is the Progressive Supranuclear Palsy (PSP), where a significant deterioration of the hypocretin neurons is observed [29]. Despite this well established fact there are few cases of secondary narcolepsy in PD reported in the literature, all of which occurring in older individuals. The most recent case was of a 58-year-old man with 15-year history of PD and EDS who had low CSF hypocretin levels [30]. Scouring the literature also revealed 17 other cases who either had MSLT confirmed narcolepsy or low CSF hypocretin confirmed narcolepsy starting late in life with PD [27]. Other neurological conditions associated with late onset secondary narcolepsy (either with MSLT evidence or low CSF hypocretin) have been elegantly summarized in a 2005 paper by Nishino and Kanbayashi, and include a case of hypothalamic tumor (age of onset 65), two brain stem infarcts (ages 40–45), two of encephalitis (ages 40 and 65), two of MS (ages 43–45), three paraneoplastic syndromes (ages 38–67), a 65-year-old with Hashimoto’s encephalopathy and a 38-year-old with Acute Disseminated encephalomyelitis (ADEM) [27]. Since 2005 there have been a few additional case reports as well and these include: Whipple’s disease in a 45-year-old man in whom hypocretin levels were not checked [31], neurocysticercosis in a 54-year-old man [32], a case of brain stem encephalitis with a mediotegmental lesion in a 30-year-old man [33], both with normal CSF hypocretin levels and MS in a 37-year-old woman with low CSF hypocretin levels [34]. Iatrogenic narcolepsy has also been described in a few older individuals. Dempsey et  al. described a 60-year-old man who developed atypical cataplexy (not triggered by emotion but occurring spontaneously) and EDS 2 weeks after completing radiotherapy for a pituitary adenoma. A MSLT confirmed the diagnosis of narcolepsy with a mean sleep latency of 6.4 min and two SOREMPs. His CSF hypocretin levels were normal. He failed traditional therapies but responded to mazindol 2 mg twice daily [35]. Two other cases of radiotherapy induced radiation were reported as part of an 18 case series of secondary

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narcolepsy in 2001. Both had typical cataplexy and one had MSLT-confirmed narcolepsy. No information is available on their age of onset or hypocretin levels although only one out of all 18 cases was above 35 years of age (45) at the time of diagnosis [36]. Another example of iatrogenic narcolepsy with cataplexy was described by Nissen et  al. in a 55-year-old woman who presented with EDS and typical cataplexy after discontinuation of the antidepressant venlafaxine. She had MSLT-confirmed narcolepsy with normal hypocretin level. The symptoms resolved after restarting venlafaxine [37] (Table 6.1 summarizes all these cases).

Implications of Narcolepsy in the Older Adult and Therapeutic Challenges Narcolepsy patients, in general, have more impairment of attention and some executive functions such as verbal fluency despite intact memory compared to controls. These cognitive impairments were similar to

H. Attarian

those encountered in people who are deprived of sleep [49]. In the narcolepsy population of over 40 years of age, these cognitive problems become more pronounced [10]. There is also a significant reduction in healthrelated quality of life (HQoL) scores [50], indicating that patients with narcolepsy, in addition to cognitive impairment, have a reduced quality of life. Older people, in general, have a lower HQoL scores because of multiple other medical issues that become more prevalent as one ages [51]. The longer the daytime sleepiness goes without treatment, the greater is the psychosocial impairment from both of these factors. There is also good evidence that treatment will reverse the impairment and relief of the symptoms of narcolepsy are associated with good psychosocial adjustment [52]. Therefore, the cognitive and psychosocial impairments inherent to untreated individuals become magnified in older individuals; hence, it is extremely important to recognize the symptomatology of narcolepsy early in the course of illness to prevent the complications mentioned above. In addition, it is important to periodically reevaluate these patients because although narcolepsy

Table 6.1  Summary of case reports of secondary narcolepsy in patients of age 35 and above (Adapted in part from Nishino and Kanbayashi (2005) [27]) Primary condition Age Gender MSLT Hypocretin Reference Radiation for pituitary adenoma 60 M Abnormal Normal Dempsey (2003) [35] Effexor withdrawal 55 F Abnormal Normal Nissen (2005) [37] Hypothalamic tumor 65 F Abnormal Low Nokura (2004) [38] Pontomedullary infarct 40 M Abnormal Normal Bassetti (2003) [39] Thalamic infarct 45 M Abnormal Normal Nokura (2004) [38] Rasmussen’s encephalitis 40 M Abnormal Low Lagrange (2003) [40] Limbic encephalitis 65 M Not done Low Yamato (2004) [41] Neurocysticercosis 54 M Abnormal Normal Watson (2005) [32] PD 69 M Abnormal Normal Overeem (2002) [42] PD 64 M Abnormal Normal Overeem (2002) [42] PD 52 M Abnormal Normal Overeem (2002) [42] PD 43 M Abnormal Low Maeda et al. (2006) [42] PSP 74 M Abnormal Low Hattori (2003) [43] MS 45 F Not done Low Kato (2003) [44] MS 43 F Not done Borderline Nozaki (2004) [45] MS 37 F Borderline Low Vetrugno (2008) [34] ADEM 38 F Abnormal Low Gledhill (2004) [46] Whipple’s disease 54 M Abnormal Not checked Maia (2006) [31] Hashimoto’s encephalopathy 65 M Not done Low Castillo (2004) [47] 45 M Not done Low Overeem (2004) [48] Paraneoplastic Anti-Ma associated encephalitis with germ cell tumor of testes Paraneoplastic Anti-Ma associated encephalitis 38 M Not done Low Overeem (2004) [48] with germ cell tumor of testes Paraneoplastic Anti-Ma associated encephalitis 67 F Not done Low Overeem (2004) [48] with adenocarcinoma of lung

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6 Narcolepsy in the Older Adult

does not get worse per se the chronic nature of it makes the impact of the condition worse with time and with its interaction with other age-related sleep disruptions and health problems. Although treatment options are available for this condition, the different medications used may pose certain challenges when it comes to an older population. Modafinil is a well tolerated and safe wake-promoting agent that, in the initial trials, did not cause any significant blood pressure and heart rate changes [16]. Since then, however, there have been some reports of modafinil-induced hypertension and a recent study showed significant disturbance of autonomic cardiovascular regulation manifested as an increase in heart rate and blood pressure. This may not be significant for someone with a healthy cardiovascular system but may create a potential problem in people with heart disease [53]. The prevalence of heart disease tends to be higher in the older population. Older individuals have higher plasma levels of modafinil because of a combination of slowed metabolism and the higher likelihood of being on concomitant medications that may slow the metabolism of modafinil [54]. Therefore, even a medication as safe as modafinil should be administered with caution and if need be at reduced doses to older individuals. Amphetamines and methylphenidate are traditional stimulants used in the treatment of EDS associated with narcolepsy, and although generally thought to be safe in the older population, they are associated with a risk of hypertension and increased heart rate because of their sympathomimetic activities [55–58]. Although the risk is modest in the healthy young adult, the situation is different when dealing with an older individual who already has a pre-existing hypertension or cardiac disease. In addition, there have been rare reports of cardiomyopathy with both methylphenidate and amphetamines [57, 59]. Other agents include selegiline, monoamine-oxidase B (MAO-B) inhibitor, protriptyline an activating tricyclic antidepressant and codeine. Selegiline has the potential of hypertensive crisis if a strict tyramine free is not followed; therefore, its use in the treatment of a lifelong illness is limited [18]. Protriptyline at higher doses has the potential of cardiac arrhythmias and in the older population can lead to significant anticholinergic effects including urinary retention [18]. Codeine can also cause significant constipation which potentially can be worse if there is age related slowing of gastric motility [60].

Anti cataplexy agents also have their set of adverse effects. The mainstay of treatment is clomipramine or similar tricyclic antidepressants. Here again, the problem when used in the older individual is the potential of urinary retention and other exaggerated anticholinergic effects. Also, these medications have the potential of exacerbating RLS/PLMD and RBD conditions that tend to occur more frequently in the older narcoleptic [18]. Other agents used are high doses of the selective serotonin receptor inhibitors (SSRIs) and atypical antidepressants such as venlafaxine. Here as well, the potential side effects in the older population are similar to those discussed above with clomipramine and related drugs. Sodium Oxybate is the newest medication for the treatment of cataplexy and although it is generally well tolerated the amount of sodium per dose makes it a suboptimal choice for an individual with salt sensitive hypertension or congestive heart failure. In addition, because of the profound sedation it may be a fall hazard for an older person with nocturia [61, 62]. The treatment of other related sleep problems such as RBD, PLMD and nighttime sleep disruptions, all three more common in older individuals, has primarily been clonazepam, a benzodiazepine with a long half-life. In the elderly, benzodiazepines, regardless of half-life, have been associated with more night time falls and hip fractures [63, 64]. Clonazepam can also cause morning hangover worsening the already existing daytime sleepiness in a patient with narcolepsy, especially an older individual not able to metabolize and clear the drug as fast [65]. Lastly, the impact of medications prescribed for other conditions on the symptoms of narcolepsy are discussed. In addition to trying to avoid sedative medications in order to avoid worsening the EDS, and tipping the fragile balance of wakefulness and drowsiness that narcoleptics live in, is important to remember that the commonly prescribed alpha 1 agonists, for either hypertension, or benign prostatic hypertrophy, e.g., prazosin can frequently severely exacerbate cataplexy [66].

Conclusion In our aging population, narcolepsy is no longer an illness exclusive to teenagers and young adults. A certain number of these patients start having symptoms late in life,

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others are not diagnosed until later because of lack of awareness about this syndrome in both the general population and the medical community, and a third category presents with other conditions that cause secondary narcolepsy. Overall, the number of people presenting later in life with narcolepsy is small but awareness of this condition in the older age group is important even if these patients present and get diagnosed early on. As they get older their sleepiness should be reevaluated because of comorbid sleep disorders and there are therapeutic challenges that the medications used to treat the various symptoms of narcolepsy pose in the setting of age-related medical conditions.

Case Example A 65-year-old man started having episodes of brief knee weakness when excited and persistent EDS in his mid to late 20s. He thinks both symptoms started simultaneously but is not absolutely sure. Shortly afterwards, he developed infrequent episodes of sleep paralysis especially when napping together with auditory hypnopompic hallucinations. It took him a couple of years to seek medical attention. For the next 10 years he was unsuccessfully treated for anxiety and depression. The falls were attributed to his preexisting congenital spinal stenos. He finally got referred to a sleep center where he underwent an overnight sleep study without a MSLT, and the next day was diagnosed with narcolepsy. He was started on methylphenidate 20  mg slow release in the morning and then another two tablets of 10 mg immediate release methylphenidate as needed in the late morning and every afternoon. Up until 6 years ago this was enough to control his EDS. His cataplexy remained under partial control with protriptyline10 mg tablets five times a day. He was content with the control as long as he was able to ride his motorcycle without falling. Over the past 6 years he developed loud snoring, nocturia and severe back pain which led him to not be as physically active and put on weight. His cataplexy also got a bit worse with his worsening EDS. When he presented to our sleep center he was sleeping from 10:30 pm till 7:00 am every day and taking 2–3 brief 5–10 min naps. His Epworth sleepiness scale score was 23/24. His sleep paralysis and hypnopompic hallucinations were no longer bothersome and occurred

H. Attarian

very rarely. He also was drinking four to five 12  oz cups of coffees a day. In addition to his narcolepsy medications, he was taking omeprazole for heartburn, gabapentin for low back pain and a statin for his hyperlipidemia. On examination, the remarkable findings were a BMI of 30.2 kg/m2, blood pressure of 140/95 mmHg and an antalgic gait because of back pain. Otherwise, the complete physical and neurological examination was normal. An overnight sleep study was performed 2 weeks later that revealed moderate obstructive sleep apnea syndrome (OSAS), with an apnea/hyopnea index of 20.2/h and a nadir oxyhemoglobin saturation of 84%. He had early REM sleep. He was treated with CPAP and a pressure of 7.0 cm of H2O completely controlled the OSAS. Two months of using CPAP only modestly improved his EDS. He was due to come in to have his medications adjusted but suffered angina and was admitted to the hospital and underwent two vessel coronary bypass graft complicated by a transient ischemic attack and arrythmias. The latter was attributed to protriptyline so his dose was reduced to 20  mg a day, which did not control his cataplexy at all so it was discontinued altogether. He recovered from his surgery quite well and was started on Xyrem at 3  g a night. He had nausea with it and had no control of his cataplexy which started occurring multiple times a day even when only minimally excited. Xyrem dose was increased to 4.5 g then to 6 g a night and although his nausea subsided and the cataplexy only marginally improved, his blood pressure which was under good control on lisinopril started creeping up. Xyrem was discontinued and the blood pressure control improved once more. His methylphenidate was also tapered off after his surgery and he was started on modafinil. At 200 mg three times a day, his EDS was well controlled. For his cataplexy he was tried on sertraline, and at 75  mg a day his cataplexy was reduced by 50% but still not enough for him to ride his motorcycle which was his main hobby especially after retirement. Higher doses of sertraline caused sexual dysfunction with no improvement of his cataplexy. Clomipramine was introduced at 25 mg once a day dosing. The goal was to taper him off sertraline once clomipramine reached a therapeutic dose but on 50 mg of clomipramine, 75 mg of sertraline and 600 mg of modafinil and his CPAP, both his EDS and cataplexy came under excellent control. At his last visit, to which he rode his motorcycle, his symptoms were under control for over a year on the above regimen.

6 Narcolepsy in the Older Adult

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75 23. Dauvilliers, Y., et  al., Effect of age on MSLT results in patients with narcolepsy-cataplexy. Neurology, 2004. 62(1): p. 46–50. 24. Furuta, H., M.J. Thorpy, and H.M. Temple, Comparison in symptoms between aged and younger patients with narcolepsy. Psychiatry Clin Neurosci, 2001. 55(3): p. 241–2. 25. Nightingale, S., et al., The association between narcolepsy and REM behavior disorder (RBD). Sleep Med, 2005. 6(3): p. 253–8. 26. Castriotta, R.J., et al., Prevalence and consequences of sleep disorders in traumatic brain injury. J Clin Sleep Med, 2007. 3(4): p. 349–56. 27. Nishino, S. and T. Kanbayashi, Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med Rev, 2005. 9(4): p. 269–310. 28. Baumann, C., et  al., Parkinsonism with excessive daytime sleepiness--a narcolepsy-like disorder? J Neurol, 2005. 252(2): p. 139–45. 29. Yasui, K., et al., CSF orexin levels of Parkinson’s disease, dementia with Lewy bodies, progressive supranuclear palsy and corticobasal degeneration. J Neurol Sci, 2006. 250(1–2): p. 120–3. 30. Maeda, T., et al., Parkinson’s disease comorbid with narcolepsy presenting low CSF hypocretin/orexin level. Sleep Med, 2006. 7(8): p. 662. 31. Maia, L.F., et  al., Hypersomnia in Whipple disease: case report. Arq Neuropsiquiatr, 2006. 64(3B): p. 865–8. 32. Watson, N.F., M.J. Doherty, and J.R. Zunt, Secondary narcolepsy following neurocysticercosis infection. J Clin Sleep Med, 2005. 1(1): p. 41–2. 33. Mathis, J., C.W. Hess, and C. Bassetti, Isolated mediotegmental lesion causing narcolepsy and rapid eye movement sleep behaviour disorder: a case evidencing a common pathway in narcolepsy and rapid eye movement sleep behaviour disorder. J Neurol Neurosurg Psychiatry, 2007. 78(4): p. 427–9. 34. Vetrugno, R., et  al., Narcolepsy-like syndrome in multiple sclerosis. Sleep Med, 2009. 10: p. 389–91. 35. Dempsey, O.J., et al., Acquired narcolepsy in an acromegalic patient who underwent pituitary irradiation. Neurology, 2003. 61(4): p. 537–40. 36. Malik, S., et al., Narcolepsy associated with other central nervous system disorders. Neurology, 2001. 57(3): p. 539–41. 37. Nissen, C., et al., Transient narcolepsy-cataplexy syndrome after discontinuation of the antidepressant venlafaxine. J Sleep Res, 2005. 14(2): p. 207–8. 38. Nokura, K., et al., Hypersomnia, asterixis and cataplexy in association with orexin A-reduced hypothalamic tumor. J Neurol, 2004. 251(12): p. 1534–5. 39. Bassetti, C., et al., The narcoleptic borderland: a multimodal diagnostic approach including cerebrospinal fluid levels of hypocretin-1 (orexin A). Sleep Med, 2003. 4(1): p. 7–12. 40. Lagrange, A.H., et al., Rasmussen’s syndrome and new-onset narcolepsy, cataplexy, and epilepsy in an adult. Epilepsy Behav, 2003. 4(6): p. 788–92. 41. Yamato, H., et al., [A hypersomnia case due to limbic encephalitis with decreased orexin level]. Rinsho Shinkeigaku, 2004. 44(7): p. 482. 42. Overeem, S., et al., Normal hypocretin-1 levels in Parkinson’s disease patients with excessive daytime sleepiness. Neurology, 2002. 58(3): p. 498–9.

76 43. Hattori, Y., et  al., [Excessive daytime sleepiness and low CSF orexin-A/hypocretin-I levels in a patient with probable progressive supranuclear palsy]. No To Shinkei, 2003. 55(12): p. 1053–6. 44. Kato, T., et  al., Hypersomnia and low CSF hypocretin-1 (orexin-A) concentration in a patient with multiple sclerosis showing bilateral hypothalamic lesions. Intern Med, 2003. 42(8): p. 743–5. 45. Nozaki, H., et al., [A case with hypersomnia and paresthesia due to diffuse MS lesions from hypothalamus to spine]. Rinsho Shinkeigaku, 2004. 44(1): p. 59. 46. Gledhill, R.F., et al., Narcolepsy caused by acute disseminated encephalomyelitis. Arch Neurol, 2004. 61(5): p. 758–60. 47. Castillo, P.R., et  al., Undetectable CSF hypocretin-1 in “Hashimoto’s encephalopathy” associated with coma. Neurology, 2004. 62(10): p. 1909. 48. Overeem, S., et  al., Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis. Neurology, 2004. 62(1): p. 138–40. 49. Naumann, A., C. Bellebaum, and I. Daum, Cognitive deficits in narcolepsy. J Sleep Res, 2006. 15(3): p. 329–38. 50. Dodel, R., et  al., Health-related quality of life in patients with narcolepsy. Sleep Med, 2007. 8(7–8): p. 733–41. 51. Hickey, A., et al., Measuring health-related quality of life in older patient populations: a review of current approaches. Pharmacoeconomics, 2005. 23(10): p. 971–93. 52. Wilson, S.J., et al., Psychosocial adjustment following relief of chronic narcolepsy. Sleep Med, 2007. 8(3): p. 252–9. 53. Taneja, I., et  al., Modafinil elicits sympathomedullary activation. Hypertension, 2005. 45(4): p. 612–8. 54. Wong, Y.N., et al., Open-label, single-dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects. J Clin Pharmacol, 1999. 39(3): p. 281–8.

H. Attarian 55. Weisler, R.H., et  al., Long-term cardiovascular effects of mixed amphetamine salts extended release in adults with ADHD. CNS Spectr, 2005. 10(12 Suppl 20): p. 35–43. 56. Wilens, T.E., et al., Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry, 2005. 66(2): p. 253–9. 57. Nymark, T.B., et al., A young man with acute dilated cardiomyopathy associated with methylphenidate. Vasc Health Risk Manag, 2008. 4(2): p. 477–9. 58. Godfrey, J., Safety of therapeutic methylphenidate in adults: a systematic review of the evidence. J Psychopharmacol, 2009. 23: p. 194–205. 59. Marks, D.H., Cardiomyopathy due to ingestion of Adderall. Am J Ther, 2008. 15(3): p. 287–9. 60. Mikus, G., et al., Effect of codeine on gastrointestinal motility in relation to CYP2D6 phenotype. Clin Pharmacol Ther, 1997. 61(4): p. 459–66. 61. 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): p. 42–9. 62. Owen, R.T., Sodium oxybate: efficacy, safety and tolerability in the treatment of narcolepsy with or without cataplexy. Drugs Today (Barc), 2008. 44(3): p. 197–204. 63. French, D.D., et al., Benzodiazepines and injury: a risk adjusted model. Pharmacoepidemiol Drug Saf 2005. 14(1): p. 17–24. 64. Wagner, A.K., et al., Benzodiazepine use and hip fractures in the elderly: who is at greatest risk? Arch Intern Med, 2004. 164(14): p. 1567–72. 65. Wolkove, N., et al., Sleep and aging: 2. Management of sleep disorders in older people. Cmaj, 2007. 176(10): p. 1449–54. 66. Aldrich, M.S., and A.E. Rogers. Exacerbation of human cataplexy by prazosin. Sleep, 1989. 12(3): p. 254–6.

Chapter 7

Diurnal and Nocturnal Sleep in Narcolepsy with Cataplexy Yves Dauvilliers and Giuseppe Plazzi

Introduction Chronic hypersomnia, defined by a constant complaint of excessive daytime sleepiness (EDS) that occurs every day for at least three months, is common in the general population, affecting 5–15% of individuals. In the last few years, considerable progress has been made in the identification of different types of hypersomnia with several methods available to affirm the existence of EDS and to differentiate among the different causes of hypersomnia [1, 2]. Narcolepsy is classically reported as one of the most severe conditions of EDS. It is a disabling disorder characterized by cataplexy (sudden loss of muscle tone triggered by strong emotions), sleep paralysis, hypnagogic hallucinations, and the presence of sleep onset REM periods [3]. EDS is usually the first symptom to appear, either isolated or accompanied by cataplexy occurring within the same year, often with improvement throughout the lifetime [3]. Despite its low prevalence, narcolepsy with cataplexy has been extensively studied with the main clinical features becoming increasingly known to the medical community. However, the presence of other sleep disturbances in narcolepsy, such as parasomnias and nighttime sleep disruption, has clearly been underestimated [3]. Typically, the nighttime sleep of narcoleptics is interrupted by multiple and long awakenings and abnormal movements or behaviours that may be severe, during REM or NREMsleep [4]. The general course of narcolepsy

Y. Dauvilliers (*) Service de Neurologie, Hôpital Gui-de-Chauliac, 80 Avenue Augustin Fliche, 34295, Montpellier Cedex 5, France e-mail: [email protected]

is difficult to predict, with huge variability from one patient to another, but nocturnal sleep disturbances usually worsen with aging.

Clinical Characteristics Daytime Clinical Features Excessive Daytime Sleepiness Phenotype In the presence of a complaint of EDS, the first step is to determine the phenotype of EDS by clinical interview. Typically, patients with EDS complain of drowsiness that may be present only during inactivity or reoccur typically at two-hourly intervals. EDS can occur daily, only on several consecutive days, or intermittently. Sleep episodes can be irresistible, of short duration, and associated with dreaming [5]. The method of morning awakening should also be determined, whether it is spontaneous, with an alarm, or only possible by means of a family member [1, 6]. The age of onset of EDS, the existence of possible precipitating circumstances at onset, and the factors that led to exacerbation or improvement also need to be reviewed. In cases of long-standing sleep problems, it is necessary to determine why the patient is seeking help at the present time. Narcoleptic patients generally do not sleep excessive amounts of time over the 24-h day. Rather, they are unable to stay awake or asleep for long periods of time. It is exacerbated when the patient is physically inactive, for example, when watching television,

M. Goswami et al. (eds.), Narcolepsy: A Clinical Guide, DOI 10.1007/978-1-4419-0854-4_7, © Humana Press, a part of Springer Science + Business Media, LLC 2010

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riding in a car, or even driving. The sleep episodes are characterized by a premature onset of REM sleep [8]. The characteristics of sleep episodes in narcoleptic patients are: • Always greatly interfere with daytime activities • Often irresistible, despite efforts to fight against the sleepiness • Usually of short duration, but with variation depending upon age and environmental factors • Frequently associated with dreaming • Typically capable of restoring normal vigilance for several hours after short naps, a characteristic of narcolepsy with significant diagnostic value. However, in children, the refreshing value of short naps is of less diagnostic value for narcolepsy.

Severity EDS can be variable in severity from one patient to another. A patient with mild sleepiness might fall asleep while reading a paper, while in contrast, sleepiness, when severe, produces episodes of irresistible sleep, sleep attacks or unconscious lapses occurring while talking, eating, or driving [1, 2, 9]. Severe sleepiness may lead the patient to impaired driving and a high prevalence of car or machine accidents, as well as deficits in work performance leading to unemployment and working disability [10]. The severity of the condition helps in the differential diagnosis of hypersomnia. Sleep questionnaires should be used to quantify the severity of the complaint and to assess different aspects of sleepiness. All questionnaires require a subject’s accurate perception of his or her own sleepiness; they do not rely on any objective measure of sleepiness. The Epworth Sleepiness Scale (ESS) is the most widely used, with a score greater than 10 supporting a complaint of hypersomnia [11]. This scale documents the average sleep propensity during eight soporific situations over prior two-week period. The information from the patient’s bed partner and/ or family members is often useful, as many sleep problems are either not evident to the patient or their existence is denied by the patient. Some patients overreport their degree of sleepiness and note EDS even during periods of normal alertness, while other individuals

underreport periods of EDS. In certain cases, it would be helpful to compare sleepiness scale scores completed by the patient and the bed partner. Narcolepsy is classically reported as one of the most severe disorders of EDS, with a major impact on the quality of life [3, 10]. The number of hours during which the patient does not feel sleepy after a sleep episode reflects the severity of the disease. EDS can also lead to automatic behaviours and unconscious microsleep episodes or lapses.

Symptoms of Dissociated REM Sleep Cataplexy Cataplexy is distinct from EDS, specific to narcolepsy, and the best diagnostic marker for the disease. It is rare for cataplexy to be the first clinical manifestation of narcolepsy. Cataplexy frequently occurs at the same time as EDS or is delayed by several years [7]. It is characterized by a sudden drop of muscle tone triggered by emotional factors, most often by positive emotions such as laughter, repartee, good surprise, less often by anger, and almost never by stress, fear, and physical effort [3, 12]. Cataplectic attacks may be limited to facial muscles or to the upper or lower limbs, with dysarthria, facial flickering, jaw tremor, head or jaw dropping, dropping objects or weakness of the knees. Patients remain fully conscious during the episode. The duration of cataplexy varies from a few seconds to several minutes, and the frequency of cataplexy ranges from less than one episode per year to several episodes per day. Cataplexy usually worsens with poor sleep and fatigue. (See for further details chapter X C Bassetti).

Hypnagogic Hallucinations Approximately two-thirds of narcoleptic patients will report hallucinations in the course of their illness. These manifestations may be dreamlike auditory, visual, or tactile hallucinations occurring at sleep onset (hypnagogic) or, less frequently, upon awakening (hypnopompic). These symptoms are more prevalent in young individuals and tend to decrease with time, although some patients will experience these auxiliary symptoms throughout their lifetime. Sleeprelated hallucinations also exist in the general

7 Diurnal and Nocturnal Sleep in Narcolepsy with Cataplexy

population (prevalence around 20%) but are more frequent and more intense in narcoleptics, and sometimes so scary that the subject becomes fearful of going to bed [3, 13].

Sleep Paralysis Partial or total sleep paralysis occurs in approximately 50% of the narcoleptic population. Sleep paralysis is an inability to move the limbs or the head or to speak and breathe normally. It occurs either at sleep onset or upon awakening (mainly from REM sleep). This feeling of being “blocked in armour” is frightening, and can be associated with hallucinations [3, 14]. Sleep paralysis is usually of short duration but can last several minutes. Sleep paralysis is not specific to narcolepsy (around 10–20% of the general population), and is therefore not predictive of the diagnosis but is more severe and more frequent in patients with narcolepsy [14].

Automatic Behaviour During the daytime, patients may have automatic behaviour, i.e. automatic continuation of activity without memory of the event. In these cases, the patient may suddenly say something inappropriate or out of context in a conversation, continue to write automatically off the topic or write unreadable words, or may drive to a location with no memory of the event [3]. Whether automatic behaviour is caused by microsleep or cognitive impairment when drowsy, is unknown.

Other Diurnal Symptoms Unrelated to Dissociated REM Sleep Several other features may be observed in narcolepsy with cataplexy but are of less diagnostic value: −− Higher body mass index, frequently with rapid weight gain at disease onset, especially in children [15] −− Depression, reported in up to 50% of cases that may contribute to disturbed nighttime sleep [16] −− Memory impairment −− Increased frequency of migraine −− Olfaction dysfunction

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Nocturnal Clinical Features Disturbed nocturnal sleep may be considered the fifth component of the “narcolepsy tetrad.” Typically, narcoleptics fall asleep almost instantly when they go to bed, but their sleep is afterward interrupted by several awakenings. Nighttime sleep is disrupted in at least one-third of narcoleptic patients and classically worsens over the years. The number of awakenings at night are more frequent than in controls but with huge variability from one patient to another, as it is for longer awakenings of some patients reporting staying awake for several hours [4, 8]. The presence of poor sleep at night may lead to severe chronic maintenance insomnia. The nighttime sleep disturbance may be as severe as daytime symptoms. As daytime and nighttime sleep are classically in close relationship, one may propose that an accumulation of daytime sleep with planned or unplanned naps may aggravate sleep at night. However, most studies investigating the relationship between the complaint of nocturnal sleep disturbance and EDS in narcolepsy have rarely found significant correlation [17, 18]. The mechanisms involved in sleep fragmentation vary from one narcoleptic patient to another, particularly with regard to nocturnal awakenings, and abnormal movements or behaviours during REM or NREM sleep [4]. Nightmares, and REM sleep behaviour disorders (RBD, patients enacting their dreams with possible vivid frightening dreams) are associated with fragmented REM sleep and observed in at least one-third of patients and may contribute to sleep maintenance insomnia [4]. A recent study revealed that patients with narcolepsy-cataplexy present more frequent RBD than those without cataplexy [20]. Hypnagogic hallucinations, frightening dreams, or sleep paralysis may occur not only at sleep onset but also in the middle of the night or early in the morning upon awakening from REM sleep and be associated with sleep fragmentation [3, 4]. In addition, NREM parasomnias, such as sleep-related eating disorder, sleepwalking, and nocturnal terror that are more frequent in narcolepsy may also disturb nighttime sleep [4, 21]. Other symptoms that may disturb sleep at night such as snoring, nocturia, headache whether or not due to obstructive sleep apnea, and discomfort of the extremities during periods of inactivity in bed or repetitive nocturnal agitation, need to be investigated.

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A clear understanding of the daily schedule is also needed in narcolepsy. It should include the usual bedtime and detailed sleep/wake weekday and weekend schedules. Other information regarding sleep habits, the environment, and mood disorders may disclose important contributing factors. Finally, treatment of cataplexy and/or EDS may induce and/or aggravate nocturnal sleep disturbance, restless leg syndrome, and periodic leg movements at night, as well as REM and NREM parasomnias.

Laboratory Characteristics Clinical suspicion of hypersomnia needs to be confirmed or excluded through objective measurements. The dia­ gnosis of narcolepsy with cataplexy is essentially clinical, but requires, whenever possible, a nocturnal PSG recording followed by a multiple sleep latency test (MSLT) that shows the presence of sleep onset REM periods.

Daytime MSLT The MSLT is the best scientifically validated objective test to detect EDS, and the most frequent tool used to quantify the level of EDS in clinical practice [22, 23]. In addition, the MSLT has a high test-retest reliability in normal subjects but also in pathological conditions [23]. The MSLT consists of five nap opportunities, scheduled at 2-h intervals, starting 1.5–3 h after awakening. Subjects need to discontinue psychotropic medications at least two weeks (depending on the half-life) before the date of the test. Subjects are asked to lie in a quiet darkened and comfortable bedroom during the test and are instructed not to resist sleep. Each test is terminated after a 15-min sleep period or after 20 min if the patient does not fall asleep. Sleep latencies are measured with a mean sleep latency below 8 min confirming the EDS [24]. Latencies below 5 min indicate severe sleepiness. The MSLT latency increases with age [25]. A sleep onset REM period (SOREMP) is defined as the occurrence of REM sleep within 15 min after sleep onset. Since typical patients with narcolepsy frequently present two to five SOREMPs during MSLT, two or

more SOREMPs are required for the diagnosis [24]. This criterion, however, may be absent in rare patients with clear-cut cataplexy, especially the elderly [25]. Finally, a recent intriguing study revealed that both men and women who experience several SOREMPs are frequently found in the general population [26].

Polysomnographical Findings The aim of the nighttime PSG is to eliminate other causes of daytime sleepiness and to assess for the presence of sufficient sleep (at least 6 h) before the MSLT. As the complaint of nocturnal sleep disturbances is frequent in narcolepsy, PSG is indicated to pinpoint the presence of possible comorbid conditions such as OSAS, PLM, and RBD. Those associated conditions may modify the management of narcolepsy.

Sleep Structure Patients affected with narcolepsy-cataplexy frequently display different sleep pattern than controls. The occurrence of a SOREM at sleep onset in less than 15 min that is typical of narcolepsy is present in only 40% of cases but exceptionally occurs in controls. SOREM during the day, but above all at night, represents the polygraphic marker of narcolepsy [3, 19]. In addition, the nighttime PSG may also show a shortened sleep latency (less than 10 min), a reduced sleep efficiency due to increased amounts and duration of wake time after sleep onset, and fragmentation in REM sleep with intermittent loss of muscle tone. These changes lead to an increased percentage of NREM stage 1 sleep, with a relative augmentation in slow wave sleep (SWS) at the end of the night (Fig.  7.1) [27]. Normal durations of REM sleep and SWS occur in most narcoleptic patients, but NREM/REM cycles appear longer than in controls, frequently, with the absence of increased duration of REM sleep across sleep cycles [19, 27]. Elderly narcoleptics and those with a longer course of the disorder present higher NREM and REM sleep fragmentation at night that decreases sleep efficiency but without any modification in REM sleep latency [25]. Only a few and slight correlations have been reported between objective sleep fragmentation and MSLT latency [4, 17, 18]. One study revealed that

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7 Diurnal and Nocturnal Sleep in Narcolepsy with Cataplexy

Fig. 7.1  Typical nighttime hypnogram of a narcoleptic patient with cataplexy. We may see a SOREM, NREM and REM sleep

fragmentation, high wake time after sleep onset, and persistence of slow wave sleep at the end of the night

narcoleptics with good nighttime sleep efficiency present less severe objective and subjective sleepiness compared to patients with high nighttime sleep fragmentation [18]. However, the REM sleep efficiency has been correlated with the frequency of daytime cataplexy [28].

We also found a correlation between PLMS in REM sleep and REM efficiency; REM efficiency being highly altered in narcolepsy [36]. It is, however, difficult to determine whether PLMS in REM sleep are directly responsible for the decreased REM efficiency or whether both phenomena are consequences of the REM sleep instability characteristic of this condition. These results favor an impaired mechanism responsible for motor inhibition during REM sleep in narcolepsy. Another study revealed that leg motor activity periodicity is lower in patients with narcolepsy compared to patients with restless leg syndrome (RLS) [37]. In contrast to RLS patients, PLMS had little effect on nocturnal sleep parameters, such as sleep efficiency, wake time after sleep onset, or total sleep time, that may be explained by the low index of PLMS associated with microarousals in narcoleptics compared to RLS patients [38]. However, we have reported a small but significant decrease in sleep latency on the MSLT in patients with narcolepsy with a high PLMS index [36]. All these results suggest that REM sleep associated with PLMS may play a role in diurnal symptoms of narcolepsy.

Sleep Microstructure REM sleep phasic activity differs between narcoleptics and controls. REMs and mentalis muscle twitches density were significantly increased in narcoleptics [29, 30]. In contrast, the differences in the frequency of NREM sleep spindles and K-complex between narcoleptics and controls are still controversial as one study reported an increase in sleep spindles density in narcoleptic patients compared to controls [31, 32]. Another study revealed a decrease in K-complex index in narcolepsy [32]. Finally, the so-called cyclic alternating pattern (CAP) as a quantification of NREM sleep microstructure has recently been studied in narcolepsy-cataplexy with a reduction observed in the total CAP rate [33].

Dissociated Sleep Periodic Limb Movements Periodic leg movements in sleep (PLMS) are frequent in narcoleptic patients. There is progressive increase in the PLMS index with age as also previously reported in normal controls [27, 34, 35]. Hence, we have recently confirmed in a large cohort of subjects, that narcoleptic patients with cataplexy had a higher frequency of PLMW and PLMS, associated or not with microarousals, compared to age-matched normal controls [36]. PLMS indices were higher both in NREM and REM sleep in narcoleptic patients, but the between-group difference was greater for REM sleep.

Patients with narcolepsy-cataplexy present dissociated sleep, including REM sleep without atonia and frequent shift from REM to NREM sleep, but also mixed sleep stages [8]. Hence, the presence of intermediate stages of sleep is frequent in narcolepsy-cataplexy where features of REM and NREM sleep are present simultaneously, such as the presence of atonia in sleep stage 2 or the presence of sleep spindles in REM sleep leading to ambiguous sleep [4, 8, 19, 39]. According to this narcolepsy sleep/wake dyscontrol theory, also called “loss of state boundary control,” cataplectic attacks may represent a REM sleep atonia intrusion

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Fig. 7.2  REM sleep without atonia. Epoch of 30 s of persistence of tonic and phasic EMG activity during REM sleep on bilateral anterior tibial muscles. Montage from top to bottom: right and left electrooculogram, chin electromyogam, electroencephalogram (C4-A1, C3-A2, C4-O2), electrocardiogram and electromyogram of the right (JAD) and left (JAG) anterior tibial muscles. Recording speed: 1 cm/s

during wakefulness [39]. We also believe that PLMS are part of the REM sleep dissociation phenomena characteristic of narcolepsy. The more studied dissociated sleep was the REM sleep without atonia (See for further details chapter X G Plazzi). Normal REM sleep is characterized by tonic features including cortical EEG desynchronisation and muscle atonia and phasic events, including bursts of REMs , phasic activities of both chin and limb, and EMG and cardiorespiratory variability (Fig. 7.2). Abnormalities in REM sleep motor regulation have been described in narcolepsy, including persistence of muscle tone, excessive twitching, and PLMs during sleep [29, 40–42]. Indeed, RBD is often found in association with narcolepsy [20, 42], but behavioral REM sleep manifestations seem to be less frequent and severe compared to “idiopathic” RBD. We have recently reported higher percentages of REM sleep without atonia and phasic EMG and REM density in patients with narcolepsy when compared to normal controls, even if patients were without any significant REM sleep behavioral manifestation (Fig.  7.3) [29]. In contrast, “idiopathic” RBD patients also included within the same study had a higher percentage of REM sleep without atonia compared to patients with narcolepsy or normal

controls but with a lower REM density [29]. Based on a threshold of 80%, this study revealed that 50% of narcoleptics and 87.5% of RBD patients had abnormal REM sleep muscle activity [29]. Hence, the two subgroups of narcoleptic patients with normal or abnormal percentages of REM sleep without atonia were compared, but no between-group difference was found for any of the clinical or polygraphic variables.

Sleep Apnea/Hypopnea Syndrome The prevalence of obstructive sleep apnea/hypopnea syndrome (OSAHS) is larger in narcoleptic patients than in the general population, ranging from 10 to 20% among studies [18, 35, 43]. These associations could be partially explained by an intrinsic tendency to weight gain and side effects of medications. Hence, as up to one-third of narcoleptics are obese, the risk of developing sleep apnea increases [3]. The increase in the respiratory disorder index led to increased arousals, awakenings, and stage 1, but was not consistently associated with greater sleepiness. There is no documented effect of OSAHS treatments in narcoleptic patients, but OSAHS should be treated as in the general population [44].

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Fig. 7.3  REM sleep without atonia. Epoch of 30 s of persistence of tonic and phasic EMG activity during REM sleep on chin muscle. Montage from top to bottom: right and left electrooculogram, chin electromyogam, electroencephalogram (C3-A2, C4-A2, O2-A2), and electrocardiogram. Recording speed: 1 cm/s

Conclusion We report here general information on EDS and nocturnal sleep in narcolepsy. The complaint of EDS is typical in narcolepsy, and is often the first symptom to appear and the most severe one too. In contrast, disturbed nocturnal sleep is less frequently reported and not included in diagnostic criteria for narcolepsy, but may represent a significant and severe symptom in patients especially with the evolution of the disorder. As the nocturnal sleep period is highly fragmented in narcolepsy, PSG is frequently indicated to assess the presence of possible comorbid conditions such as OSAS, PLMS and abnormal movements or behaviours during REM or NREM sleep. Although still unclear, dysfunctions in the hypocretin/dopaminergic system are likely to be the most important mechanisms involved in the pathophysiology of narcolepsy, leading to dissociated sleep/wake states with cataplexy, alterations in arousal systems, and sleeprelated motor activation. All narcolepsy symptoms and associated conditions need to be considered important in the management of the disorder, but daytime sleepiness in narcolepsy seems independent of the amount and quality of nighttime sleep.

Diagn ostic criteria for narcolepsy with cataplexy [24] (a) Complaint of EDS occurring almost daily for at least 3 months. (b) Definite history of cataplexy, defined as sudden and transient (less than 2 min) episodes of loss of muscle tone, generally bilateral, triggered by emotions (most reliably laughing and joking) with preserved consciousness. (c) Diagnosis should, whenever possible, be confirmed by − Nocturnal polysomnography (with a minimum of 6 h sleep) followed by a day-time MSLTs: Mean daytime sleep latency is less or equal to 8  min and two or more sleep onset in REM periods. − Alternatively, hypocretin-1 levels in the cerebrospinal fluid are less or equal to 110 pg/mL, or one-third of mean control values. (d) The hypersomnia is not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder.

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Chapter 8

Hypnagogic Hallucinations and Sleep Paralysis Armando D’Agostino and Ivan Limosani

I am quite desperate at times … things tend to get annoying in my relationship with others … the main problem is I tend to mix things that happen in my dreams with real elements of my everyday life. The things I see and hear especially when I fall asleep during the daytime are so realistic that afterwards I find myself struggling to remember whether I dreamt them or actually saw them, and if I saw them … was it because it actually happened or did I have an hallucination? The other day at work I lay my head down on the desk because I was so drowsy … I had to take a nap … my boss and my colleagues know about my condition so it’s okay for me to do so during my lunch time or coffee break. Just as I lay my head down I began to hear two of my colleagues arguing over something right beside my desk, and I could feel they were there but couldn’t move my head to see them … and they began to be very aggressive, verbally aggressive, as they argued. Then I must have fallen asleep, and when I woke up I kept thinking they had had a row over something important, so when I saw one of them the following day I asked him why he and M. were so upset the previous day. He looked at me as if I were crazy. He said he hadn’t even been anywhere near my desk the previous day, and that he hadn’t spoken to M. for a week … and of course, he also specified he hadn’t argued with anyone! I felt ashamed, as I always do … even if I’m used to it … people often think I’m strange, and though now I know it’s related to my being narcoleptic, I still struggle to come to terms with all these things, because they seem so real.

A. D’Agostino (*) Unità Operativa Psichiatria 52, Azienda Ospedaliera San Paolo, Università degli Shedi di Milano, Milan, Italy e-mail: [email protected]

C.C., a 35-year-old female patient with a recent diagnosis of narcolepsy with cataplexy, tape-recorded oral account transcribed by the authors.

Introduction According to the 2nd edition of the International Classification of Sleep Disorders (ICSD-2), hypnagogic hallucinations and sleep paralysis are associated clinical features which commonly occur in subjects affected by narcolepsy [1]. Data belonging to different lines of research indicate the presence of these phenomena in 40–80% of subjects who have a diagnosis of narcolepsy with cataplexy, while their incidence appears to be lower in narcolepsy without cataplexy. Hypnagogic hallucinations are abnormal perceptions that occur while falling asleep, whereas hallucinations that occur upon awakening are termed hypnopompic; sleep paralysis is a generalized inability to move or speak during the transition between wakefulness and sleep. The two phenomena often occur together but may also be independent, and it is relatively more common to find hallucinations without sleep paralysis than sleep paralysis without some form of hallucinatory experience. From a clinical perspective, neither sleep-related hallucinations nor sleep paralysis can be considered pathognomonic of this disorder, because occasional episodes may be precipitated by sleep deprivation, significant changes in sleep schedule or other factors disrupting normal sleep patterns in susceptible subjects without a diagnosis of narcolepsy. Because of the considerable departure from physiological sleep–wake transitions and of the intense emotional response provoked in terms of fear when

M. Goswami et al. (eds.), Narcolepsy: A Clinical Guide, DOI 10.1007/978-1-4419-0854-4_8, © Humana Press, a part of Springer Science + Business Media, LLC 2010

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first experienced, the understanding of these phenomena has posed a fascinating challenge over time, leading to various supernatural interpretations – from visitations of devils and spirits to possibly alien abduction – according to the cultural setting in which they were interpreted. The Latin word incubus (from incubare, to sit on) derives from a typical experience of sleep paralysis with frightening hallucinations, that has evolved to a belief universal to men across a variety of cultures: the Incubus has been described with colourful variations as a malignant spirit responsible for terrifying dreams that sits on people’s chest paralyzing them and crushing their breath away. Over time, the meaning of the word has changed towards denoting frightening dreams, and is now synonymous to nightmare [2]. Etymological evidence can indeed be found in various languages correlating these sleep-related phenomena to the conceptualization of nightmares [3]. In narcolepsy, isolated hallucinatory phenomena were previously thought to occur predominantly in the transition from wakefulness to sleep, whereas sleep paralysis and associated hallucinatory experiences were thought to usually occur upon awakening. Current knowledge seems to indicate that both types of experiences can, in truth, occur in any transition between these two states of consciousness. In this chapter, the term hypnagogic will be used in relation to clinical and neurobiological aspects also shared by hypnopompic hallucinations. Distinct features of these sleep-related hallucinations and of sleep paralysis will be treated separately in various parts of the chapter to promote a clearer description of these symptoms, but it must be stressed that they often belong to the same articulate and transient brain-mind state.

Hypnagogic Hallucinations Clinical Features A broadly accepted definition of hallucinations is that of sensory perceptions in absence of an objective stimulus; when they occur during transitions between sleep and wakefulness they are specified as hypnagogic (occurring while falling asleep) or hypnopompic (occurring upon awakening). Alfred Maury first used

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the term hypnagogic by fusing the classical Greek words ϋpnoV (hypnos, sleep) and άgwgeύV (agōgeús, conveyor) with reference to his own hallucinations just before falling asleep [4]. Such hallucinations can involve all senses but are more often visual: perceived objects range from simple forms that can be coloured or not to complex figures such as animals or humans. Auditory hallucinations are also common: patients can hear simple sounds, structured melodies or complete sentences that are often described as threatening or menacing [5]. The third type of hallucination often described is somesthetic, ranging from simple tactile sensations including paraesthesia to more complex cenesthopathic experiences, such as sudden changes in the perception of body parts’ location or the sensation of movement of the entire body; these articulate forms of proprioceptive phenomena are commonly referred to as out of body experiences [6]. In general, hypnagogic hallucinations appear more often as complex and vivid dreamlike experiences rather than simple shapes or sounds [7]. Patients who experience these phenomena, especially when associated with sleep paralysis, often report an intense feeling of anxiety because of the terrifying nature of the hallucinations and the clear subjective awareness of being awake, without the possibility of escaping the frightening situation by running away or calling for help [8]. Compared to other cardinal manifestations of narcolepsy, hallucinatory phenomena usually appear later in the course of disorder, with daytime sleepiness often the first symptom and cataplexy usually occurring within the first year of onset. When hypnagogic hallucinations cause severe anxiety they can seriously disrupt sleep; in some subjects, this condition evolves into sleep-onset insomnia.

Hypnagogic Hallucinations and Dreams Hallucinatory phenomena on the edge of sleep are often described as dreamlike intrusions into waking cognition. The content of these hallucinations has never been investigated in detail, but the most common themes seem to be of attack and aggression, similarly to those found in REM sleep nightmares; in the untreated narcoleptic disorder, where subjects tend to fall asleep frequently and often enter the REM stage of

8 Hypnagogic Hallucinations and Sleep Paralysis

sleep rapidly, hallucinations can be difficult to distinguish from nightmares and unpleasant dreams because of the fast transition between these conditions and the continuity found in terms of content. Though dreams occur across all stages of sleep, it seems appropriate to consider REM sleep as the neurophysiological framework for the most vivid, complex and bizarre dream mentation [9]. The extreme vividness of the two phenomena may also be an explanation for the difficulty in distinguishing the two experiences often reported [10]. Sometimes, detail and vividness of hypnagogic hallucinations seem to exceed anything experienced in real life, with the only condition in which hallucinations are as vivid being in the course of intoxication with hallucinogenic drugs such as LSD [11]. Major differences between dreaming and hallucinations lie, however, in the engagement of the visual field and in the action: dreams fill the whole visual field with the dreamer actively participating, whereas visual hallucinations occupy the centre only, with the hallucinator as an observer [9].

Hypnagogic Hallucinations and Schizophrenia The tendency to experience hypnagogic hallucinations frequently during the daytime may suggest the wrong diagnosis of psychosis in some cases of unrecognized narcolepsy [12]; though patients are usually retrospectively aware of the hallucinatory nature of these phenomena, and the majority can easily distinguish them from dreams even in presence of similar contents, a minority of narcoleptic subjects report constant difficulties in discerning reality from dreams and dreamlike hallucinations. Various causes leading to limitations or decline in critical thinking may be hypothesized as a mechanism leading to secondary delusional elaborations of these phenomena, and some patients might occasionally be misdiagnosed as schizophrenic [6, 13, 14]. Though “voices” remain by far the most common type of hallucination, visual hallucinations are now thought to be more frequent than traditionally reported in schizophrenia [15]. Indeed, narcolepsy-related hallucinations – confused with florid refractory schizophrenia – have been successfully treated by stimulants [16].

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Overlapping aspects of narcoleptic hallucinations and hallucinations occurring in psychopathological conditions such as psychosis stand along the conceptual continuum linking threat sensations to frank persecutory delusions. The presence of threatening hallucinatory voices is commonly described by schizophrenic subjects, and similar contents can be found in descriptions of narcoleptic subjects’ hypnagogic hallucinations. Interestingly, REM initiation of a threat-activated vigilance system and a threat-simulation function of REM mentation have been proposed in evolutionary theories of REM-related subjective experiences [17, 18].

Hypnagogic Hallucinations and other Neurological Disorders Complex visual hallucinations can be found in a number of clinical conditions, which differ significantly from narcolepsy, such as Charles Bonnet’s syndrome [19], peduncular hallucinosis [20, 21] treated Parkinson’s disease (PD) [22], Lewy body dementia (LBD) [23], hallucinations associated with migraine [24] or focal epilepsy [25]. Narcolepsy with cataplexy appears to be the single pathological condition in which such hallucinatory phenomena occur more frequently, followed by LBD, PD with cognitive decline, schizophrenia and narcolepsy without cataplexy [26]. Drowsiness is often described as a predisposing factor for the emergence of hallucinations in all of these neurological conditions, indicating a common basis across different disorders that correlates with abnormalities in the sleep–wake cycle. Hypnagogic hallucinations can also be reported by patients as an isolated symptom, typically with a low frequency of occurrence. The quality of sleep must be investigated in these patients along with the presence of insomnia related to psychopathological conditions; given that any condition causing sleep deprivation may induce these hallucinatory phenomena, behaviourally induced insufficient sleep syndrome must also be considered as a diagnosis [1]. Finally, it must be stressed that hypnagogic hallucinations, like all other clinical aspects of narcolepsy, can be found in the symptomatic form of the disorder, with the most important underlying conditions being cranial trauma, brain tumours and vascular disorders [27, 28].

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Sleep Paralysis Clinical Features Sleep paralysis is the total or partial paralysis of the skeletal muscles in the transitions between wakefulness and sleep, during which the subject retains clear consciousness; it belongs to the classical tetrad of narcolepsy symptoms (hypersomnolence, cataplexy, sleep paralysis and hypnagogic hallucinations) and commonly occurs in narcoleptic patients with cataplexy. Occasional episodes may be experienced by subjects without a diagnosis of narcolepsy – especially after a dream or nightmare in the middle of the night – and can be distinguished from generalized fatigue and difficulties waking up because the subjects are unable to perform the slightest of movements, such as lifting a finger. As a transient, generalized inability to move or speak when falling asleep or upon awakening, sleep paralysis can be very frightening, particularly when initially experienced. Control over gross movements is inhibited and respiratory muscles are often paralyzed, causing what has been described as an inability to breathe, oppressiveness or the more acutely distressing sensation of suffocation. The eyes can usually be opened and this state is often accompanied by intense fear, especially in episodes that are accompanied by frightful hallucinatory phenomena. However, although the first events are often extremely frightening, subsequent episodes tend to be only benign annoyances rather than terrifying experiences. Sleep paralysis usually lasts a few minutes and ends spontaneously or after mild sensory stimulation but sometimes continues even after vigorous attempts at arousal. Sleep deprivation, a change in sleep schedule, or other factors that disrupt normal sleep patterns can precipitate episodes in susceptible persons [29].

Isolated Sleep Paralysis and Culturally Determined Interpretations Sleep paralysis can be found as a symptom independent of narcolepsy (“isolated sleep paralysis”) and has a high lifetime prevalence in the general population [18, 30]. Isolated sleep paralysis, however, differs in terms of severity from the paralysis found in

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narcoleptic subjects: the suppression of tonic muscle atonia appears to be in isolated sleep paralysis, with subjects being able to terminate the experience voluntarily much more frequently than narcoleptic subjects, who often require external aid to terminate the episode [30]. The mentation connected to this motor paralysis is also often characterized by intrusions of frightening dreamlike hallucinations. Frightening experiences of this nature are known to be similarly interpreted across different cultures, usually in relation to nightly visitations of spirits, demons or other grotesque creatures belonging to traditional folklore. In British and Anglophone North American popular cultures, the term “Old Hag” refers to a nocturnal spirit essentially identical to the Anglo-Saxon mæra, a being with roots in ancient Germanic superstition. According to folklore, the Old Hag sat on a sleeper’s chest inducing terrifying dreams (thus eventually called “nightmares”) and causing successive inability to breathe or even move for a short period of time upon awakening. Similarly, subjects belonging to African American communities refer to the experience as “being ridden by the witch.” Though the cause remains unclear and may be related to higher levels of psychosocial stressors, sleep paralysis appears to be more common in this population, especially in subjects with panic disorder [31]. The rich body of work on the subject by authors of Japanese origin has also made the term Kanashibari (“bound or fastened in metal”) quite widespread in medical literature [32]. In late nineteenth century medical literature, sleep paralysis was referred to in French as crise de l’état de veille (“crisis of the waking state”) or cataplexi du réveil (“cataplexy of awakening”). The term ‘sleep paralysis’ was first used by the British neurologist Samuel Wilson in 1928, in his description of an experience occurring in the transition between sleep and wakefulness during which the individual feels awake, yet incapable of voluntary motor movement [33]. In 1876, the phenomenon had been described as “night palsy,” with other terms being “delayed psychomotor awakening”, “cataplexy of awakening” or “waking fit” [34, 35]. In his landmark study on dreaming and the unconscious, Sigmund Freud spoke of dreams in which the individual felt his movements impaired, referring to the sensation of inhibited motor movement as “conflicts of will” reflecting both a desire and the restraint of the same action [36]. Stephen Schonberger addressed the “waking nightmare” more specifically in one patient,

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whom he interpreted to have felt a desire to replace his father upon witnessing parental coitus. According to the classical psychoanalytic theory, the nightmare attack represented a punishment for his sexual and aggressive fantasies and the motor paralysis and breathing inhibition in particular were a defence against the incestuous wish: by pretending to be dead, the patient heard and saw nothing, thus avoiding sexual excitement [37]. Many authors who described the nightmare in these terms stressed the accompanying exhaustion, malaise and tendency to fall asleep of their patients, so it seems plausible to suspect that some of those subjects described essentially as susceptible to sleep paralysis attacks would today be diagnosed with some form of narcolepsy.

Neurobiology of Hypnagogic Hallucinations and Sleep Paralysis General View Although unanimous consensus has not been reached over the neurobiological substrates of sleep paralysis and sleep-related hallucinations, these phenomena are usually referred to as dissociated manifestations of REM sleep [7, 9]. The first REM sleep period physiologically arises out of deep NREM sleep, while hallucinations may be a transitory manifestation of entrance into REM sleep from a relatively higher level of arousal. Indeed, narcoleptic subjects tend to enter this stage of sleep with a more direct continuity from waking, as shown by the frequency of sleep-onset REM periods (SOREMPs). SOREMPs may, as such, be considered a neurophysiological substrate for these phenomena and early polysomnographic studies in narcoleptic subjects did show that sleep paralysis and hallucinatory phenomena only occurred in this particular stage [38, 39]. These data have been confirmed in non-narcoleptic subjects, when isolated sleep paralysis episodes with accompanying hallucinations were found to be associated with SOREMPs in sleep-deprived healthy subjects [30, 40]. At the other end of sleep, paralysis has been found to occur during offset-REM, thus confirming the hypothesis of an underlying dissociation of the REM stage in the transition between wakefulness and sleep [41]. Moreover, these phenomena have been linked

with various conditions that predispose to SOREM episodes, such as sleep deprivation, sleep fragmentation and withdrawal from REM-suppressant medication. Alcohol withdrawal – a well-recognized cause of visual hallucinations – determines a significant REM rebound, with analogous associations also found in barbiturate and benzodiazepine withdrawal syndromes [42, 43]. From a neurochemical point of view, the mutual interplay between cholinergic and aminergic systems involved in the control of wake–sleep transitions seems to play a significant role in the abnormal phenomena experienced by narcoleptic subjects on the edge of sleep: an imbalance in these systems is thought to underlie these unstable states of consciousness by shifting the brain towards cholinergically driven hallucinatory cognition and inhibition of motility [9].

Neurobiology of Hallucinations Neurological conditions in which complex visual hallucinations are often reported such as dementia, Parkinson’s disease and delirium, all share disturbances in sleep patterns and alertness – as of course is the case in narcolepsy – and virtually all non-pathological hallucinations occur between sleep and full wakefulness or in sleep-deprived patients [26]. Many authors have speculated that hallucinations may result from the intrusion of dream images into waking and semi-waking mentations [14, 44–47]. Evidence from an early brain imaging study seems to support this view, with regional gray matter blood flow values being maximally increased in right parietal occipital regions during both visual dreaming and hypnagogic hallucinations in narcoleptic subjects [48]. This common neurofunctional substrate points to a shared pattern of brain activation underlying these two cognitive processes; the activated area corresponds to the visual association cortex, which is responsible for higher-order integration of visual percepts and images, thus representing a neuroanatomical correlate of visual hallucinosis. Though the available functional imaging studies have thus far failed to yield consistent results in terms of neuromodulatory abnormalities in narcolepsy [49], various data from other confining fields of research point to specific changes in aminergic – cholinergic balance as a possible substrate for hallucinations.

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From a neurochemical point of view, serotonin and acetylcholine appear to be particularly relevant to the formation of visual hallucinations, with high concentrations of both found in visual thalamic nuclei and in the visual cortex [11]: 1. A linear correlation appears to exist between the serotonergic activity of hallucinogens and their hallucinogenic potential [50]. 2. The association with the human leukocyte antigen (HLA) DR2 – DQ6 (DQB1*0602) as well as the low level of hypocretin-1 – orexin A in the CSF of narcoleptic patients are well-known biological markers in narcolepsy [51, 52]. Hypocretin – orexin neurones are involved in maintaining wakefulness and their deficiency has been causally linked to excessive daytime sleepiness [53]; the major deficits in the hypocretin – orexin-driven stimulation of basal forebrain cholinergic neurones indicate that hallucinations may arise in this disorder as an indirect dysfunction of the cholinergic pathway [54, 55]. 3. Though the general function of dopamine in sleep is less clear than that of acetylcholine and serotonin, the possibility of its involvement in the formation of oneiric and hallucinatory phenomena must also be stressed. Attentional binding has been suggested to play an important role in the formation of complex visual hallucinations and many clinical data point strongly to the critical role of this neurotransmitter in attention [26]. Moreover, its relevance is wellknown in schizophrenia, a disorder in which mainly auditory but also visual hallucinations are typically found along with a waking mentation similar to that of dreams [56]. Postmortem studies in narcolepsy have indeed shown an increase in striatal dopamine binding, but the failure to confirm this finding in functional imaging studies has led to the hypothesis that increases in dopamine activity may be due to long-term effects of treatment rather than to pathophysiological modifications accounting for the symptoms of the disorder [49].

Neurobiology of Sleep Paralysis Sleep paralysis is considered to be the persistence of typical REM muscle atonia into wakefulness, with the waking brain-mind seemingly trapped in a paralysed

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body. In these terms, sleep paralysis can be understood as a dissociation occurring along the physiological transition from REM sleep to waking [45]. REM atonia is thought to be controlled by a small center in the pons, near to the locus coeruleus, and by the magnocellular nucleus in the descending medullary reticular formation to which it is connected. Activation of cholinergic REM-on cells in the pontine reticular formation leads to modifications in this system that cause hyperpolarization of alpha spinal motoneurons and consequent inhibition of skeletal muscle activity [9]. Sleep paralysis may reflect the anomalous functioning of the system regulating REM sleep, possibly because of the hyperactivation of cholinergic REM-on neural populations or the hypoactivation of noradrenergic – serotonergic REM-off populations in the pons during REM onset and offset [41]. Clinical evidence of the efficacy of serotonin – noradrenaline reuptake inhibitors in reducing the incidence of this symptom in narcoleptic subjects seems to support this view. Two different types of state dissociation have been polysomnographically documented in sleep-deprived healthy subjects: the intrusion of an alpha EEG pattern (usually found in waking) into REM sleep and the persistence of muscular atonia into waking [30].

Dissociated REM Phenomena in the AIM State Space Model The conditions in which sleep-related hallucinatory phenomena and sleep paralysis occur can be considered in terms of abnormal states of consciousness along the continuum between sleep and wakefulness. The AIM state space model seems useful to explain the fluidity of this type of drifting across different states of consciousness [9]. According to this model, consciousness states can be interpreted in terms of mutual interplay among three parameters that can be graphically represented as axes of a tridimensional space, within which the unit of consciousness shifts from state to state. The activation parameter (A) is conceptually derived from data on the firing of reticular formation neuronal populations and EEG correlates of cortical activation; the input source parameter (I) represents the source of information processed by the brain, along a continuum from purely internal to purely external inputs; the modulation parameter (M) expresses the ratio between

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the aminergic and cholinergic discharge systems, that are considered to be competitors in the maintenance of a specific state. Both systems are constantly activated, and whereas high values of this parameter indicate a relative prevalence of aminergic firing, low values indicate a shift towards cholinergic control of brain activity. Physiological variations in consciousness represented by REM sleep, NREM sleep and wakefulness all occupy different positions within the tridimensional model, and can be read in terms of a brain-mind isomorphism, with specific neurobiological changes underlying different mental processes (Fig.  8.1). Alertness with attention focused on the outside world corresponds to maximal levels of brain activation, maximal external input sources, and maximal aminergic neuromodulation; lower levels of brain activation, intermediate levels of both neurotransmitter systems modulation and minimal levels of both input sources are typical of a shift towards NREM sleep, where mentation is characterized by minimal hallucinatory activity and non-progressive thinking, reflected in the relative poverty of dream reports collected from this phase; REM sleep, on the other hand, sees brain activation return to the high levels of wakefulness, with a shift towards cholinergic modulation and internal input reflected in the rich hallucinatory experience of dreams collected from REM awakenings, with vivid and complex storylines. The mind in this stage is alert yet

demodulated and as such driven by powerful internal stimuli, thus becoming both hallucinatory and unfocused. Beyond these three coarsely defined states of consciousness, the AIM state space is useful to explain a variety of intermediate conditions in which both mentation and neurobiology are less clearly understood. The advantage of this model becomes evident when one considers that each point within the graphic cube can be filled by transient conditions, such as the dissociated REM phenomena we address here.

Hypnagogic Hallucinations in the AIM Model According to this model, hallucinatory experiences at opposite ends of sleep reach the same position in the AIM state space from different starting points: hypnagogic hallucinations can be interpreted as a result of an activated REM-like increase of internal stimuli coupled with an activated, aminergically modulated waking brain. During the transition towards sleep, the typical shift towards an alpha-wave EEG pattern reflects a decrease in cerebral activity (A) and the I parameter reflects the reduction of external inputs; as far as the M parameter is concerned, neuromodulatory balance begins to shift towards a lower aminergic output. We can describe the mechanism underlying the emergence of hallucinatory phenomena in this condition of drowsiness as a sudden increase in internal input; the source of information can be considered unstable, with the hallucinatory experience often vivid and dreamlike but integrated in external perception (for example, an hallucinatory human figure appearing inside a properly perceived bedroom). In this model, the peculiarity of the state of consciousness in which hypnagogic hallucinations appear would be the coexistence of high internal and external inputs. The subjective intensity of the experience reflects a return to high levels of brain activation, with the aminergic modulation sustaining wakefulness (Fig. 8.2).

Sleep Paralysis in the AIM Model Fig. 8.1  AIM state space model, illustrating the physiological transitions across the three basic states of consciousness in the sleep–wake cycle; each unit of consciousness is represented by a grey figure

In sleep paralysis, motor output is inhibited, resembling the muscle atonia typically found in the REM stage of sleep. This inability to control movement is in

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Fig.  8.2  Hypnagogic hallucinations (HH) are represented graphically as a gray area along the high activation (A) surface of the AIM state space. The broad extension of HH within this surface indicates the transitory nature of this state along the input source (I) and modulation (M) parameters. HH could occur within a state of consciousness that may occupy any of the points on this broad area, with inputs oscillating from external to internal and modulation ranging from a predominant wake-like aminergic modulation to a REM-like cholinergic modulation of the brain-mind. After the hallucinatory experience, the subject may either return to full wakefulness or enter sleep, typically into the REM stage in narcoleptic subjects. The opposite transition can be hypothesized for hypnopompic hallucinations, with the unstable state being reached from REM – NREM sleep upon awakening, with subsequent return to sleep or progression to full wakefulness

contrast with the subjective awareness of being awake. This type of dissociation, with waking awareness sustained by upward projections from the brainstem and motor ability blocked by inhibition of downward projections, appears to be the opposite of what happens in REM Behaviour Disorder, where typical REM mentation is in contrast with a disinhibition of downward mechanisms that physiologically promote muscle atonia. Graphically, this can be shown as a division of these two functions occurring somewhere along the transition from sleep to wakefulness or vice versa (Fig. 8.3); when the episode occurs upon awakening, the subject progresses towards a waking mentation, though downward projections remain briefly in a REM-like state. If sleep paralysis occurs when falling asleep an inverted dissociation in the progression towards sleep can be hypothesized, with the motor function inhibited in presence of a waking mentation.

Fig. 8.3  A schematic representation of sleep paralysis (SP) in narcoleptic subjects. In the figure, the state of consciousness characterized by SP is shown to derive from REM sleep to imply that conceptually the motor inhibition belongs to a REM-like state. The unit is divided into a main portion that indicates the brain-mind’s progression towards wakefulness, and a smaller portion that indicates a REM-like residue of motor control which keeps the subject in a paralysed state

Treatment of Hypnagogic Hallucinations and Sleep Paralysis According to the latest guidelines issued by the American Academy of Sleep Medicine, various pharmacological agents ranging from psychostimulant to antidepressant drugs may be useful in treating narcolepsy and its associated features, though the quality of published clinical evidence supporting them varies [57, 58]. Adequate explanation of the hypothesized mechanisms underlying the symptoms should, however, be considered the first step in the treatment of these patients, as the peculiar and often frightening nature of the subjective experience associated with sleep paralysis and hallucinatory phenomena can be very distressing.

Sodium Oxybate Sodium oxybate (g-hydroxybutyrate, GHB) is currently used to treat all core symptoms of narcolepsy: daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis. Its mechanism of action remains uncertain,

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though the recent cloning of its specific receptor in the human brain may lead to developments in this field [59]. In one study in which narcoleptic patients received 4,500–9,000 mg per night doses, the efficacy of sodium oxybate was confirmed by significant self-reported decreases in the incidence of hypnagogic hallucinations and sleep paralysis episodes [60]. These data, however, were not confirmed in a large, randomized, placebo-controlled trial that nonetheless supported the efficacy of GHB in treating daytime sleepiness and disrupted sleep in these subjects [61].

Antidepressant Medications Tricyclic antidepressants such as clomipramine, selective serotonin reuptake inhibitors (SSRIs) and venlafaxine may be useful in treating sleep paralysis and hypnagogic hallucinations, though no randomized trials have reported significant changes in the incidence of these symptoms after antidepressant treatment. Because of the rather disturbing side effects that can be associated with this type of medication, it should only be considered when both the physician and the patient believe that benefits of the treatment would outweigh the risks [57, 58]. Tricyclic drugs have been reported to be effective in controlling cataplexy and sleep paralysis but not in controlling daytime sleepiness, whereas amphetamines are considered mainstays for treatment of sleepiness but do not seem useful in controlling the auxiliary symptoms [62]. The reason for this appears to be that tricyclics suppress the REM state but do not inhibit sleep, and the amphetamines inhibit sleep – or increase wakefulness – but have a weak REM suppressant effect to which tolerance is quickly developed [63, 64]. That sleep paralysis may be alleviated by serotonin and adrenergic reuptake inhibitors seems consistent with the hypothesis of a cholinergic–aminergic imbalance underlying this specific symptom.

Conclusive Remarks Hypnagogic hallucinations and sleep paralysis in narcoleptic subjects can be considered dissociated manifestations of REM sleep, caused by the intrusion of REM-like

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mentation and REM sleep atonia into the waking state [29]. The hypocretins–orexins belong to a major excitatory system affecting the activity of momoaminergic and cholinergic systems, so that the hypocretin–orexin deficiency underlying narcolepsy may well induce a neurochemical imbalance, with effects on the regulation of vigilance and internal architecture of sleep [7]. The relative efficacy of antidepressant drugs which increase aminergic tone and inhibit cholinergic tone in contrasting REM abnormalities in narcoleptic subjects seems to support this view [65]. While cataplexy only occurs in narcoleptic subjects, sleep paralysis and hallucinatory phenomena can be found within the context of other neurological or psychopathological conditions, all of which include abnormalities of the physiological sleep–wake cycle. Although plausible neurobiological hypotheses seem to explain these phenomena, the full understanding of their complex nature will probably require the convergence of various fields of research. Bridging core elements of psychopathology, evolutionary psychology and cognitive neuroscience may prove successful in terms of elaborating satisfactory interpretations of the brain-mind’s shift across varying states of consciousness. Detailed analyses of sleep paralysis episodes in the general population have suggested that the experience of a threatening presence during the episode may involve subcortical circuits responsible for a rough analysis of stimuli that are necessary to prepare emergency responses before addressing the perilous context in major detail through the sensory cortex. The impossibility of assessing the nature of the stimulus because of its objective absence may lead to a prolonged fear response and consequent misinterpretation of various sources of activation, ranging from benign external inputs to bizarre internal representations that will be perceived as dreamlike hallucinations [18]. Addressing this type of subjective experience in the context of its biological framework may prove useful in terms of developing future treatment strategies for dissociated REM phenomena in narcolepsy and other neurological and psychiatric disorders presenting overlapping clinical features. “Just a few minutes after I shut the lights out last night I heard noises, and it seemed someone was trying to break into my apartment by forcing the lock to my door. Then these noises gradually grew louder, and a number of people tried to break into my bedroom by taking down the shutters. At this point I was in panic

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and I heard steps in the kitchen, which is close by, and I thought “someone has got in.” So I tried to get up to see whether someone had broken into the house but I realized I could not move. I was breathing heavily at this point and I thought that something terrible would happen to me. It was a very peculiar dream, as there were no images, only very loud sounds in complete darkness. When I woke up this morning I wasn’t actually sure it was a dream, because it did seem so real and vivid, especially my feeling of helplessness. And I had a distinct sensation of having been awake during the noises, and of having fallen asleep afterwards.” A.R., a 44-year-old male patient with narcolepsy with cataplexy, written report

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Chapter 9

REM Sleep Behavior Disorder in Narcolepsy with Cataplexy Giuseppe Plazzi and Yves Dauvilliers

Introduction In the 1970s, Jouvet and Delorme [1] documented the crucial role of tegmental pontine structures in generating abnormal REM sleep without atonia (RWA) in animals; this finding was confirmed by further lesional studies [2]. Electrolytic lesions of the dorsal pontine tegmentum in the cat created REM sleep without muscle atonia and the animals displayed dream-enacting motor behavior. Though not uncommon in humans, a dissociated REM sleep condition, comparable to the animal model, was formally identified by Schenck and Mahowald 20 years later [3] and named REM sleep behavior disorder (RBD). Since 1990 RBD has been included in the International Classification of Sleep Disorders (ICSD) within the REM sleep parasomnias [4]. Formerly, two forms were described, acute and chronic, but the term RBD mostly refers to the second one, the acute form often being associated with drug abuse [5, 6] or drug and alcohol withdrawal [5–8], and part of a complex dissociated circadian condition of wake and sleep [5, 8, 9]. Thus, the term RBD is more properly referred to a condition in which the dysfunction is confined to the REM sleep, and the sleep/wake pattern as well as the sleep architecture are grossly preserved, as we typically find in the chronic form. RBD is characterized by intense motor or verbal paroxysmal dream-enacting episodes arising in REM sleep during loss of muscle atonia, as indicated by elevated chin EMG tone [6, 10, 11]. Clinical manifestations range from increased muscle twitching and jerks to G. Plazzi (*) Dipartimento di Scienze Neurologiche, Università di Bologna, Via Ugo Foscolo 7, 40123, Bologna, Italy e-mail: [email protected]

complex, organized and finalistic motor and verbal activities, leading to an enacted dream behavior. Such motor and verbal manifestations, as well as the content of dreams, are often agitated and sometime fearful and violent, and can lead to physical injuries to partners and patients alike. When patients wake up during the episode they always recall a dream. The first episode may appear at least 1 h after falling asleep, coinciding with the first REM sleep period and may occur intermittently during the night. Due to the increase in REM sleep in the last third of the night, episodes are often more intense during the early morning hours, and are accompanied by the recall of vivid, fearful dreams. Like other REM sleep parasomnias, autonomic activation is not dramatic. Episode frequency ranges from one or a few attacks per month to one or more every night, but usually increases over the years. RBD is more frequent in males with a mean age of onset ranging between 55 and 60 years of age, and can be “idiopathic” or linked with neurological diseases. Isolated RBD can even be the telltale sign of a pontine lesion [12–15], but more often of a neurodegenerative disease, in particular a parkinsonian syndrome. Clonazepam is the drug of choice in RBD, in both “idiopathic” and symptomatic cases, and withdrawal of treatment usually leads to reappearance of attacks [10, 16]. Following the original series by Schenck and Mahowald where RBD was associated in 42.9% of cases with neurological diseases such as Parkinson’s disease (PD), Shy–Drager syndrome, olivopontocerebellar atrophy, dementia, ischemic encephalopathy, alcoholism, multiple sclerosis, brainstem astrocytoma, Guillain–Barré syndrome and narcolepsy, RBD has been reported in association mostly with PD [17], Lewy body disease [18–21] and multiple system atrophy [22–25]. The 10-year follow-up study performed on

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the original patients with “idiopathic” RBD reported by Schenck et al. disclosing the appearance of a parkinsonian disorder in 38% of patients, confirmed that the initial RBD diagnosed as “idiopathic” and responsive to clonazepam, can precede the clinical onset of these neurodegenerative diseases [26]. The common association of RBD with extrapyramidal disorders and the finding that RBD can herald the clinical onset of at least a subgroup of parkinsonisms, the so-called “synucleinopathies” [27], has spurred a growing interest in this disorder in recent years.

Diagnostic Criteria for RBD RBD is currently classified as a parasomnia related to REM sleep, characterized by loss of the stage-specific muscle atonia, and an enactment of dream content; when the latter is violent it may result in self or bedpartner injuries. Polygraphically, tonic and phasic electromyographic activities are evident during REM sleep. When not symptomatic, this activity is called RWA. The importance of this altered sleep stagedependent muscular activity was stressed in the latest international classification of sleep disorders − the ICSD-2 [4]. Indeed, this classification only advises considering a diagnosis of RBD in the “presence of RWA,” but no quantitative parameters are given. According to the ICSD-2 [4], the diagnosis of RBD is based on the following criteria: (a) presence of RWA, that is, the EMG finding of excessive amounts of sustained or intermittent elevation of submental EMG tone or excessive phasic submental or (upper or lower) limb EMG twitching; (b) at least one of the following: (i) sleep-related injurious, potentially injurious, or disruptive behaviors by history; (ii) abnormal REM sleep behaviors documented during polysomnographic monitoring; (c) absence of EEG epileptiform activity during REM sleep unless RBD can be clearly distinguished from any concurrent REM sleep-related seizure disorder; (d) the sleep disturbance is not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder. Most of the prevalence studies on RBD are questionnaire surveys or semistructured clinical interviews based on the clinical criteria that do not account for the gold standard tool for RBD: polysomnography (PSG).

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PSG with extended montage, including at least EEG, right and left EOG, surface EMG from mylohyoideus or chin muscle, right and left tibialis anterior (right and left extensor digitorum communis muscles are recommended for research) are crucial to confirm the diagnosis [6]. In fact, the diagnosis of RBD is certain only when the clinical and the polysomnographic criteria formulated by Mahowald and Schenck are fulfilled: (1) an excessive increase in chin EMG tone or excessive limb or chin EMG twitching, irrespective of chin EMG tone, during REM sleep, associated with (2) abnormal behavior during REM sleep or a history of injurious or disruptive sleep behaviors. The videoPSG, documenting the dream-enacting behavior with the typical EEG and EMG findings, can finally help to solve the most challenging cases. Studies based on questionnaire surveys produce equivocal results. In particular, from studies on parkinsonian patients, the discrepancies in the frequency of RBD disclosed by clinical versus PSG studies, suggest that the clinical data alone are overly lax, that in general they tend to underestimate the frequency of RBD in this population, and that the diagnosis of RBD in these subjects requires PSG. Despite the crucial relevance of the increased chin EMG activity during REM sleep for the diagnosis of RBD, the reliability of polysomnographic criteria for the identification of RWA is largely unexplored [28]. There have been very few systematic attempts to measure submentalis muscle EMG activity during sleep [29], probably because of decades of paper recordings in sleep research. Scant literature reports have quantified submentalis muscle EMG activity in RBD patients [30–32] and only one included narcoleptic patients [33]. A visual quantitative approach specifically developed for the scoring of RBD was proposed by Lapierre and Montplaisir in 1992 [30]. Sleep stages from stage 1 to stage 4 are scored following standard criteria [34] on 30-s epochs. Since muscle atonia can be absent in RBD, REM sleep is scored without submental EMG atonia, using electroencephalogram and electrooculogram only. According to the criteria listed by Lapierre and Montplaisir, the occurrence of the first REM is used to determine the onset of a REM sleep period. The occurrence of a specific EEG feature indicative of another stage (K complex, sleep spindle, or EEG sign of arousal) or the absence of REM for 3 consecutive minutes ends the REM sleep period. Each 30-s epoch is scored as tonic or atonic depending on whether tonic

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chin EMG activity is present for more or less than 50% of the epoch; then, the percentage of the total REM sleep epochs scored as tonic is calculated. Phasic EMG density is evaluated as the percentage of the total number of 2s miniepochs of REM sleep containing phasic EMG events (defined as any burst of EMG activity lasting 0.1−5  s, with an amplitude exceeding four times the background EMG activity). A new computer quantitative analysis describing both basal and transient modifications in chin EMG amplitude during sleep has been validated in normal controls and idiopathic and symptomatic RBD patients [35], and recently applied to narcolepsy [36].

patients without clinical RBD also frequently present increased electromyographic activity during REM sleep [42] and have a higher prevalence of RWA, phasic EMG activity and REM density than controls [33]. Generally speaking, the studies suggest that although it is highly frequent, RBD is not an every-night phenomenon in narcolepsy with cataplexy [38, 39], being more frequently disclosed by questionnaires or by clinical interviews than by (video) polysomnography. This finding is peculiar, and differentiates narcolepsy with cataplexy from neurodegenerative diseases (i.e., multiple system atrophy) in which the typical RBD acting-out dream is easily documented by videopolysomnography [25]. In this light, the availability of a tool to detect subclinical signs of RBD on polysomnographic tracings might be of great interest not only for research but also for clinical decision-making [36]. The application of quantitative and computerized methods of analysis of the EMG signal, especially designed for the evaluation of the chin motor phenomena accompanying RBD [44, 45] disclosed an abnormal quantity of motor activity also present in patients with narcolepsy with cataplexy without a clear clinical complaint of RBD, as specified by the current diagnostic criteria [4]. The increased index of motor dyscontrol in REM sleep in the patients with narcolepsy with cataplexy, irrespective of the presence of RBD, can be considered an intrinsic finding of the disease and a sort of “status dissociatus” (a condition characterized by ambiguous, multiple, or rapid oscillation of statedetermining variables which can be observed in a wide variety of experimental and clinical situations) [5, 46], opening the way to acting out dream contents (i.e., RBD) [33, 36]. Another finding disclosed by a recent study is that the altered REM sleep atonia index in patients with narcolepsy with cataplexy is mostly due to an increase in short-lasting EMG activity (approximately from 0 to 5 s). This phenomenon, already described by Geisler et al. [43], is also in agreement with the increased limb phasic EMG activity in REM sleep [33, 47], and might differentiate patients with narcolepsy with cataplexy and RBD from patients with other forms of secondary RBD (i.e., multiple system atrophy). RBD in patients with narcolepsy differs from idiopathic RBD because patients with idiopathic RBD have a higher prevalence of RWA than narcolepsy subjects, with smaller REM density [33], and RBD in

RBD in Narcoleptic Patients The occurrence of RBD in narcolepsy was reported in 1986 by Schenck et al. [3], but it had been observed even in earlier patients and termed “ambiguous sleep” [37] because of its “low phasic atonia with an extreme abundance of twitches and muscular discharges.” The prevalence of RBD in narcolepsy with cataplexy seems to be fairly high: according to two recent studies, it is clinically evident in 45−61% of patients and polysomnographically detectable in 36−43% of them [38, 39]. Patients with narcolepsy with cataplexy are more frequently affected by RBD than those without cataplexy [38] and in many narcolepsy with cataplexy patients RBD can be induced or aggravated by anticataplectic treatment (antidepressants) [40]. RBD may also be an early sign in childhood narcolepsy with cataplexy [41]. An increased electromyographic activity during REM sleep has frequently been observed in narcoleptic patients without RBD [42]. The prevalence of RWA, phasic EMG activity and REM density is also higher in these patients than in controls [33, 43], while patients with idiopathic RBD have a higher prevalence of RWA and a lower REM density than narcoleptic patients and controls [33], RBD in narcolepsy also differs from the idiopathic form because of its much earlier age of onset [39, 40] and different sex ratio (in the idiopathic form, RBD mostly affects men) [38–40]. In conclusion, several recent studies confirm that RBD is highly prevalent in narcolepsy [38–40], but has an even higher prevalence in narcolepsy-cataplexy [38, 39]. Interestingly, several findings suggest that narcoleptic

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narcolepsy has a much earlier age at onset and a different sex ratio (in the idiopathic form, RBD mostly affects men) [38, 40]. The pattern of motor dyscontrol of narcoleptic subjects is less severe than that found in idiopathic RBD and also different from that of symptomatic RBD in patients with multiple system atrophy. Multiple system atrophy patients present a very high number of RWA epochs compared to idiopathic RBD. These differences might indicate different neurochemical and neurophysiological mechanisms underlying an apparently similar sleep disturbance, from a strictly clinical point of view, occurring in different conditions such as narcolepsy, idiopathic RBD and multiple system atrophy [25, 48]. Even if the occurrence of RBD is remarkable in narcolepsy, there are no available controlled studies of any drug specific for RBD in narcoleptic patients. The efficacy of clonazepam was reported in few cases [49, 50], but in one case clonazepam led to the development of obstructive sleep apnea syndrome [49]. Melatonin also was successfully used in 57% of cases in a sample of RBD patients, two of whom had narcolepsy [51]. An alternative treatment is potentially represented by sodium oxybate, given its beneficial effects on disturbed nocturnal sleep, but no systematic study of sodium oxybate on RBD of narcoleptics has ever been conducted [52]. In conclusion, a certain degree of polysomnographically evident RBD is present in many patients with narcolepsy with cataplexy. This disorder might be specific and correlated to the specific neurochemical and neuropathological substrates of narcolepsy with cataplexy.

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Symposium on Narcolepsy, July 1975, Montpellier, France, New York: Spectrum publications, 1976. pp. 57–75. 38. Nightingale S, Orgill JC, Ebrahim IO, de Lacy SF, Agarwal S, Williams AJ. The association between narcolepsy and REM behavior disorder (RBD). Sleep Med 2005;6:253–258. 39. Mattarozzi K, Bellucci C, Campi C, et al. Clinical, behavioural and polysomnographic correlates of cataplexy in patients with narcolepsy/cataplexy. Sleep Med 2008;9:425–433. 40. Schenck CH, Mahowald MW. Motor dyscontrol in narcolepsy: rapid-eye-movement (REM) sleep without atonia and REM sleep behavior disorder. Ann Neurol 1992;32:3–10. 41. Nevsimalova S, Prihodova I, Kemlink D, Lin L, Mignot E. REM behavior disorder (RBD) can be one of the first symptoms of childhood narcolepsy. Sleep Med 2007;8:784–786. 42. Mayer G, Meier-Ewert K. Motor dyscontrol in sleep of narcoleptic patients (a lifelong development?). J Sleep Res 1993;2:143–148. 43. Geisler P, Meier-Ewert K, Matsubayshi K. Rapid eye movements, muscle twitches and sawtooth waves in the sleep of narcoleptic patients and controls. Electroencephalogr Clin Neurophysiol 1987;67:499–507. 44. Burns JW, Consens FB, Little RJ, Angell KJ, Gilman S, Chervin RD. EMG variance during polysomnography as an assessment for REM sleep behavior disorder. Sleep 2007;30: 1771–1778. 45. Mayer G, Penzel T, Kesper K, Leonhardt E. New findings on the pathogenesis and pathophysiology of REM sleep behaviour disorder (RBD). J Sleep Res 2006;15(Suppl. 1):29. 46. Mahowald MW, Schenck CH. Evolving concepts of human state dissociation. Arch Ital Biol 2001;139:269–300. 47. Ferri R, Zucconi M, Manconi M, et al. Different periodicity and time structure of leg movements during sleep in narcolepsy/cataplexy and restless legs syndrome. Sleep 2006;29: 1587–1594. 48. Vetrugno R, Provini F, Cortelli P, et  al. Sleep disorders in multiple system atrophy: a correlative video-polysomnographic study. Sleep Med 2004;5:21–30. 49. Schuld A, Kraus T, Haack M, Hinze-Selch D, Pollmächer T. Obstructive sleep apnea syndrome induced by clonazepam in a narcoleptic patient with REM-sleep-behavior disorder. Journal of Sleep Research 1999; 8:321–322. 50. Yeh SB, Schenck CH. A case of marital discord and secondary depression with attempted suicide resulting from REM sleep behavior disorder in a 35-year-old woman. Sleep Medicine 2004; 5:151–154. 51. Boeve BF, Silber MH, Ferman TJ. Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Medicine 2003; 4: 281–284. 52. Billiard M, Bassetti C, Dauvilliers Y, Dolenc-Groselj L, Lammers GJ, Mayer G, Pollmächer T, Reading P, Sonka K; EFNS Task Force. EFNS guidelines on management of narcolepsy. Eur J Neurol. 2006;13:1035–1048.

Chapter 10

Narcolepsy and Other Comorbid Medical Illnesses Lori A. Panossian and Alon Y. Avidan

Introduction Narcolepsy is a chronic disorder of sleep that typically presents between 10 and 25 years of age in most cases, but may occur at any age [1]. It is associated with symptoms of severe, unremitting, excessive daytime sleepiness (EDS) and rapid eye movement (REM) intrusion phenomena such as cataplexy, sleep paralysis, and hypnagogic hallucinations. The pathophysiology of narcolepsy is thought to be related to a deficiency in the neuropeptide hypocretin in the central nervous system [2] and has a genetic association with certain human leukocyte antigen (HLA) alleles such as HLA-DR2 and HLA DQB1*0602 [3]. It is postulated that as yet unknown environmental factors may trigger an autoimmune process, resulting in destruction of the hypothalamic cells responsible for hypocretin production [4]. Narcolepsy is associated with a number of other comorbid medical problems. These include eating disorders, obesity, diabetes, psychiatric conditions including schizophrenia and depression, fibromyalgia, neurological symptoms including migraine headaches and cognitive dysfunction, as well as psychosocial impairment (Fig. 10.1).

Comorbid Eating Disorders and Obesity There has been a long-standing correlation between narcolepsy and increased body-mass index (BMI expressed as kg/m2), as well as a possible association A.Y. Avidan () UCLA Sleep Disorders Center, 710 Westwood Blvd., Room 1-169 RNRC, Los Angeles, CA, 90095-6975, USA e-mail: [email protected]

with comorbid eating disorders. Growing evidence suggests that patients with narcolepsy are more likely to be overweight or obese [5–7]. For instance, one study examining 35 patients who had narcolepsy with cataplexy and were HLA-DR2 positive demonstrated that they have significantly elevated BMI compared to population controls [7]. The BMI increase was seen in both men and women; male narcolepsy patients exhibited mean BMI in the 75th percentile and female patients had mean BMI in the 61st percentile. While approximately half of the patients studied had never undergone pharmacological treatment for narcolepsy, this subgroup showed no significant difference in BMI compared to the treated patients, thereby suggesting that the medications commonly used to treat narcolepsy are not significantly contributing to weight increases [7]. These results were also demonstrated in a group of patients with childhood-onset narcolepsy that was diagnosed prior to age 18. This population had significantly higher BMIs compared to controls, and again use of medications did not make a significant difference in weight [8]. The effect on BMI may be due to narcolepsy-associated behavioral changes related to eating, physical activity and reduced energy expenditure. Alternatively, weight gain may be related to the underlying pathophysiology of narcolepsy. While narcolepsy is commonly associated with a positive HLA-DR2 haplotype, healthy non-narcoleptic patients who are HLA-DR2 positive do not demonstrate any increased risk for elevated BMI; thus, there does not appear to be a genetic linkage between the HLA-DR2 allele and obesity in and of itself [6]. It has been postulated that the neuroendocrine changes in narcolepsy may result in altered energy homeostasis [2, 7]. Weight gain in narcolepsy may be due to changes in endocrine and autonomic regulation

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Fig. 10.1  Comorbid conditions associated with narcolepsy. Patients affected by narcolepsy are at risk for a variety of conditions including obesity, diabetes mellitus type 2 (DM-2), psychiatric conditions including schizophrenia and depression, fibromyalgia, neurological symptoms such as migraine headaches and cognitive dysfunction, as well as psychosocial impairment

resulting from deficiency in hypothalamic hypocretin neurons. Hypocretin, the neuropeptide that is deficient in most patients with narcolepsy, is normally thought to stimulate eating behavior as well as to regulate energy expenditure and physical activity [9, 10]. It might then be inferred that hypocretin deficiency would result in less food intake and reduced BMI; however, this is not the case in narcolepsy. A possible explanation may be that hypocretin deficiency reduces energy expenditure to a greater degree than it reduces food intake, thus resulting in a net weight gain [10]. Studies have also examined the association between narcolepsy and the adipose-tissue derived hormone leptin, which is involved in signaling the size of adipose cells to the central nervous system [11]. A deficiency in leptin may be predicted to reduce feedback to the central nervous system and result in obesity. Leptin and hypocretin appear to work synergistically to inhibit

REM sleep [12, 13] and thus their loss may play a role in the increased sleep-onset REM periods that are observed in patients with narcolepsy. A study measuring serum and cerebrospinal fluid (CSF) levels of leptin found a significant reduction in serum leptin in narcolepsy patients as compared to the two control groups. There was no significant difference in CSF leptin levels, and no significant association between leptin levels and use of narcolepsy medications [11]. However, subsequent studies of leptin in narcolepsy have yielded contradictory results. A study by Arnulf et al. measured CSF-to-serum leptin ratios as an indicator of leptin transport across the blood–brain barrier [10]. In this study, there was no significant reduction in serum leptin in narcolepsy patients, more than half of whom had hypocretin deficiency, compared to normal controls. There was also no significant difference in CSF leptin levels or in the CSF-to-serum leptin ratio.

10 Narcolepsy and Other Comorbid Medical Illnesses

Because CSF leptin levels were unchanged in narcoleptic patients, the authors concluded that leptin is unlikely to be involved in the weight changes seen in narcolepsy patients. This finding has been corroborated by other studies also showing no difference in serum leptin levels between narcolepsy patients and controls [14]. Increases in BMI seen in narcolepsy may be related to behavioral factors. A study comparing food intake in patients with narcolepsy with cataplexy to normal controls found that narcoleptics actually consumed fewer kilojoules of food per day [15]. However, other studies found a significant association between narcolepsy and eating disorders. Using a clinical assessment tool for eating disorders, Fortuyn et  al. found that patients with narcolepsy with cataplexy scored significantly higher on almost all measures in the eating disorders assessment compared to healthy controls [5]. When compared to controls that were matched for BMI, narcoleptics continued to demonstrate increased rates of overeating, binge eating, and cravings for food [5]. Although many patients with narcolepsy exhibited symptoms of eating disorders, and approximately onequarter of patients met formal criteria for an eating disorder, there was no predilection for a specific type of eating disorder. The eating disorders present in the narcoleptic group included anorexia nervosa, bulimia nervosa, and eating disorders not otherwise specified [5]. However, there are again conflicting findings across studies, as other groups have found no association between narcolepsy and eating disorders, including no increase in hyperphagic behavior among patients with narcolepsy [16]. These differences may be due to the time in the disease course during which the symptoms of eating disorders are assessed. The weight gain seen in narcolepsy may occur early on at the time of diagnosis [8, 16]. Metabolic rate has been measured in narcolepsy as a possible contributor to weight gain. Because of the lack of unequivocal data implicating increased caloric intake or abnormal eating behavior as the cause of weight gain in narcolepsy, it has been hypothesized that decreased basal metabolic rate may be a cause. However, in a trial comparing hypocretin-deficient narcoleptic men with healthy controls, there was no difference in resting metabolic rate [17]. In summary, no clear etiology for the increased BMI seen in narcolepsy has been elucidated. There is no unambiguous association between weight gain and a positive HLA-DR2 haplotype [6], caloric intake [15], or resting metabolic rate [17]. There is conflicting data

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on the role of eating disorders and behavioral factors on weight gain in narcolepsy [5, 16]. The most likely etiology involves dysregulation of neuroendocrine mechanisms involved in the hypocretin system, but data regarding the role of leptin have also been contradictory [10, 11]. It is possible that other hormonal pathways, both in the systemic circulation as well as in the CSF, are involved and interact with hypocretin neurons to cause weight alterations [18].

Diabetes Mellitus Diabetes mellitus is another neuroendocrine disturbance that has been associated with narcolepsy in some studies. In a study by Honda et al., a group of patients with narcolepsy were given a 50 g oral glucose tolerance test, and their subsequent blood glucose and insulin levels were measured [19]. In this relatively small sample of 48 adult patients, a diabetes prevalence of 12.5% was established based on abnormal glucose tolerance test results. There was no significant association with obesity in this sample. Their patient prevalence was higher than the historical prevalence of diabetes mellitus in the general adult population of Japan, which was 1.75–5.50%, suggesting an increased risk of diabetes mellitus among patients with narcolepsy [19]. Both diabetes mellitus type 1 (insulin-dependent diabetes) and narcolepsy are thought to have an autoimmune pathophysiology. Both are associated with specific HLA haplotypes, and both involve the selective, likely autoimmune-mediated, destruction of particular cell types (pancreatic islet cells in type 1 diabetes and hypocretin-producing hypothalamic neurons in narcolepsy) [20]. To explore a potential genetic association between narcolepsy and diabetes mellitus type 1, studies have examined the role of HLA subtypes. Results have demonstrated that the HLA DQB1*0602 haplotype, which is known to confer susceptibility to narcolepsy with cataplexy, is however strongly protective against type 1 diabetes [21, 22]. This implies that patients with narcolepsy with cataplexy who are positive for the HLA DQB1*0602 allele are expected to have much lower rates of type 1 diabetes than the general population. However, studies to determine the incidence of type 1 versus type 2 (noninsulin dependent) diabetes mellitus in narcolepsy have not yet been carried out. It may be surmised from

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this data that narcolepsy patients are expected to have much lower rates of type 1 diabetes, but may exhibit higher rates of type 2 diabetes due to the increased risk of insulin resistance associated with elevated BMI and obesity [20].

Psychiatric Disorders There is an association between narcolepsy and comorbid psychiatric disorders, including depression and schizophrenia [1]. Sleep disturbances, particularly insomnia and hypersomnia, are known comorbidities of depression [23, 24]. In addition, the diagnosis of narcolepsy, particularly narcolepsy without cataplexy, may be arrived at with the diagnosis of major depressive disorder due to similar presenting symptoms. For instance, approximately 10–20% of patients with major depression have been reported to exhibit EDS [24]. A large study investigated the presence of symptoms associated with narcolepsy, including sleep paralysis, hypnagogic and hypnopompic hallucinations, cataplexy, and automatic behaviors, among patients with depression but without a diagnosis of narcolepsy [23]. They found a strong correlation between severe depression and sleep paralysis, hypnagogic or hypnopompic hallucinations and automatic behaviors, even after controlling the usage of antidepressant medications, age, sex, and BMI. In addition, both severe and milder forms of depression showed a strong correlation with cataplexy [23]. Cataplexy has been proposed to have a similar pathophysiology to depression, and both conditions respond to antidepressant medications [25]. Sleep paralysis can also occur in otherwise healthy people suffering from disturbed sleep or insomnia, and it may be that the sleeping problems and insomnia in depression exacerbate symptoms of sleep paralysis [23]. However, despite the potential confounding effects of sleep deprivation, sleep paralysis does appear to occur more frequently among patients with comorbid mental disorders and users of anxiolytic medication as compared to the healthy population, even after controlling for the effects of sleep problems [26]. In addition to depression, sleep paralysis also has an association with trauma and post-traumatic panic symptoms, with particularly high prevalence among African-Americans [27]. However, this effect again

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may be due to post-traumatic disturbed sleep and insomnia that then precipitates sleep paralysis, rather than a clear association between sleep paralysis and a psychiatric diagnosis [27]. Another study examined the prevalence of psychiatric disorders among patients with narcolepsy as compared to healthy controls; it found a slightly increased rate of major depression, as well as anxiety disorder not otherwise specified and depressive disorder not otherwise specified, based on Diagnostic and Statistical Manual (DSM)-IV criteria. However, these differences were not statistically significant when compared to controls [28]. The authors conclude that while depressive symptoms are common among patients with narcolepsy, there is no clear association with clinical depression or other psychiatric disorders meeting DSM IV criteria [28]. Narcolepsy is frequently associated with hypnagogic and hypnopompic hallucinations, which have symptoms similar to those of psychosis including visual and tactile perceptual phenomena. In general, the hallucinations associated with schizophrenia tend to be primarily auditory rather than visual or tactile; however, some hypnagogic hallucinations can be complex and multi-modal with an auditory component also present [28]. A small number of narcolepsy patients may also experience hallucinations while fully awake [28]. This can make it difficult at times to distinguish between narcolepsy and schizophrenia, and there have been several reports of narcolepsy patients being misdiagnosed as having refractory schizophrenia [28–31]. There is thought to be a psychotic form of narcolepsy, in which patients have hallucinations while awake, as well as nocturnal hypnagogic and hypnopompic hallucinations. Typically, these patients have good insight into their illness, with appropriate affect and interpersonal interactions and no loose associations. The psychotic form of narcolepsy does not typically respond to antipsychotic medications, but does improve with central nervous system stimulants such as methylphenidate or modafinil [30]. At times, schizophrenia and narcolepsy can coexist in the same individual, although this is rare [30, 32]. Some studies have shown a higher incidence of comorbid schizophrenia among patients with narcolepsy compared to the general population; documented rates of schizophrenia among narcoleptics vary, with reports citing a prevalence ranging from 0 to 14% [28]. There are cases in the literature of narcolepsy patients with comorbid schizoaffective disorder, who had psychotic

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symptoms and paranoid delusions that began prior to initiating any stimulant treatment for narcolepsy [29]. There is, however, some dispute about the true incidence of waking psychosis symptoms among patients with narcolepsy. Another study found that only 4 out of 45 narcolepsy patients had ever experienced psychotic symptoms, and those cases seemed to be secondary to stimulant medication use, as their psychosis remitted after lowering the dose or discontinuing the stimulant drug altogether [28]. The treatments for EDS in narcolepsy, including central nervous system stimulants such as methylphenidate, may induce psychotic symptoms as a result of their dopamine stimulatory effect [29, 32]. The effects of medication can confound data regarding the true prevalence of comorbid psychosis among patients with narcolepsy, unless carefully controlled for in clinical studies.

Fibromyalgia Case reports have documented patients with longstanding narcolepsy that went on to develop classic symptoms of fibromyalgia [33, 34], as well as fibromyalgia patients who were found to have concurrent narcolepsy with cataplexy [35]. Fibromyalgia is a chronic pain disorder with symptoms of diffuse musculoskeletal soreness as well as widespread points of muscle tenderness to palpation on the body [36]. Approximately 2% of the population suffers from fibromyalgia syndrome, with a higher prevalence in women [36, 37]. Fibromyalgia is also frequently associated with fatigue and non-restorative sleep [36]. While instances of narcolepsy with comorbid fibromyalgia are exceedingly rare, the pathophysiology of the two disorders may share a common mechanism. As also evidenced by narcolepsy’s association with headaches, it is possible that the underlying pathophysiology of narcolepsy plays a role in pain sensation [38]. Hypocretin has been shown to interact with pain modulation and sensory input pathways [39] and may thus play a role in the development of pain syndromes such as fibromyalgia. Taiwo et  al. investigated the levels of hypocretin in the CSF of patients with fibromyalgia compared to healthy controls [36]. They found no significant difference in mean hypocretin levels between fibromyalgia patients and healthy controls, suggesting that fatigue or pain in

fibromyalgia is not mediated by hypocretin deficiency [36]. Genetic studies in fibromyalgia found an association with the HLA DR4 allele, but not with the HLA subtypes most commonly associated with narcolepsy (HLA DR2 and HLA DQB1*0602) [40]. Therefore, there is no clear evidence of a pathophysiological association between fibromyalgia and narcolepsy, and only rare instances of narcolepsy being associated with comorbid fibromyalgia.

Migraines and Other Headaches Studies have shown that the prevalence of migraine headaches (either with or without aura) is increased by twofold to fourfold among patients with narcolepsy as compared to the general population [41, 42]. The presence of migraines in patients with narcolepsy has not been significantly linked to the severity of their narcolepsy symptoms, daytime sleepiness, BMI, or HLA-DR2 phenotype [42]. However, those patients who develop migraines tend to have narcolepsy onset at a younger age, and typically have their first migraine headache approximately 12  years after experiencing their first symptoms of narcolepsy [42]. In addition, migraine prevalence among narcoleptics remains high even when controlling the usage of stimulant and antidepressant medications. This suggests that migraines may be a comorbid medical problem associated with narcolepsy itself, rather than an adverse effect of pharmacological treatments for narcolepsy [42]. It has been postulated that both narcolepsy and migraines arise from pathology in similar neuroanatomical areas in the brainstem, including the dorsal raphe nuclei and the locus ceruleus [42]. These brain areas exhibit increased blood flow during migraine headaches, and are also involved in control mechanisms for REM sleep [42]. Alternatively, migraines may be more prevalent among patients with narcolepsy due to the underlying sleep disturbances associated with narcolepsy, with poor quality sleep and frequent nocturnal awakenings [43]. Migraines may be triggered or exacerbated by changes in sleep, either due to excessive sleep or sleep deprivation [44]. Data regarding the prevalence of migraine headaches in narcolepsy have been conflicting. A multi-center case-control study found no significant association between migraines and narcolepsy [45]. However, this

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trial did find that narcoleptics had a much higher rate of unspecific non-migraineous headaches, particularly tension-type headaches, when compared to healthy controls [45]. These unspecific headaches may be secondary to sleep disturbance associated with narcolepsy or may be secondary to medications used to treat narcolepsy, which were not controlled for in this study [45]. There is also a case report of one patient who had cluster headaches that preceded the onset of his narcolepsy symptoms [46]. Cluster headaches consist of episodic bouts of severe unilateral pain centered around the periorbital area, often with associated rhinorrhea and lacrimation [46]. The onset of narcolepsy, with symptoms of hypersomnia and disturbed nocturnal sleep, did not have any significant effect on this patient’s cluster headache frequency or severity. This suggests that there is no pathophysiological association between cluster headaches and narcolepsy [46]. The demographics and genetic associations also differ between the two disorders; narcolepsy has no clear gender predilection, while cluster headaches are much more common in men. In addition, cluster headaches have an association with the HLA DR5 haplotype, rather than HLA DR2 which is commonly found in narcolepsy [46]. Thus, cluster headaches do not appear to be a significant comorbid disorder in narcolepsy. To address the question of whether migraines and narcolepsy may have a direct association, one study by Coelho et al. investigated the frequency of the HLADQB1*0602 allele in patients with migraine but not sleep disorder [38]. This HLA subtype is present in the majority of patients who have classic narcolepsy with cataplexy, particularly those with low CSF hypocretin levels [3]. They found no increase in the frequency of the HLA-DQB1*0602 allele among migraine patients with aura or without aura, compared to healthy controls [38]. While this does not rule out the possibility that migraines and narcolepsy may have a direct association through another mechanism, further research needs to be done to elucidate the association between these two disorders.

Cognitive Dysfunction Narcolepsy has also been associated by some investigators with specific impairments in several cognitive domains. This effect is apparent among both older and

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younger age groups [47]. A study by Ohayon et al. has found significant impairments in attention and concentration, delayed recall, and difficulty with orientation to persons (recalling names or recognizing acquaintances), among narcolepsy patients younger than age 45 as compared to healthy controls [47]. Narcolepsy patients older than age 45 exhibited cognitive difficulties that were significantly worse than age-matched healthy controls across multiple areas, including attention and concentration, praxis, delayed recall, orientation to persons, temporal orientation, and prospective memory [47]. Because sleepiness alone may account for some degree of cognitive impairment, the authors subsequently controlled for sleepiness (as measured by the Epworth Sleepiness Scale scores) as well as for physical health, use of psychotropic medications, age and sleep apnea; they again found that narcolepsy was still associated with a significantly higher risk of attention and concentration deficits and difficulty with prospective memory [47]. Thus, while the majority of cognitive dysfunction found in narcolepsy appears to be secondary to EDS, some degree of cognitive impairment seems directly related to the underlying disease pathophysiology and is independent of age or degree of sleepiness. Various investigators have had conflicting results in examining objective cognitive impairment in narcolepsy, and have found no evidence for specific cognitive deficits, although the majority of patients in these studies did have subjective cognitive complaints. For example, Aguirre et al. found that a small sample of 10 narcolepsy patients, untreated with medications, had no significant difference compared to controls on tests of verbal and nonverbal learning, digit span, naming and fluency [48]. Other studies also failed to show any significant difference, or only mild impairment, between narcoleptics and age and education-matched healthy controls on an extensive battery of neuropsychological tests, except that narcolepsy patients did exhibit more lapses in attention and some difficulty with executive function as compared to controls [49, 50]. These attention-lapse problems did not impair their performance on cognitive tests in a laboratory setting compared to controls [49]. Medication use also had no significant effect on memory tasks among subgroups of narcolepsy patients [50]. These results suggest that rather than a problem in a specific cognitive area, narcolepsy patients appear to exhibit a limitation or reduction in cognitive processing resources [50].

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Psychosocial Comorbidities Narcolepsy, along with other disorders of EDS, may result in a significant difficulty with social functioning and quality of life. This effect is apparent among both children and adults. In adults, narcolepsy has been shown to have a negative effect on health-related qualityof-life assessments, particularly in the domains of bodily pain, social function, and general health, as compared to data from the general population [51]. A study of children ages 4–18 also showed significant problems in behavior, emotional state, quality of life, educational progress and family impact among children with narcolepsy when compared to healthy age and gendermatched controls [52]. The rate of such problems was also found increased among children with EDS not due to narcolepsy. Problem areas included difficulties with peer interactions, behavioral conduct, and emotional symptoms. Children with narcolepsy as well as those with isolated EDS had significantly higher scores on the Child Depression Inventory as compared to controls. These data suggest that the symptom of excessive sleepiness, which is present in children with narcolepsy as well as in children with idiopathic EDS, is responsible for many of the apparent psychosocial and quality-of-life

issues that arise [52]. Figure 10.2 shows quality of life using the SF-36 [Short Form (36)] Health Survey of patient health. Patients with narcolepsy had similar and at times worse psychosocial function when compared to other neurologic disorders including lower vitality and reduced social functioning [53].

Conclusion Narcolepsy can be associated with a wide range of medical and psychiatric comorbidities. Some comorbidities, such as the increased rate of obesity and overweight, have been well established in the literature. Other associations, such as between narcolepsy and schizophrenia or between narcolepsy and migraine headaches, have been inconsistent and have occasionally demonstrated contradictory findings. While the true incidence of many of these disorders in narcolepsy is unknown or disputed, it is important to be aware of possible medical comorbidities when caring for patients with narcolepsy. Clinician vigilance in screening for these conditions can prevent delays in the diagnosis and treatment of many comorbid medical illnesses.

Fig. 10.2  Quality of life in patients with narcolepsy using the short-form 36 (SF-36) compared to patients with other neurologic disease (epilepsy, and patients with Parkinson’s disease) and the general population. Modified after Beusterien et al. [53]

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10 Narcolepsy and Other Comorbid Medical Illnesses 45. Migraine and idiopathic narcolepsy--a case-control study. Cephalalgia, 2003. 23(8): p. 786–9 46. Alberca, R., et al., Episodic cluster headache and narcolepsy: a case report. Cephalalgia, 1991. 11(3): p. 113–5 47. Ohayon, M.M., et al., How age influences the expression of narcolepsy. J Psychosom Res, 2005. 59(6): p. 399–405 48. Aguirre, M., R. Broughton, and D. Stuss, Does memory impairment exist in narcolepsy-cataplexy? J Clin Exp Neuropsychol, 1985. 7(1): p. 14–24 49. Rogers, A.E. and R.S. Rosenberg, Tests of memory in narcoleptics. Sleep, 1990. 13(1): p. 42–52

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Chapter 11

Humor Processing in Human Narcolepsy with Cataplexy Aurélie Ponz and Sophie Schwartz

Introduction Patients with narcolepsy–cataplexy (NC) experience excessive daytime sleepiness as well as sudden and reversible episodes of postural muscle atonia, i.e., cataplexy [1]. Additional symptoms of this disease include sleep paralysis, hypnagogic hallucinations, and fragmented night-time sleep [see Chapter Narcolepsy and Cataplexy in this book]. Human narcolepsy–cataplexy has been recently found to be associated with a reduction or loss of a hypothalamic peptide called hypocretin (Hcrt, also called orexin; [2–6]). In this chapter, we review the existing evidence suggesting that the Hcrt system is implicated not only in sleep–wake regulation [7–11], but also in emotional functions [12–17]. More specifically, we propose that the Hcrt system has the potential to modulate activity in limbic regions, in particular in the amygdala, and that such modulatory influence may be disturbed in NC patients due to Hcrt deficiency. Emotion-triggered cataplexy would thus implicate an abnormal affective response caused by Hcrt deficiency in human NC. Consistent with this hypothesis, several observations suggest an involvement of the hypothalamus and amygdala in human cataplexy. First, structural and functional brain imaging studies have revealed abnormalities in both structures in NC patients. Second, neuroimaging studies have shown that the amygdala is critically involved in emotional information processing in humans, including during joking and laughing, S. Schwartz () Neurology and Imaging of Cognition, Department of Neurosciences, University Medical Center, Michel-Servet 1, 1211, Geneva, Switzerland e-mail: [email protected]

the two main ­triggers of cataplexy. Finally, functional magnetic resonance imaging (fMRI) data collected from NC patients while they experienced humor showed reduced hypothalamic response together with enhanced amygdala response compared to healthy matched controls. The data reviewed in this chapter demonstrate that functional neuroimaging data at the macroscopic systems level may help bridge the gap between molecular/cellular results in animals and clinical symptoms observed in NC patients. Neuroimaging studies of the impact of Hcrt deficiency on emotional processing can thus help identify some key neural components of the pathophysiology of NC, and provide new constraints for current models of cataplexy. Recent research on Hcrt functions and human NC patients converge to reveal unsuspected links between emotion and sleep regulation.

Emotional Triggers of Cataplexy Cataplexy is a diagnostic feature of NC disease that is associated with the reduction or loss of hypothalamic Hcrt [10, 18–20]. One most intriguing feature is that cataplexy attacks are typically triggered by intense emotional experiences, mainly positive emotions such as joking, laughing, and elation [1, 21–26]. These observations provide a first hint about functional interactions between the hypothalamic Hcrt system and emotional-limbic brain circuits. Whether Hcrt deficiency might cause the cataplectic response to positive emotions observed in NC patients is a main question addressed by this chapter. Clinically, laughter is the most common triggering factor for cataplexy, while other emotions such as

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excitement, anger, or surprise are also frequently reported [1, 21, 23, 27, 28]. Anic-Labat et  al. [23] performed a survey on 983 individuals (patients entering the Stanford Sleep Disorder Clinic) using a 51-item cataplexy-related questionnaire. When comparing patients with clear-cut cataplexy to patients with no or doubtful cataplexy, clear-cut cataplexy was best differentiated by one main factor characterized by positive emotions such as telling or hearing a joke, feeling elated, remembering a happy moment, making a quick verbal response in a playful or funny context (e.g., witty repartee), laughing, and playing an exciting game. Based on a Receiver Operating Curve analysis, a decision tree for quick and optimal assessment of cataplexy risk was proposed. The first and most discriminative question identified by the analysis is whether a patient would experience muscle weakness when he/she “tells or hears a joke.” If the patient answers “yes” to this first question, then anger would be the next most predictive factor; if the patient answers “no” to muscle weakness when hearing or telling a joke, then laughter is the second most useful discriminator. Humor processing thus appears to be both the most frequent and the most discriminative trigger for clear-cut cataplexy. This important finding implies that humor processing may engage selective neural processes (see later in this chapter) and may have functional links with the Hcrt system. While cataplexy can be observed in animals, is it the case that cataplexy episodes in animals also somehow relate to positive emotions? Like humans, dogs with familial narcolepsy (due to a mutation of the Hcrt-2 receptor gene) display cataplexy, fragmented sleep, and excessive daytime sleepiness [29]. In these animals, positive excitation, such as the presentation of food or playing with congeners elicits cataplexy attacks. The presentation of appetitive food can be used as an experimental tool to trigger cataplexy episodes in these narcoleptic dogs (“Food Elicited Cataplexy Test”) [29, 30]. Cataplexy-like episodes is also observed in Hcrt knockout mice [19, 20]. It has been suggested that positive emotions or reward may also trigger cataplexy in these knockout mice, because wheel running was found to increase the probability of transitioning into cataplexy [31]. Overall, positive emotions trigger cataplexy in people with NC, and also in rodent and dog models of narcolepsy.

Weak with Laughter One surprising finding from Anic-Labat et al.’s study [23] (see previous section) was the high prevalence of cataplexy-like symptoms in non-narcoleptic subjects. In this survey, 46% of the 905 non-narcoleptic subjects reported episodes of muscle weakness, mostly in the context of athletic activities (26.2–28.8%), as well as while being tense or stressed (16.0–18.0%), or while experiencing emotions (1.8–15.5%). Cataplexy attacks might thus be an exaggeration of the physiological muscle weakness occurring during emotional experiences, such as when being “weak with laughter” [32– 34]. Laughter-induced hypotonia may precipitate further motor inhibition, i.e., cataplexy in NC patients. Lammers et  al. [33] measured the amplitude of the H-reflex,1 while NC patients and controls saw emotional pictures, including funny or humorous images that could induce laughter. The results showed a similar decrement of H-reflexes during laughter in NC patients and controls, thus suggesting that the H-reflex reduction corresponds to a normal physiological phenomenon related to laughter itself, without any specific relation to cataplexy [32]. Yet, there was a trend towards more attenuation of the H-reflex in patients with more severe cataplexy and less attenuation in patients using anti-cataplectic medication. Hence, the disappearance of the H-reflex might constitute a feature of the NC pathophysiology, though not highly selective. In another study, Tucci et  al. [37] found reduced ERP amplitude (P3 and N2), and lower cardiovascular and electrodermal reactivity to the presentation of negative or unpleasant emotional pictures in NC patients compared to controls. Patients and controls did not differ in subjective emotional experience associated with the negative pictures, but the patients reported a feeling of low control over these aversive stimuli (lower dominance scores).

 The H-reflex or Hoffmann reflex relies on the contraction of the flexors of the calf, monosynaptically activated following excitation of sensory nerve fibers in the tibial nerve. Its amplitude, measured electromyographically, reflects interneuron modulation of motor-neuron excitability, and diminishes when inhibitory interneurons are excited. The H-reflex strongly decreases during cataplexy episodes triggered by amusement in NC patients [25, 35]. It is decreased during NREM sleep and abolished during REM sleep [36].

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In a recent study, Khatami et al. [38] investigated the emotional modulation of the acoustic startle (blink) reflex (ASR) in NC patients. The ASR is a useful tool for testing the integrity of the reticulospinal activity, which was shown to be attenuated by pleasant emotions and enhanced by unpleasant stimuli in healthy individuals [39]. In Khatami et al’s study, NC patients showed intact ASR, but no startle potentiation during the presentation of unpleasant pictures. The authors proposed that the absence of aversive ASR potentiation could suggest an amygdala dysfunction in narcoleptics. This interpretation is consistent with findings in narcoleptic dogs that show axonal degeneration at the time of symptom onset in regions known to be involved in startle response, such as the amygdala and the medial septum region [40], as well as changes in neuronal firing rates in the amygdala during cataplexy [41]. Taken together, these results point to a dysfunction of emotional-­ limbic circuits in NC disease, a hypothesis that was confirmed by a recent functional MRI study in NC patients [42]; see details in Section 11.6).

Anatomical Findings in Human Narcolepsy Low CSF hypocretin-1 level is a common finding in narcolepsy with definite cataplexy [18]. Since about 10 years or so, researchers have looked for corresponding regional anatomical changes in the brains of NC patients [43]. Postmortem autopsy studies showed a selective loss of Hcrt cells and a reduction or loss of hypocretin peptides in the hypothalami of narcoleptic patients [3, 5]. A few recent studies have combined the use of high-resolution MRI scans and voxel-basedmorphometry (VBM) to identify differences in brain morphology that may remain undetected by routine inspection of individual structural MRI scans. VBM allows between-group statistical comparisons of tissue composition (gray and white matter) across all brain regions. An early study found no structural change in brains of patients with hypocretin-deficient narcolepsy, suggesting that functional abnormalities of hypocretin neurons could either be associated with microscopic alterations not detectable by VBM, or not be associated with any structural changes whatsoever [44]. Two

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subsequent studies did find cortical gray matter reduction in patients with narcolepsy, predominantly in frontal brain regions as well as in inferior temporal regions [45, 46]. In another study, comparing 29 narcoleptic patients with 29 age- and sex-matched healthy volunteers [47], significant decrease in gray matter concentration was found in the hypothalamus, cerebellum (vermis), superior temporal gyrus and right nucleus accumbens. Given the major projection sites of hypocretin-1 (the hypothalamus among others) and hypocretin-2 (the nucleus accumbens among others), these regional decreases in gray matter could reflect secondary neuronal losses due to damage of specific hypocretin projections. A recent VBM study corroborated a significant reduction of hypothalamic gray matter volume in 19 patients compared with 16 controls [48]. However, VBM studies with larger samples of drug-naive patients might be required to confirm these results. Proton magnetic resonance spectroscopy (1HMRS) was also used to assess the N-acetylaspartate (NAA) and creatinine plus phosphocreatinine (Cr + PCr) content in the hypothalamus of narcoleptic patients. An analysis of spectral peak area ratios revealed a decrease in the NAA/Cr + PCr ratio in the hypothalamus of 23 narcoleptic patients compared with 10 control subjects [49]. Another study found similar NAA/Cr + PCr ratios in the ventral pontine areas of 12 narcoleptic patients compared to 12 controls [50]. Reduced NAA/Cr + PCr ratio indicates reduced neuronal function which could reflect neuronal loss (i.e., fewer neurons) or reduced activity of existing neurons. The partial reversibility of NAA deficit during recovery from acute brain pathology [51] suggests that reduced brain NAA may be due to neuronal dysfunction rather than neuronal loss. Even though most cases of narcolepsy with cataplexy are idiopathic, patients presenting narcolepsy with cataplexy, or even isolated cataplexy have been reported. In a review of symptomatic narcolepsy associated with central nervous system disorders, Nishino and Kanbayash [52] found that most of the patients presenting with tumors and NC-like symptoms had a clear involvement of the hypothalamus. Thus, despite some inconsistencies, anatomical (perhaps reversible) changes in the hypothalamus have been found in several studies, compatible with a dysfunction of the hypothalamic Hcrt system.

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Functional Abnormalities in Narcolepsy Functional brain imaging methods can provide measurements of baseline regional brain activity, and of relative changes in activity during specific behavioral conditions or during external stimulation. Baseline activity in narcoleptic patients during wakefulness was assessed with F-18 fluorodeoxyglucose positron emission tomography (F-18 FDG-PET), by measuring the cerebral metabolic rate for glucose (CMRGlu) [53]. Compared to normal controls, narcoleptic patients had reduced CMRGlu in bilateral precuneus, bilateral posterior hypothalami and mediodorsal thalamic nuclei. A subsequent SPECT study confirmed hypoperfusion in bilateral anterior hypothalami [54]. A few recent studies obtained data in NC patients during a cataplexy episode. In one SPECT study performed on two patients during cataplexy (compared to REM sleep or baseline wakefulness), perfusion increased in limbic areas (including amygdala, insula and cingulate gyri) and basal ganglia, thalami, premotor cortices, sensorimotor cortices, and brainstem, whereas perfusion decreased in prefrontal cortex and occipital lobe [55]. Increased cingulate and amygdala activity may relate to concomitant emotional processing. Hyperperfusion in the pons, thalami and amygdalae was not replicated in a recent single-case report [56] which revealed increased activity in several cortical areas including cingulate cortex, orbitofrontal cortex, and right putamen during status cataplecticus (here, in the absence of emotional trigger). Brain imaging methods also allow the measurement of brain activity during external stimulation to assess the function of specific brain networks. Brain responses to visual and auditory stimuli were studied in 12 narcoleptic patients and 12 control subjects using functional MRI [57]. In this study, no difference in spatial extent of cortical activation was found when comparing control and narcoleptic subjects. Studies using well-designed fMRI protocols on large samples of patients are needed to better characterize potential changes in regional brain function in NC patients, in particular when they experience emotions (see Section 11.6) [42]. The previous sections point to the hypothalamus and limbic-amygdala regions as brain sites whose dysfunction might contribute to cataplexy in NC. In the next section, we review the recent neuroimaging evidence showing that both the amygdala and the hypothalamus mediate affective responses associated to humor and laughter, which representing potent triggers of cataplexy.

A. Ponz and S. Schwartz

Neural Correlates of Humor and Laughter Positive emotions, in particular those experienced during joking and laughing are the primary triggers of cataplexy. Hence, the study of the brain networks recruited during humor and laughter may provide important insights into the suprapontine brain mechanisms associated with the cataplectic effect of emotions in human NC. In their important review on the cerebral bases of pathological laughter, normal laughter, and humor, Wild et al. [58] proposed that the expression of laughter relies on two partially independent neuronal circuits: (1) an “involuntary” or “emotionally-driven” system involving the amygdala, thalamic, hypo- and subthalamic areas, and the dorsal/tegmental brainstem, and (2) a “voluntary” system engaging premotor/frontal opercular areas, motor cortex, and the ventral brainstem. These systems would be orchestrated by a laughtercoordinating center in the dorsal upper pons. Although a comprehensive review of pathological laughter is beyond the scope of this chapter, several neurological findings suggest a possible role of the hypothalamus and the amygdala in laughter, both areas also potentially relevant to the pathophysiology of cataplexy. One most striking expression of pathological laughter occurs in the context of epileptic seizures, and is called gelastic epilepsy. The brain areas frequently found to be involved in patients suffering from gelastic epilepsy include the hypothalamus, most commonly in the form of hypothalamic hamartomas (non-neoplastic malformations composed of hyperplastic neuronal tissue resembling the gray matter), the frontal poles, and the temporal poles [58, 59]. Stimulation of the hypothalamus was also found to produce laughter in a patient with a hamartoma [60]. By contrast, the “fou rire prodromique,” in which unmotivated, inappropriate laughter occurs after cerebral ischaemia, does not involve the hypothalamus, the hippocampus, nor the amygdala. In total, data obtained in neurological patients suggest that the hypothalamus (and possibly the amygdala) may play a key role in the production of affective reactions associated with laughing. Several recent neuroimaging studies of normal laughter and humor processing confirmed and extended some of the anatomical findings from neurological observations. In an fMRI study of facial reactions to pictures of faces expressing emotions, activation of both basal temporal cortices, including the amygdalae, was observed when

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subjects generated smiles in response to pictures of smiling faces [61]. In an early fMRI study on humor-related activation, Goel and Dolan [62] found that the semantic comprehension of online jokes involved posterior middle temporal regions, while humor experience activated ventromedial prefrontal cortex. A functional dissociation between cognitive (comprehension) and affective (appreciation) components of humor was also observed in another fMRI study using popular television sitcoms as humorous stimuli [63], with increased left inferior frontal and posterior temporal activity time-locked to humor detection, and increased bilateral regions of insular cortex and the amygdala during humor appreciation. Using high-field (3 Tesla) event-related functional MRI, Moobs et al. [64] found that funny cartoons (compared to non-funny cartoons) engaged a network of subcortical structures, including the ventral tegmental area (VTA), the hypothalamus, the nucleus accumbens (NAcc), and the amygdala, i.e., key components of the mesolimbic dopaminergic reward system that are known to be activated by rewards in humans [65]. In addition, humor intensity positively correlated with fMRI signal intensity in these regions. Recently, Watson et al. [66] replicated these results, showing that both visual (sight gags) and language-based humor engaged a common brain network that included the midbrain regions, the amygdala, the hypothalamus, and the NAcc, presumably reflecting the euphoric component of humor. Because both the amygdala and the hypothalamus send descending projections to autonomic output nuclei, they could also play a role in the peripheral autonomic changes associated with the emotional response to humor [66, 67]. Taken together, these recent fMRI findings in jokeinduced humor implicate increased activity in rewardand emotion-related areas.

comparing the neural activity elicited by humorous vs. neutral pictures in NC patients and healthy volunteers. We predicted that NC patients would show abnormal brain responses in regions previously reported to be activated by humorous stimuli in normal controls, including the hypothalamus, amygdala, and ventral striatum (see previous section). Below, we report the experimental paradigm and results from this first fMRI assessment of regional brain responses to positive emotions in human narcolepsy. Twelve drug-free, hypocretin-deficient (in all eight patients tested) NC patients with clear-cut cataplexy (based on clinical examination and standard questionnaires) and 12 healthy volunteers (matched for age, gender, and body-mass index) were scanned while performing a humor judgment paradigm [42]. In this task, the subjects watched humorous or neutral picturesequences. These mini-sequences comprised a first picture that was always neutral followed by a second picture that revealed either a humorous or a neutral element (Fig.  11.1). On each trial, the participants reported whether they found the sequence funny or not by pressing a button. Note that before their inclusion in the study, all the patients had reported to us that joking and laughing would frequently trigger cataplexy attacks. Whole-brain event-related fMRI data were acquired on a 3.0-Tesla scanner, with scanning parameters optimized to avoid signal loss in hypothalamic and amygdala regions. Statistical data analyses were first performed in each participant using the general linear model to reveal the brain regions that were more activated by humorous than neutral trials (second picture in the sequence), as classified by each participant during the scanning. Linear contrasts between the humor and neutral conditions from each subject were then submitted to a group analysis, using a two-way ANOVA, treating subjects as a random effect. This analysis allowed us to identify regions showing group differences in humorspecific activation.

Neuroimaging of Humor Processing in Narcolepsy–Cataplexy

Abnormal Hypothalamic Based on the clinical observation that NC patients often and Amygdala Activity have cataplexy attacks when they experience positive emotions, we hypothesized that these patients may show abnormal processing of external emotional inputs within limbic-affective and/or mesolimbic-reward circuits. In a recent fMRI study, we tested this hypothesis by

Behavioral responses provided in the scanner showed that NC patients and their matched controls did not differ in the proportion of images judged as humorous. This suggests that there was no general alteration of

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a

b

Fig. 11.1  Examples of two mini-sequences. On each trial, a neutral scene was first presented (3  s), followed by a brief blank (300  ms), which was subsequently replaced by a second picture revealing a new element that was either neutral or humorous. Subjects made a humor judgment response after the offset of the second picture. (a) Sequence usually judged funny. (b) Sequence typically judged neutral

humor perception in the patients. At the brain level, NC patients had an increased amygdala activity together with reduced medial prefrontal activity during humor processing, in addition to a complete lack of hypothalamic activity (compared to controls; Fig. 11.2). The absence of hypothalamic activity in NC patients is consistent with a hypothalamic dysfunction in these patients [10, 18]. Humor-selective increase of activity in regions that integrate both emotion- and rewardrelated functions (amygdala, inferior frontal cortex, insula and ventral striatum, including NAcc) suggests exaggerated responses to positive emotions, and ­provides a neural basis for the patients’ subjective reports and well-documented clinical observation that positive emotions often trigger cataplexy attacks in NC patients. These results have subsequently been replicated in another fMRI study of humor processing in NC patients, except that in this later study hypothalamic

response to humor was found to increase (rather than decrease) in the patients, while decreased hypothalamic activity was suggested in one patient during cataplexy [68]. While connections from the amygdala to the hypothalamus are known to modulate reflex responses to emotional stimuli [69–71], these fMRI results in NC patients suggest that the hypothalamus might also influence amygdala activity during positive emotions, possibly via direct projections from hypothalamic Hcrt neurons to the amygdaloid complex [3, 72–74]. Reduced hypothalamic activation and exaggerated amygdala response to humor could thus both result from the loss of hypothalamic Hcrt neurons in NC patients. Because the Hcrt system also sends projections to the ventral tegmental area (VTA) [75], another possible pathway would involve these projections to mediate increased prefrontal dopamine (DA) efflux [76], which

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fMRI effect size

a Controls > 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

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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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124 hypothalamic hypocretin/orexin system. Sleep Med Rev 9, 269–310 (2005) 53. Joo, E.Y., Tae, W.S., Kim, J.H., Kim, B.T. & Hong, S.B. Glucose hypometabolism of hypothalamus and thalamus in narcolepsy. Ann Neurol 56, 437–440 (2004) 54. Joo, E.Y. et al. Cerebral perfusion abnormality in narcolepsy with cataplexy. Neuroimage 28, 410–416 (2005) 55. Hong, S.B., Tae, W.S. & Joo, E.Y. Cerebral perfusion changes during cataplexy in narcolepsy patients. Neurology 66, 1747–1749 (2006) 56. Chabas, D. et al. Functional imaging of cataplexy during status cataplecticus. Sleep 30, 153–156 (2007) 57. Ellis, C.M. et  al. Functional magnetic resonance imaging neuroactivation studies in normal subjects and subjects with the narcoleptic syndrome. Actions of modafinil. J Sleep Res 8, 85–93 (1999) 58. Wild, B., Rodden, F.A., Grodd, W. & Ruch, W. Neural correlates of laughter and humour. Brain 126, 2121–2138 (2003) 59. Arroyo, S. et al. Mirth, laughter and gelastic seizures. Brain 116(4), 757–780 (1993) 60. Kuzniecky, R.I. et al. Multimodality MRI in mesial temporal sclerosis: relative sensitivity and specificity. Neurology 49, 774–778 (1997) 61. Wild, B., Erb, M., Eyb, M., Bartels, M. & Grodd, W. Why are smiles contagious? An fMRI study of the interaction between perception of facial affect and facial movements. Psychiatry Res 123, 17–36 (2003) 62. Goel, V. & Dolan, R.J. The functional anatomy of humor: segregating cognitive and affective components. Nat Neurosci 4, 237–238 (2001) 63. Moran, J.M., Wig, G.S., Adams, R.B., Jr., Janata, P. & Kelley, W.M. Neural correlates of humor detection and appreciation. Neuroimage 21, 1055–1060 (2004) 64. Mobbs, D., Greicius, M.D., Abdel-Azim, E., Menon, V. & Reiss, A.L. Humor modulates the mesolimbic reward centers. Neuron 40, 1041–1048 (2003) 65. O’Doherty, J.P., Buchanan, T.W., Seymour, B. & Dolan, R.J. Predictive neural coding of reward preference involves dissociable responses in human ventral midbrain and ventral striatum. Neuron 49, 157–166 (2006) 66. Watson, K.K., Matthews, B.J. & Allman, J.M. Brain activation during sight gags and language-dependent humor. Cereb Cortex 17, 314–324 (2007) 67. Critchley, H.D., Mathias, C.J. & Dolan, R.J. Neural activity in the human brain relating to uncertainty and arousal during anticipation. Neuron 29, 537–545 (2001) 68. Reiss, A.L. et  al. Anomalous hypothalamic responses to humor in cataplexy. PLoS ONE 3, e2225 (2008) 69. Sullivan, G.M. et al. Lesions in the bed nucleus of the stria terminalis disrupt corticosterone and freezing responses elicited by a contextual but not by a specific cue-conditioned fear stimulus. Neuroscience 128, 7–14 (2004) 70. Price, J.L. Free will versus survival: brain systems that underlie intrinsic constraints on behavior. J Comp Neurol 493, 132–139 (2005) 71. LeDoux, J.E. Emotion circuits in the brain. Annu Rev Neurosci 23, 155–184 (2000) 72. Bisetti, A. et  al. Excitatory action of hypocretin/orexin on neurons of the central medial amygdala. Neuroscience 142, 999–1004 (2006) 73. Marcus, J.N. et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435, 6–25 (2001)

A. Ponz and S. Schwartz 74. Date, Y. et  al. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci U S A 96, 748–753 (1999) 75. Fadel, J. & Deutch, A.Y. Anatomical substrates of orexin– dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience 111, 379–387 (2002) 76. Vittoz, N.M. & Berridge, C.W. Hypocretin/orexin selectively increases dopamine efflux within the prefrontal cortex: involvement of the ventral tegmental area. Neuropsychopharmacology 31, 384–395 (2006) 77. Hariri, A.R., Mattay, V.S., Tessitore, A., Fera, F. & Weinberger, D.R. Neocortical modulation of the amygdala response to fearful stimuli. Biol Psychiatry 53, 494–501 (2003) 78. Milad, M.R. & Quirk, G.J. Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420, 70–74 (2002) 79. Phelps, E.A., Delgado, M.R., Nearing, K.I. & LeDoux, J.E. Extinction learning in humans: role of the amygdala and vmPFC. Neuron 43, 897–905 (2004) 80. Georgescu, D. et al. Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J Neurosci 23, 3106–3111 (2003) 81. Parkes, J.D., Baraitser, M., Marsden, C.D. & Asselman, P. Natural history, symptoms and treatment of the narcoleptic syndrome. Acta Neurol Scand 52, 337–353 (1975) 82. Schwartz, S. et  al. Emotional and motor responses during game playing in narcoleptic patients: a functional MRI study. J Sleep Res 15, 32 (2006) 83. Overeem, S., Lammers, G.J. & van Dijk, J.G. Cataplexy: ‘tonic immobility’ rather than ‘REM-sleep atonia’? Sleep Med 3, 471–477 (2002) 84. Talarovicova, A., Krskova, L. & Kiss, A. Some assessments of the amygdala role in suprahypothalamic neuroendocrine regulation: a minireview. Endocr Regul 41, 155–162 (2007) 85. Misslin, R. The defense system of fear: behavior and neurocircuitry. Neurophysiol Clin 33, 55–66 (2003) 86. Phan, K.L., Wager, T., Taylor, S.F. & Liberzon, I. Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 16, 331–348 (2002) 87. LeDoux, J. The emotional brain, fear, and the amygdala. Cell Mol Neurobiol 23, 727–738 (2003) 88. Bassetti, C. Cataplexy: ‘REM-atonia or tonic immobility’? Sleep Med 3, 465–466 (2002) 89. Kayaba, Y. et al. Attenuated defense response and low basal blood pressure in orexin knockout mice. Am J Physiol Regul Integr Comp Physiol 285, R581–R593 (2003) 90. Zhang, W., Sakurai, T., Fukuda, Y. & Kuwaki, T. Orexin neuron-mediated skeletal muscle vasodilation and shift of baroreflex during defense response in mice. Am J Physiol Regul Integr Comp Physiol 290, R1654–R1663 (2006) 91. Winsky-Sommerer, R. et  al. Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J Neurosci 24, 11439–11448 (2004) 92. Winsky-Sommerer, R., Boutrel, B. & de Lecea, L. Stress and arousal: the corticotrophin-releasing factor/hypocretin circuitry. Mol Neurobiol 32, 285–294 (2005) 93. Fuse, T., Forsyth, J.P., Marx, B., Gallup, G.G. & Weaver, S. Factor structure of the Tonic Immobility Scale in female sexual assault survivors: an exploratory and Confirmatory Factor Analysis. J Anxiety Disord 21, 265–283 (2007) 94. Maquet, P. et al. Functional neuroanatomy of human rapid-eyemovement sleep and dreaming. Nature 383, 163–166 (1996)

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].

13 Psychoanalysis and Narcolepsy

131

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

132

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:

133

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.

References 1. Freud S. (1900) The interpretation of dreams I, vol. 4, A dream is the fufillment of a wish, chap. 3, pp. 122–133. In Strachey J (ed.), The complete Psychological Works of Sigmund Freud. London: Hogworth, 1953. 2. Gilineau E. (1880) De la Narcolepsie. Gaz des Hopitaux 53:626–628. 3. Carlill H. (1920) Hysterical sleeping attacks. Lancet ii:1128–1131. 4. Goetz P. (1950) Shock therapy of narcolepsy. Ugeskr Laeger 112(27):963. 5. Weitzmer HA. (1952) Insulin hypoglycemia of narcolepsy with temporary improvement. Perm Found Med Bull 10(1–4):153–156. 6. Meyers CS. (1920) Treatment of a case of narcolepsy. Lancet I:491–493. 7. Missreiger A. (1924) Zur psychogenese de narkolepsie. Fortscritte der sexualwissenschaft und der psychoanalyse 1:217–271.

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

135

136

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

<40 pg/ml

104 pg/ml

Intermediate

Normal

Intermediate

Low

Low

Low

Normal

151 pg/ml

503 pg/ml

176 pg/ml

<40 pg/ml

93 pg/ml

61 pg/ml

275 pg/ml

Mean = 133 pg/ml Control level Mean = 133 pg/ml Control level Mean = 133 pg/ml Control level Mean = 133 pg/ml Control level Mean = 133 pg/ml Normal 518 pg/ml

Control level

Low

Low

Hypocretin

GCS12

Acromegaly+

Note

[69]

[68]

[68]

[108]

[107]

[61]

[60]

[59]

[56]

[56]

[56]

[56]

[56]

[55]

[58]

(continued)

Dauvilliers et al. 2003 Dauvilliers et al. 2003 Arii et al. 2004

Dauvilliers et al. 2007

Dempsey et al. 2003 Nokura et al. 2004 Tachibana et al. 2005

Arii et al. 2001 Marcus et al. 2002 Snow et al. 2002 Snow et al. 2002 Snow et al. 2002 Snow et al. 2002 Snow et al. 2002 Krahn et al. 2002

References Author

14 Symptomatic Narcolepsy or Hypersomnia, with and Without Hypocretin (Orexin) Deficiency 137

Left frontotempo- 40 ral and insular Hypothalamus 5

Encephalopathies (n = 3) Rasmussen’s syndrome Wernicke encephalitis Limbic encephalitis

NC by Brain stem ICSD2 encephalitis

E

E

NC

Thalamus

Infarction

E

Limbic, hypothalamus Pontine tegmentum adjacent and rostral to both fourth nerve nuclei

Thalamus

30

65

15

45

40

Infarction

Ponto-medullary

34

23

N

Hypothalamus

Vascular disorders (n = 5) Infarction

58

Infarction

Nonspecific

Head trauma

22

26

E

Nonspecific

Head trauma

Thalamus

Nonspecific

Head trauma

18

Age

Infarction

Nonspecific

Head trauma

Location

E

NC

NC by ICSD2 NC by ICSD2 NM by ICSD2 NM by ICSD2  

Tumors (n = 12)

Lesion

Table 14.1  (continued) Narcoleptic symptoms

M

M

F

M

M

M

M

M

M

?

M

M

M

+

+

+

+

+

+

+

+

+

+

+

+

+

<3 min/MSLT

?

?

1.6 min/MSLT

?

5 min/MSLT

1 min/MSLT

9 min/MSLT

0.5 min/MSLT

2.5 min/MSLT

5.6 min/MSLT

2.9 min/MSLT

6.3 min/MSLT

Gender EDS Sleep latency

+

−

−

+

−

+

−

−

+

+

+

+

+

+

−

−

+

−

−

−

−

+

−

±

−

−

−

?

?

+

?

?

?

?

−

?

?

−

−

DR2/ DQB1*0602 (DQw1)

SOREMP CA HLA

Normal

Low

Low

Low

Normal

Normal

Normal

Normal

Intermediate

Low

Low

Low

Normal

Hypocretin

266 pg/ml

87 pg/ml

<40 pg/ml

<40 pg/ml

274 pg/ml

312 pg/ml

316 pg/ml

265 pg/ml

167 pg/ml

211 pg/ml

225 pg/ml

289 pg/ml

468 pg/ml

RBD

AHI: 25/h

Note

[115]

[113]

[112]

[114]

[109]

[61]

[8]

[8]

[87]

[143]

[143]

[143]

[143]

Lagrange et al. 2003 Kashiwagi et al. 2004 Yamato et al. 2004 Mathis et al. 2007

Scammell et al. 2001 Bassetti et al. 2003 Bassetti et al. 2003 Nokura et al. 2004 Tohyama et al. 2004

Baumann et al. 2007

Baumann et al. 2007 Baumann et al. 2007 Baumann et al. 2007

References Author

138 T. Kanbayashi et al.

Parkinson’s disease

N

E

MS or neuromyelitis optica MS or neuromyelitis optica Neuromyelitis optica

E

NC by ICSD2 NC by ICSD2

48 49

Hypothalamus

43

45

22

51

74

74

Hypothalamus

Hypothalamus

Hypothalamus

MS

N

 

E

Enlargement of the 3rd V Enlargement of the 3rd V

69– 82

58

Nonspecific

Cortical atrophy

?

Nonspecific

enlargement of the 3rd V, brainstem atrophy Immune-mediated Demyelinating disorders (n = 9) Multiple sclerosis Hypothalamus (MS)

Heredogenerative disorders (n = 1) ADCA-DN

Dementia with Lewy bodies (n = 10) Progressive supranuclear palsy Progressive supranuclear palsy

?

52

64

69

Nonspecific

Nonspecific

Nonspecific

Nonspecific

Nerve nuclei

NC

NC/ NM by ICSD2

E

E

Parkinson’s disease (n = 16) E/REF Parkinson’s disease (n = 3) NC/ Parkinson’s disease NM by ICSD2

Parkinson’s disease

E

E

Degeneration (n = 33) Parkinson’s disease

F

F

F

F

F

M

M

F

M = 7, F = 3

M

?

?

M

M

M

+

+

+

+

+

+

+

+

+

+

±

+

+

+

+

?

?

?

?

2.8 min/MSLT

?

2.9 min/MSLT

2 min/MSLT

?

2 min/MSLT

?

?

4.4 min/MSLT

4.9 min/MSLT

6.1 min/MSLT

−

−

−

−

+

?

+

−

−

+

?

?

−

+

−

−

−

−

−

−

+

+

−

−

+

−

−

−

−

−

?

?

?

?

−

−

+

+

?

+

?

?

−

−

−

Low

Low

Intermediate

Low

Low

Low

Low

Low

Normal

Low

Intermediate

Low

Normal

Normal

Normal

158 pg/ml

106 pg/ml

191 pg/ml

<40 pg/ml

<40 pg/ml

96 pg/ml

<40 pg/ml

<40 pg/ml

382– 667 pg/ml

<50–97 pg/ ml 138– 169 pg/ml 86 pg/ml

319 pg/ml

307 pg/ml

253 pg/ml

AQP4+

AQP4+

AQP4+

[153]

[152]

[151]

[148]

[75, 76]

[86]

[129]

[128]

[124]

[122]

[117]

[117]

[116]

[116]

[116]

(continued)

Iseki et al. 2002,Oka et al. 2004 Kato et al. 2003 Nozaki et al. 2004 Nakamura et al. 2005 Carlander et al. 2008

Melberg et al. 2001

Hattori et al. 2003 Sugiura et al. 2007

Baumanna et al. 2004

Overeem et al. 2002 Overeem et al. 2002 Overeem et al. 2002 Drouot et al. 2003 Drouot et al. 2003 Maeda et al. 2006

14 Symptomatic Narcolepsy or Hypersomnia, with and Without Hypocretin (Orexin) Deficiency 139

ADEM

Hypothalamus

Acute disseminated Hypothalamus encephalomyllitis ADEM Hypothalamus, coronaradiata, aqueduct, raphe ADEM Hypothalamus

Location

Immune-mediated polyneuropathy (n = 3) E Guillain-Barre Nonspecific syndrome E Guillain-Barre Nonspecific syndrome EM by Bickerstaff’s Brainstem ICSD2 brainstem encephalitis Paraneoplastic autoimmune syndromes (n = 6) E Anti-Ma associated Lesions in both encephalitis mesiotemporal regions, ventricular enlargement, temporal lobe atrophy E Anti-Ma associated Left temporal encephalitis enhancing abnormalities REF Anti-Ma associated Brainstem, encephalitis periventricular region, basal ganglia

E

E

N

E

Tumors (n = 12)

Lesion

Table 14.1  (continued) Narcoleptic symptoms

M M F

M

M

F

19 33

45

22

82

F

F

F

F

−

+

+

+

+

+

+

+

+

+

?

?

?

?

0.8 min/TNST

0.7 min/TNST

?

?

4.4 min/MSLT

4.5 Min/MSLT

Gender EDS Sleep latency

28

0.9

7

38

12

Age

?

?

?

−

−

−

−

−

+

−

−

−

−

−

−

−

−

−

−

−

?

?

?

?

?

?

?

−

+

-

DR2/ DQB1*0602 (DQw1)

SOREMP CA HLA

Normal

Low

Low

Intermediate

Intermediate

Low

Low

Intermediate

Low

Low

Hypocretin

GBS

AQP4+

[174]

[165]

[165]

[157]

[156]

[155]

[154]

237 pg/ml

Poorly differentiated lung cancer

[169]

<100 pg/ml Mixed germ-cell [169] tumor of the testis

Overeem et al. 2004

Overeem et al. 2004

Overeem et al. 2004

Nishino et al. 2003 Nishino et al. 2003 Saji et al. 2007

Yoshikawa et al. 2004 Yano et al. 2004

Kubota et al. 2008 Gledhill et al. 2004

References Author

<100 pg/ml Nonseminomatous [169] germ cell tumor of the testis

128 pg/ml

151 pg/ml

<40 pg/ml

<40 pg/ml

146 pg/ml

87 pg/ml

102 pg/ml

Note

140 T. Kanbayashi et al.

PWS

PWS

PWS

Niemann-Pick type C NPC

NPC

NPC

NPC

NPC

Myotonic dystrophy

MYD

MYD

REF

REF

REF

C

NC

E

E

E

C

N

E

E

E

Nonspecific

Nonspecific

Nonspecific

Nonspecific

Nonspecific

Nonspecific

Nonspecific

Nonspecific

Nonspecific

Nonspecific

Nonspecific

Nonspecific

Anti-Ma associated Nonspecific encephalitis Genetic/congenital disorders (n = 14) Prader-Willi Nonspecific syndrome PWS Nonspecific

REF

E

Anti-Ma associated encephalitis

E

Thalamus, superior collicular, medial temporal lesions Hippocampus, midbrain

Anti-Ma associated encephalitis

E

19

47

46

10

31

24

25

14

5

0.5m

6

23

10

16

53

38

67

?

?

?

F

M

M

F

F

M

M

M

M

M

M

F

M

F

+

+

+

−

+

+

+

+

-

?

−

−

+

+

−

+

+

−

−

−

−

−

?

?

?

−

−

+

8 min/MSLT

7 min/MSLT

4.7 min/MSLT

?

−

−

+

−

10.7 min/MSLT −

3.2 min/MSLT

3.5 min/MSLT

5.1 min/MSLT

16.5 min/TNST −

?

?

?

6 min/MSLT

3 min/MSLT

?

?

?

−

−

−

+

−

−

−

+

+

−

−

−

−

−

−

−

−

−

−

−

?

−

−

−

+

−

?

?

?

?

−

?

?

?

Intermediate

Normal

Low

Intermediate

Intermediate

Normal

Normal

Intermediate

Intermediate

Intermediate

Normal

Intermediate

Intermediate

Low

Normal

Low

Low

187 pg/ml

200 pg/ml

91 pg/ml

174 pg/ml

190 pg/ml

245 pg/ml

226 pg/ml

157 pg/ml

142 pg/ml

192 pg/ml

226 pg/ml

191 pg/ml

130 pg/ml

109 pg/ml

[169]

[169]

[169]

BMI 25.8, AHI0

[21]

[21]

[21]

[99]

[95]

[95]

[95]

[95]

[97]

[16]

[93]

BMI 48.1, AHI [2] 5.6 BMI29.8, AHI [93] 3.1 BMI49, AHI 46.8 [93]

<100 pg/ml Germ-cell tumor of the testis (seminoma) 218 pg/ml Adenocarcinoma of the ovary

<100 pg/ml Adenocarcinoma of the lung

(continued)

Mignot et al. 2002 Nevsimalova et al. 2005 Nevsimalova et al. 2005 Nevsimalova et al. 2005 Arii et al. 2004 Kanbayashi et al. 2003 Vankova et al. 2003 Vankova et al. 2003 Vankova et al. 2003 Vankova et al. 2003 Oyama et al. 2006 MartinezRodriguez et al. 2003 MartinezRodriguez et al. 2003 MartinezRodriguez et al. 2003

Overeem et al. 2004

Overeem et al. 2004

Overeem et al. 2004

14 Symptomatic Narcolepsy or Hypersomnia, with and Without Hypocretin (Orexin) Deficiency 141

MYD

N

?

?

Nonspecific

Nonspecific

Nonspecific

Location

53

65

23

25

50

Age

M

M

M

?

?

?

+

+

+

+

?

?

6.4 min/MSLT

5.7 min/MSLT

1.8 min/MSLT

Gender EDS Sleep latency

Narcoleptic symptoms

−

−

+

−

+

−

−

−

−

−

?

?

−

−

−

DR2/ DQB1*0602 (DQw1)

SOREMP CA HLA

Intermediate

Low

Normal

Normal

Normal

Hypocretin

113 pg/ml

<40 pg/ml

401 pg/ml

235 pg/ml

206 pg/ml

Full recover by steroid

Note

[176]

[175]

[68]

[21]

[21]

Castillo et al. 2004 Voderholzer et al. 2002

MartinezRodriguez et al. 2003 MartinezRodriguez et al. 2003 Dauvilliers et al. 2003

References Author

Abbreviations used: NC symptomatic narcolepsy-cataplexy, EDS excessive daytime sleepiness, N symptomatic narcolepsy, CA cataplexy, E symptomatic EDS, V ventricle, C symptomatic cataplexy, MSLT multiple sleep latency test, + present, − absent, ? not assessed, ADCA-DN autosomal dominant cerebellar ataxia, deafness and narcolepsy, O other, TNST two-nap sleep test, REF reference cases (no EDS), EEG electroencephalogram

O

Others (n = 2) Hashimoto’s encephalopathy Whipple’s disease

MYD

E

E

MYD

N

Tumors (n = 12)

Lesion

Table 14.1  (continued)

142 T. Kanbayashi et al.

14 Symptomatic Narcolepsy or Hypersomnia, with and Without Hypocretin (Orexin) Deficiency

measures (typically less than 10 min [less than 8 min is used in second edition of ICSD] during MSLT), the diagnosis of symptomatic EDS was made. In particular cases, such as EDS associated with ADEM, EDS may rapidly disappear with steroid treatments and may not last for 3 months. We diagnosed these cases arbitrarily as symptomatic EDS, and the duration of the EDS episode is noted. Since the causal relationship between these two conditions was mostly judged by the statements of the authors’ original case reports, it may be impossible to exclude cases in which the neurological condition is only a coexistence of idiopathic narcolepsy/idiopathic hypersomnia. In rare cases, isolated cataplexy (without EDS) associated with neurological conditions occurs. If the authors emphasize the occurrence of cataplexy as a significant underlying neurological disorder and no EDS is associated, we classified these as “symptomatic (isolated) cataplexy.” In addition, international classification of sleep disorders second edition (ICSD2) was published in 2005, and both “narcolepsy due to medical condition” and “hypersomnia due to medical condition” were defined as classifications independent from idiopathic narcolepsy and idiopathic hypersomnia. Within the classification of symptomatic narcolepsy (i.e., there is a significant underlying medical or neurological disorder accounting for the daytime sleepiness, and no other sleep disorder, mental disorder, medication use, or substance use disorder explains the hypersomnia better), hypocretin status was also considered for “narcolepsy due to medical condition.” If CSF hypocretin levels are less than 110 pg/ml (or less than 30% of normal control values), the diagnosis, “narcolepsy due to medical condition” can be made. In this chapter, we will also discuss the recent cases that meet the ICSD-2 criteria of “narcolepsy due to medical conditions.” Using the previous criteria, we had counted about 116 symptomatic cases of narcolepsy reported in the literature until 2005 (the details of all cases will be reported in our review article for symptomatic narcolepsy [41]). As reported previously by several authors, tumors, inherited disorders, and head trauma are the three most frequent causes for symptomatic narcolepsy: 33 cases (29%) of symptomatic narcoleptic cases were due to brain tumors with 55% among them exhibiting cataplexy [30, 42–61]. The results of HLA typing were reported

143

in 14 cases, and 8 cases were HLA DR2 negative. We also analyzed the brain structures involved in symptomatic cases of narcolepsy with brain tumors, and found that hypothalamic lesions (70%) are most often associated. The brainstem lesions were much less frequent, found in only 10% of these cases. Other structures reported were 12% cases and 9% multiple sites. Thirty-eight cases (34%) were due to inherited diseases, and 58% among them exhibited cataplexy. HLA typing was performed in 19 cases, and 11 of them were HLA negative. The lesions of inherited diseases were not specified by neuroimaging. Nineteen cases (16%) were due to head trauma, and 74% among them exhibited cataplexy [22, 28, 40, 54, 62–70]. In contrast to tumor cases, it is often difficult to determine the structure impaired for the symptomatic narcoleptic cases associated with head trauma, and there was no clear tendency regarding the brain structures responsible. Ten cases (9%) of symptomatic narcolepsy studied were associated with multiple sclerosis (MS) [22, 54, 71–76]. Most old cases were reported to exhibit both EDS and cataplexy, but many of them lack clinical details. It is thus difficult to exclude if some of these cases are only coexistence of idiopathic narcolepsy. HLA typing was performed in four cases, and two of them were HLA DR2 negative. Six cases (5%) were due to vascular disorders. The lesions impaired were reported to be the hypothalamus (n = 1), thalamus (n = 1), brainstem (or both) (n = 2), or unspecified (n = 2). HLA typing was done in four cases, and two cases were HLA DR2 negative.

Anatomical Substrate for the Symptoms of Narcolepsy Analysis of symptomatic narcolepsy with tumor cases clearly showed that the lesions were most often (about 70% of cases) involved in the hypothalamus and adjacent structures (the pituitary, supra seller, or optic chasm). von Economo [77] was probably the first person to suggest that narcolepsy may have its origins in the posterior hypothalamus and in some cases a secondary etiology. Neuropathological studies on encephalitis lethargica pandemic (1916–1923) revealed involvements of the midbrain periaqueducal gray matter and posterior hypothalamus in the hypersomnolent variant,

144

with frequent extension to the oculomotor nuclei. This led von Economo to speculate that the anterior hypothalamus contained a sleep-promoting area while an area spanning from the posterior wall of the third ventricle to the third nerve was involved in actively promoting wakefulness. Along with von Economo’s cases, two case reports for narcolepsy–cataplexy after encephalitis lethargica were also available by Stiefler [78] and Adie [18]. The cause of idiopathic narcolepsy was also speculated to involve this general area by von Economo [17]. A postulated hypothalamic cause of narcolepsy was widespread until the 1940s [62], but was then ignored during the psychoanalytic boom [79, 80], thereafter replaced by a brainstem hypothesis [81], along with establishments of the brainstem roles of generating REM sleep and REM sleep atonia [82]. The involvement of the hypothalamus in occurrence narcoleptic symptoms was nicely refined by Aldrich et  al. [30], who noted that tumors or other lesions located close to the third ventricle were associated with symptomatic narcolepsy and hypothesized that the posterior hypothalamic region may be the culprit. The hypothesis is finally confirmed by the discovery of hypocretin deficiency in idiopathic cases of human narcolepsy [3, 83, 84]. The fact that impairments in the hypothalamus are noted in most symptomatic cases of narcolepsy also suggests a possible involvement of impaired hypocretin neurotransmission for this condition.

Hypocretin Status in Various Neurological Conditions Hypocretin Status in Symptomatic Narcolepsy–Cataplexy Associated with Distinct CNS Lesions Soon after the discovery of the involvement of hypocretin impairments in idiopathic narcolepsy, Melberg et al. [85] reported a reduced CSF hypoocretin-1 level (96 pg/ ml) in a previously reported 51-year-old male case with autosomal dominant cerebellar ataxia (ADCA), deafness and narcolepsy (DN). In this Swedish pedigree (ADCA-DN; OMIM, Online Mendelian Inheritance in Man, accession number 604121), four out of five ADCA subjects are affected with narcolepsy–cataplexy [86],

T. Kanbayashi et al.

and CSF previously collected from one of these subjects (patients III-2) was available for the hypocretin measures. The patient was negative for HLA-DR2. Since this case is a heredodegenerative disease with an enlargement of the third ventricle, moderate atrophy of the cerebellum and the cerebral hemispheres by MRI were observed, we listed this case under narcolepsy associated with distinct CNS lesions. Scammell et al. [87] subsequently reported a 23-yearold male who developed narcolepsy–cataplexy due to a large hypothalamic stroke after a resection of a craniopharyngioma. This lesion included 2/3 of the caudal hypothalamus except for the most lateral component on the right, and extended into the mediodorsal thalamus bilaterally, the left amygdala, and parts of the basal forebrain and the rostral midbrain. His postoperative course was complicated by panhypopituitarism, staphylococcal meningitis, and hydrocephalus. He experienced HH. He became obese with a body mass index (BMI) of 31.7. Sleep latency by MSLT was 0.5 min and REM latency was 3.5  min. An overnight polysomnography showed 1 and 1.5 min of SL and REM latency, respectively, without significant sleep apnea. His HLA was negative for DQB1*0602 and CSF hypocretin level was 167 pg/ml. Nokura et  al. [61] reported one case with narcolepsy and cataplexy-like phenomena, a 66-year-old female with hypersomnia due to a hypothalamic tumor. She showed EDS and cataplexy-like symptoms, such as an abrupt falling without loss of consciousness, but the emotional triggers were unclear. An MRI revealed lesions with high signal intensities in the hypothalamus, thalamus, and midbrain bilaterally (Fig. 14.1). This case was accompanied with mild anterior hypopituitarism and an SOREMP in a daytime polysomnography. Hypocretin-1 level was 61 pg/ml. Her symptoms were improved with reduction of the tumor after 46 gray (Gy) radiation, and the intravenous administrations of nimustine hydrochloride and interferon beta. The causes of the lesions in these three cases had different etiologies: degeneration, infarction, and tumor. Although the number of cases is still limited, the hypothalamic lesions were noted in all three cases. Moderate reduction of CSF hypocretin levels (2 low and 1 intermediate) also confirmed the functional impairment of the hypothalamus. It is likely that a massive impairment of hypocretin projections and projection sites are involved in the second case (hypothalamic stroke after a resection of a craniopharyngioma), implying that

14 Symptomatic Narcolepsy or Hypersomnia, with and Without Hypocretin (Orexin) Deficiency

145

Fig.  14.1  A narcolepsy–cataplexy case with hypothalamic tumor and low hypocretin level (61 pg/ml). A 66-year old female case with hypothalamic tumor. (a, b) Axial T2-weighted image of MRI at admission exhibits high signal intensities in the midbrain, hypothalamus, and thalamus. (c) Coronal T1-weighted

image with gadolinium exhibits enhancement in the same lesion. This case also accompanied with mild anterior hypopituitarism. Her symptoms and MRI findings were improved with reduction of the tumor after 46 Gy radiation and nimustine hydrochloride and interferon beta were administered intravenously [173]

more severe impairment hypocretin neurotransmission (than that estimated from CSF hypocretin-1 level) may exist. Although these results are consistent with the hypothesis of the hypothalamic hypocretinergic involvement in symptomatic cases of narcolepsy, it is not certain if all cases with low hypocretin levels associated with hypothalamic damage develop narcoleptic symptoms.

16-year-old male with EDS, HLA-DQB1*0602 positive, obese (BMI = 48.1), with documented 15q11-13 deletion, limited number of sleep-disordered breathing events (apnea hypoxia index [AHI] was 5.6), and no cataplexy; SL = 3.0 min, no SOREMPs by MSLT, and hypocretin 109  pg/ml. Nevsimalova et  al. [93] also measured CSF hypocretin-1 in another three PWS cases with one of subject (10  years) exhibited EDS (SL = 6.0 min) with no SOREMPs and AHI is 3.1. All three subjects were obese and did not exhibit cataplexy. CSF hypocretin-1 levels in the PWS case with EDS and DQB1*0602 were low (130 pg/ml, 10 years, BMI = 29.8, AHI = 3.1) and others without EDS are intermediate (191 pg/ ml, 23 years, BMI = 49, AHI = 46.8) or in the normal range (226 pg/ml, 6 years, BMI = 25.8, AHI = 0). Interestingly, AHI in these PWS subjects are correlated with age and BMI, but not with CSF hypocretin-1 levels and EDS. Arii et al. [16] reported a 2-week-old PWS male with severe hypotonia, poor feeding, documented 15q11-12 deletion, and hypocretin was intermediate (192 pg/ml). These reports raised the possibility that EDS in PWS may also be attributed to the hypocretin system, not to sleep-disordered breathing caused by obesity. Dr. Nevsimalova also proposed that PWS cases may be a model for congenital dysfunction/developmental failure of the hypocretin system. However, no decrease in the number of hypocretincontaining neurons was observed in post-mortem human adult and infant brains [94], which suggests a lack of

Status in Symptomatic Narcolepsy– Cataplexy and/or EDS Associated with Inherited Disorders There are clusters of cases of genetic or congenital disorders associated with primary central hypersomnolence and/or cataplexy, and CSF hypocretin-1 has also been assessed in several patients with PWS, NPC, and MYD. Prader-Willi Syndrome EDS is a common symptom in PWS [88–90]. Sleep disordered breathing (SDB) and narcoleptic traits such as SOREMPs and cataplexy have also been reported in these subjects [91, 92]. If SDB exists, primary hypersomnia should only be diagnosed if EDS does not improve after adequate treatment of sleep-disordered breathing. Mignot and Nevsimalova et al. [2] reported a

T. Kanbayashi et al.

146

involvement of hypocretin in the pathogenesis of the disorder. More generally, this latter result underlies the need for larger studies to determine whether decreased CSF hypocretin-1 remains anecdotal in inherited neurological conditions.

Niemann-Pick Type C Disease NPC is an autosomal recessive and congenital neurological disorder characterized by the accumulation of cholesterol and glycosphingolipids in the peripheral tissues and of the glycosphingolipids in the brain. Classic NPC symptoms include hepatosplenomegaly, vertical supranuclear gaze palsy, ataxia, dystonia, and dementia. Subjects with NPC have been reported to frequently display narcolepsy-like symptoms, including cataplexy [19, 29, 95–97]. This condition is remarkable as cataplexy is often triggered by typical emotions (laughing) and responsive to anticataplectic treatments. Kanbayashi et  al. [97] measured CSF hypocretin levels in two NPC cases with and without cataplexy. The first case was a 5-year-old boy with NPC, cataplexy, and an intermediate hypocretin level (142  pg/ ml). Cataplexy was evoked by laughter since the age of 2.3 years. EDS was not claimed by the patient, and normal SL (16.5 min) without SOREMPs was observed by a two-nap sleep test (TNST) [98]. No abnormal findings in the hypothalamus were detected by MRI scans. He was negative for HLA DR2. The second case was a 3-year-old girl with NPC with a normal hypocretin level (299 pg/ml). This patient exhibited neurological symptoms such as tremor, ataxia, and akathisia, but did not exhibit cataplexy or EDS. Vankova et  al. [95] reported five patients with juvenile NPC. Deterioration of intellectual function; the presence of pyramidal, dystonic and cerebellar signs, and splenomegaly were observed in all cases. Cataplexy was reported in one patient. Nocturnal polysomnography revealed disrupted sleep in all patients. Total sleep time, sleep efficiency, REM sleep, and delta sleep amounts were decreased when compared to age-matched controls. Shortened mean sleep latencies were observed in three patients during the MSLT, but SOREMPs were observed only in the case with cataplexy, and this case met with the criteria of symptomatic cases of narcolepsy. This patient was HLA DQB1*0602 positive, while the other subjects were HLA DQB1*0602 negative. CSF hypocretin-1 levels were reduced in patients (190 pg/ml and

157  pg/ml in the subject with cataplexy) while in the two other patients, the CSF hypocretin-1 were at the lower level (226 pg/ml, 245 pg/ml) of the normal range. The authors speculated that lysozomal storage abnormalities in NPC patients may also have the impact on the hypothalamus including area hypocretin-containing cells are located. Oyama et al. [99] reported a Japanese patient with NPC caused by a homozygous c.2974 G>T mutation of the NPC1 gene, which predicts a glycine (GGG) to tryptophan (TGG) change at codon 992 (designated as p.G992W). This is a well-known NPC1 gene mutation that causes a unique phenotype of NPC, which has been limited to a single Acadian ancestor in Nova Scotia, Canada. The patient characteristically started presenting with cataplexy at the age of 9 years, and the level of hypocretin-1 was determined as moderately low, 174 pg/ml (normal > 200 pg/ml). In these three reports, all of the NPC patients with cataplexy have an association with reduced hypocretin-1 levels, while CSF hypocretin-1 levels in the NPC cases without cataplexy are in the lower limit of normal, suggesting a degree of impairments of the hypocretin system may contribute to the occurrence of cataplexy in this inherited diffuse CNS impairment condition.

Myotonic Dystrophy Myotonic dystrophy type 1 (MYD1) is a multisystem disorder with myotonia, muscle weakness, cataracts, endocrine dysfunction, and intellectual impairment [100–102]. This disorder is caused by a CTG triplet expansion in the 3¢ untranslated region of the DMPK gene on 19q13. MYD1 is frequently associated with EDS, sharing with narcolepsy a short sleep latency and the presence of SOREMPs during the MSLT. The disease is also often associated with SDB, and thus this may also count for appearances of SOREMPs. MartinezRodriguez [21] reported six patients with MYD1 complaining of EDS. The mean sleep latency on MSLTs was abnormal in all patients (<5 min in 2, <8 min in 4) and two SOREMPs were observed in two subjects, being met with the criteria for symptomatic narcolepsy. It should be noted that these two cases also had SDB. All patients were HLA-DQB1*0602 negative. Hypocretin-1 levels (181 pg/ml) were significantly lower in patients versus controls (340 pg/ml); one case with two SOREMPs had hypocretin-1 levels in the range

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generally observed in narcolepsy (<110 pg/ml). Three cases had intermediate levels (110–200  pg/ml). The authors suggested that a dysfunction of the hypothalamic hypocretin system may mediate sleepiness and abnormal MSLT results in patients with MYD1. In one case of late-onset congenital hypoventilation syndrome, a disorder with reported hypothalamic abnormalities [103], Martinez-Rodriguez found very low CSF hypocretin-1 levels in an individual with otherwise unexplained sleepiness and cataplexy-like episodes [21]. Excellent response to anticataplectic medication was observed in this case. However, a larger study failed to confirm these results [104]. Hypocretin-1 concentrations did not correlate clinically with disease severity or duration, or with subjective or objective reports of sleepiness. Because CSF concentrations are often only slightly decreased in some patients, a functional abnormality that causes sleepiness and SOREMPs in myotonic dystrophy type 1 is unlikely to be a common occurrence. Although only a limited number of cases with genetic or congenital neurologic conditions associated with EDS and/or cataplexy was studied, moderate decreases in CSF hypocretin levels was observed in almost all cases with EDS and/or cataplexy. However, the degree of reduction was small in contrast to idiopathic narcolepsy–cataplexy. Moreover, CSF hypocretin-1 levels in other genetic and congenital neurological condition without EDS/cataplexy are not systematically studied, it is still uncertain for the specificity of impaired hypocretin system in EDS and cataplexy in these abovementioned neurological conditions.

Status in Hypersomnia in Various Neurological Conditions: Focal/ Generalized CNS Invasion Symptomatic narcolepsy is relatively rare, but sleepiness without other narcoleptic symptoms can often occur with a variety of neurological disorders; they are more likely to be due to multifocal or global disturbances of the brainstem, diencephalon, and cerebral cortex. Recently, several clinical studies also suggested that the disruption of the hypothalamic hypocretin system in EDS associated with various neurological conditions.

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Cerebral Tumors Arii et al. [58] reported a case with hypersomnia in a 16-year-old female after removal of a hypothalamic suprasellar Grade II pilocystic astrocytoma. MRI showed the bilateral, medial, and lateral hypothalamic areas and right posterior hypothalamus were damaged. This case was accompanied with DI, hypothyroidism, weight gain, no cataplexy, MSLT: sleep latency: 1.7  min, no SOREMPs, HLA-DR2 negative, and hypocretin-1 104 pg/ml. Marcus et al. [55, 105] reported an 11-year-old boy in a vegetable state following astrocytoma resection and CNS hemorrhage. An MRI revealed a large suprasellar mass that extended into the sella inferiorly and was displaced posteriorly. The boy developed hypothyroidism and syndrome of inappropriate antidiuretic hormone (SIADH). In the nocturnal EEG study, sleep was fragmented with 16 short REM cycles. The daytime EEG showed frequent REM periods. HLA-DR2 and DQB1*0602 was negative. Hypocretin-1 was undetectably low level. His EDS had improved with 200 mg modafinil and 5 mg methylphenidate. Snow et al. [56] reported five patients (11–19 years, mean: 15  years) with EDS. The mean sleep latency by MSLT in the five patients was 10.3  min, but no detailed sleep data were reported for each case. Three patients underwent surgeries for craniopharyngioma, one for germ cell tumor, and one for a thalamic arachnoid cyst. The craniopharyngiomas and germ cell tumor were located in the hypothalamus–hypophysis region, and the arachnoid cyst was in the thalamic region. All patients received relatively extensive surgeries involving the hypophysis and hypothalamus and hormone replacement therapies. Patients had significantly higher BMI (mean: 28), and this was primarily attributable to two morbidly obese patients associated with obstructive sleep apnea. Although treatment with continuous positive airway pressure resulted in complete resolution of their sleep-disordered breathing in these two cases, no changes in daytime somnolence occurred. Krahn [59] reported a patient who developed a narcoleptic-like sleep disorder after receiving treatment for a choroid plexus carcinoma of the pineal gland. She underwent a pinealectomy, chemotherapy, and radiation treatment. Immediately after surgery, the patient developed EDS that she attributed to severe insomnia and an irregular sleep/wake rhythm. She had a few

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episodes of SP and HH but no cataplexy. An increased percentage of REM sleep was seen in nocturnal polysomnography, and three out of four SOREMPs were seen during the MSLT. She was negative for HLADQB1*0602 and had a normal CSF hypocretin level (518 pg/ml). The author proposed that her symptoms be caused by an unknown mechanism unrelated to hypocretin depletion. Dempsey et al. [60] reported a case of 60-year-old male with acromegaly, who developed narcolepsy– cataplexy 2  weeks after completing radiotherapy (45 Gy) for a pituitary adenoma. He had both HH and SP. Sleep latency by MSLT was 6.4 min and REM latency was 9 min (three SOREMPs/five naps). He was obese (BMI: 35) and his AHI was 17/h. HLA was not typical for narcolepsy. Hypocretin-1 was within normal range (275  pg/ml). The authors have speculated that the radiotherapy or the tumor was associated with damage to a locus rich in hypocretin receptors. In contrast to the case with Nokura et al. [61], the same 45–46 Gy radiation resulted in the opposite outcomes. Kubota et  al. [106] reported one typical case of narcolepsy–cataplexy with a ganglioma in the right amygdala in a 7-year-old girl. She showed HH and an SOREMP in the nocturnal polysomnography. Sleep latency by MSLT was 6.5 min without SOREMP. Her HLA was DR2/DQw1 and hypocretin-1 level was 79 pg/ml. This case is likely to be the comorbidity of idiopathic narcolepsy and a brain tumor, since her symptoms were not changed after the resection of the tumor. This case is not listed in Table 14.1. Tachibana et  al. [107] reported a hypersomnolent girl (11  years) with extensive hypothalamic damage after removal of a craniopharyngioma. The presence of a short sleep latency, SOREMPs during an MSLT, and negative HLA DQB1*0602 typing suggested a diagnosis of symptomatic narcolepsy. Low CSF hypocretin-1 level (93  pg/ml) indicated destruction of hypocretinproducing neurons in the hypothalamus. Dauvilliers et  al. [108] reported a patient with severe symptomatic narcolepsy caused by a primary CNS lymphoma with undetectable CSF hypocretin-1 level whose symptoms reversed after chemotherapy. Brain MRI revealed an infiltrative hyperintensity in the left basal ganglia, thalamus, cerebral pedunculus, splenium of the corpus callosum, and the right internal temporal lobe. CSF hypocretin-1 level was undetectable. He was negative for DQB1*0602. His increased sleep resulted in a permanent hypersomnia status,

related to a coma-like state. A stereotactic biopsy was performed on the right temporal lobe. The patient was diagnosed with primary CNS B-cell lymphoma. A highdose methotrexate-based chemotherapy IV plus in CSF was used in combination with BCNU, cytosine arabinosine, VePesid, and corticosteroids. After chemotherapy, hypersomnia resolved completely with an Epworth Sleepiness Scale at 3, and without any abnormal REM sleep manifestation. Eight months later, a 24-h polysomnography was performed with normal results, and without daytime sleep episodes. Control brain MRI and FDG PET scan were normal. Finally, he was confirmed the undetectable level at baseline and revealed a normal hypocretin-1 level (244 pg/ml) after treatment. Overall, five symptomatic cases with EDS had low hypocretin-1 levels; however, two other cases and Snow’s five cases had normal levels. It should be noted that all five cases with low CSF hypocretin-1 levels are HLA-DR2 or HLA-DR2 and DQB1*0602 negative. Therefore, EDS in these HLA negative cases are likely to be secondary due to the hypocretin deficiency being caused by the tumors. EDS in the remaining seven cases with normal or high hypocretin-1 levels were thought to be caused by other factors, although there is also a possibility of impaired hypocretin projections, terminals, or postsynaptic receptors caused by the tumors in these cases.

Infarctions Bassetti et  al. [8] reported two cases with EDS and cerebral infarction. The first case was a 34-year-old male. He suffered from thalamic infarction and his mean sleep latency by MSLT was 9 min. His hypocretin level was 265 pg/ml. The second case was a 40-yearold male who suffered pontomedullary infarction. His sleep latency by MSLT was 1 min and hypocretin level was 316 pg/ml. Nokura et al. [61] and Tohyama et al. [109] independently reported two hypersomnia cases with bilateral paramedian thalamic infarctions. The paramedian thalamus believed to play an important role in the regulation of sleep, and disturbances of sleep regulation are known to occur in paramedian thalamic stroke [110, 111]. The first case was a 45-year-old male [61] (Fig. 14.2). He suffered from bilateral paramedian thalamic infarctions and had EDS with SOREMPs (two times in four naps) by MSLT (met with the criteria for symptomatic narco-

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Fig. 14.2  A hypersomnia case with bilateral paramedian thalamic infarctions and normal hypocretin level. Nokura et al. [61] reported a 45-year-old male case. He admitted to our hospital with a chief com-

plaint of disturbed consciousness. MRI DWI revealed bilateral paramedian thalamic infarction. There was no lesion in the hypothalamus and midbrain. His hypocretin-1 level was 312 pg/ml

lepsy). His hypocretin-1 level was 312 pg/ml. The second case was a 15-year-old male who suffered from bilateral paramedian thalamic infarctions and hypersomnia. His hypocretin level was 274 pg/ml [109]. Since the lesions of infarctions did not include the hypocretin cell bodies, their hypocretin levels seemed to be normal. However, impairments of hypocretin projection still could be involved. It should be also noted that Guilleminault et al. [110] pointed out that patients with bilateral paramedian thalamic lesions do not present a typical hypersomnia but a de-arousal or subwakefullness with an inability to develop sleep outside the normal circadian boundary (pseudohypersomnia). Indeed these patients showed reduced latency to stage 1 during MSLT, but did not develop other normal non-REM sleep and REM sleep status during daytime. It may also be possible that hypocretin deficiency is not involved in the so-called pseudohypersomnia associated with bilateral paramedian thalamic lesions, and other pathophysiology needs to be considered for these unique sleep symptoms.

developed sleepiness and an abnormal sleep/wake schedule. Her sleep time was 15–20 h per day and fell asleep frequently even while eating. She developed ocular symptoms and neurological symptoms (such as involuntary movements, hemiparesis, depression of speech, and global confusional state). An MRI revealed lesions in the bilateral hypothalamus in addition to the dorsomedial nucleus of thalamus and mammillary bodies and periaqueductal gray and floor of fourth ventricle. Vitamin B1 levels were low (38.7  ng/ml, normal range: 52–176 ng/ml) and the level of hypocretin of CSF was decreased (<40 pg/ml). Her sleepiness and MRI findings gradually improved with thiamine therapy. Six months after the onset of sleepiness, both MRI lesion and CSF hypocretin level (158  pg/ml) recovered to some degree. Although it is likely that brain lesions in the cases with tumors, Wernicke’s encephalopathy affect the hypothalamic hypocretin system directly or indirectly, it is not fully studied whether the change in the hypocretin neurotransmission is solely responsible for the occurrence of the EDS in these cases.

Encephalopathies Limbic Encephalopathy Wernicke’s Encephalopathy Kashiwagi et al. [112] reported a 5-year-old girl with Wernicke’s Encephalopathy (Fig. 14.3). She gradually

Yamato et al. [113] reported a patient with nonparaneoplastic immune-mediated limbic encephalitis exhibiting low hypocretin-1 concentrations (87 pg/ml).

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Fig. 14.3  A hypersomnia case with hypothalamic lesion due to Wernicke’s encephalopathy and undetectable hypocretin level. Kashiwagi et  al. [2004] [112] reported a 5-year-old girl with Wernicke’s encephalopathy. She gradually developed sleepiness and an abnormal sleep/wake schedule. Her sleep time was 15–20 h per day and fell asleep frequently even while eating. She developed ocular symptoms and neurological symptoms (such as involuntary movements and hemiparesis and depression of

speech and global confusional state). MRI revealed lesions in bilateral hypothalamus in addition to dorsomedial nucleus of thalamus and mammillary bodies and periaqueductal gray and floor of fourth ventricle. The level of vitamin B1 was low. The level of hypocretin was decreased (<40  pg/ml). Her sleepiness and MRI findings gradually improved with replacement of vitamin B1. Six months after the onset of sleepiness, both MRI lesion and CSF hypocretin level (158 pg/ml) recovered to some degree

A 65-year-old male developed chronic progressive hypersomnia. An MRI of the brain showed bilateral signal abnormalities in the medial temporal lobes and the hypothalamus, but systemic examinations for malignant tumors were negative. Acyclovir treatment failed to amend his condition. Subsequent steroid treatment improved his hypersomnia and reduced the extent of abnormal signals on MRI. The CSF hypocretin concentration increased to 148  pg/ ml in 23 days after.

etiologies was negative. There was no further progression of the residual lesion on serial MRI. Although the pathophysiological bases of narcolepsy and Rasmussen’s syndrome are unknown, the author speculated the possibility of a common underlying disease processes related to autoimmune mechanism. It is, however, a temporal relationship between hypocretin deficiency and the onset of the disease in this case that is not known. It may also be possible for the comorbidity with idiopathic narcolepsy, since the subject is HLA positive, and late onset cases of idiopathic narcolepsy are also reported.

Rasmussen’s Syndrome Lagrange et al. [114] reported a case of narcolepsy and Rasmussen’s syndrome in a previously healthy 40-year-old man. He developed severe EDS, cataplexy, HH, and SP over the course of a few months. Brain MRI was normal and polysomnography with MSLT confirmed a diagnosis of narcolepsy (SL: 1.6  min, three SOREMPs in four naps). His HLA haplotype is DQB1*0602, and CSF analysis showed no detectable hypocretin. Approximately 18 months later, he developed complex partial seizures. Further MRI showed a progressively enlarging lesion involving the left frontotemporal and insular areas. Pathology from a partial resection samples was consistent with Rasmussen’s syndrome. Evaluation for tumor, infectious, and paraneoplastic

Brain Stem Encephalitis Mathis et  al. [115] describe the case of a previously healthy young man who concurrently developed a narcoleptic syndrome and a full-blown RBD after an acute brain stem encephalitis with an isolated inflammatory lesion in the dorsomedial pontine tegmentum. Presenting with hypersomnia, sleep paralysis, HH, and SOREMPs, the patient fulfilled the criteria of narcolepsy, although cataplexy was mild and rare. CSF hypocretin was normal (266  pg/ml) and HLA haplotypes were not typically associated with narcolepsy and RBD (DQB1*0602, DQB1*05).

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Neurodegenerative Disorders

Dementia with Lewy Bodies

Parkinson’s Disease

The dementia with Lewy bodies (DLB) is the second major type of senile, degenerative dementia, after the AD. DLB shares many features with PD. EDS, hallucinations, and REM sleep behavior disorder are symptoms reported in both DLB and narcolepsy. However, Baumann et al. [124] reported that patients with DLB had normal hypocretin-1 levels. No histological studies focusing on hypocretin neurons in the DLB were available. CSF hypocretin-1 concentrations have also been assessed in multiple system atrophy, dementia with Lewy bodies, and corticobasal degeneration [13, 68, 124–127]. In almost all cases, CSF hypocretin-1 concentrations were normal. The observation of a rare case with low concentration – for example, in one case with corticobasal degeneration [121] – is difficult to interpret in the absence of larger studies, and might be incidental.

Thirty percent of patients with PD have been reported to have EDS. Sleep problems are often related to the disease itself (e.g., difficulties in maintaining sleep because of motor disabilities), but they can also occur secondary to pharmacological treatment especially with dopamine D2/3 agonists. Ripley et al. [13] initially reported that CSF hypocretin-1 in seven PD subjects were in the normal range, but sleep abnormalities of these subjects were not assessed. Overeem et al. [116] measured CSF hypocretin levels in three PD patients with EDS, and all had normal hypocretin-1 levels. Drouot et al. [117] reported that patients with latestage PD had low ventricular CSF hypocretin-1 levels (n = 16: <50–97  pg/ml, n = 3: 138–169  pg/ml). Hypocretin-1 levels decreased with increasing disease severity. The author described that CSF hypocretin-1 levels may reflect the size of the hypocretin neuron pool, and a decrease in hypocretin-1 levels may indicate degeneration of hypocretin neurons in PD. The sleepiness of the patients was assessed by Epworth sleepiness scale (ESS). The mean ESS of these PD patients (11 ± 1) was significantly higher than that of controls (4 ± 1), but hypocretin-1 level was not correlated with ESS among PD subjects. Two recent studies reported significant (50%) hypocretin cell loss in post-mortem hypothalami of patients with PD, and the presence of Lewy bodies in some hypocretin-producing cells [118, 119]. In PD, hypocretin cell loss is 23–62% and correlates with disease severity [119], as measured on the Hoehn and Yahr scale [120]. However, hypocretin cell loss was not specific, and nearby neurons containing melanin-concentrating hormone were similarly lost (12–74%) in proportion to disease severity [119]. Furthermore, almost all studies measuring CSF hypocretin-1 have found normal concentrations in PD [13, 68, 116, 121, 122], even if associated with severe sleepiness [116, 123]. Interestingly, however, significant reductions in the number of hypocretin cells in the hypothalamus [118, 119] and in hypocretin-1 concentrations in ventricles [117, 118] are evident and thus moderate hypocretin deficiency that could not be detected by lumbar CSF hypocretin-1 measures likely exist in a subset of PD subjects. Specificity of these finding and functional correlate, especially with EDS are not known still not known.

Progressive Supranuclear Palsy Hattori et  al. [128] reported a 74-year-old woman with EDS who was diagnosed as probable progressive supranuclear palsy (PSP). Her EDS mimicked narcolepsy without cataplexy, because MSLT showed short latencies (less than 2 min without SOREMPs), HLA was positive for DR2/DQB1 and CSF hypocretin-1 concentration was undetectable. It is not clear that the coincidence of these disorders is due to a common process or comorbidity. The author speculated that the existence of neuropathological changes, such as neurofibrillary tangles in hypothalamus of the patient with PSP, might cause decreased hypocretin neurotransmission. Sugiura et al. [129] reported a 74-year-old man with narcolepsy with cataplexy and probable PSP. From the 20 years, he often fell asleep easily and had cataplexy induced in laughter. But by the 40 years the cataplexy was almost diminished and the daytime sleepiness could not hinder his work. At age 69 years he showed cataplexy again and often fell asleep. From age 70 years he showed dysarthria and had difficulty in writing, and soon he developed gait disturbance with short steps and freezing. He was introduced to Juntendo hospital because of the EDS and gait disturbance. ESS was 14 points. He showed the sleep paralysis in eating and the

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cataplexy induced by laughter. He did not show cognitive impairment. He had limitation of vertical gaze, and Meyerson sign, small voice, and masked-like face. He walked at wide base and easily fell down backward without any support. He had mild muscular rigidity both in neck and in wrists, bradykinesia in the extremities, and no resting tremor. Muscle power and deep tendon reflexes were normal and there were no pathological reflex, cerebellar signs, or sensory disturbance. In the MRI, the third ventricular enlargement, midbrain tegmentum atrophy, and mild frontal lobe atrophy were detected. CSF hypocretin-1 was less than 40 pg/ml and HLA DR2 and DQB1 were positive. In PSG, total sleep time was short with 274 min, 43.1% wake after sleep onset were present. The AHI was 14/h. In MSLT, mean sleep latency was shortened less than 2.9 min and SOREMPs were present in all four naps. He was diagnosed as narcolepsy with cataplexy and probable PSP. L-Dopa and Amantadine were slightly effective for gait, but never effective for other motor symptoms. Methylphenidate (20  mg/day) was effective for daytime sleepiness and Clomipramine was effective for cataplexy. Yasui et al. [121] also reported that hypocretin levels were significantly lower in the PSP group compared to PD (p < 0.001). Hypocretin levels were inversely correlated with duration of morbidity in PSP but not in the other conditions studied. They speculated that loss of hypocretin neurons or impaired hypocretin neurotransmission might exist as a part of the neurodegeneration associated with advanced PSP with long duration of morbidity. Taken together with the above two case reports [128, 129], PSP may be a susceptible factor for EDS and/or symptomatic narcolepsy associated with hypocretin deficiency. However, accumulating more cases is needed to address this question.

Alzheimer’s Disease Ripley et al. [13] also reported that CSF hypocretin-1 levels in 24 patients with AD were normal. This condition was known with established sleep abnormalities [130]. Dysfunction of other neurochemical systems, for example, cholinergic systems in AD, may be more directly involved in sleep abnormalities in these subjects. Subsequently few studies have explored hypocretin abnormalities in AD. Studies in older rats have suggested a very slight hypocretin cell loss and decreased

CSF hypocretin-1 concentrations of unknown significance [131]. By contrast, lumber CSF hypocretin-1 concentrations have been shown to be normal in all patients with AD [68, 125, 132], although wake fragmentation was correlated with lower CSF hypocretin-1 concentrations in one study [125]. No histological studies focusing on hypocretin neurons in the AD was available.

Hungtington’s Disease In Huntington’s disease, disrupted hypocretin transmission was first suggested through the study of R6/2 mice, a murine model of Huntington’s disease with accelerated disease progression, in which low CSF hypocretin-1 concentrations and decreased hypocretin cell counts were reported [133]. Huntington’s disease is an autosomal dominant disorder with impaired motor coordination, caused by a CAG triplet repeat extension in the Huntington’s disease gene (HTT). Huntington’s disease is not associated with hypersomnia, cataplexy, or SOREMPs. Widespread cell loss occurs in Huntington’s disease, including in the hypothalamus [134]. A slight (27%) loss of hypocretin neurons was also reported in post-mortem human brains [133]. More recent studies have shown that the cell loss is not associated with low CSF hypocretin-1 concentrations [135–138]. Functional roles of hypocretin cell loss in the Huntington’s disease are not known, but may not strong. Indeed, studies in rats have shown that decreased CSF hypocretin occurs only when more than 50% of cells are lost or affected [139, 140].

Head Trauma The association of narcolepsy/EDS with head injury is controversial. Most people with hypersomnolence after closed head injury do not have narcolepsy [63], but some patients with narcolepsy report that their symptoms began after a head injury [40, 64–67, 70]. Lankford et al. [40] reported nine detailed cases with narcolepsy (five HLA positive, two HLA negative, and two undetermined). However, these cases lacked hypocretin-1 measurements. (Later, low to undetectable CSF hypocretin-1 concentrations have been found in many patients with acute brain trauma or post-CNS hemorrhage [13, 141, 142].) Ripley et al. [13] reported

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decreased CSF hypocretin-1 levels (five out of six cases) after the head trauma. Because adding blood to CSF in vitro does not alter CSF hypocretin-1 concentrations, the possibility of a functional connection has been raised. Dauvilliers et  al. [68] reported that the patient severely affected with post-traumatic hypersomnia with brain lesions (as determined by MRI) had an intermediate CSF hypocretin-1 level (176 pg/ml, HLA negative), while the next severely affected patient had a normal level (503 pg/ml, HLA positive). These two patients had no cataplexy but had shortened sleep latencies (4.5, 3.0 min, respectively) without SOREMPs by MSLT. Arii et al. [69] reported a 15-year-old male affected with post-traumatic hypersomnia with an intermediate hypocretin-1 level. His Glasgow scale at 48  h after injury was 12 (E2V4M6). An MRI showed severe cerebral contusion of the bilateral basalis of the frontotemporal lobe and medial part of right occipital lobe with CSF leakage. One year after injury, he needed more than 9  h nocturnal sleep and one or two 1–3  h naps daily. The hypocretin-1 level was 151 pg/ml. MRI showed atrophies in the basalis of temporal lobe and medial part of right occipital lobe. The hypothalamus showed moderate atrophy with dilatation of third ventricle but no localized lesion. Baumann et al. [141] reported abnormally low CSF hypocretin-1 concentrations immediately after traumatic brain injury in approximately 95% of patients with severe-to-moderate brain injury. However, hypocretin-1 concentrations improved to normal in most patients 6 months after traumatic brain injury, suggesting a functional alteration rather than neuronal loss [143]. Further studies are assessing the prevalence of residual hypersomnia and narcolepsy in correlation with CSF hypocretin-1 concentration and areas of focal damage. A temporary decrease in CSF hypocretin-1 could indicate a decrease in hypocretin tone (e.g., if CSF flow dynamics or dilution occurs) and/or contribute to changes in consciousness in patients with traumatic brain injury. Baumann reported two male patients (18 and 26 years old) in whom MSLT revealed >2 SOREMPs and abnormally short mean sleep latencies (6.3 and 2.9 min, respectively) [143]. ESS scores were 13 and 9, respectively. In both patients, Ullanlinna and Swiss Narcolepsy Scales were normal. Neither patient had cataplexy-like episodes, HH, or sleep paralysis. CSF hypocretin-1 levels in the acute phase were 63 and

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83  pg/ml. Six months after TBI, levels were normal (468  pg/ml) and low (289  pg/ml), respectively. HLA typing was negative for both patients. In the younger patient, TBI was mild, but severe in the 26-year-old patient. Brain CT scans did not reveal hypothalamic lesions. These patients were asymptomatic before TBI. Based on the MSLT findings and according to the international classification of sleep disorders, these two patients can be diagnosed as narcolepsy without cataplexy [ICSD2] [15]. One male patient (22  year old) reported HH and cataplexy-like episodes (subjective weakness in both knees with laughter), which did not fulfill the criteria of cataplexy [144]. ESS was 11, Ullanlinna Narcolepsy Scale 15, Swiss Narcolepsy Scale normal, mean sleep latency 5.6  min, and there were no SOREMPs. This patient with a narcolepsy– cataplexy-like phenotype reported that he had not observed these symptoms prior to TBI. CSF hypocretin-1 was low 6 months after TBI (225 pg/ml). There were two other patients with a low CSF hypocretin-1 level 6 months after TBI (besides one patient with narcolepsy, and one patient with a narcolepsy-like phenotype, see earlier). In a 58-year-old patient (211 pg/ml), PSG revealed a moderate sleep apnea syndrome (apnea hypopnea index: 25/h), and a short mean sleep latency on MSLT (2.5 min). In a 19-year-old patient (234 pg/ ml), all findings were normal. The four cases with low hypocretin were included in the table. EDS appearing during the first year following a head injury may be considered as post-traumatic [145]. This typically presents itself as extended night sleep and episodes of daytime sleep. Sleepiness is usually associated with other characteristics such as headaches, difficulties in concentration, or memory disorder. Radioimaging studies may reveal several possibilities: lesions affecting the hypothalamic region or brainstem, midbrain or pontine tegmentum, or more often than not, the absence of any significant lesions. Sleepiness should be objectively evaluated by an MSLT but is often not in clinical situation. Cases with hypersomnia after head or brain trauma associated with sleep apnea syndrome were also reported [63]. Although two out of three patients with post-traumatic EDS had decreased CSF hypocretin-1 levels moderately, it is not known whether all post-traumatic subjects with declined CSF hypocretin-1 levels exhibit EDS. Similarly, it has not been studied whether more pronounced degree of hypocretin-1 impairments is evident for the post-traumatic symptomatic narcolepsy.

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CNS Diseases Mediated with Neuroimmune Mechanisms In this section, we will specifically discuss neuroimmunological disorders that meet the ICSD2 criteria of “narcolepsy due to medical conditions.” There are three reasons for discussing this topic: (1) The etiology of idiopathic (hypocretin deficient) narcolepsy is not yet known, but an involvement of neuroimmune-interaction is suggested; (2) functional significance of CSF hypocretin levels in symptomatic narcolepsy and symptomatic EDS has not been evaluated systematically; and (3) our recent study suggests an existence of a new clinical syndrome, symptomatic EDS associated with NMO and with anti-AQP4 antibody, with low CSF hypocretin-1 levels. Symptomatic narcolepsy cases with NMO and/ or MS cases with anti-AQP4 antibody are extremely interesting both in the clinical practice and in research. Some of these cases were previously categorized as an MS subtype, and our findings may explain why some of MS cases show EDS and selective lesions in the paramedian hypothalamus and periventricular area. We will include clinical data of “narcolepsy due to medical condition” from the following three subcategories, (1) MS, (2) NMO and Anti-AQP4 antibody, and (3) ADEM.

Demyelinating Diseases Multiple Sclerosis Symptomatic narcolepsy in MS patients has been reported from several decades ago. Since both diseases are associated with the HLA-DR2 positivity, an autoimmune target on the same brain structures has been proposed to be a common etiology for both diseases [146]. However, the discovery of the selective loss of hypothalamic hypocretin neurons in narcolepsy rather indicates that narcolepsy coincidently occurs in MS patients when MS plaques appear in the hypothalamic area and secondary damage the hypocretin/orexin neurons. In favor of this interpretation, the hypocretin system are not impaired in MS subjects who do not exhibit narcolepsy [13], although MS patients frequently show other sleep problems such as insomnia, parasomnia, and sleep-related movement disorders [147].

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It should be also noted that recent cases of MS associated with EDS do not exhibit cataplexy [41] in contrast to MS cases reported in the past (In Nishino2005, nine out of ten cases exhibited these symptoms). The lack of cataplexy was observed even in the MS cases with undetectably low CSF hypocretin-1 levels. Considering the fact that an early intervention with steroids (and other immune modulating substances) was often made and early remission can occur with improvement of hypocretin deficient status in recent cases, it is speculated that chronic and a significant degree of hypocretin/orexin system dysfunction must exist in order to cause cataplexy and relevant REM sleep abnormalities. Kato et al. [148] reported a 45-year-old female with manifested hypersomnia in a relapse of MS. The left panel (a) of Fig. 14.1 is an MRI of her brain taken half a month before the occurrence of hypersomnia. There was a lesion in only the right hypothalamus, which was fluid attenuated inversion recovery (FLAIR) high. Five days before admission, she suffered a hypersomnia attack, suddenly falling asleep during a conversation and later again while cooking. After being admitted to hospital, she slept almost all day. MRI revealed a new lesion in the left hypothalamus. The lesions in the patient’s brain had become bilateral (Fig. 14.1b). The CSF hypocretin-1 level was below 40  pg/ml. Methylprednisolone pulse treatment was started, followed by oral prednisolone treatment. Three days after the initiation of methylprednisolone, the patient’s hypersomnia was completely resolved. Twenty days later, hypocretin-1 levels recovered to 167 pg/ml. The right panel (c) of Fig. 14.1 is an MRI of the patient’s brain taken on the 32nd day of hospitalization when the hypersomnia had already subsided. It is noteworthy that the left hypothalamic lesion has disappeared. This case points out that lesions need to be bilateral to cause symptoms of hypersomnia. A causal relationship between hypersomnia and decreased hypocretin-1 was suggested [148]. Iseki et al. and Oka et al. [75, 76] reported a 22-yearold female case of MS presenting with hypersomnia and several SOREMPs secondary to bilateral hypothalamic lesions (Fig. 14.4). Her nocturnal sleep time was 15 h, sleep latency by MSLT was 2.8 min, and REM latency was 4.7 min (five SOREMPs in five naps). She did not experience cataplexy, HH, or sleep paralysis. Her HLA was DR4 and DR6, and an MRI revealed FLAIR hyperintensity in the hypothalamus bilaterally

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a

b

2002.3

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Fig.  14.4  A case with MS, EDS, and SOREMPs with low hypocretin (<40 pg/ml). This is a 22-year-old female MS case with bilateral hypothalamic lesions [75, 76]. Her nocturnal sleep time was 15 h, sleep latency by MSLT was 2.8 min, and REM latency was 4.7 min with five SOREMPs. Her HLA was DR2

negative and a MRI revealed bilateral FLAIR hyperintensity in the hypothalamus. (a) Axial section of FLAIR image. Bilateral hypothalamic plaque is demonstrated as a median high intensity area. (b) The plaque disappeared 1  month later with steroid treatments

(Fig. 14.2a) and CSF hypocretin-1 level was <40 pg/ ml. After intravenous methylprednisolone was started and followed by oral predonisolone treatment, her symptoms resolved and her MRI findings improved (Fig. 14.2b). On the second evaluation 2 months later, the patient had no symptoms of hypersomnia. Hypothalamic lesions were diminished. MSLT showed a mean sleep latency of 17.4  min and SOREMP appeared only once. CSF hypocretin-1 level was 167 pg/ml. On the third evaluation 4 months after the first, MSLT showed a mean sleep latency of 14.8 min and no SOREMP. CSF hypocretin level was normal (211  pg/ml). In the present case, CSF hypocretin-1 level was markedly decreased. More importantly, hypersomnia and the abnormal occurrence of REM sleep were reversible in parallel with the recovery of CSF hypocretin-1 level. The first case of MS with hypothalamic lesions suggested a causal relationship between hypersomnia and decreased hypocretin-1 [148]. This second case suggested that the disturbed hypocretin-1 secretion from the hypothalamus caused not only hypersomnia but also abnormal occurrence of REM sleep.

Pathophysiological Considerations of MS Cases Although symptomatic narcolepsy associated with MS cases reported in the past (before the discovery of hypocretin) showed cataplexy, none of our recent MS cases [75, 148] with low hypocretin levels (<40 pg/ml) exhibit cataplexy. In these cases, extended nocturnal sleep as well as hypersomnia was observed. Since diagnostic methods and therapies for MS have improved, especially treatments using steroid, interferon, intravenous immunoglobulins (IVIg), and other immunosuppressants became common, early interventions possibly lead the acute relapse phases to the rapid remissions. These situations may possibly change the symptomatology of sleep abnormalities associated with these MS cases that have been recently reported. Interestingly, in each of these two reported MS cases, CSF hypocretin-1 levels increased and the sleep abnormalities subsided with a relatively short period of steroid treatments. Therefore, it is likely that damage of hypocretin neurons is not specific and may be secondary to the lesions in the same area. It is also suggested that a chronic impairment of hypocretin

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neurotransmission may be required to exhibit cataplexy. If this hypothesis be correct, the necessity of the early intervention is optimal to prevent irreversible damage to hypocretin neurons.

Neuromyelitis Optica and Anti-AQP4 Antibody In addition to case reports of these two MS cases, we also reported several symptomatic narcolepsy cases due to hypothalamic lesions with MS and low hypocretin-1 levels. Some of these cases showed shape and location of the lesions atypical for classical MS, such as extremely localized hypothalamic and periaqueductal lesions. The cause of these shapes was unknown initially. NMO is a disorder that was previously categorized as one type of MS typically manifesting transverse myelitis and bilateral optic neuritis. NMO-IgG, a disease-specific autoantibody, was discovered in several patients, and the target antigen of NMO-IgG was recently identified as the AQP4 water channel protein [149]. Brain lesions of NMO were identified and reported to be seen preferably in the bilateral hypothalamic region [149, 150]. Since some of our MS cases had bilateral hypothalamic regions similar to that of NMO patients and since the relationship of the symptomatic narcolepsy and antiAQP4 antibodies were reported, we measured the

a

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Fig.  14.5  A patient with anti-aquaporin four antibody who presented with hypersomnia, low hypocretin level, and symmetrical hypothalamic lesions. Nozaki et al. (2008) [151] reported a 43-year old female case of MS presenting with a period of hypersomnia and febrile. MRI presented bilateral T2 high lesion of

anti-AQP4 antibodies in our three cases (Table 14.1) of symptomatic narcolepsy/EDS due to hypothalamic lesions of MS. A 42-year-old Japanese woman developed acute onset hypersomnia within several days with no apparent causes or triggers [151] (Fig. 14.5). She slept for more than 16 h per day and exhibited EDS (Epworth sleepiness score, ESS: 19/24). She experienced no symptoms suggestive of cataplexy, sleep paralysis, or HH. Her hypersomnia and EDS persisted for 1 month and disappeared spontaneously. At the age of 43, she suffered from acute-onset hypersomnia again with a 3  months history of sensory disturbance of her limbs and was admitted to Niigata University Hospital for evaluation of her symptoms. Neurological examinations revealed hypersomnia (approximately 14  h of sleep per day), ESS: 13/24, and transverse myelopathy at the cervical level. No optic nerve involvement could be detected by ophthalmologic examination or by analyses using visual evoked potential. CSF analysis revealed mild pleocytosis (24/mm3) and an elevated IgG index of 0.77. The level of CSF hypocretin-1 was mildly decreased (191  pg/ml) (not significant as a diagnosis criteria and meets that of Hypersomnia Due to Medical Condition). A brain MRI revealed bilateral symmetrical hypothalamic and periaqueductal lesions (Fig. 14.5), and a spinal MRI revealed an extensively longitudinal spinal cord lesion. Intravenous methylprednisolone (1,000  mg/day) was administered for 3

C

hypothalamus. CSF hypocretin level was 191 pg/ml. Intravenous Methylprednisolone was started which was followed by oral predonisolone treatment, and her symptoms resolved and MRI findings were improved. The level of hypocretin increased to 290 pg/ ml. Her plasma AQP4 antibody is positive

14 Symptomatic Narcolepsy or Hypersomnia, with and Without Hypocretin (Orexin) Deficiency

successive days, followed by oral prednisolone at a dose of 60 mg, which was then tapered. Her hypersomnia gradually resolved. Two months after steroid administration, she recovered completely from her sleep disturbance and slightly from her sensory disturbance. After the treatment, her CSF hypocretin-1 level increased to 291  pg/ml, and her CSF-IgG index and CSF cell count normalized. Symmetrical hypothalamic lesions on the MRI became undetectable and the size of the spinal cord lesions was reduced. Her plasma taken at admission was tested for the anti-AQP4 antibody by the indirect immunofluorescence methods and turned out to be positive. The patient showed hypersomnia but her hypocretin-1 was at an intermediated level, and thus the case should be diagnosed as hypersomnia due to medical conditions. The treatment improved hypocretin-1 level from 190 to 291 pg/ml and her MRI hypothalamic lesion disappeared. This case brought an argument about a continuum in pathophysiology between “narcolepsy due to the medical condition” and “hypersomnia due to the medical condition.” If we use the CSF hypocretin criteria for narcolepsy due to medical condition, the degree of the hypocretin disruption determines the final diagnosis and transitions between two diagnostic categories may occur. The patient was a 39-year-old Japanese female [152]. In 1988, she had developed symptoms of nausea and vomiting, and has since experienced symptoms of double vision, ataxic gait, and weakness of the right hand. Brain MRI showed multiple lesions in the white matter, and the patient has been diagnosed with MS. Fever, EDS, and loss of appetite have appeared since May 2004. From July 2004, loss of sight in the left eye was observed. The brain MRI taken at that time showed a high T2 density in both sides of the hypothalamus and the left optic nerve. The CSF hypocretin-1 level was 106 pg/ml. After steroid pulse treatment, the EDS improved and the CSF hypocretin-1 level increased to a normal level at 345  pg/ml. Her plasma taken on admission was tested for the anti-AQP4 antibody, and turned out to be positive. Carlander et  al. [153] reported a case with NMO and low hypocretin-1 level. She was 49 year old and suffered from a second episode of NMO. She had a hypersomnia with coma-like state and acute dysautonomia. MRI revealed a long spinal lesion, and an optic neuritis and a hypothalamic lesion. The hypocretin-1 was decreased from 874 pg/ml (before this episode) to 158 pg/ml. Cataplexy, sleep paralysis, or HH did not

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occur during these episodes. She was positive for plasma AQP4 antibody.

Pathophysiological Considerations of MS Cases and NMO Cases It has been demonstrated that in some NMO patients who are seropositive for anti-AQP4 antibody that hypothalamic and periaqueductal lesions correspond to brain regions where high AQP4 expression is observed [149, 150]. We considered that hypothalamic lesions of two of our cases and the one case of Carlander et al. [153] with symptomatic narcolepsy are caused by the immune reactivity of anti-AQP4 antibody. This may be the reason for the rareness of the shape of the lesion. Furthermore, this may also be why only a subset of MS patients exhibit symptomatic narcolepsy (with low CSF hypocretin levels). We propose to measure plasma anti-AQP4 antibody in patients with symmetrical hypothalamic lesions and hypersomnia. Anti-AQP4 antibody is not likely involved in hypocretin deficient idiopathic narcolepsy since anti-AQP4 antibody was detected in none of the three patients with idiopathic hypocretin deficient narcolepsy we measured.

Acute Disseminated Encephalomyelitis Symptomatic narcolepsy was recently reported in four ADEM cases [154–157]. All these cases associated with EDS had hypothalamic lesions and low CSF hypocretin-1 levels, suggesting an involvement of the hypothalamic hypocretin system in these conditions. Gledhill et al. [155] reported a 38-year-old female with ADEM and hypersomnia. She had no REMrelated symptoms such as cataplexy, HH, or sleep paralysis. An MRI revealed lesions in the hypothalamus, walls of third ventricle, corona radiata, floor of the aqueduct, and raphe nuclei. She was positive for DR2/DQB1*0602 and her hypocretin-1 levels were 87 pg/ml. She was treated with a high dose of steroid, and a subsequent MRI showed smaller and fewer lesions. Six months later, her subjective sleepiness was partially improved. Her mean sleep latency by MSLT (four naps) was 4.4  min with four SOREMPs, and hypocretin-1 level was 148 pg/ml at this point in time. One year after her initial examination, her sleepiness

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persisted and the results of MSLT were almost unchanged. AQP4 antibody was not measured at the time of the manuscript submission. Yoshikawa et  al. [156] reported a 7-year-old girl with ADEM, visual symptoms, and hypersomnia (Table 14.1). An MRI revealed bilateral lesions in the white matter, basal ganglia, and hypothalamus. Her CSF hypocretin-1 level was intermediate (146 pg/ml) at admission, and with steroid plus treatment, the hypocretin level gradually recovered to the normal range (263 pg/ml) within 47 days, and her excessive sleepiness was reduced. Decreased hypothalamic hypocretin neurotransmission may be involved in this symptomatic case of hypersomnia associated with a clinical course of ADEM, and interestingly, double vision was also noted in this case during the course of the disease.

Pathophysiological Considerations of MS Cases and ADEM Cases EDS can be associated with immunological or postinfectious brain pathology such as ADEM and other encephalitis. von Economo’s reports suggested that the hypothalamus may be a target site for immune-mediated post-infectious damage by encephalitis lethargica [17]. An immunologic reaction to hypothalamic antigens, including the hypocretin system, may also be involved in immune-mediated encephalitis; however, after a series of von Economo’s publications, relatively few cases of secondary EDS associated with post-viral infection were reported. Recently, four ADEM cases with hypocretin measurements were reported. Although a decreased level of consciousness is frequently shown in cases with ADEM, ADEM cases with well-defined hypersomnia are relatively rare [158, 159]. The two ADEM cases previously reported and recent four cases show both extended nocturnal sleep time and daytime hypersomnia, and only one case [155] shows SOREMPs, indicating sleep abnormalities in ADEM or post-infectious damage may be distinct from those seen in symptomatic narcolepsy and idiopathic narcolepsy. Similar to MS cases, early diagnosis and treatment are likely to be critical to reduce the severity of sleep symptoms.

Conclusions of Demyelinating Disease Prevalence of symptomatic narcolepsy/hypersomnia due to neuroimmunological disorders is not high, but

these rare cases give us many insights about the pathophysiology of the disease that are useful for clinical practice. Although hypocretin status of neuroimmunological disorders without EDS is not systematically evaluated, our results demonstrated that cases with EDS are often associated with reduced levels of CSF hypocretin levels. A causal relationship between hypersomnia and decreased hypocretin-1 was not proved. However, we had identified several cases in which hypersomnia and the abnormal occurrence of REM sleep were reversed along with the recovery of CSF hypocretin-1 level. Hypothalamic lesions in patients with EDS associated with MS and ADEM are often bilateral. Hypothalamic lesions of some MS and NMO cases with symptomatic narcolepsy are caused by the immune reactivity of antiAQP4 antibody. This may be the reason for the rareness and shape of the lesion. Immune reactivity of anti-AQP4 antibody is not involved in idiopathic hypocretin deficient narcolepsy. Symptomatic EDS has been recently reported in several ADEM cases. All these cases associated with EDS had hypothalamic lesions and low CSF hypocretin-1 levels, suggesting an involvement of the hypothalamic hypocretin system in EDS of these conditions.

Guillain-Barre’s Syndrome GBS is an acute autoimmune polyradiculoneuritis with sensory and motor impairment. Since GBS may also cause autonomic dysfunction, aspiration pneumonia, and respiratory failure, some patients undergo intensive care including invasive ventilation. Although GBS is generally restricted to the peripheral nervous system, clinically and pathologically, but central dysfunctions have also been documented [160]. These include hyponatremia caused by abnormal antidiuretic hormone secretion [161], a case of rapid eye movement sleep (REM sleep) motor behavior disorders [162], EDS [163], and abnormally low CSF hypocretin-1 levels [13, 164, 165]. A subset of Miller-Fisher syndrome subjects, but not CIDP subjects, also has significantly low CSF hypocretin-1 [165]. Undetectably low CSF hypocretin-1 levels were found in seven cases of GBS in the Japanese population [13, 164, 165]. Reduced CSF hypocretin-1 levels in GBS are not likely due to an increase in protein levels in the CSF, nor to the secondary effects due to the treatment or associated health conditions, since two

14 Symptomatic Narcolepsy or Hypersomnia, with and Without Hypocretin (Orexin) Deficiency

GBS patients showed undetectable levels at the time of admission to the hospital (before treatment), but only exhibited general fatigue and/or lower limb weakness, with no increase in CSF protein levels [165]. This finding was rather unexpected, since GBS is a presumed autoimmune disorder of the peripheral polyradiculoneuropathy. However, additional CNS involvements (i.e., hypothalamus), such as occurrence of syndrome of inappropriate secretion of ADH and diabetes insipidus, have also been suggested in severe cases. Interestingly, all these GBS subjects with low hypocretin-1 were severe cases and they develop tetraplegia, bulbar symptoms, and/or respiratory failure shortly after the disease onset. Since the clinical picture of these subjects is quite different from that of narcolepsy, it is unlikely that there will be any diagnostic confusion by measurement of CSF hypocretin-1 levels. The occurrence of sleep abnormalities in GBS, especially in severe cases, has received little attention. The sleep latency of two CSF hypocretin-deficient GBS subjects, who complained of sleepiness after the recovery of GBS neurological symptoms, was significantly shortened (less than 1 min) in both cases [165]. However, this finding was not confirmed in two studies of white patients [68, 160, 166]. In one study, CSF hypocretin-1 concentrations were lower but within the normal range in GBS patients with hypnagogic-like hallucinations and severely disturbed sleep [160]. One possible explanation of this discrepancy is the difference in ethnic origin of the recruited patients (Japanese patients vs. Caucasian patients) and thus the possibility that the different pathophysiological pathways in GBS may be responsible for the discrepancy [166]. Griffin et  al. suggested that GBS in northern China (which is acute motor axonal neuropathy [AMAN] associated with Campylobacter) is a different disease than GBS seen in western countries [Griffin, 1995; Ho, 1995] [167, 168]. Our seven undetectable CSF hypocretin GBS cases exhibited severe and rapid onsets with frequent respiratory involvement which may suggest a link between AMAN and hypocretin deficiency, but there was no association between low hypocretin levels and anti GM1 and Gal NAc-GD1a antibodies, nor Campylobacter infection. Hypocretin deficiency in the brain, as observed in idiopathic hypocretin-deficient narcolepsy, has not yet been confirmed in GBS subjects with low CSF hypocretin-1 levels. For these reasons, we consider future studies regarding the mechanism of low CSF hypocretin levels in a subset of GBS subjects to be important.

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Paraneoplastic Syndrome Anti-Ma2 associated encephalitis. A recent report described four patients with paraneoplastic anti-Ma2 antibodies who had hypothalamic inflammation, EDS, and undetectable CSF hypocretin-1 levels [169]. Interestingly, CSF hypocretin levels in two other patients with paraneoplastic anti-Ma2 antibodies, who did not exhibit EDS, were in the normal range [169]. The MRI showed abnormalities involving medial temporal lobes, hypothalamus, basal ganglia or upper brainstem in these four patients. In addition, one case also had DI and hypothyroidism. The author claimed that anti-Ma associated encephalitis is the identified immune-mediated disorder of the CNS that may result in low hypocretin-1 levels. In contrast to MS and ADEM, distinct CNS lesions are not observed in GBS and neoplastic syndromes. Nevertheless, a significant degree (undetectable level) of hypocretin deficiency was observed in both conditions. This suggests that a hypocretin deficiency in these conditions may occur at the neuron or ligand levels. In view of the fact that an autoimmune hypothesis is the most popular theory for hypocretin cell death in narcolepsy [170, 171], but no gloss inflammation was observed in the hypothalamus [83], a subset of GBS and Ma2 antibody positive paraneoplastic syndromes (the two neuroimmune conditions associated with hypocretin deficiency) may be important models for studying a possible autoimmune cell damage/ligand deficiency in narcolepsy.

Conclusion Symptoms of narcolepsy can occur during the course of neurological conditions. Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, the review of literature reveals numerous unquestionable cases with symptomatic narcolepsy. These include cases with HLA negative and/or late onset, and cases in which the occurrences of the narcoleptic symptoms are parallel with the rise and fall of the causative disease. Symptomatic cases of narcolepsy are most often associated with brain tumors and inherited disease followed by head trauma. Cases associated with vascular diseases, degeneration, and autoimmune/immune-mediated diseases are also reported. Review of these cases, especially with brain tumors, illustrates a clear picture that the hypothalamus is most

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often involved. Several cases of symptomatic cataplexy (without EDS) are also reported. In contrast, symptomatic cataplexy appeared to be often associated with nonhypothalamic structures. Recently, it was revealed that the pathophysiology of idiopathic narcolepsy was linked to hypocretin ligand deficiency. CSF hypocretin-1 measures were also carried out in a limited number of symptomatic cases of narcolepsy/EDS. Reduced CSF hypocretin-1 levels were seen in most symptomatic cases of narcolepsy/EDS with various etiologies, and EDS in these cases is sometimes reversible with an improvement of the causative neurological disorder, and also an improvement of the hypocretin status. It is also noted that some symptomatic EDS cases (with Parkinson diseases and the thalamic infarction) are not linked with hypocretin ligand deficiency, though nonspecific reduction of hypocretin neurons may occur in a subset of PD patients. Since CSF hypocretin measures are still experimental, cases with sleep abnormalities/cataplexy are habitually selected for CSF hypocretin measures. Therefore, it is still not known whether all or a large majority of cases with low CSF hypocretin-1 levels with CNS intervention exhibit EDS/cataplexy. Occurrences of cataplexy in idiopathic narcolepsy cases are tightly associated with hypocretin ligand deficiency. However, this link is less clear in symptomatic cases. Since none of the acute and subacute symptomatic cases (such as MS, GBS, and ADEM) with undetectable CSF hypocretin-1 levels are found to develop cataplexy, chronic hypocretin deficiency may therefore be required to express cataplexy. Even when a very strict criterion for cataplexy is applied, about 10% of narcolepsy–cataplexy patients have normal CSF hypocretin-1 [2, 4, 7]. Whether or not hypocretin neurotransmission is abnormal in these rarer cases is unknown. Considering the fact that hypocretin production and hypocretin neurons appeared to be normal in hypocretin receptor 2-mutated narcoleptic Dobermans [172], it is possible that deficiencies in hypocretin receptors and a downstream pathway may exist in some of these patients. However, this cannot be tested currently. Similarly, it is not known whether narcoleptic subjects without cataplexy simply have milder neuropathology. Narcoleptic subjects without cataplexy may have sufficient hypocretin production to maintain normal CSF levels and stave off cataplexy, but the partial loss may still be great enough to produce

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sleepiness. With regard to this, it is also possible that some hypocretin nondeficient hypersomnia patients would show altered responses after various manipulations that normally increase hypocretin levels (i.e., exercise, sleep deprivation, food restrictions), if this was testable in humans. A large number of HLA DR2/DQ6(DQB1*0602) negative symptomatic narcolepsy/EDS (53% [31/59] in narcolepsy and 87% [13/15] in EDS) were found (see Sect. 2.1 and Ref. [41]). The brain system critical for these sleep abnormalities (i.e., the hypocretin system) could be damaged by certain neurological conditions (such as tumors, vascular diseases). These cases are often associated with detectably low or intermediate CSF hypocretin levels, and are in contrast to the undetectable idiopathic narcoleptic cases. Nevertheless, increased HLA DR2/DQ6 (DQB1*0602) positively (47% [28/59]) was still observed in symptomatic narcoleptic cases. Although some HLA positive hypocretin-deficient symptomatic cases may be due to simple comorbidities of idiopathic narcolepsy, HLA may also play a role(s) in other cases: brain insult may trigger/ facilitate the HLA-mediated hypocretin cell damage in which the mechanism may also be shared with that in the hypocretin deficient idiopathic cases of narcolepsy. Regarding hypocretin deficiency among immune-mediated neurological conditions, hypocretin deficiency with the hypothalamic lesions was noted in some MS and ADEM cases. In contrast, no clear local lesions were noted in hypocretin deficiency in GBS and Ma2 positive paraneoplastic syndromes. Thus, it appears that hypocretin ligand deficiency in GBS and Ma2 may possibly be more selective at the cellular or ligand level, and the mechanism involved in these conditions should be ­further studied. Finally, further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiological mechanisms for occurrence of EDS and cataplexy. Measuring CSF hypocretin-1 may be also useful to choose treatment options, such as using wake-promoting compounds, anticataplectic medications, and ultimately, for starting treatment with hypocretin agonists when they become available. Acknowledgment  We would like to thank Dr. Yasunori Oka for his helpful comments on the clinical aspects of MS patients with sleep disorders. We would also like to thank Ms. Yoshiko Sakai for writing and editing English for this chapter.

14 Symptomatic Narcolepsy or Hypersomnia, with and Without Hypocretin (Orexin) Deficiency

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T. Kanbayashi et al. 145. Billiard M. Other hypersomnias. In: M. B, ed. Sleep: Physiology, Investigations, and Medicine. New York: Kluwer Academic/Plenum, 2003. 146. Poirier G, Montplaisir J, Dumont M, et  al. Clinical and sleep laboratory study of narcoleptic symptoms in multiple sclerosis. Neurology 1987;37:693–5. 147. Tachibana N, Howard RS, Hirsch NP, Miller DH, Moseley IF, Fish D. Sleep problems in multiple sclerosis. Eur Neurol 1994;34:320–3. 148. Kato T, Kanbayashi T, Yamamoto K, et  al. Hypersomnia and low CSF hypocretin-1 (orexin-A) concentration in a patient with multiple sclerosis showing bilateral hypothalamic lesions. Intern Med 2003;42:743–5. 149. Pittock SJ, Weinshenker BG, Lucchinetti CF, Wingerchuk DM, Corboy JR, Lennon VA. Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol 2006;63:964–8. 150. Nakashima I, Fujihara K, Miyazawa I, et al. Clinical and MRI features of Japanese patients with multiple sclerosis positive for NMO-IgG. J Neurol Neurosurg Psychiatry 2006;77:1073–5. 151. Nozaki H, Katada S, Sato M, Tanaka K, Nishizawa M. A case with hypersomnia and paresthesia due to diffuse MS leisons from hypothalamus to spine. Rinsho Shinkeigaku 2004;44:59. 152. Nakamura M, Nishii M, Maki S, Nakamuara M, Suenaga T. A MS cases with EDS and bilateral hypothlamic lesions. Rinsho Shinkeigaku 2005;45:187. 153. Carlander B, Vincent T, Le Floch A, Pageot N, Camu W, Dauvilliers Y. Hypocretinergic dysfunction in neuromyelitis optica with coma-like episodes. J Neurol Neurosurg Psychiatry 2008;79:333–4. 154. Kubota H, Kanbayashi T, Tanabe Y, Takanashi J, Kohno Y. A case of acute disseminated encephalomyelitis presenting hypersomnia with decreased hypocretin level in cerebrospinal fluid. J Child Neurol 2002;17:537–9. 155. Gledhill R, Bartel P, Yoshida Y, Nishino S, Scammell T. Narcolepsy caused by acute disseminated encephalomyelitis. Arch Neurol 2004;61:758–60. 156. Yoshikawa S, Suzuki S, Yamamoto K, et al. A case of acute disseminated encephalomyelitis associated with hypersomnia and low CSF hypocretin levels. Pediatric Neurology 2004. 157. Yano T, Kanbayashi T, Sawaishi Y, Shimizu T, Takada G. An infant case of hypersomnia with acute disseminated encephalomyelitis due to hypothalamic dysfunction. Sleep 2004;27:A238. 158. Yamashita S, Ueno K, Hashimoto Y, Teramoto H, Uchino M. A case of acute disseminated encephalomyelitis accompanying Mycoplasma pneumoniae infection. No To Shinkei 1999;51:799–803. 159. Kanbayashi T, Goto A, Hishikawa Y, et  al. Hypersomnia due to acute disseminated encephalomyelitis in a 5-yearold girl. Sleep Med 2001;2:347–50. 160. Cochen V, Arnulf I, Demeret S, et al. Vivid dreams, hallucinations, psychosis and REM sleep in Guillain-Barre syndrome. Brain 2005;128:2535–45. 161. Hochman MS, Kobetz SA, Handwerker JV. Inappropriate secretion of antidiuretic hormone associated with GuillainBarre syndrome. Ann Neurol 1982;11:322–3. 162. Schenck CH, Bundlie SR, Ettinger MG, Mahowald MW. Chronic behavioral disorders of human REM sleep: a new category of parasomnia. Sleep 1986;9:293–308.

14 Symptomatic Narcolepsy or Hypersomnia, with and Without Hypocretin (Orexin) Deficiency 163. Guilleminault C, Mondini S. Mononucleosis and chronic daytime sleepiness. A long-term follow-up study. Arch Intern Med 1986;146:1333–5. 164. Kanbayashi T, Ishiguro H, Aizawa R, et al. Hypocretin-1 (orexin-A) concentrations in cerebrospinal fluid are low in patients with Guillain-Barre syndrome. Psychiatry Clin Neurosci 2002;56:273–4. 165. Nishino S, Kanbayashi T, Fujiki N, et al. CSF hypocretin levels in Guillain-Barre syndrome and other inflammatory neuropathies. Neurology 2003;61:823–5. 166. Baumann CR, Bassetti CL. CSF hypocretin levels in Guillain-Barre syndrome and other inflammatory neuropathies. Neurology 2004;62:2337; author reply 167. Griffin JW, Li CY, Ho TW, et al. Guillain-Barre syndrome in northern China. The spectrum of neuropathological changes in clinically defined cases. Brain 1995;118(Pt 3): 577–95. 168. Ho TW, Mishu B, Li CY, et al. Guillain-Barre syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain 1995;118(Pt 3):597–605. 169. Overeem S, Dalmau J, Bataller L, et al. Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis. Neurology 2004;62:138–40.

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170. Lecendreux M, Maret S, Bassetti C, Mouren M, Tafti M. Clinical efficacy of high-dose intravenous immunoglobulins near the onset of narcolepsy in a 10-year-old boy. J Sleep Res 2003;12:347–8. 171. Mignot E. Sleep, sleep disorders and hypocretin (orexin). Sleep Med 2004;5:S2–8. 172. Ripley B, Fujiki N, Okura M, Mignot E, Nishino S. Hypocretin levels in sporadic and familial cases of canine narcolepsy. Neurobiol Dis 2001;8:525–34. 173. Nokura K, Kanbayashi T, Ozeki T, et  al. Hypersomnia, asterixis and cataplexy in association with orexin A-reduced hypothalamic tumor. J Neurol 2004;251:1534–5. 174. Saji N, Kawarai T, Tadano M, Shimizu H, Kita Y, Susuki K, Kanbayashi T. Does CSF hypocretin-1 decrease in Bickerstaff’s brainstem encephalitis? Clin Neurol Neurosurg 2007;109(6):547–8. 175. Castillo PR, Mignot E, Woodruff BK, Boeve BF. Undetectable CSF hypocretin-1 in Hashimoto’s encephalopathy associated with coma. Neurology 2004;62(10): 1909. 176. Voderholzer U, Riemann D, Gann H, et al. Transient total sleep loss in cerebral Whipple’s disease: a longitudinal study. J Sleep Res 2002;11(4):321–9.

Chapter 15

Hypersomnias Other than Narcolepsy: Differential Diagnosis Michel Billiard

Introduction Narcolepsy is definitely the most severe form of hypersomnia and probably the one which has most benefited the entire field of sleep due to the very special symptom of cataplexy, the sleep onset REM periods (SOREMPs), the extraordinary association with HLA and the recent finding of the role of hypocretin (orexin) in its pathophysiology. However, narcolepsy is by far not the most frequent type of hypersomnia, to the extent that many general practitioners (GPs) never have the opportunity to diagnose and follow narcoleptic patients. A variety of other hypersomnias may be encountered. In this chapter we will first consider how to evoke and confirm the positive diagnosis of hypersomnia, then suggest a decision tree to orient the differential diagnosis of hypersomnias on a purely clinical basis, and finally review the different causes of hypersomnia other than narcolepsy.

Positive Diagnosis of Hypersomnia In comparison with insomnia, which is experienced by a large fraction of the general population and is therefore extremely familiar to GPs, hypersomnia is rarely complained about by patients and much less familiar to GPs. Therefore, the first issue is not to make a differential diagnosis of hypersomnia, but to recognize it. The circumstances of diagnosis are multiple: some M. Billiard (*) Department of Neurology, Gui de Chauliac Hospital, 80, Avenue Augustin Fliche, 34295, Montpellier Cedex 5, France e-mail: [email protected]

subjects may consult for excessive daytime sleepiness, sometimes associated with a large increase in total daily amount of sleep, but few of them do so. Some subjects may consult for fatigue, which turns out from the interview to be excessive daytime sleepiness. Some subjects consult for loud snoring and other symptoms of obstructive sleep apnoea syndrome (OSAS), leading to the discovery of excessive daytime sleepiness. Some subjects are referred by company doctors due to poor performance at work or repeated accidents, while some subjects are found abnormally sleepy in the context of organic or psychiatric conditions. Once suspected, the excessive daytime sleepiness should be confirmed by a subjective test, most commonly the Epworth sleepiness scale, a scale posing eight situations such as sitting and reading or watching TV [1]. Patients are asked to rate their chance of dozing in each situation on a scale of 0–3. The highest possible score is 24 and the normal upper limit is generally considered to be 10–11.

Differential Diagnosis of Hypersomnia Clinical Approach A clinical approach should always precede the choice of laboratory tests. There are several reasons for that: some etiologies such as behaviorally induced insufficient sleep syndrome or the intake of a drug or substance do not require the use of laboratory tests at all; the laboratory tests to be performed depend on the suspected type of hypersomnia; last but not least, results of laboratory tests may be uninformative or even misleading in some cases, like a mean sleep latency of 10 min or more in an

M. Goswami et al. (eds.), Narcolepsy: A Clinical Guide, DOI 10.1007/978-1-4419-0854-4_15, © Humana Press, a part of Springer Science + Business Media, LLC 2010

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ostensibly sleepy subject or the presence of two sleep onset REM periods (SOREMP) in a subject with OSAS or following withdrawal of REM-suppressant medication. The decision tree (Table  15.1) will follow logical steps and in most cases lead to a reasonably welladjusted clinical impression, sufficient by itself or orienting towards laboratory tests to be performed.

Laboratory Tests Neurophysiological Tests

ings repeated every 2 h (four or five times a day) starting about 2 h after morning awakening. The test should be conducted during the day following a polysomnographically documented night of adequate sleep, that is, at least 6 h of sleep. All psychotropic medications that can cause sleepiness or suppression of REM sleep should be discontinued two weeks before the date of the test [2]. A mean sleep latency of less than 5 min indicates pathological sleepiness, a mean sleep latency from 10 to 20 min is considered as normal, while latencies falling between the normal and the pathological values are considered a grey diagnostic area [3].

Multiple Sleep Latency Test Maintenance of Wakefulness Test This test was developed on the basis of the following principle: the sleepier the subject, the faster he falls asleep. This test is based on 20 min polygraphic record-

The maintenance of wakefulness test (MWT) is a variant of the MSLT, designed to evaluate treatment efficiency

Table 15.1  Decision tree I. The complaint of excessive daytime sleepiness is directly related to Insufficient sleep time

®

Behaviorally induced insufficient sleep syndrome

¯ No Use of a medication or substance responsible for sedation

®

Hypersomnia due to drug or substance

II. The complaint of excessive daytime sleepiness is independent of the above referred causes and of any medical or psychiatric condition ® Obstructive sleep apnoea syndrome Sleepiness of various degree (from none to extreme) associated with one or several of the following signs: loud snoring, nycturia, tiredness on awakening, cognitive impairment, irritability, depression, reduced libido, impotence ¯ No Severe sleepiness and unwanted episodes of sleep, associated with ® Narcolepsy with cataplexy cataplexy, +/- hypnagogic hallucinations and sleep paralysis ¯ No ® Narcolepsy without cataplexy or Idiopathic Severe sleepiness and unwanted episodes of sleep, not associated with cataplexy, +/- hypnagogic hallucinations and sleep paralysis hypersomnia without long sleep time ¯ No Severe sleepiness, associated with long non-refreshing nap(s), prolonged ® Idiopathic hypersomnia with long sleep major sleep episode and difficulty in morning and nap awakening time ¯ No ® Kleine-Levin syndrome Severe sleepiness recurring at one or several month(s) intervals, lasting about a week, associated with behavioural and cognitive impairment and sometimes depression, interspersed by periods of one or several months during which the subject is normal III. The complaint of excessive sleepiness falls in the context of a medical or psychiatric condition or of a head traumatism Sleepiness of various degree associated with a neurologic, infectious, → Hypersomnia due to medical condition metabolic or endocrine condition, or consecutive to a head traumatism ¯ No Sleepiness of various degree associated with a psychiatric condition → Hypersomnia not due to substance or known physiological condition (nonorganic hypersomnia)

15 Hypersomnias Other than Narcolepsy: Differential Diagnosis

in patients with excessive sleepiness. The major difference with the MSLT is in the instruction given to the subject. The subject is asked to attempt to remain awake. He is seated in a comfortable position in bed, as opposed to lying down in the MSLT, with low light behind him (7.5 W, 1 m). In contrast to MSLT, drug therapy should not be changed before the study. The recommendation is to use a four-trial method. The duration of the test is 40 min [2]. As in the MSLT the mean sleep latency is calculated. The choice of a reasonable mean sleep latency to indicate acceptable alertness is not determined once and for all. Requiring patients to remain awake for 40 min on all four trials implies a standard of alertness achieved by less than half of the normal population. Mean sleep latency at the 15th percentile (approximately 22.5 min) has been suggested as an arbitrary lower limit of acceptable alertness [4], but this value has not been validated and it might be equally reasonable to use the 25th, 50th or 75th percentile.

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Various Causes of Hypersomnia Hypersomnia as a Direct Consequence of a Behaviour or of the Use of a Drug or Substance Behaviorally Induced Insufficient Sleep Syndrome According to the International Classification of Sleep Disorders, 2nd ed. [5], this syndrome occurs when an individual persistently fails to obtain the amount of sleep required to maintain normal levels of alertness. The rate of the syndrome was 7.1% in a population of 1,243 consecutive Japanese patients [6]. However, according to Ohayon, the prevalence is more likely to be between 1 and 4% of the general population [7]. The main symptoms are excessive sleepiness in the afternoon or early evening, decrease of diurnal performances, irritability, nervousness, and sometimes depression. Diagnosis of the syndrome is relatively easy provided that a thorough interview is conducted.

Prolonged Polysomnographic Recording A 24-h continuous polysomnographic recording can be obtained by either conventional laboratory polysomnography or ambulatory recording. It provides an accurate account of the actual time asleep within the 24-h period and of the overall sleep architecture. However, the procedure still awaits standardization and validation.

Hypersomnia Due to Drug or Substance Hypersomnia due to drug or substance covers sedation associated with tolerance to or withdrawal from various prescribed or street drugs. Of note, this adverse effect occurs only in a fraction of subjects using these drugs or substances and their severity can vary considerably. In some cases failure to provide treatment may be more disruptive than hypersomnia.

Brain Imaging Computed tomography (CT) and/or magnetic resonance imaging (MRI) should be performed whenever there is a clinical suspicion of an underlying brain lesion.

Psychometric/Psychiatric Evaluation It should be made in all cases where there is some doubt on the role of the patient’s personality in the development of hypersomnia.

Psychotropic Drugs Anxiolytics and Hypnotics Benzodiazepines have sedative effects but these effects vary with dose, pharmacokinetics (more important with longer elimination half-lives), administration (single or repeated dose), age and state of the subject (normal or anxious). Non-benzodiazepines tend to induce limited sedation only. First-generation H1 antihistamines, including diphenhydramine, doxylamine, hydroxyzine, promethazine, etc., are sedating drugs.

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Antidepressants Tricyclic antidepressants may be sedating during the daytime through histamine blockade, but effects may lessen with time. Selective serotonin reuptake inhibitors (SSRI) may cause sedation with high withinpatient variability. The selective noradrenaline reuptake inhibitor (SNRI) venlafaxine induces sedation in 12–31% of patients [8]. Trazodone and nefazodone are serotonin antagonists and reuptake inhibitors. Trazodone induces sedation in 15–49% of patients [8] and nefazodone in 6–24% [9]. Mirtazapine, a noradrenergic and specific serotonergic antidepressant, is a sedative. Neuroleptics The incidence of sedation varies considerably among drugs, probably as a function of variation in affinity for cholinergic and histaminic receptors as well as blockade of alpha1 adrenoreceptors [10]. Among the newer agents, clozapine is the most sedating drug, followed by olanzapine and quetiapine. Risperidone and sertindole are the less sedating drugs.

disease itself being the most consistent. Concerning the former factor, the development of excessive daytime sleepiness is related to total amount of levodopa dose equivalent rather than with the use of levodopa or any particular agonist [13, 14]. In contrast patients taking dopamine agonists are at a higher risk of sudden onset of sleep episodes than subjects on levodopa [15, 16].

Antiepileptic Agents Sedation is one of the most common adverse effects of the older antiepileptic drugs, especially phenobarbital and, at a lower degree, carbamazepine, valproate, and phenytoin. Among the newer antiepileptic drugs (gabapentine, lamotrigine, levetiracetam, tiagabine, vigabatrin, zonisamide, topiramate), the incidence of reported sedation is much lower (with the exception of zonisamide and topiramate) [17].

Analgesics Opioïds

Stimulants Excessive daytime sleepiness may be the result of an abrupt cessation of stimulant abuse. It can also be a residual complaint in those who have used stimulants in the past but have subsequently stopped for many years.

Sedation is a common adverse effect of opioïd medication. The degree of sedation may depend on the specific drug, dosage, and duration of use, as well as on the severity of the underlying disease.

Substances Cardiovascular Drugs Antihypertensive Drugs Sedation is the most common adverse effect of alpha-2 agonists such as clonidine and methyldopa. It occurs in 30–75% of patients, but the severity apparently diminishes with time [11].

Drugs Used in Neurology Antiparkinsonian Drugs Daytime sleepiness in Parkinson’s disease is common [12]. It involves multiple factors with the intrinsic effect of the dopaminergic medication and the

Alcohol intoxication typically causes sedation for 3–4 h and then insomnia, whereas intake of caffeine or cocaine causes insomnia and their withdrawal sedation.

Hypersomnias in the Context of Sleep-Related Breathing Disorders Obstructive Sleep Apnoea Syndrome The most frequent cause of excessive daytime sleepiness among sleep-related breathing disorders is the OSAS, characterized by repeated episodes of complete (apnoeas) or partial (hypopnoeas) upper airway

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obstruction occurring during sleep, associated with a various degree of nighttime and daytime symptoms This syndrome was first described by Guilleminault et al. in 1976 [18]. It is most frequent in 50-year-old males. According to Young et al. [19] the prevalence of obstructive sleep apnoeas accompanied by excessive daytime sleepiness in North America is 4% in men and 2% in women aged 30–60 years, though the actual prevalence may be higher. Nighttime symptoms include apnoea/hypopnoea episodes terminated by loud snoring, nycturia, fatigue and sometimes headache on awakening. Daytime symptoms consist in excessive daytime sleepiness, which can vary from light to severe, irritability, negligence, impairment in cognitive functions, depression, loss of libido and impotence. Interestingly the frequency of apnoeas/hypopnoeas during sleep correlates poorly with daytime symptom severity. A body mass index (weight in kg/height in m2) greater than 30 and a neck circumference greater than 40 cm are frequent although non systematic. Systemic hypertension is a common finding. The ear, nose and throat examination usually reveals a narrow upper airway due to close-set posterior tonsillar pillars, an abnormally long and hypotonic soft palate, a hypertrophic uvula, and macroglossia. The positive diagnosis rests on polysomnography allowing the observation of nocturnal disrupted sleep, the identification of obstructive apnoeas (cessation of airflow but ongoing respiratory efforts) and/or hypopnoeas (reduction rather than a cessation of airflow with ongoing respiratory effort), and their quantification (number of apnoeas/hypopnoeas per hour of sleep or apnoea index or respiratory disorder index), as well as their consequences on heart rate and oxygen saturation. Of note, some subjects do not have apnoeas or hypopnoeas, but increasing respiratory effort resulting in respiratory effort related arousals (RERAs). This condition is a variety of OSAS referred to as upper airway resistance syndrome [20]. It is most accurately identified with a quantitative measurement of airflow and oesophageal manometry. Obstructive sleep apnoea patients are at risk for systemic hypertension, heart failure, pulmonary hypertension, cardiac arrhythmias, cardiac ischemia, stroke and metabolic syndrome. Fifty to sixty percent of subjects with systemic hypertension, 60% of subjects with congestive heart failure, 30% of subjects with acute

coronary disease, and 60% of subjects with stroke, have OSAS [21]. From a pathophysiological point of view, pharyngeal airway patency is maintained by two counteracting forces: the activity of the upper airway muscles, which dilate and stiffen the airway, and the negative intraluminal pressure created during thoracic expansion by the diaphragm. A lack of coordination between upper airway dilators and inspiratory muscles will lead to upper airway occlusion during sleep [22]. In the case of OSAS, this balance is disturbed by abnormalities in upper airway anatomy (skeletal factors, soft tissues factors, obesity, hormonal factors) and neural control (altered reflex arc because of damage to the muscle and nerves, possibly due to the vibratory trauma of snoring [23].

Central Sleep Apnoea Syndrome Central sleep apnoea syndrome (CSAS) is characterized by recurrent cessation of respiration during sleep with the apnoea having no associated ventilatory effort. Ventilation and ventilatory effort cease simultaneously in a repetitive fashion over the course of the night. Prevalence is unknown but probably low. Patients present with symptoms of excessive daytime sleepiness or frequent nocturnal awakenings or both. Diagnosis of primary central sleep apnoeas rests on polysomnography demonstrating recurrent cessations in ventilatory effort and ventilation during sleep. CSAS is caused by instability of the respiratory control system in the transition from wakefulness to sleep, and less commonly during stable NREM sleep. Central sleep apnoeas tend to occur in individuals with a high or increased ventilatory responsiveness to CO2 [24].

Hypersomnias of Central Origin These include sleep disorders in which the primary complaint is excessive daytime sleepiness and in which the cause of the primary symptom is not a sleep related breathing disorder, another cause of disturbed nocturnal sleep or a circadian rhythm sleep disorder. The three main disorders are narcolepsy, idiopathic hypersomnia and recurrent hypersomnia. The two latter conditions will be reviewed.

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Idiopathic Hypersomnia Idiopathic hypersomnia is a disease with a less accurate clinical, neurophysiological and biological picture than narcolepsy. Its history goes back to the 1950s, when the symptoms of the disorder were first described in detail [25]. The term idiopathic hypersomnia was eventually coined by Roth in 1976 [26]. No prevalence study is available. However, a ratio of one to two patients with idiopathic hypersomnia for every ten with narcolepsy is suggested in series from sleep disorders centers. The onset of idiopathic hypersomnia is generally before 25 years of age. Idiopathic hypersomnia includes two forms, referred to as idiopathic hypersomnia with long sleep time and idiopathic hypersomnia without long sleep time [5]. The first category is remarkable for three symptoms: a complaint of constant or recurrent excessive daytime sleepiness and unwanted nap(s), usually longer and less irresistible than in narcolepsy and non refreshing irrespective of their duration; night sleep is sound, uninterrupted and prolonged; morning or nap awakening is laborious to the point that subjects do not awaken to the ringing of a clock, or a telephone, and often rely on their family members who must use vigorous and repeated procedures to wake them up. Even then, patients may remain confused and unable to react adequately to external stimuli, a state referred to as “sleep drunkenness.” In contrast, idiopathic hypersomnia without long sleep time consists in isolated excessive daytime sleepiness. Daytime sleep episodes may be more irresistible and more refreshing than in idiopathic hypersomnia with long sleep time and nighttime sleep may be restless with frequent arousals, establishing a bridge with narcolepsy without cataplexy. Hypnagogic hallucinations and sleep paralysis are not exceptional [27]. However, it has not yet been investigated whether they belong to idiopathic hypersomnia with long sleep time, to idiopathic hypersomnia without long sleep time or to both. Associated symptoms such as migraine headache, orthostatic hypotension, fainting episodes and Raynaudlike symptoms, are not uncommon. They suggest a change in the autonomic nervous system. The diagnosis of idiopathic hypersomnia with long sleep time is based mainly on clinical features, whereas the diagnosis of idiopathic hypersomnia without long sleep time rests only on polysomnography and the

M. Billiard

multiple sleep latency test (MSLT). However, laboratory tests are necessary in both conditions to rule out hypersomnias of other origins. Polysomnography demonstrates normal sleep except for its abnormally prolonged duration in the case of idiopathic hypersomnia with long sleep time. NREM sleep and REM sleep are in normal proportions. Sleep apnoeas and periodic limb movements should theoretically be absent, but may be acceptable in the case of an early onset of idiopathic hypersomnia and of their late occurrence. The mean sleep latency on the MSLT is supposed to be less than 8 min [5]. However, a mean sleep latency of less than 8 min can be found in up to 30% of the normal population and it is not rare to find a mean sleep latency of 8 min or more in a subject with a typical idiopathic hypersomnia with long sleep time. Besides, in the case of idiopathic hypersomnia with long sleep time, the MSLT seems somewhat questionable, as it may be difficult to wake the patient in preparation for the test or to keep the patient awake between the MSLT sessions. Moreover, awakening the patient in view of the first MSLT session precludes documenting the abnormally prolonged night sleep, and the following MSLT sessions preclude recording of prolonged daytime sleep episode(s) of major diagnostic value [28]. Thus, in cases with normal MSLT findings, the use of prolonged polysomnographic recording (24-h to 36-h) or actigraphy is advisable to document both prolonged night sleep and prolonged nap(s). Whether in the case of idiopathic hypersomnia with long sleep time or in the case of idiopathic hypersomnia without long sleep time a maximum of one SOREMP may be accepted. There is no consistent association with HLA and a decreased CSF hypocretin-1level has not been evidenced [29–32]. In comparison with narcolepsy with or without cataplexy, the onset of idiopathic hypersomnia is generally much more progressive. Once established, the condition is stable in severity and long lasting. Spontaneous disappearance of the symptom(s) leads to cast doubt about the initial diagnosis. Complications are mostly encountered in social relationships and professional functions [33]. The pathophysiology of idiopathic hypersomnia is still almost totally unknown. Neurochemical studies have been performed. According to one study assessing mean CSF concentrations of monoamine metabolites and using principal component analysis, all four monoamine metabolites (DOPAC, MHPG, HVA and

15 Hypersomnias Other than Narcolepsy: Differential Diagnosis

5-HIAA) were highly intercorrelated in normal volunteers. In contrast, HVA and DOPAC, the dopamine metabolites, did not correlate with the other two metabolites in narcoleptic patients, and MHPG, the norepinephrine metabolite, did not correlate with the other three metabolites in idiopathic hypersomnia patients [34]. Accordingly, an alteration of the dopamine system in narcolepsy and an alteration of the norepinephrine system in idiopathic hypersomnia were suggested. More recently, decreased CSF histamine has been found in a group of 14 subjects with idiopathic hypersomnia [35]. Besides, a genetic basis is likely in the case of idiopathic hypersomnia with long sleep time, given the high rate of relatives affected with the same symptoms [36].

Recurrent Hypersomnias Recurrent hypersomnias refer to a group of rare sleep disorders characterized by recurrent episodes of more or less continuous sleep, with an average duration of one week. These episodes recur at highly variable intervals of one to several months. The most classical form is the Kleine-Levin syndrome, first described by Kleine [37] and Levin [38]. The term Kleine-Levin syndrome was coined by Critchley and Hoffman in 1942 [39]. Roughly 300 cases have been published in the world literature. Adolescents are most commonly affected and the male to female ratio is between 3:1 and 2:1 [40, 41]. The Kleine-Levin syndrome is predominantly a sporadic condition. However, a few multiplex families have been identified [41–45]. The Kleine-Levin syndrome is characterized by recurrent episodes of hypersomnia, accompanied by behavioral and cognitive abnormalities, and in about half of cases depression. The first episode is frequently preceded by precipitating factors, among which infection or fever is the most common [40, 46]. The onset of episodes may occur in a couple of hours or gradually over one or several days. During the episode the subject may sleep as long as 16–18 h per day, waking and getting up only to eat and void. Sleep may be calm or agitated. Behavioral abnormalities include binge eating, hypersexuality, irritability and other odd behaviors. Binge eating refers to the consumption of a large amount of food, especially sweet foods such as candies, chocolates and cakes, in a compulsory manner, to the point that some patients may steal food in shops or

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in the plates of other patients in hospital. This behavior does not necessarily occur during all episodes and some patients may experience decreased appetite in one or a few episodes only during some episodes. Hypersexuality can take the form of sexual advances, shamelessly expressed sexual fantasies or masturbation in public. It is more frequent in boys than in girls. Irritability is present in almost all patients and can build up into outright aggressiveness, hence the frequent difficulty to perform polysomnography and MSLT in a satisfactory way. Other odd behaviours are diverse and surprising. They include talking in a childish manner, singing loudly, talking on the telephone without dialing, doing a headstand, writing on walls, etc. Cognitive abnormalities include an unbearable altered perception (people and objects seem distorted, unreal, dreamlike), confusion, fragmentary delusions, visual or auditory hallucinations. Depression is present in almost half of the patients, and some of them may report suicidal thoughts [40]. It is to be noted that the simultaneous occurrence of many of these symptoms is the exception rather than the rule and any symptom, except hypersomnia, may be present in only one or two of several episodes. A reddish face and severe perspiration can be noticed during physical examination. Weight gain of a few kilograms can be observed in relation to binge eating. A higher body mass index in patients versus control subjects has been found [41]. The episode of hypersomnia may end abruptly or insidiously. It is not uncommon for the episode to be followed by amnesia, manic behavior with insomnia lasting one or two days, as if the subject was trying to make up for lost time, or depression. The defining element is the recurrence of episodes after a lapse of one to several months. Between episodes the alertness and behavior of subjects is normal, even if neurotic traits or slight mental deficiency can be noted in some cases. A diagnosis of Kleine-Levin syndrome should be reserved for cases in which recurrent episodes of hypersomnia are clearly associated with behavioural and cognitive abnormalities. Laboratory tests merely serve to exclude the possibility of rare recurrent hypersomnias of organic origin (tumour, encephalitis, head trauma, stroke). The course is classically benign, with episodes lessening in frequency, duration and severity [47]. However, in the systematic study of 108 patients with the Kleine-Levin syndrome by Arnulf et  al. [41], the

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median disease duration was 13.6 ± 4.3 years. Compli­ cations are mainly social and occupational. The symptoms observed in the Kleine-Levin syndrome may reflect an intermittent dysfunction of the hypothalamus, given the critical role of this structure in the regulation of sleep, appetite and sexual behavior. However, no consistent hypothalamic abnormalities have been identified up to now and a few SPECT studies are in favour of a thalamic involvement [48, 49]. A hypocretin neurotransmission abnormality is suggested by a few case reports [31, 50]. Whatever the primary location of the dysfunction, the origin of the syndrome could lie in environmental factors, infectious or other, acting on a vulnerable genetic background. Given the frequent infectious precipitating factors, the young age at onset and the recurrence of the episodes, an autoimmune process has been suggested [44]. Menstrual-related hypersomnia is characterized by periodic episodes of sleepiness that occur in association with the menstrual cycle. The condition occurs within the first month(s) after menarche. Hormonal imbalance is probably involved in the pathophysiology, since oral contraceptives will usually lead to prolonged remission [51].

marking the initial period of the stroke and a later state of psycho-motor slowing, abulia or akinetic mutism [55]. The most typical causes are uni or bilateral paramedian infarct, paramedian pedunculo-thalamic infarct and upper pontine tegmentum infarct.

Neurodegenerative Diseases Fifteen to fifty-one percent of Parkinson’s disease patients experience excessive daytime sleepiness as a constant pressure for falling asleep and difficulty at remaining awake [12, 56, 57]. The use of MSLT has documented the existence of Parkinson’s disease patients with short mean sleep latency and the presence of SOREMPs [58]. In this context it is of special value that hypocretin cell loss has been evidenced in Parkinson’s disease [59, 60]. Excessive daytime sleepiness is even more frequent in patients with multiple system atrophy [61]. Finally an increased tendency to fall asleep during daytime together with increased wakefulness during the night is a hallmark of the breakdown in the normal sleep/wake rhythm that occurs in Alzheimer’s disease [62, 63].

Neuromuscular Diseases Hypersomnias Associated with Various Medical Disorders Hypersomnia Associated with Neurological Diseases Brain Tumours Clinically, sleepiness is continuous, of variable severity, interspersed with brief arousals [52]. Sleepiness may occur in any intracranial hypertension syndrome, but more rarely results from tumours of the diencephalic or peduncular region, with no associated intracranial hypertension [53]. These tumours particularly affect the posterior hypothalamus and the pineal region. Brain tumors are one of the most frequent causes of symptomatic narcolepsy [54].

Stroke Excessive daytime sleepiness is often a transient state between confusional states, agitation or even coma,

Any neuromuscular disease, whether motoneuron diseases, motor neuropathy, damaged neuromuscular junction, or muscular disease, is likely to be accompanied by sleep-related breathing impairment possibly resulting in excessive daytime sleepiness. A case in point is myotonic dystrophy, an inherited disorder in which daytime sleepiness is common [64]. Its origin is not equivocal. Central and obstructive sleep apnoeas have been extensively reported in myotonic dystrophy. However, in a group of 19 patients with dystrophic myotony referred for excessive daytime sleepiness, who all benefited from polysomnography and for 13 of them from an MSLT the following day, 14 had a respiratory disorder index > or = 5/h indicative of clinically insignificant sleep apnea, and 2 or more SOREMPs were seen in 5 of 13 patients [65]. This observation implies that an intrinsic excessive daytime sleepiness, sometimes accompanied by abnormal REM sleep pressure, may be an integral part of excessive daytime sleepiness in myotonic dystrophy. Along this line a neuronal cell loss has been documented in the dorsal raphe nucleus and the superior central nucleus in myotonic dystrophy [66].

15 Hypersomnias Other than Narcolepsy: Differential Diagnosis

Multiple Sclerosis Multiple sclerosis is well known to produce fatigue. However, patients may also complain about excessive sleepiness. In a recent study using the Fatigue Severity Scale and the Epworth Sleepiness Scale in 60 outpatients with multiple sclerosis, 64 % showed fatigue and 32% excessive sleepiness on these scales [67]. Epilepsy Sleepiness is a common complaint in epilepsy patients. It is frequently attributed to antiepileptic medications or uncontrolled seizures. However, it has been shown that symptoms of treatable sleep disorders, such as sleep apnoeas or restless legs syndrome, were stronger predictors of subjective sleepiness than the number or type of antiepileptic medications or the frequency of seizures [68]. Chiari Malformation Whether or not it is associated with syringomelia, Chiari malformation is a recognized cause of sleep apnoea syndrome and daytime sleepiness, no doubt via the effect of the malformation on the neurons involved in controlling the upper airway muscles [69]. Rare Inherited Disorders Excessive daytime sleepiness and/or cataplexy may be associated with several inherited disorders. According to the extensive review by Nishino and Kambayashi, excessive daytime sleepiness is constant in the PraderWilli syndrome and in the Moebius syndrome, inconstant in the Niemann-Pick type C disease, and absent in the Norrie disease and in the Coffin-Lowry syndrome [54]. In addition, SOREMPs are documented in Prader-Willi syndrome, in Nieman-Pick type C, and in Norrie disease. In these diseases CSF hypocretine-1 levels are most often normal or intermediate.

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have been reported [71]. Hypersomnia tends to go into gradual remission after several months or years. Over half of the patients with human immunodeficiency virus in stages B and C complain of fatigue and/ or excessive daytime sleepiness [72]. Impaired alertness or consciousness is a feature of virtually all patients affected by arbovirus encephalitis. Human African Trypanosomiasis (sleeping sickness) is a subacute or chronic parasitic disease caused by the inoculation of a protozoan, Trypanosoma brucei, transmitted by the tsetse fly (Glossina palpalis). It is endemic to certain regions of tropical Africa. The form found in West and Central Africa is due to Trypanosoma brucei gambiense. The invasion of the central nervous system (stage 2) is characterized by meningoencephalitis with abnormal sleepiness, headache, trembling, dyskinesia, choreoathetosis, mood changes, and death in the absence of treatment. Polysomnography shows episodes of sleep occurring randomly day and night, and sleep onset REM periods [73]. The diagnosis of stage 2 is founded on the examination of the CSF showing the presence of trypanosomas, an increased number of cells and an increased protein concentration with thresholds of 250–450 mg/L.

Hypersomnia Associated with Metabolic and Endocrine Diseases Postprandial sleepiness is common in untreated diabetes. A malaise, with reduced mental activity and gradual sleepiness may signify subacute hypoglycaemia. Hepatic encephalopathy is initially accompanied by abnormal sleepiness which may develop into a state of obnubilation or coma. Hypothyroidism is accompanied by fatigue, and mental and physical slowing down. If sleepiness is present it should prompt the investigation for an associated OSAS. Acromegalia may also be accompanied by an OSAS.

Post-traumatic Hypersomnia Hypersomnia Associated with Infectious Disease Intense fatigue and severe excessive sleepiness may develop in the months following Epstein-Barr disease [70]. The same holds true of atypical viral pneumonia, Hepatitis B viral infection, and the Guillain-Barré syndrome in which indetectable levels of CSF hypocretin-1

Excessive sleepiness appearing during the year following a head injury may be considered a priori as post-traumatic [74]. The patient typically shows an extended night sleep and episodes of daytime sleep. Sleepiness is frequently associated with headaches, concentration difficulties or memory impairment. CT or MRI may reveal lesions affecting the hypothalamus

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region or the brainstem, midbrain or pontine tegmentum, but most often the absence of any significant lesion. Post-traumatic hypersomnia is another cause of symptomatic narcolepsy [54]. In a recent study, low CSF hypocretin-1 levels were found in 25 out of 27 patients in the first day after traumatic brain injury and in only 4 out of 21 patients 6 months after [75].

Hypersomnia not due to Substance or Known Physiological Condition (Psychiatric Hypersomnia) This category covers about 5–7% of cases of hypersomnia seen in sleep disorders centers. Women are more susceptible than men. A severe complaint of excessive daytime sleepiness is reported, congruous with an elevated score on the Epworth Sleepiness Scale. Night sleep is perceived as nonrestorative and is generally of poor quality. Patients are often intensely focused on their hypersomnia and reject any psychiatric component. Poor work attendance and abruptly leaving work because of an irresistible need to sleep are common. Polysomnography typically shows a prolonged sleep latency, an increased wake time after sleep onset, and a low sleep efficiency [76]. REM sleep latency may be shortened in the case of bipolar disorder. Contrasting with the elevated score on the Epworth sleepiness scale, the mean sleep latency on the MSLT is often within normal limits. Twenty-four hour continuous recording generally documents considerable time spent in bed during day and night, asleep and awake, a behavior referred to as clinophilia, from the Greek klinh (bed) and filew (love) [77]. A psychiatric interview is essential to diagnose the underlying disease. Causative psychiatric conditions include bipolar type II disorder, undifferentiated somatoform disorder, adjustment disorder, or personality disorder. The pathophysiology is unknown. However, given normal or subnormal mean sleep latency on the MSLT and clinophilia, excessive sleepiness may in fact consist in lack of interest, withdrawal, decreased energy, rather than to increase in true sleep propensity [78]. CSF hypocretin-1 levels are normal in all patients with psychiatric hypersomnia [32]. In the group of psychiatric disorders a separate place should be reserved for seasonal affective disorder, which is remarkable for episodes of major depression

occurring only during the winter season, associated with anergia, hypersomnia, fatigue, increased appetite for carbohydrates and weight gain.

The Issue of Periodic Limb Movements in Sleep (PLMS) and Excessive Daytime Sleepiness There has long been an assumption that the sleep disruption associated with periodic limb movements in sleep (PLMS) produces significant excessive daytime sleepiness, and a periodic limb movement disorder characterized by PLMS and either insomnia or hypersomnia has been identified. However, this concept may turn to be invalid [79]. Indeed several studies have failed to document any relationship between PLMS per hour or PLMS with arousal per hour of sleep and the mean sleep latency on the MSLT [80–82].

Conclusion Besides obstructive sleep apnea syndrome and narcolepsy a number of disorders may be responsible for hypersomnia. Most of these disorders are either unfrequent or not known as hypersomnia providers. Therefore, the cause of hypersomnia may remain undiagnosed or misdiagnosed, leaving the patient untreated. CSF hypocretin-1 levels may be abnormally low or intermediate in a few conditions only.

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M. Billiard 64. Laberge L, Begin P, Montplaisir J, Mathieu J. (2004) Sleep complaints in patients with myotonic dystrophy. J Sleep Res 13, 95–100 65. Gibbs III JW, Ciafaloni E, Radtke RA. (2002) Excessive daytime somnolence and increased rapid eye movement pressure in myotonic dystrophy. Sleep 25, 672–675 66. Ono S, Kanda F, Takahashi K, Fukuoka Y, Jinnai K, Kurisaki H, Mitaki S, Inagaki T, Nagao K. (1995) Neuronal cell loss in the dorsal raphe nucleus and the superior central nucleus in myotonic dystrophy: a clinicopathological correlation. Acta Neuropathol 89, 122–125 67. Stanton BR, Barnes F, Silber E. (2006) Sleep and fatigue in multiple sclerosis. Mult Scler 12, 481–486 68. Malow B, Bowes R, Lin X. (1997) Predictors of sleepiness in epilepsy patients. Sleep 20, 1105–1110 69. Dauvilliers Y, Stal V, Abril B, Coubes P, Bobin S, Touchon J, Escourrou P, Parker F, Bourgin P. (2007) Chiari malformation and sleep related breathing disorders. J Neurol Neurosurg Psychiatry 12, 1344–1348 70. Guilleminault C, Mondini S. (1986) Infectious mononucleosis and excessive daytime sleepiness. A long-term follow-up study. Arch Intern Med 146, 1333–1335 71. Kanbayashi T, Ishiguro H, Aizawa R, Saito Y, Ogawa Y, Abe M, Hirota K, Nishino S, Shimizu T. (2002) Hypocretin-1 (orexin-A) concentrations in cerebrospinal fluid are low in patients with Guillain-Barre syndrome. Psychiatry Clin Neurosci 56, 273–274 72. Darko DF, Mc Cutchan JA, Kripke DF, Gillin JC, Golshan, S. (1992) Fatigue, sleep disturbance, disability and indices of progression of HIV infection. Am J Psychiatry 149, 514–520 73. Buguet A, Bisser S, Josenando T, Chapotot F, Cespuglio R. (2005) Sleep structure: a new diagnostic tool for stage determination in sleeping sickness. Acta Trop 93, 107–117 74. Guilleminault C, Faull KF, Miles L, van den Hoed J. (1983) Post-traumatic excessive sleepiness: a review of 20 patients. Neurology 33, 1584–1589 75. Baumann CR, Werth E, Stocker R, Ludwig S, Bassetti CL. (2007) Sleep-wake disturbances 6 months after traumatic brain injury: a prospective study. Brain 130, 1873–1883 76. Dolenc C, Besset A, Billiard M. (1996) Hypersomnia in association with dysthymia in comparison with idio­pathic hypersomnia and normal controls. Plfugers Arch 431, R303–R304 77. Billiard M, Dolenc L, Aldaz C, Ondze B, Besset A. (1994) Hypersomnia associated with mood disorders: a new perspective. J Psychosomat Res 38(Suppl 1), 41–47 78. Nofzinger EA, Thase M, Reynolds CF, Himmelhoch JM, Mallinger A, Houck P, Kupfer DJ. (1991) Hypersomnia in bipolar depression: a comparison with narcolepsy using the multiple sleep latency test. Am J Psychiatry 148, 1177–1181 79. Allen R. (2006) Periodic leg movements in sleep and restless legs syndrome. Relation to daytime alertness and sleepiness. Sleep Med Clin 1, 157–163 80. Mendelson WB. (1996) Are periodic leg movements associated with clinical sleep disturbances? Sleep 19, 219–223 81. Nicolas A, Lespérance P, Montplaisir J. (1998) Is excessive daytime sleepiness with periodic leg movements during sleep a specific diagnostic category? Eur Neurol 40, 22–26 82. Chervin RD. (2001) Periodic leg movements and sleepiness in patients evaluated for sleep-disordered breathing. Am J Resp Crit Care Med 164, 1454–1458

Section III

Psychosocial Considerations

Chapter 16

Psychosocial Impact of Narcolepsy in Children and Adolescents Gregory Stores

Preamble Under the banner headline ‘Sleeping Illness Boy’s School Ban’ an article was published in a UK local newspaper which illustrated many of the psychosocial difficulties mentioned later in this chapter from which young people with narcolepsy can suffer, mainly because of general unawareness of the condition, its nature and its possible consequences. Salient points in the article were as follows. The 12-year-old boy was expelled from his school. He had fallen asleep in class, on the bus home, even half way up the stairs, and was said to be irritable and even violent when woken up. This led to him being expelled because of his ‘disruptive behaviour’. His mother said that she had always felt that that there was something wrong to make him behave so badly. Eventually he was referred to a child psychiatrist who diagnosed him as suffering from narcolepsy (the article made no mention of cataplexy). Medication was prescribed following which his behaviour improved but, despite this, other schools were reluctant to accept him, especially when his behaviour deteriorated after he stopped taking his medication regularly. The best that could be arranged was attendance for just three mornings a week in a special tutorial group. His tutor there described him as meticulous and conscientious with a past record of being particularly good at maths. He had previously been good at sport but

G. Stores (*) Emeritus Professor of Developmental Neuropsychiatry, University of Oxford, North Gate House, 55 High Street, Dorchester on Thames, Oxfordshire, OX10 7HN, UK e-mail: [email protected]

now spent most of his time at home where he said he was bored and missing his school friends. Unfortunately, no information could be obtained about subsequent events.

Introduction Present-day concepts of the nature of narcolepsy in adults and children have been described in Chapters 6 and 5. Quality of life issues and mental health aspects in adults with narcolepsy are considered in Chapters 17 and 22. The present account is confined to psychological and social considerations in young people with this disorder. These aspects have been paid relatively little attention so far, despite having potentially crucial relevance for adult life. A high proportion of narcolepsy patients have symptoms starting in childhood or adolescence. At this age there is a special risk of the condition not being recognised because of its wide range of clinical manifestations due to the condition itself, or complications which can easily distract attention away from the underlying disorder [1]. For example, there are special problems of identifying sleepiness as excessive in young children and particular problems of identifying lesser degrees of cataplexy at an early age. The limited descriptive powers of children add to the difficulties of recognising auxiliary symptoms, and psychological reactions are not specific to narcolepsy and are usually the result of much more common circumstances. Add to this the paradoxical possibility of sleepiness causing overactivity and other ‘ADHD’ symptoms [2] and it is no surprise that various misinterpretations of this sleep disturbance are not unlikely [1].

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All things considered, it is understandable that paediatricians brought up the rear in the ‘league table’ of the proportions of different physician groups correctly recognising narcolepsy before the diagnosis was definitively made by a sleep specialist [3]. All these complexities are capable of profoundly influencing a child’s psychosocial well-being directly (and also through effects on the family) and, in the process, compromising his or her future.

Review of the Literature Not everyone has neglected the importance of psychosocial aspects of narcolepsy in young people, although, for the most part, published accounts have been anecdotal or impressionistic, or there has been only passing reference to children or adolescents in reviews concerned essentially with adults. There are, however, a few reports of empirical research studies of young patients. These will be considered separately from general reviews. Single case observations have not been included.

General Accounts ‘From the time of symptom onset to a patient’s death, the stresses of each decade differ’. This telling quotation is taken from the instructive 1994 review of the psychosocial impact of narcolepsy, mainly in adults, by Broughton and Broughton [4]. Regarding children, they mention a relatively early observation from an international study [5] that more than a half of people with narcolepsy attributed their poor performance at school to their condition, and that over a third considered their conflicts with teachers to their narcoleptic symptoms which consistently caused them embarrassment. The authors considered that poor self-image and other psychological upset were likely. In the same review, it was emphasised that the majority of people with narcolepsy have their first symptoms as teenagers or young adults. The point is made that, at this particular time, self-esteem can be undermined in various ways: out of embarrassment, catalepsy can lead to social isolation; hallucinatory experiences can lead to doubts about one’s own sanity and, indeed, are sometimes mistakenly misdiagnosed as psychotic phenomena.

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The wide range of other mistaken psychiatric diagnoses at this age or younger (such as major depressive disorder, ADHD and oppositional defiant disorder) has been emphasised by Dahl [6]. Other observers have emphasised the tendency of some pre-teenagers with narcolepsy (and no doubt others) to deny their condition and to make unsatisfactory attempts to conceal their symptoms which may well contribute to them becoming irritable and easily frustrated, and subject to the anger and severe mood swings that are often reported [7, 8]. In his review, principally concerned with psychosocial aspects of adult narcolepsy [9], Douglas remarked how young people can be victimised at school including being bullied by other children who sometimes also attempt to precipitate attacks of cataplexy by frightening them or causing them to laugh. Other authors have pointed out difficulties that can arise in providing help and advice even when narcolepsy has been correctly diagnosed. These include the reluctance of some adolescents in particular to accept the need for careful supervision of their medication or to advise on social activities or career ambitions at a time that they want to develop their independence in life [10]. Sometimes complications arise from parents (and even teachers) having difficulty accepting the diagnosis as an explanation for the child’s behaviour [11]. The personal observations on which the above accounts have been based are important in raising awareness of what might go wrong in the lives of young people with narcolepsy. However, the points made are something of a miscellany. Kavey [12] provided a more systematic and structured approach which, although it overlaps somewhat with some of the points already stated, deserves special attention in also being thoughtful and detailed, and seemingly based on extensive clinical experience of children and adolescence with narcolepsy. Kavey concentrated on the effects of sleepiness and (less so) cataplexy rather than medication issues or the problems of having any serious illness or disorder, all of which, of course, may also apply in the individual case. Although not necessarily fully comprehensive, combined with points made by other authors, his article, nevertheless, provides a rich source of hypotheses for the still much needed detailed empirical studies to explore. Only a paraphrased listing of the problems he discussed is provided here. His article should be consulted for further explanation.

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His account is divided into problems in childhood and those in adolescence.

Childhood Problems Related to Sense of Self and Others • Child less responsive to others because of sleepy state. • For the same reason, others less responsive to the child. • Consequently, self image in relation to what other people think of child is impaired. • Feeling different from others. • Feelings may be avoided in order to prevent cataplectic attacks. • Hypnagogic hallucinations and sleep paralysis may be terrifying and lead to feeling crazy. • As sleepiness and cataplexy are hard to conceal, other children are likely to pick on child. • May be victimised because of feeling socially awkward.

Problems with Social Functioning • Awkwardness and embarrassment in social situations. • Impaired sporting skills and activities.

Problems with Mood and Family • Looking and actually being depressed. • Impaired relations with parents because of their difficulty coping with child’s condition and its consequences. • Restrictions imposed by parents.

Problems at School • Effects on concentration, memory, test performance and educational progress. • Teachers’ misinterpretation of narcolepsy symptoms. • Teachers’ annoyance at child’s sleepiness in class. • Behaviour problems in class including being overactive and disruptive, perhaps to combat sleepiness or as a manifestation of it. • Restrictions and punishments imposed by teachers.

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Adolescence The problems just mentioned can also occur at this stage of development but additional difficulties more specific to this age may be experienced. These include: • Effects on teenage friendships and other social relationships outside the home. • Overprotection by parents. • Social awkwardness, for example, falling asleep at social gatherings or elsewhere in public. • Being mistaken for a drug user. • Abusing stimulants in an attempt to combat sleepiness and appear normal. • Intensification of worries or depression about other problems generally faced by teenagers. • Complications regarding sleepiness and alcohol consumption, driving and judgements about sexual matters. • Educational issues such as difficulty studying, examination performance, career aspiration and choices, and academic prospects.

Empirical Research Studies As mentioned earlier, such studies concerned exclusively with psychological and social problems in children and adolescents have been few and far between. Each, in its own way, has produced interesting and relevant findings but collectively they illustrate the need for much improvement in scope and methodology in exploring this complicated subject. Kashden and colleagues [13] published an abstract (therefore lacking detail) of their study involving only a small number of children with narcolepsy who had been assessed using standardised psychosocial assessment scales which allowed comparisons with normative data. Main findings were that the narcoleptic children were reported to be more moody than average, to have more ‘adjustment’ problems, and to be more often involved in delinquent behaviour. Their parents expressed concern about their children’s academic performance and emotional lability. Recently, Stores et  al. [14] described an international cross-sectional questionnaire survey of a relatively large group of children aged 4–18 years who had received from a physician a diagnosis of narcolepsy.

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These children were compared with a group of matched healthy controls. Standardised or otherwise systematic assessment methods were used covering various aspects of behaviour, mood, quality of life and educational aspects. Normative data were available for most of these measures. The clinical group of children were separated into those who met internationally accepted clinical criteria for the diagnosis of narcolepsy (n = 42) and those whose primary complaint was excessive daytime sleepiness without definite additional features of narcolepsy (n = 18). It was accepted that the latter subgroup might have included some who had not yet developed cataplexy which would have confirmed the diagnosis of narcolepsy, or exhibited it in such subtle form that it had not been recognised. There was no convincing evidence that any children in either clinical subgroup had another sleep disorder to account for their excessive sleepiness. Compared with controls (n = 23), children with definite narcolepsy, and also those with excessive sleepiness alone, showed statistically significantly higher rates of behavioural disturbance (peer problems, conduct disorder and emotional difficulties), depressive symptoms, impaired quality of life aspects and educational difficulties. There were no significant differences between the two clinical subgroups in these various respects but, compared with controls, only the definite narcolepsy group showed significantly worse scores on a measure of adverse effects of their condition on the family. This study was subject to certain actual or possible limitations. These include the likelihood of some degree of referral bias the children with narcolepsy had been recruited through sleep disorder centres and, that being so, they are unlikely to be representative of children with narcolepsy in general, as discussed later. A tighter case-control methodological design would have been preferable although the information available on the clinical group and control children suggested that they were legitimately comparable. Unfortunately, attempts to identify certain factors possibly associated with poor psychosocial outcome in the children with narcolepsy (such as delay in diagnosis and misdiagnosis, possible medication effects, and inappropriate reactions to the children’s symptoms on the part of peers, parents and teachers) were frustrated by a lack of reliable retrospective information on these points. Despite these limitations, the findings in this study lend substantial support to the opinions expressed by the clinicians quoted earlier that children with narcolepsy

are at particular risk of a wide range of psychosocial difficulties. There is also a strong indication that it is excessive sleepiness that characterises the condition (rather than features more specific to narcolepsy) that most undermines satisfactory psychosocial development. In a preliminary study reported of late by Dorris et  al. [15], 12 children with narcolepsy between the ages of 7 and 16 years were assessed by means of a clinical interview and the use of standardised intelligence tests and also behaviour as judged by their parents. Normative data were available for these measures. All but one child scored within the normal range for overall IQ but five showed significant differences between their Verbal and Performance IQs (three in favour of Verbal and two in favour of Performance). In the absence of measures of basic cognitive abilities, explanations of these differences are unclear and their significance is uncertain. The main measured behavioural finding was high levels of ‘internalising’ behaviours (anxiety, withdrawal and depressed behaviour). The clinical interviews were said to demonstrate further evidence of mainly emotional concerns on the part of the children themselves and also their parents, as well as various types of school problems mentioned earlier.

Issues Arising Collectively, the reviews and reports described in the last section provide good reason to believe that children and adolescents with narcolepsy are at high risk of many forms of psychosocial disadvantage. They also give rise to possible ways in which such disadvantage might be prevented or alleviated. Nevertheless, many issues remain to be addressed by the further, much needed research that is required to inform and improve clinical practice. The following is an attempt to consider in a preliminary fashion just some of these issues.

What Do We Know About the Psychosocial Problems of Children with Narcolepsy in General? Clearly, we do not know enough if only because it seems that many such young people are not known to appropriate medical services and, therefore, have

16 Psychosocial Impact of Narcolepsy in Children and Adolescents

not been studied psychosocially or in other respects for that matter. The reported series in the above literature review mainly consist of relatively few children. The comparatively high number in our own study [14] was only achieved by casting the net wide internationally. According to accepted prevalence rates, the small proportion recruited from the UK represented only a fraction of children with narcolepsy in the country and those from other sources are also likely to have represented referral bias. The possible reasons why so few cases seem to be known to medical services include the potential for misdiagnosis as mentioned earlier resulting in inappropriate referral to psychiatric or educational services or, indeed, failure to receive professional attention of any sort. To achieve a balanced representative view, a careful population survey would be required, possibly organised on a multicentre basis. More basically, there is a need for both the general public and professionals to know much more about narcolepsy in order for it to be recognised and managed more effectively, as soon as possible after its first appearance. Of course, the same can be said of other sleep disorders.

What Aspects Need to Be Considered in Describing Narcoleptic Children’s Psychosocial Problems and How Should They Be Assessed? The clinicians mentioned in the earlier literature review have, in the light of their experience, varied somewhat in the psychosocial difficulties that they have emphasised. Also, different assessments have been used in the few research studies that have been published. Ideally, agreement would be reached about what (preferably psychometrically sound) assessments are appropriate for adequately exploring possible psychosocial difficulties in narcoleptic young people. This is particularly true for research but the same basic principle applies to clinical practice although, of course, it is necessary to be realistic about what is acceptable and feasible in the latter setting. Appropriately supplemented with additional considerations, Kavey’s account [12] could act as a template for devising an assessment schedule about which consensus should be possible based on discussion by

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those familiar with the field. It would not be necessary to try to re-invent the wheel in deciding on standardised assessment methods as largely appropriate measures are already available for some of the psychological and social domains. An agreed assessment schedule would need to be updated as new findings come to light such as the recent report of high rates of eating disorders associated with narcolepsy [16].

Which Aspects of Narcolepsy Determine the Likelihood, Nature and Extent of Psychosocial Difficulties? As mentioned earlier, various authors have placed the emphasis on the non-specific factor of excessive sleepiness as the root cause of such difficulties [5, 12, 14]. In this connection, it is interesting to compare the psychosocial effects of narcolepsy and those associated with other sleep disorders characterised by excessive sleepiness, although information on this point is limited. However, Broughton et al. [17] reported some time ago that adults with narcolepsy and those with idiopathic hypersomnia showed very similar socioeconomic effects on which basis they concluded that, in the absence in the latter group of the auxiliary symptoms of narcolepsy, daytime sleepiness was the major source of these effects. Obstructive sleep apnoea offers the possibility of another interesting comparison with narcolepsy but one which, it seems, has not been pursued directly although it is of interest that preliminary findings from the use of standardised measures indicate that children with this condition show a similarly wide range of behavioural and cognitive deficits to those reported in children with narcolepsy [18]. An issue related to the relative importance of sleepiness in narcolepsy is the nature of the cognitive impairment that the sleepiness is likely to cause. This has implications not only for educational performance but also wider aspects of social awareness and interaction. Ideally, studies of adults with narcolepsy would inform the issue regarding their childhood counterparts who do not seem to have been investigated from this point of view. The findings in several recent adult studies are somewhat difficult to compare because different aspects of cognitive function have been assessed but the essence of the findings is that it seems that higher level (‘executive’) attention processes are principally

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compromised in narcolepsy in contrast to simpler cognitive tasks which are relatively unaffected – see, for example [19]. Refinement and adaptation for childhood studies are required bearing in mind the need to measure cognitive abilities of likely relevance to reallife situations. The possible bearing on psychosocial problems of factors more specific to narcolepsy than excessive sleepiness which need to be explored include cataplexy, hallucinatory experiences, delays in diagnosis especially combined with interim misinterpretation of the child’s symptoms, possible adverse medication effects or disappointing response to treatment, and people’s inappropriate reactions to the child’s condition based, for example, on inadequate understanding or intolerance.

What Resources Are Needed to Prevent or Offset the Psychosocial Difficulties to Which Children and Adolescents Are Apparently Prone? The following can be considered basic requirements some of which have been touched on already. • A much improved general understanding of the nature of narcolepsy in young people and the risks to which they are subject because of their condition. • Early referral to an informed paediatric service, preferably neurological, or children’s sleep disorders centre. • Thereby, correct diagnosis and avoidance of misinterpretation of the child’s symptoms. • Comprehensive evaluation, not only neurologically but also behavioural, family, cognitive and educational, as well as social aspects. • Ideally, systematic standardised assessments (rather than partial subjective impressions) would be used which permit subsequent developments to be monitored objectively. • Employment of whatever therapeutic measures needed, given the child’s medical condition and psychological state. This might need to include support and counselling, behavioural treatment, special educational assistance, or other psychiatric measures appropriate for children and adolescents [20].

• Detailed explanations of the condition for the child (depending on his/her level of development and understanding), parents, siblings, school, friends and possibly others. • Careful regular review and checks on the possible development of the various psychosocial difficulties reviewed in this chapter. • Longer-term follow up ensuring continuity of care into adult life with appropriate action taken as required. It is appreciated that such a programme as this will already be practiced in some services. The challenge is to try to make its use more widespread.

Are Preventive or Intervention Measures Effective in Reducing Psychosocial Complications to the Lives of Young People with Narcolepsy and Lessening the Risk of such Problems Persisting into Adult Life? It seems highly likely that this is the case but, as there appears to be no published follow-up studies addressing this issue, this is something of an open question and, of course, much would depend on the nature of the preventive or intervention measures employed. Yet again, there is a need to investigate by sufficiently thorough means this aspect of the care of young people with narcolepsy, care which, by the nature of the condition, has to be long-term – indefinite even.

Conclusion Narcolepsy is a complex condition, not least because of its diverse manifestations and effects, perhaps particularly in children because of their continuously changing development. Failures of recognition and mistaken alternative diagnoses add to the complications faced by many young people with this condition and their families. Adverse psychological and social effects are particularly likely during early life which can already be a time of change, challenge and potential upset, especially in the teenage years. Because narcolepsy is so complex

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a condition in its nature and possible consequences, both clinical care and research strategies need to be commensurately complex and considered.

References 1. Stores, G. (2006) The protean manifestations of childhood narcolepsy and their misinterpretation. Dev Med Child Neurol 48, 307–310 2. Lewin, D.S. and Pinto, M.S. (2004) Sleep disorders and ADHD: shared and common stereotypes (editorial). Sleep 27, 188–189 3. Kryger, M.H., Walld, R., and Manfredi, J. (2002) Diagnosis received by narcolepsy patients in the year prior to diagnosis by a sleep specialist. Sleep 25, 36–41 4. Broughton,W.A. and Broughton, R.J. (1994) Psychosocial impact of narcolepsy. Sleep 17, S45–S49 5. Broughton, R., Ghanem, Q., Hishikawa, Y., Sugita, Y., Nevsimalova, S., and Roth, B. (1981) Life effects of narcolepsy in 180 patients from North America, Asia and Europe compared to matched controls. Can J Neurol Sci 8, 299–304 6. Dahl, R.E. (1996) Narcolepsy in children and adolescents. Child Adolesc Psychiatr Clin N Am 5, 6496–6459 7. Kotagal, S., Hartse, K.M., and Walsh, J.K. (1990) Characteristics of narcolepsy in preteenaged children. Pediatrics 85, 205–209 8. Allsopp, M.R. and Zaiwalla, Z. (1992) Narcolepsy. Arch Dis Child 67, 302–306 9. Douglas, N.J. (1998) The psychosocial aspects of narcolepsy. Neurology 50 Supplement 1, S27–S30 10. Wise, M. S. and Lynch, J. (2001) Narcolepsy in children. Semin Pediatr Neurol 8, 198–206

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11. Guilleminault, C. and Pelayo, R. (1998) Narcolepsy in prepubertal children. Ann Neurol 43, 135–142 12. Kavey, N.B. (1992) Psychosocial aspects of narcolepsy in children and adolescents. In: Goswami, M., Pollack, C.P., Cohen, F.L., Thorpy, M.J., and Kavey, N.B. (editors) Psychosocial aspects of narcolepsy in children and adolescents. New York: Haworth Press, 91–101 13. Kashden, J., Wise, M., Alvarado, I., Williams, M., and Boll, T. (1996) Neurocognitive functioning in children with narcolepsy (abstract). Sleep Res 25, 262 14. Stores, G., Montgomery, P., and Wiggs, L. (2006) The psychosocial problems of children with narcolepsy and those with excessive daytime sleepiness of uncertain origin. Pediatrics 118, e1116–e1123 15. Dorris, J., Zuberi, S.M., Scott, N., Moffat, C., and McArthur, I. (2008) Psychosocial and intellectual functioning in childhood narcolepsy. Dev Neurorehabil 1, e1–e8 16. Fortuyn, H.A., Swinkels, S., Buitelaar,J., Renier, W.O., Furer, J. W., Rinders, C.A., Hodiamont, P.P., and Overeem, S. (2008) High prevalence of eating disorder in narcolepsy with cataplexy: a case-control study. Sleep 31, 335–341 17. Broughton, R., Nevsimalova, S., and Roth, B. (1978) The socio-economic effects of idiopathic hypersomnia – comparison with controls and with compound narcoleptics. In: Popoviciu, L., Argian, B., and Badiu, G. (editors) Sleep. Basel: Karger, 229–233 18. Lewin, D.S., Rosen, R.C., England, S.J., and Dahl, R.E. (2002) Preliminary evidence of behavioural and cognitive sequelae of obstructive sleep apnea in children. Sleep Med 3, 5–13 19. Naumann, A., Bellebaum, C., and Daum, I. (2006) Cognitive deficits in narcolepsy. J Sleep Res 15, 329–328 20. Gillberg, C., Harrington, R., and Steinhausen, H.-C. (2006) A clinician’s handbook of child and adolescent psychiatry. Cambridge: Cambridge University Press

Chapter 17

Quality of Life and Psychosocial Issues in Narcolepsy Meeta Goswami

Introduction Changing medical technology and novel treatment modalities have increased life expectancy with a concurrent rise in chronic illnesses. Improved management techniques enable patients to cope better with their illnesses, thus generating demands and expectations to lead satisfying lives despite having chronic illnesses or disabilities. These dynamics have propelled a vigorous interest in improving the quality of life of patients with chronic medical illnesses and, more recently, those with sleep disorders [1]. Despite successful relief of physical symptoms, patients may report psychosocial symptoms such as depressed mood, inability to accomplish activities of daily living, decrements in social and recreational activities, and low self esteem. QOL assessments allow researchers to compare differences in well-being in different conditions and detect subtle changes in patients’ and clinicians’ responses to medical or psychosocial interventions. Studies on QOL provide valuable information for evaluating health outcomes, identifying problems and needs and tailoring the management plan to suit patients’ needs. Furthermore, results from these studies may be applied to enhance communication between the patient and the professional and improve overall quality of care for patients. New information could be valuable for family members who care for the disabled and could help them to understand the patient’s disability and provide M. Goswami (*) Narcolepsy Institute, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210 Street, Bronx, NY, 10467, USA e-mail: [email protected]

an effective support system [2]. Data generated from QOL studies are important in conducting cost-benefit analyses, evaluating health programs, making appropriate changes in program development, and justifying funding.

QOL, Health-Related Quality of Life, and Health Status The World Health Organization defines QOL as individuals’ perceptions of their positions in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards, and concerns [3]. This definition is generic. Health-Related Quality of Life (HRQOL) refers to domains that affect the health of a person. Researchers generally consider the domains of physical functioning (including pain), emotional state (including concentration and memory), performance of social roles, intellectual function, and general feelings of wellbeing or life satisfaction [4–6]. Subjective well-being, health, and welfare [7] are noteworthy areas under consideration as are social performance and social well-being [8]. These social variables are investigated by developing measures of social support and social adjustment. Veenhoven describes four components of quality of life: life chances, life ability, appreciation of life, and utility of life [9]. Wilson and Cleary [10] proposed a model incorporating several measures of health outcome, including biological and physiological factors, symptoms, functioning, general health perceptions, and overall quality of life. They argue that these different factors have a causal relationship among

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them, and since no one single instrument can capture all dimensions of health, a combination of instruments is suggested [10]. Scholars pursue methodologies and seek data that are measurable, quantifiable, and amenable to statistical analysis to enable meaningful comparison among studies. Although this concept is scientifically sound, many of us can attest that often highly functional people are dissatisfied with their lives whereas some who have disabilities are quite happy. Thus disability itself may not produce decrements in QOL. Moreover, levels of contentment, happiness, satisfaction, and patients’ perspectives of what is salient in their lives, domains that could be meaningful to the patient, are not captured by these measures. Clearly, the measurement of function alone cannot fully express the meaning of quality of life to different individuals. Furthermore, the importance of these domains is determined by professionals. Although not explicitly stated, the values of the researcher influence the construction of indices. Individualized QOL measurement methods and instruments offer the patient or research participant the chance to indicate those domains that are salient or meaningful to them [11]. Dijkers [11] has reviewed some of these QOL measurements that offer individuals the opportunity to indicate and/or select the domains of life, e.g., The Patient Specific Index, The Flannagan Quality of Life Scale, Schedule for the Evaluation of Individual Quality of Life, Individual Quality of Life Interview, and The Duggan–Dijkers Approach, among others. These instruments give subjects the opportunity to select domains, specify aspirations, and record their feelings or opinions on various domains. The construction of these indices is time- and effort-intensive, and the subject has the responsibility of domain selection. Moreover, proxy measures cannot be used as in HRQOL indices. Another point to consider is the limited cognitive and communication skills of some patients to express their preferences [11] or they may not have pondered the topic of preferences of life’s major concerns. Ware [12] proposed a conceptual paradigm that incorporates construction, scoring, and interpretation of “role participation” as distinct from the physical and mental aspects of health. It is suggested that this would “facilitate studies of the implications of differences in physical and mental capacities for an individual’s participation in life activities.” The application of Item Response Theory and computerized adaptive

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testing-based methods can be useful in attaining assessments that are more precise and practical [12]. Could the social milieu and cultural environment affect one’s perception of quality of life? A study in India on cancer patients showed that nearly two-thirds of the respondents believed that peace of mind, spiritual satisfaction, and social satisfaction were very important for a high quality of life; the level of individual functioning was not one of the top five important factors [13]. These results may reflect the influence of cultural practices, religious beliefs, and spirituality on one’s perception of quality of life. Other variables such as sociodemographic variables and the type of illness and its salience and severity level may also affect perceptions of QOL. The study points to the importance of social support and spirituality in ­measuring QOL. According to U.S. national surveys, 95% of Americans believe in God or a universal spirit and indicate that religious or spiritual beliefs are important in their lives. Studies suggest that religiosity and spirituality may indeed be related to positive health behaviors and satisfaction with life [14–17]. Often religiosity is measured by church attendance. This indicator may not capture intrinsic spirituality, a deeper sense of an all-pervading universal power. One study measured the relationship of a person’s health, physical pain, and intrinsic spirituality [18]. The investigators used the Index of Core Spiritual Experiences (INSPIRIT) to measure intrinsic spirituality. The Dartmouth Primary Care Cooperative Chart was used to assess overall health and pain. The response rate was 95% (442 patients). Overall health was significantly related to spirituality. Significant differences were found in overall health and physical pain across levels of spirituality: high, moderate, and low. Differences for men and women were observed for overall health but not for pain. In a study at Duke University, health-impaired subjects reported a history of seeking/receiving divine aid (God Helped). Lifetime Religious Social Support and current religious attendance were positively correlated at every level of impairment. Those who reported higher Lifetime Religious Social Support received more instrumental social support, irrespective of current attendance. Healthy behaviors were associated with both God Helped and Lifetime Religious Social Support. Cost of Religiousness (a measure of the occurrence of physical, emotional, and interpersonal losses

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and difficulties associated with one’s past religious life) predicted depressive symptoms and impaired-social support. Family History of Religiousness was unrelated to late-life health [19]. Research shows that religious and spiritual coping may affect the immune system. In a review, Seeman et al. [20] found that evidence from randomized interventional trials showed the beneficial physiological impact of meditation (primarily transcendental meditation) to physiological processes. They concluded that available evidence is generally consistent with the hypothesis that religiosity/spirituality is linked to health-related physiological processes including cardiovascular, neuroendocrine, and immune function [20]. Seybold [21] discussed the physiological mechanisms that could mediate the relationship between religion/spirituality and health [21]. In an exploratory study on 112 women with metastatic breast cancer, controlling for demographic, disease status, and treatment variables, women who rated spiritual expression as more important had greater numbers of circulating white blood cells and total lymphocyte counts. Those who reported greater spirituality showed higher helper and cytotoxic T-cell counts [22]. The beneficial role of spirituality warrants closer examination of this dimension of health and its incorporation in assessing overall QOL. Although QOL is accepted as a critical end result in biomedical research, little consensus exists pertaining to the definition of the construct of QOL and its differentiation from the concept of health status. Health status and QOL are separate concepts, since people may attribute high scores to their QOL despite having a disorder or disability depending on their attitudes toward pain and disability, their coping strategies, social networks and support, their expectations from family and friends, and varying levels of spirituality. Often, health status has been described as QOL [11, 23, 24]. A meta analysis of relationships between the constructs QOL and perceived health status and three domains (i.e., mental, physical, and social functioning) in 12 chronic disease studies illustrated that, from the patient’s perspective, QOL and health status are distinct constructs. When rating QOL, patients gave greater emphasis to mental health than to physical functioning, whereas appraisals of health status showed physical functioning was more important than mental health. Surprisingly, social functioning did not have a major impact on either construct [23]. Consistent with

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QOL research in adults, adolescents differentiate between these two constructs and, similar to adults, their QOL ratings were more strongly correlated with the mean number of poor mental health days than the mean number of poor physical health days [25]. This analysis indicates that many health status instruments may be inappropriate for measuring QOL. Evaluations of the effectiveness of medical treatment may be affected depending on whether QOL or health status is the study outcome [23].

Measuring Health-Related Quality of Life in Narcolepsy The Short Form 36 The most commonly used generic measures developed from the Medical Outcomes Study are SF-36, SF-12, and SF-8. The Short Form 36 (SF-36) is the most comprehensive [26, 27] and has been tested extensively in the U. S. and other countries and has been translated into many languages. Generic instruments may not be responsive to clinical changes in specific patients and may not be as sensitive to change as disease-specific ones [28, 29]. The SF-36 is suitable for a range of disorders and for the general population to elicit normative data for comparison among different disorders. It is considered the current acceptable standard measure for HRQOL with high reliability and validity. The instrument measures eight domains: physical functioning, role functioningphysical, role functioning-emotional, mental health, social functioning, vitality, bodily pain, and general health. It does not ask questions about sleep and uses vitality as a proxy – a term that can be misinterpreted by the respondent. Vitality is included in the mental health summary score but correlates significantly with both mental and physical health [30]. Shorter versions of the SF-36, i.e., SF-12 and SF-8, are available to ensure easy administration in less time [31]. The SF-36 version 2, a new modification, has improved wording and instructions, better internal consistency and reliability, and reduced floor and ceiling effects compared to the older version, thus improving its sensitivity to change and its precision (differentiation among groups) [32, 33].

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Sickness Impact Profile The Sickness Impact Profile (SIP) is a generic measure designed to evaluate functional status of patients with chronic diseases. It is a behaviorally based evaluation of dysfunction due to sickness. The aim was to create a sensitive, appropriate, and valid instrument to discern differences in health status and aid in evaluating the outcome of health services [34]. It includes 136 items grouped in 12 categories, namely, sleep and rest, alertness behavior, work, mobility, ambulation, body care and movement, eating, recreation and pastimes, home management, communication, social interaction, and emotional behavior. It has high test-retest reliability (r = 0.92) and internal consistency (r = 0.94). Clinical validity was determined by assessing the relationship between clinical measures of the disease and the SIP scores [35]. It may lack face validity for those who define themselves as well [32].

Functional Outcomes of Sleep Questionnaire The Functional Outcomes of Sleep Questionnaire (FOSQ) is a disease-specific, 35-item instrument that assesses the impact of excessive daytime sleepiness on physical, mental, and social functioning in daily activities. It measures activity level, vigilance, intimacy and sexual relationships, general productivity, and social outcome. The instrument is reported to have content validity, internal consistency, test-retest reliability, construct validity with the Epworth Sleepiness Scale as well as concurrent validity with the SIP and SF-36 [36]. A Norwegian version showed satisfactory internal consistency, test-retest reliability, and construct validity [37]. It is not as comprehensive as the SIP or the SF-36 as it does not include burden of symptoms and overall well-being [32]. It could serve as an adjunct to the SF-36 in assessing HRQOL in narcolepsy. Disease-specific instruments are focused on distinct diseases and are clinically relevant. Items that are not relevant to the specific disorder or disease should not be included in the instrument [38]. Scores cannot be compared to the general population or used to make comparisons across treatments for different diseases, Also, it may not pick up effects due to other coexisting conditions [38].

Points to Consider in Critical Appraisal of Research on HRQOL in Narcolepsy While evaluating studies in HRQOL, it is important to bear in mind the reliability and validity of the measuring instruments, their appropriateness for the aim of the study, and the external validity (generalizability) of the instrument. Consider, also, ordering and method of administration of the instrument. There may be a difference in responses when questionnaires are administered face-to-face by the researcher or by mail or telephone [39]. To reduce bias from ordering of administration of any instrument, the generic instrument should precede the disease-specific one, because subjects are likely to exclude their responses to the disease-specific measure from the responses to the generic measure [40]. Furthermore, the method of subject selection must be considered to avoid institutional bias and self-selection. Finally, patients are often confused between the symptoms of sleepiness and fatigue. The concepts of sleepiness and fatigue are often not clear to patients, and questionnaires may have items that are not mutually exclusive, thus confounding the results [41, 42]. Bailes et al. [41] found that the measures on all four popular sleepiness and fatigue scales (Stanford Sleepiness Scales, Epworth Sleepiness Scale, Chadler Fatigue Scale, and Fatigue Severity Scale) were highly correlated, indicating that the constructs of sleepiness and fatigue are confounded. By culling those items that were not significantly correlated, the authors created a six-item sleepiness and a three-item fatigue scale that eliminates the problems of confounded measures. In this study, the sleepiness items were related exclusively to a subject’s chances of dozing during daytime activities; the fatigue items were related to perceptions of lack of energy, weakness, or tiredness resulting from engaging in physical exercise and other daytime activities. There was good test-retest reliability in the scales, although retest was done at 4 h [41].

Quality of Life in Narcolepsy Most professionals and lay people know little about the pervasive effects of the symptoms of narcolepsy on the life of the individual. In fact, studies show that diagnosis may be delayed by as long as 10 or more

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years from the time the symptoms first appeared. During this time, the affected individual may drop out of school, lose a job, and develop relationship problems with family, friends, or teachers because of the inability to keep awake. The impact of narcolepsy and the quality of life issues has been documented, showing the negative effects of this disorder on work, education, recreation, sexual life, interpersonal relations, memory, personality, and marital life [43–48]. It is estimated that the prevalence of sexual dysfunction is approximately 25% in patients with narcolepsy. Possible etiological factors are, secondary to sleepiness: cataplexy, concomitant diabetes mellitus, or the medications prescribed for cataplexy [49]. The adverse effects of tricyclic antidepressants on erectile ­function is known [50]. High divorce (18% versus U.S. 7.3%) [51] and unemployment rates (16% versus U.S. 7.5%) [52] were reported in one study in New York City [53]. Respondents expressed need for counseling, transportation services, home maker and home care services. Patients reported pervasive feelings of tiredness and low levels of energy and motivation. Narcolepsy patients have poor driving records and high rates of automobile accidents [54, 55] as well as accidents at home and at work. In a survey on members of the American Narcolepsy Association using a mailed questionnaire, 539 members responded (68% response) out of a total of 783 members. About onethird (165) reported that they had accidents at work or at home. The most frequent accidents were falls, followed by burns from objects other than cigarettes, cuts, breaking things, cigarette burns, and spills. The study did not differentiate between accidents that occurred before or after treatment for narcolepsy [56]. The economic costs of having narcolepsy can be high and is comparable to diseases such as Parkinson’s disease [57]; Alzheimers disease [58]; epilepsy [59]; and stroke [60]. In a study in Germany [61] on 75 patients diagnosed with narcolepsy, information on the symptoms of narcolepsy and their economic impact was obtained through a standardized telephone interview and a mailed questionnaire to assess healthrelated quality of life (SF-36 and EQ-5D). The total annual cost of having narcolepsy was $15,410 per patient and direct cost amounted to $3,310. Total annual indirect costs of $11,860 per patient were due to early retirement because of narcolepsy. Thirty-two

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out of 75 patients reported narcolepsy as the cause of unemployment. Depression is a common feature in narcolepsy [62– 65]. It is reported that 49% of patients have depression versus 9–31% of the normal population [66]. A rate of 56.9% was revealed in a survey of narcolepsy patients in the U.K. [67] Memory and concentration problems, noted earlier, as well as depression were noted in a recent study. Sturzenegger and Bassetti [62] in Switzerland, conducted a prospective study including 57 subjects with narcolepsy and cataplexy, 56 patients with non-narcoleptic hypersomnia (H), and 40 normal controls (No). Patients were sub-categorized as narcolepsy subjects with definite cataplexy (N) and those without cataplexy or possible cataplexy (NpC). Comparisons were made with 12 hypocretin-deficient narcolepsy subjects (N-hd). There were significant differences between N and NpC (including mean sleep latency on MSLT) but none between N and N-hd. People with narcolepsy and possible cataplexy had a less severe form of narcolepsy as measured by standardized scores. The Epworth Sleepiness Scale (ESS) was significantly higher in N (17 ± 5) than in H (15 ± 4, p = 0.003). Problems with concentration (78%), problems with memory (68%) and depression (50%) were frequent in N and H (79, 61 and 60%) but not in No (30%, P < 0.001; 33%, P = 0.001; 23%, P = 0.01) [62]. Psychopathology was noted by Kales and Krishnan [68, 69]. However, a recent study in UK found that narcolepsy is not associated with psychiatric disorders nor with diagnosable depressive disorders. This study was conducted on 45 patients with narcolepsy and 50 normal controls matched for age and sex. Thirty-six patients were on modafinil without stimulants. No significant differences were found between patients and controls for depression or neurotic symptoms. These surprising results could be due to differential effects of medications taken over the years (amphetamines in the past and modafinil at the time of the study), differences in sample size, lack of standardized measures of symptoms, selection bias, and confusing hypnagogic hallucinations of narcolepsy, especially auditory hallucinations, with schizophrenia [70]. Cognitive deficits in narcolepsy have recently received the attention of researchers. Rieger et  al. reported impairment in the vigilance attention network as well as impairment in the executive attention network in subjects with narcolepsy [71]. Researchers in Germany found a pattern of slower information processing for patients with

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narcolepsy on more complex cognitive tasks that require a higher degree of executive function. The results indicated a mild verbal deficit and a consistent impairment in executive function in the narcolepsy group in comparison with matched controls [72]. Most of the patients were on medications (Ritalin or Vigil) and their confounding effect is not known. In a recent study in Korea, patients with narcolepsy showed impairment of vigilance, attention, and execution [73]. A newly devised computerized neurocognitive function test (Vienna Test System) was administered for this study of 24 subjects with narcolepsy with cataplexy and 24 controls matched on age, gender, and IQ. Narcolepsy subjects responded more slowly than controls to acoustic and visuoacoustic stimuli. In the vigilance test, the number of both omission and commission errors was much higher for subjects with narcolepsy (p < 0.05), probably, it is suggested, due to a qualitative deficit in information processing. The response time in narcolepsy subjects was slower than healthy controls, and this difference was more pronounced in complex tasks. Contrary to our clinical observation of memory problems in day-to-day activities in the lives of most patients with narcolepsy, even when they are attentive, this study showed no significant difference in the maximum memory function between the narcolepsy and control subjects. Appropriate measuring instruments that assess memory function in normal daily activities would be helpful in accurately eliciting information on memory problems. The small sample size does not allow for generalizability. In one meta analysis [74], reduction across different psychological functions was found in 22.9% of persons with insomnia, 34.6% in narcolepsy, and 36.9% of those who had sleep-related breathing disorders (SRBD). Research was undertaken in Germany [75] to elucidate daytime differences of performance in psychological tests along with subjective measures of sleepiness and tiredness in narcolepsy (NAR), treated and untreated obstructive sleep apnea (OSAS), psycho-physiological insomnia (INS), and a control group (CON). All participants were free of drugs acting on the central nervous system except for those in the NAR group who took medication for cataplexy. The NAR group showed consistently higher levels of impairment in alertness, selective attention, and subjective ratings of tiredness/sleepiness. The dominant pattern was curvilinear. In all three measures of cognitive functioning, performance decreased between

08:00 and 14:00 h and increased again or leveled off. Subjective ratings showed increasing tiredness/sleepiness from morning to early afternoon followed by a decrease in the late afternoon hours. Sleepiness/tiredness was correlated with higher self-rated depression scores and was more pronounced in untreated patients than in control subjects. Small sample size (ten subjects in each group) may limit the external validity of the results. The authors point out other limitations of the study, i.e., semi-random selection of subjects and training and adaptation effects due to repeated measurement design. Adjustment problems were noted in a survey of 129 members of the Australian Narcolepsy Support Group. The Psychosocial Adjustment of Illness Subscale – Self Report (PAIS – SR) total score revealed more adjustment problems for men than for women and more vocational adjustment problems for younger than older respondents with narcolepsy, probably due to the older group’s better acceptance and management of their condition. Medication status significantly affected adjustment in the social environment. The Stimulant Medication group was better adjusted than the No Medication group and the Stimulants + Tricyclics group. People with narcolepsy in this study reported more adjustment problems in comparison to cardiac, mixed cancers, and diabetes patients [76]. Because of a self-selected sample and different measuring instruments, the results of this study are difficult to compare with other studies.

Health-Related Quality of Life Health-Related Quality of Life was examined in a national investigation to study the effects of modafinil on wakefulness [77]. Data were collected in two similar 9-week double-blind studies including 558 persons with narcolepsy from 38 centers. Subjects were randomized into one of three groups: placebo, 200  mg modafinil, and 400  mg modafinil. A questionnaire comprising the SF-36 and supplemental narcolepsy-specific scale was administered to assess quality of life changes with treatment. These two instruments were pretested on narcolepsy patients in two sleep centers [78]. People with narcolepsy (PWN) were more affected in vitality, ability to perform usual activities due to physical and emotional

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problems, and social functioning compared to the general population. HRQOL effects were worse among PWN than among those with migraine headaches with one exception: bodily pain. PWN experienced HRQOL effects as bad as or worse than those with Parkinson’s disease and epilepsy in several HRQOL areas. In the UK, treated PWN had significantly lower scores than treated Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) patients for mental health and general health as measured by the SF-36 [65]. No significant differences were found between treated PWN and untreated OSAHS patients in the eight domains of the SF-36. Treated PWN were sleepier than untreated OSAHS patients with a greater impact on activities of daily living. PWN had difficulties in relation to leisure activities; subjects reported falling asleep in class (50%), at work (67%), and losing or leaving a job because of narcolepsy (52%). This study suggests that treatment and ­management of narcolepsy is not optimal. In a mailed questionnaire survey of 305 members of the United Kingdom Association of Narcolepsy (UKAN), respondents scored significantly lower on all domains of the SF-36 than age- and sex-matched normative data and particularly poorly in the physical, energy/vitality, and social functioning domains. The psychosocial questions developed for this study showed that narcolepsy affected education, work, relationships, activities of daily living, and leisure activities. There was no difference among groups receiving different medications. Normal health status was not restored with medications, again suggesting that pharmacological management of narcolepsy is inadequate [67]. The diagnosis of narcolepsy was not clearly established and subjects were self-selected members of the UKAN. In a study in Italy, narcolepsy patients were compared with idiopathic hypersomnia and sleep apnea patients. The SF-36 was self-administered. The narcolepsy patients scored lower in all domains, except bodily pain, than the Italian norm. Some of the variance was explained by excessive daytime sleepiness (inverse relation) and disease duration (direct relation, probably due to adaptation) [79]. A cross-sectional study of 77 members (with narcolepsy and cataplexy) of the Norwegian Association for Sleep Disorder (NASD) showed that respondents had significantly lower scores on all domains of the scale

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of the SF-36, with the exception of the vitality domain, when compared with the normal population. Treatment with medication for narcolepsy did not affect any domain in the study. The SF-36 was mailed to the respondents. According to the authors, differences in results from other studies could be due to a difference in mindset or public education in Norway or to access to support and relevant educational material due to their membership with the NASD [80]. The FOSQ was used in a randomized trial with 285 patients with narcolepsy to study the effectiveness of sodium oxybate on HRQOL. The medication produced significant dose-related improvements in the Total FOSQ score from baseline. Similar improvements were observed in the Activity Level, General Productivity, Vigilance, and Social Outcomes subscales (p < 0.01). Intimacy and Sexual Relationships subscale was not affected [81]. The following two recent studies used the SIP to evaluate functional health status. In a study conducted by mail on 81 patients with narcolepsy by Droogleever Fortuyn et al. [42] 62.5% reported severe fatigue, and fatigued patients reported higher use of stimulant medication than those not reporting severe fatigue (64%, 40%, p = 0.02). Fatigue was differentiated from sleepiness and was measured by a 20-item Checklist Individual Strength (CIS) questionnaire. Patients with CIS-fatigue score > 35 were compared with those without severe fatigue. Daytime sleepiness did not differ in the two groups, indicating a differentiation between fatigue and sleepiness. Fatigued patients were more likely than non-fatigued patients to report less control over symptoms and “catastrophic thoughts.” Severe fatigue also significantly increased functional impairment (Sickness Impact Profile) and resulted in low quality of life (SF-36). Perhaps fatigue is partially caused by stimulant medications [42]. The questionnaire was mailed to 127 patients with narcolepsy and the response rate was 65%. Ton et al. in their research on 226 patients with narcolepsy conducted personal interviews and elicited information on their health status. The percent of total dysfunction (SIP mean 10.3) was significantly correlated with the Epworth Sleepiness Scale (0.33, p < 0.001) and the Ullanlinna Narcolepsy Scale (0.41, p < 0.001). Total dysfunction score on the SIP (mean % = 13.2) was higher than the general population score (mean % = 3.6). Psychosocial aspect was more dysfunctional (mean = 13.2) than the physical one (mean = 5.0).

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The mean percent of dysfunction was in the following areas: sleep and rest (23.6), alertness behavior (22.6), recreations and pastimes (20.6), and work (15.3). Areas of concern to patients included social isolation, reduced sexual activity, and forgetfulness [82]. How do patients adjust to a new way of life after successful treatment of narcolepsy? The amelioration or, in some cases, the removal of the negative psychosocial impact of a chronic illness may have farreaching and diverse effects on the lives of patients receiving these treatments. Psychosocial adjustment to a new way of “normal” life may pose challenges requiring psychosocial support and acquisition of coping techniques. Adjustment problems during adaptation to normal life following seizure surgery are illustrated [83]. Persons with narcolepsy face similar post-treatment adjustment experiences as those who have epilepsy according to a study conducted in Australia [84]. Researchers evaluated the “burden of normality” in 33 successfully treated patients with narcolepsy (Nar) and compared the results with 31 patients with epilepsy (Epi) who had successful epilepsy surgery. The Austin CEP interview has been validated with epilepsy patients who underwent anterotemporal lobectomy (ATL) but not with narcolepsy patients. Content analysis of the responses showed perceptions of post-treatment changes that were significant. Identity transformation was the most frequently reported psychological adjustment occurring in both groups (Nar 79%; Epi 87%).followed by increased expectations by self and others (Nar 70%; Epi 71%). Both groups described grief over missed opportunities and years “lost” because of limitations posed by a chronic illness [Nar 33%; Epi 71% (P < 0.01)]. Nar patients were more frustrated than Epi patients over the delay in effective treatment (Nar 45%; Epi 0%). This may be related to delay in diagnosis of narcolepsy and ineffective medication in some cases. Major behavioral manifestations of post-treatment adjustment were excessive activity levels (Nar 54%; Epi 42%) and shirking/avoidant behavior (Nar 52%; Epi 65%). Major sociological features of adjustment were: need to structure relationships (Nar 55%; Epi 65%); new vocational /educational goals (Nar 33%; Epi 45%); new social horizons (Nar 9%; Epi 42%; P < (0.01). This study documents the need for psychosocial support services after successful treatment

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of narcolepsy. The authors stress the need for pre- and post-treatment psycho-education and support for persons with narcolepsy currently undergoing treatment. We have examined the negative impact of narcolepsy on the lives of those who have this disorder. Can a disability have any positive consequences for the individual and the family? No study has addressed this topic in narcolepsy; however, research in other medical disorders suggests that an illness could be a catalyst for positive growth. Stress-related growth is the phenomenon of discovering or experiencing positive personal enhancement in a situation that is initially negative and devastating. In one study of women living with HIV/AIDS in New York City, 83% of the respondents reported an array of positive changes in their lives [85]. Respondents identified several areas of growth, including: relationships, health behaviors, career goals, view of self, value of life, and spirituality. What are the factors that might promote stress-related growth? Variables may include sociodemographic variables, inner resources, type of stress, and availability of support. In a study using the Schaefer and Moos model [86] to explain the phenomenon of stress-related growth, Siegel et al. [87] found that the variables positive reappraisal coping and emotional support were associated with higher levels of growth, whereas depressive affect was negatively associated with growth. Furthermore, characteristics particular to the stress, self-esteem, perceived control, practical support, and positive affect were not associated with growth. This relatively new area of research suggests that, even in the face of great stress, an overwhelming majority of human beings can still locate a silver lining. Further research with different stressors and different disorders will shed more light on the phenomenon of stress-related growth. Social factors affect health status and thus influence QOL [88–90]. In fact, social support, particularly tangible social support, may affect the immune system and, in a recent study, was positively associated with the antibody response to vaccination with pneumococcal polysaccharides [91]. Social network variables significantly affect overall health status of patients with chronic diseases [92, 93] and are reported to have a direct relationship with mortality rates [89]. People who are more socially active function better than those with few social ties [94–96]. Social support is the degree to which a person’s basic needs are satisfied

17 Quality of Life and Psychosocial Issues in Narcolepsy

through a social network. These basic needs may be emotional (affection, sympathy, understanding, acceptance, and esteem from significant others) or instrumental (advice, information, assistance with responsibilities, and economic help) [97]. Others have defined social support as the information, alliance, aid, and esteem derived from interactions with family, friends, peers with similar concerns or problems, and professionals [98]. Social network refers to the social relations with family, friends, and colleagues [99]. Social support can influence coping mechanisms [100] and promote health [101], a recent study revealed that emotional support may promote cognitive resilience while social ties provide cognitive reserve that protects against impaired cognition [102]. Support groups differ from self-help groups and psychotherapy groups. Self help groups are run by patients who share knowledge acquired through a common experience with an illness (Surgeon General C. Everett Koop’s report by Mary Huber 1987). Patients control the group and, there is no charge, but donations are often encouraged. Support groups are led by a professional facilitator [103]. The mission is to provide mutual aid in a small group structure to serve the core needs of the members, which includes sharing information and providing advocacy, support, and affirmation as well as the opportunity to socialize [104]. Traditional psychotherapy groups, on the other hand, focus on personal exploration in a group setting with the aim of producing change in themselves and in interpersonal relationships by observation, reflection, and awareness [105]. Sivisind and Baile offer the following four major differences between support groups and psychotherapy groups [103]. • Support groups offer concrete guidance, whereas psychotherapy groups do not. • Support groups are run for an indefinite period of time and the members change frequently, whereas psychotherapy groups are time-limited and have a consistent group membership. • Support group members are identified by a common problem, whereas members of a psychotherapy group are not. • Support groups help patients cope with the effect of an illness/disorder and decrease a sense of isolation of group members. In contrast, psychotherapy groups focus on making personal changes through

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insight to improve interpersonal skills or relieve intra psychic distress. Studies have shown the positive effects of support groups in chronic illnesses, including cancer, [106, 107], diabetes [108], cardiac conditions [109, 110], and in child birth [111, 112]. In a recent study on 100 women with breast cancer, researchers examined the relationship between symptom distress and QOL when religious support and personal support were introduced as intervening variables. Personal support, but not religious support, was positively related to QOL and partially mediated the effects of symptom distress [113]. Investigation of psychosocial resources (positive support, active coping) and psychosocial constraints (negative support, avoidant coping) as predictors of improvement in health following surgery revealed that psychosocial constraints, namely, negative support and avoidant coping encountered by patients were strong predictors of poor recovery [114].

Narcolepsy and Support Groups In a qualitative study, narcolepsy patients reported several benefits of attending support groups [115]. Diagnosed narcolepsy patients are registered with the Narcolepsy Institute for counseling, behavior modification, and case management. All eligible patients and their families are informed about monthly support groups organized by the Narcolepsy Institute. All participants volunteer to attend these groups. Fifteen frequent members attend most of the groups and about 15 attend infrequently. Considering that 75 members in New York City had registered for the Family Support Program in 2000–2001, the attendance rate was 40%. Frequent members have developed a bond and a spirit of camaraderie. They welcome new members and often offer suggestions and advice. Older members show compassion towards younger members and narrate their own experiences with narcolepsy when they were in their teens or twenties. The facilitator sometimes has to intervene if the discussion assumes a negative tone or diverges from the topic and steers the group unobtrusively towards a supportive and positive note. An annual program evaluation is an integral part of this program. A questionnaire with structured and

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open-ended questions was administered to 15 group members in 2000. The questionnaire was designed to assess patients’ satisfaction with services, their needs, and their perceptions of support groups. This information is valuable in making changes in program development. Content analysis of patients’ responses to the questions related to benefits of support groups at the Narcolepsy Institute and their perceptions of reasons why some members do not attend support groups is presented. All responses to an open-ended question on benefits of attending support groups were classified into three categories: emotional benefits, information, and services received from the Narcolepsy Institute. Emotional support indicated by the following comments: The give and take; I learn to share; received genuine love and caring; I am not alone; it helps me to be stronger; I feel optimistic; I get guidance; I derive emotional strength and information from other people’s experience; they have changed my life and provide continuous support. Information or Instrumental support indicated by the following comments: I receive very good information on medications, diet, and nutrition (most responses). My understanding of how narcolepsy affects my own life has been broadened immeasurably, thanks to these sessions. I learn about living with a disorder and concern for others. I learned to keep an organized schedule. I adopted good food habits that are helpful in staying awake. Services Counseling is very good; support groups; support from other patients; newsletter; staff has a positive approach; personal attention; staff members treat me well; they are always there to help me [115]. Patients’ responses reveal that they derived invaluable benefits from group meetings. The most commonly stated benefit was the amount of information they received about managing symptoms, various treatments, and new research on narcolepsy. Some felt that the group provided the drive they needed to move on with their lives. Many felt that the sincerity and friendship of the group was particularly important to them. Others expressed great relief at meeting those who have a similar disorder and sharing experiences with them. A few members stated that they developed more self-confidence since participating in groups and that the sessions on nutrition were particularly relevant to their condition. Emotional support and strength from other people’s experiences and valuable information on

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­ edications, diet, organizing tasks, and learning to m keep awake were other benefits expressed by members. Support groups provide a forum for information exchange, acceptance and understanding by peers who are similarly affected, and access to pertinent resources in a supportive and caring environment. Patients feel reassured and develop confidence and hope [115]. Thus, counseling and support are important in the comprehensive management of narcolepsy. A support group setting provides unique features not found in psychotherapy groups. Group cohesion develops from a sense of understanding, compassion, and acceptance from group members providing a “significant other” and reduces isolation and passivity that many persons with narcolepsy experience. Helping others in the group lends meaning and dignity to their lives. Group cohesion and mutual aid seem to work together to enhance the quality of the group experience [103].

Why Do Some Members Not Attend Support Group Meetings? The services provided by the Narcolepsy Institute are free for eligible members; however, many members do not avail themselves of the opportunity to participate in the groups. The reasons given by patients for not attending are: • Lack of transportation. • Inability to find a companion to accompany them to the meeting. • Difficulty traveling in the subway because of sleepiness and frequently missing the destination stop. • The discomfort of traveling or staying awake in the group due to the severity of narcolepsy and cataplexy. • The perception that they do not need support from a group. • Self-perceived need for a psychotherapy group. • Lack of motivation: I would like to attend but I can’t get myself to come up there. • Inability to attend because of work and conflicting time schedules. • Lack of knowledge about what benefits could be derived from a support group. These responses reflect difficulty in utilizing public or private transportation due to narcolepsy, low

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motivation, lack of time, and lack of understanding about what support groups have to offer.

What Characteristics Differentiate Those Who Attend Support Groups from Those Who Don’t? This question has not been addressed in narcolepsy; however, researchers in Sweden [116] conducted a study to compare the personal traits, lifestyle, and available social support of attendees and non-attendees in patients with cardiac disease. Differences were observed between attendees and nonattendees: Attendees reported more health problems and showed higher rates on several areas of social support in comparison with nonattendees. Nonattendees reported a more relaxed attitude to life and a more positive view of themselves than attendees. Attendees reported that close relationships were a source of information to a greater extent than did non-attendees; they scored higher than non-attendees on emotional satisfaction and on the degree of autonomy in their relationships; they were also more likely than non-attendees to indicate agreement concerning values in their network. Perhaps non-attendees are more independent-minded and have less need for support groups.

Implications for Management of Narcolepsy Review of studies on QOL in narcolepsy in the USA and other countries documents extensive negative effects of narcolepsy on physical health, mental health, work, and social health of patients. Keeping in mind that there are differences in methodology in different studies, a pattern of reduced function in narcolepsy is evident. Notably, PWN were sleepier than untreated OSAHS patients, with a greater impact on activities of daily living [65]; they reported more adjustment problems in comparison to patients with cardiac disease, mixed cancers, and diabetes [76]. The economic burden of illness was comparable to Parkinson’s disease, Alzheimer’s disease, epilepsy, and stroke [61]; They reported significantly higher levels of impairment in

alertness, selective attention, and subjective ratings of tiredness/sleepiness when compared with OSAS, insomnia patients, and controls [75]. Treatment of narcolepsy is not optimal [65, 66] and even after successful treatment, patients may have adjustment problems [84]. Finally, social support provides many benefits and enhances individuals’ ability to cope with their disabilities and improve the quality of their lives [115]. This review indicates that pharmacological management of symptoms is not sufficient although it is necessary in most cases. Successful management of objective and observable clinical features may be affected by other complaints of narcolepsy patients, such as low level of energy and fatigue, problems with memory, depressed mood, adjustment problems, and perception of lack of security in the environment. Patients need relief from the negative impact of narcolepsy on their mental and social lives. Medical treatment should be supplemented with behavior modification and psychosocial support and counseling.

Social Support and Counseling People with narcolepsy are often socially isolated. Even if the disorder is well controlled or not severe, patients may avoid social events because of low energy level, sleepiness, fear of embarrassment or potential injury, depression about their condition, or lack of motivation. Many patients benefit from obtaining information and counseling from a professional in order to cope with interpersonal relationships, marital problems, genetic issues, career selection, career growth, memory problems, and time management. Long-term psychosocial support is essential to the total management of narcolepsy and is best addressed by a team approach in which physician and psychologist, social worker, or qualified counselor work together in the best interests of the patient. Patients with severe coping problems should seek the assistance of a psychiatrist for more intensive counseling and therapy. Interpersonal relations are greatly affected in narcolepsy. Even families who are knowledgeable about the disorder may face significant problems. Misunderstandings, frustrations, and anger may build between parents and children. Parents may worry about the possibility that their

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children will inherit the disorder. Support and counseling by a sensitive professional individually or in support groups will clarify misunderstandings, improve communication, and enhance the quality of relationships. Support groups provide a forum for information exchange, acceptance by peers who are similarly affected, mutual understanding, and access to needed resources. A supportive and caring environment allows participants to talk freely about their feelings of isolation, lack of understanding from others, and fear of social or emotional rejection that many with narcolepsy experience. Sharing information about clinical symptoms, medications and their effects, and coping strategies in managing the psychosocial impact of narcolepsy is an important group process enabling patients to develop a positive outlook. Many emotional burdens are reduced by discussing the experiences of different group members. Social support may strengthen individual coping behavior by increasing morale or self-esteem [115]. Support groups facilitate active involvement by patients in their health care and have a unique value in the total care of a patient, thus enhancing their quality of life. Perhaps referral by professionals and explanation of benefits derived from participation in support groups will encourage more patients to engage actively in support groups. In view of recent data on stress-related growth, timely and appropriate psychosocial interventions and access to social resources to promote stress-related growth may improve the quality of life of patients with narcolepsy.

Transportation Some persons with narcolepsy cannot drive and may avoid public transportation, fearing they will fall asleep or get cataplexy. Many do not wish to be dependent on others for transportation. In support group meetings at the Narcolepsy Institute, patients report sleeping on the train or bus and missing their destination stops; missing a highway exit while driving and entering another state; and sleeping at the airport and missing their flights. The support of a companion while traveling and access to special transportation services for the disabled will ensure safety and facilitate timely and punctual visits to their professionals.

Employment Because education for persons with narcolepsy is often either inadequate or interrupted, career goals may need to be changed or adjusted. EDS may not only hinder job progress but may also result in job loss. Advocacy by a professional may be needed to enlighten employers about narcolepsy so that appropriate adjustments to working conditions can be made, such as providing intermittent work breaks for a rest or brief nap. Potential approaches that may ensure job opportunities and continued employment of valuable and valued workers are (1) flexible work schedules that allow brief nap times and take advantage of the employee’s best functioning periods; (2) work assignments that will not be hazardous to the employee or to others; (3) work assignments that do not require either rotating shifts or performance of sedentary monotonous tasks that contribute to EDS; and (4) work that provides mental stimulation as well as physical activity. To alleviate fear of job loss, to assure equity of employment, and to promote a comfortable work atmosphere, both employers and employees should be educated about narcolepsy, its symptoms, and the limitations it may place on certain job aspects. Employees and employers should be aware of legislation that prevents discrimination in hiring and employment practices. Narcolepsy is classified legally by the United States Federal and State governments as a disability and in New York State as a developmental disability. The Americans with Disabilities Act provides protection for people with disabilities [117]. With support from their health care professionals, disabled individuals can request accommodations in the work place. As patients weave the experience of having narcolepsy into the fabric of their personal and social lives, sensitive health care professionals may enhance the healing process by timely psychosocial interventions or referrals for such services. Determination of the adequacy of social support in the management of narcolepsy will enable professionals to facilitate accessibility of support services. Furthermore, inasmuch as religion and spirituality are the most prevalent and powerful coping mechanisms that lend value and meaning in the experience of stress and/or illness, professionals should become aware of the various resources that can be accessed by patients.

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Research Implications

References

Tiredness and sleepiness are different symptoms, and lack of differentiation between the two symptoms in the measuring instrument may confound the results. Combining different instruments or administering different measures for symptoms, health status, and QOL may elicit more valid results. Studies that combine standardized HRQOL instruments, individualized instruments, and subjective qualitative data may elicit richer data, and qualitative data may explain some of the processes (why and how) for making cognitive and behavioral changes to enhance the quality of life. Longitudinal studies are needed to determine the process involved in the correlation between the domain selected and perception of satisfaction with life. How do patients rate the importance of different domains? Are individuals’ levels of expectations and aspirations realistic? Are they equipped with the necessary skills to adjust their expectations when life’s circumstances thwart the fulfillment of these expectations? The beneficial role of spirituality warrants closer examination of this dimension of health and its incorporation in assessing overall quality of life. What determines self-perceived recovery in narcolepsy? Do physical factors (symptoms) play a more important role than social or mental factors in the recovery process? Do social and mental factors mediate the recovery process? Longitudinal studies in group processes in narcolepsy are needed to study the underlying mechanism of change in health behaviors to enhance the quality of life. A study of characteristics of persons with narcolepsy that differentiate those who attend support groups from those who don’t would offer valuable information on psychological and social variables that can be manipulated to promote and enhance participation in the counseling process and support groups. In conclusion, a person-centered comprehensive management approach must be designed to address narcolepsy, its disabling effects, and the role of social stressors and social supports on the quality of life of the individual and the family. Comprehensive care implies active participation by the clinician, patient, and family in treating the whole person, thus maintaining the dignity of the individual while adhering to sound scientific principles coupled with humanistic care.

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17 Quality of Life and Psychosocial Issues in Narcolepsy 56. Cohen, F., Ferrans, C. E., and Eshler, B. (1992) Reported accidents in narcolepsy. In Goswami, M, Pollak, C. P., Cohen, F. L., Thorpy, M. J.; Kavey, N. B., and Kutscher A. H. (Eds.). Psychosocial Aspects of Narcolepsy. New York, NY: Haworth Press Inc., 71–80. 57. Dodel, R., Singe, M., Kohne-Volland, R., et al. (1998) The economic impact of Parkinson’s disease Pharmaoeconomics 14, 299–321. 58. Ernst, R. L. and Hay, J. W. (1994) The US economic and social costs of Alzheimer’s disease revisited Am J Public Health 84, 1261–1264. 59. Kotsopoulos, I. A, Evers, S. M., Ament, A. J., et al. (2003) The costs of epilepsy in three different populations of patients with epilepsy Epilepsy Res 54, 131–140. 60. Martinez-Vila, E. and Irimia, P. (2004) The cost of stroke Cerebrovasc Dis 17, 124–129. 61. Dodel, R., Peter, H., Walbert, T., Spottke, A., et al. (2004) The socioeconomic impact of narcolepsy Sleep 27(6), 1123–1128. 62. Sturzenegger, C. and Bassetti, C. (2004) The clinical spectrum of narcolepsy with cataplexy: a reappraisal J Sleep Res 13, 395–406. 63. Broughton, R., Ghanem, Q., Hishikawa, Y., Sugita, Y., Nevsimalova, S., and Roth, B. (1981) Life effects of narcolepsy in 180 patients from North America, Asia, and Europe compared to matched controls Can J Neuro Sci 8, 299–304. 64. Beutler, L. E., Ware, J. C. Jr., Karacan, I., and Thornby, J. I. (1981) Differentiating psychological characteristics of patients with sleep apnea and narcolepsy Sleep 4, 39–47. 65. Teixeira, V. G., Faccenda, J. F., and Douglas, N. J. (2004) Functional status in patients with narcolepsy Sleep Med 5(5), 477–483. 66. Merritt, S. L., Cohen, F. L. and Smith, K. M. (1992) Depressive symptomatology in narcolepsy. In Goswami, M., Pollak, C. P., Cohen, F. L., Thorpy, M. J.; Kavey, N. B. and Kutscher, A. H. (Eds.). Psychosocial Aspects of Narcolepsy. New York, NY: Haworth Press Inc., 53–59. 67. Daniels, E., King, M. A., Smith, I. E., and Shneerson, J. M. (2001) Health related quality of life in narcolepsy J Sleep Res 10, 75–81. 68. Kales, A., Soldatos, C. R., Bixler, E. O., Caldwell, A., Cadieux, R. J., Verrechio, J. M., and Kales, J. D. (1982) Narcolepsy-cataplexy. II. Psychosocial consequences and associated psychopathology Arch Neurol 139, 169–171. 69. Krishnan, R. R., Volow, M. R., Miller, P. P., and Carwile, S. T. (1984) Narcolepsy: preliminary retrospective study of psychiatric and psychosocial aspects Am J Psychiatry 141, 428–431. 70. Vourdas, A., Shneerson, J. M., Gregory, C. A., Smith, I. E., King, M. A., Morrish, E., and McKenna, P. J. (2002) Narcolepsy and psychopathology: is there an association? Sleep Med 3(4), 353–360. 71. Rieger, M., Mayer, G., and Gauggel, S. (2003) Attention deficits in patients with narcolepsy Sleep 26(1), 36–43. 72. Naumann, A., Bellebaum, C., and Daum, I. (2006) Cognitive deficits in narcolepsy J Sleep Res 15, 329–338. 73. Ha, K. S., Yoo, H. K., Lyoo, I. K., Jeong, D. U. (2007) Computerized assessment of cognitive impairment in narcoleptic patients Acta Neurol Scand 116, 312–316. 74. Fulda, S. and Schulz, H. (2001) Cognitive dysfunction in sleep disorders Sleep Med Rev 5, 423–445.

203 75. Schneider, C., Fulda, S., and Schulz H. (2004) Daytime variations in performance and tiredness/sleepiness ratings in patients with insomnia, narcolepsy, sleep apnea and normal controls J Sleep Res 13, 373–383. 76. Bruck, D. (2001) The impact of narcolepsy on psychosocial health and role behaviors: negative effects and comparisons with other illness groups Sleep Med 2, 437–446. 77. Beusterien, K. M., Rogers, A. E., Walsleben, J. A., Ensellem, H. A., Reblando, J. A., Wang, L., Goswami, M., and Steinwald, B. (1999) Health-related quality of life effects of modafinil for treatment of narcolepsy Sleep 22(6), 757–765. 78. Stoddard, R. B., Goswami, M., and Ingalls, K. K. (1996) The development and validation of an instrument to evaluate quality of life in narcolepsy patients. Drug Information Journal, Drug Information Association: Amber PA, USA, 850. 79. Vignatelli, L., D’Alessandro, R., Mosconi, P., RefiniStrambi, L., Guidolin, L., DeVincentiis, A., and Plazzi, G. (2004) Health related quality of life with narcolepsy: the SF-36 health survey Sleep Med 5(5), 467–475. 80. Ervik, S., Abdelnoor, M., Heier, M. S., Ramberg, M., and Strand, G. (2006) Health-related quality of life in narcolepsy Acta Neurol Scand 114, 198–204. 81. Weaver, T. E. and Cuellar, N. (2006) A randomized trial evaluating the effectiveness of sodium oxybate therapy on quality of life in narcolepsy Sleep 29(9), 1189–1194. 82. Ton, T. G., Watson, N. F., and Longstreth, W. T. (2008) Narcolepsy and the Sickness Impact Profile: a general health status measure Sleep 31, A218. 83. Wilson, S. J., Bladin, P. F., Saling, M. M., et  al. (2005) Characterizing psychosocial outcome trajectories following seizure surgery Epilepsy Behav 6, 570–580. 84. Wilson, S. J., Frazer, D. W., Laurence, J. A., and Bladin, P. F. (2007) Psychosocial adjustment following relief of chronic narcolepsy Sleep Med 8(3), 252–259. 85. Siegel, K. and Schrimshaw, E. W. (2000) Perceiving benefits in adversity: stress-related growth in women living with HIV/AIDS Soc Sci Med 51(10), 1543–1554. 86. Schaefer, J. A. and Moos, R. H. (1998) The context for posttraumatic growth: Life crises, individual and social resources, and coping. In Tedeschi, R. J., Park, C. L., and Calhoun, L. G. (Eds.). Posttraumatic Growth: Positive Changes in the Aftermath of Crisis. Laurence Erlbaum: Mahwah, NJ. 99–126. 87. Siegel, K., Schrimshaw, E. W., and Pretter, S. (2005) Stressrelated growth among women living with HIV/AIDS: examination of an explanatory model J Behav Med 28, 403–414. 88. Srole, L., Langer, T., Michael, S., Kirkpatrick, P., Opler, M., and Rennie T. (1961) Mental Health in the Metropolis, Volume 1 in The Thomas A. C. Rennie series in Social Psychology. New York, NY: McGraw-Hill. 89. Berkman, L. and Syme, L. (1979) Social network, host resistance and mortality: a nine-year follow-up study of Alameda county residents Am J Epidemiol 190, 186–204. 90. House, J., Lepkowski, J., Kinney, A., Mero, R., Kessler, R., and Herzog, A. (1994) The social stratification of aging and health J Health Soc Behav 35(3), 213–234. 91. Gallagher, S., Phillips, A. C., Ferraro, A. J., Drayson, M. T., and Carroll, D. (2008) Social support is positively associated with the immunoglobulin M response to vaccination with pneumococcal polysaccharides Biol Psychol 78(2), 211–215.

204   92. Patrick, D. L., Morgan, M., and Charlton, J. R. H. (1986) Psychosocial support and change in the health status of physically disabled people Soc Sci Med 22, 1347–1354.   93. Fitzpatrick, R, Newman, S., Lamb, R., and Shipley, M. (1988) Social relationships and psychological well-being in rheumatoid arthritis Soc Sci Med 27, 399–403.   94. Cassel, J. (1976) The contribution of the social environment to host resistance Am J Epidemiol 104, 107–123.   95. House, J., Umberson, D., and Landis, K. (1988) Structures and processes of social support Annu Rev Sociol 14, 293–318.   96. Veiel, H. and Baumann, U. (1992) The many meanings of social support In Veiel, H. and Baumann, U. (Eds.). The Meaning and Measurement of Social Support, New York, NY: Hemisphere Publishing, 1–7.   97. Thoits, P. (1982) Conceptual, methodological and theoretical problems in studying social support as a buffer against life stress J Health Soc Behav 23, 145–159.   98. Stewart, M., Hart, G., and Mann, K. (1995) Living with hemophilia and HIV/AIDS: support and coping J Adv Nurs 22(6), 1101–1111.   99. Kroll, B., Sanderman, R., and Suurmeijer, T. (1993) Social support, rheumatoid arthritis and quality of life: concepts measurement and research Patient Educ Couns 20(2–3), 101–120. 100. Heller, K. (1990) Social and community intervention. Annu Rev Psychol 41, 141–168. 101. Maguire, L. (1991) Social Support Systems in Practice. Silver Spring, MD: National Association of Social Workers Press. 102. Glymour, M. M., Weuve, J., Fay, M. E., Glass, T., and Berkman, L. F. (2008). Social ties and cognitive recovery after stroke: Does social integration promote cognitive resilience? Neuroepidemiology 31(1), 10–20. 103. Sivesind, D. M. and Baile, W. F. (1997) An ovarian cancer support group Cancer Pract 5, 247–251. 104. Katz, A. and Bender, E. (1976) Self-help groups in western society: history and prospects J Appl Behav Sci 12, 265–282. 105. Wasserman, H. and Danforth, H. E. (1988) The Human Bond: Support Groups Mutual Aid. New York, NY: Springer. 106. Cella, D. F. and Yellen, S. B. (1993) Cancer support groups: the state of the art Cancer Pract 1(1), 56–61.

M. Goswami 107. Krupnick, J. L., Rowland, J. H., Goldberg, R. L., and Daniel, U. V. (1993) Professionally led support groups for cancer patients: an intervention in search of a model Int J Psychiatry Med 23(3), 275–294. 108. Gilden, J. L., Hendryx, M. S., Clar. S., Casia, C., and Singh S. P. (1992) Diabetes support groups improve health care of older diabetic patients J Am Geriatr Soc 40(2), 147–150. 109. Stewart, M., Davidson, K., Meade, D., Hirth, A., and WeldViscount, P. (2001) Group support for couples coping with a cardiac condition J Adv Nurs 33(2), 190–199. 110. Hildingh, C. and Fridlund, B. (2003) Participation in peer support groups after a cardiac event: a 12-month follow-up Rehabil Nurs 28(4), 23–28. 111. Campero, L., Garcia, C., Diaz, C., Ortiz, O., Reynoso, S., and Langer, A. (1998) Alone, I wouldn’t have known what to do: A qualitative study on social support during labor and delivery in Mexico Soc Sci Med 47, 395–403. 112. Klaus, M. H., Kennel, J. H., Robertson, S. S., Sosa, R. (1986) Effects of social support during parturition on maternal and infant morbidity Br Med J 293, 585–587. 113. Manning-Walsh, J. (2005) Social support as a mediator between symptom distress and quality of life in women with breast cancer J Obstet Gynecol Neonatal Nurs 34(4), 482–493. 114. Stephens, M. A., Druley, J. A., and Zautra, A. J. (2002) Older adults’ recovery from surgery for osteoarthritis of the knee: psychosocial resources and constraints as predictors of outcomes Health Psychol 21(4), 377–383. 115. Goswami, M. (2005) Quality of Life in Narcolepsy: the importance of social support. Second Interim Congress of the World Federation of Sleep Research and Sleep Medicine Societies. New Delhi (India), September 22–26. Kumar, V. M. and Mallick, H. N. (Eds.). Medimond: International Proceedings. 116. Hildingh, C. and Fridlund, B. (2001) Patient participation in peer support groups after a cardiac event Br J Nurs 10(20), 1357–1363. 117. Sundram, C. J. and Johnson, P. W. (1992) The legal aspects of narcolepsy In Goswami, M., Pollak, P. C., Cohen, F. L., Thorpy, M. J., Kavey, N. B., and Kutscher, A. H. (Eds.). Psychosocial Aspects of Narcolepsy. New York, NY: Haworth Press, 175–192.

Chapter 18

Narcolepsy, Intimacy and Sexuality Gila Lindsley

Intimacy is an intrinsically important and personal part of every individual’s life. In the mental health community it is often said that everyone – patient and clinician alike – seeks intimacy. The ability to achieve and maintain intimate relationships poses a considerable challenge to many people with or without narcolepsy, as witness the popularity of the book Dance of Intimacy [1]. In the case of narcolepsy, additional challenges are superimposed. This chapter will look at the challenges to the development and maintenance of several different kinds of intimate relationships for those with narcolepsy: the non-sexualized intimate parent–child and friendship relationships; intimate relationships with spouse or partner, both non-sexual and sexual aspects; and the intimate relationship with oneself. There have already been some excellent publications about the impact of narcolepsy on quality of life in general, and on interpersonal relationships more specifically [2–8]. However, there are very few publications which explicitly highlight intimacy issues. The paucity of prior research publications on this important topic leads to a need to rely primarily upon sources of information other than peer-reviewed journals or texts. Specifically, the content of this chapter will largely be drawn from anecdotal data derived from professional contact with a large number of people with narcolepsy. In order to maintain confidentiality, a synthesis of the main themes that emerged and several illustrative de-identified cases will be presented. With the availability of deeper insight into the way narcolepsy G. Lindsley (*) SleepWell Lexington, 7 White Pine Lane, Lexington, MA, 02421, USA e-mail: [email protected]

can impact upon intimate relationships, clinicians will hopefully attain a broadened base from which to guide people with narcolepsy toward satisfying solutions. The working description of intimacy to be used here is that it is the ability of one individual to be close to another. This requires that the person be able safely to make himself or herself vulnerable to the other person, and that the sense of self is sufficiently well developed that there is no fear either of disclosing oneself or of being engulfed by the other person [9]. The greater the identity development, the greater is the ability to achieve and maintain intimate relationships. Narcolepsy is a neurological disorder. The current understanding is that it arises from degeneration of the hypothalamic hypocretin/orexin system [10], which is one of the major arousal systems of the brain. Therefore, a person with narcolepsy is not a psychiatric patient. Nonetheless, she or he is an individual who may need psychosocial help managing the challenges of this chronic medical condition. As pertinent to this chapter, the symptoms of narcolepsy when not under control can secondarily lead to potential difficulties in establishing and maintaining intimate relationships. An understanding of the ways in which narcolepsy’s symptoms potentially pose obstacles to intimacy can assist with conceptualizing the type of psychosocial support necessary.

Symptoms The symptoms of narcolepsy are: excessive daytime sleepiness and lingering fatigue even in the absence of true sleepiness; cataplexy, which is the sudden loss, partial or complete, of skeletal muscle tone, usually in the presence of conscious awareness and usually

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in response to an affective stimulus; hypnagogic and hypnapompic hallucinations, generally visual, auditory or both; automatic behavior; and sleep paralysis. “Hypnagogic/hypnapompic hallucinations” are understood to be REM sleep dream events, but displaced from REM to partial wakefulness. While the hallucinations are occurring they are perceived as actual events. However, once the person is fully awake, the events are usually (although not invariably) recognized as hallucinations. “Automatic Behavior” refers to episodes in which the person with narcolepsy appears to be carrying out waking behaviors, but is amnestic to having done so. The automatic behavior can be as simple as repeatedly deleting text just typed into a word-processing program, to as complex as driving a car for many miles and arriving at a destination with no memory of how the destination was reached. “Sleep Paralysis” refers to a flaccid paralysis of skeletal muscle, understood as the displacement of the normal atonia of REM sleep out of sleep entirely, to the interface between sleep and wakefulness. Because the person with this symptom is therefore at least ­partially awake, the paralysis is accompanied by cognizance of it. Should sleep paralysis occur upon a sudden awakening caused by a dangerous event, that event is especially fearful because the person cannot move and do something about it. Hypnagogic/hypnapompic hallucinations often co-occur with sleep paralysis, as does the experience of being unable to breathe. Aptly, the phenomenon is embedded in the folklore of Newfoundland as the “Old Hag Phenomenon,” wherein it was understood to have been caused by an old hag (an hallucinatory event) sitting upon one’s chest. It is similarly embedded in Japanese folklore as Kanashibari, meaning literally “bound or fastened in metal,” with similar ­implications for perceived difficulty breathing [11].

Impact of Symptoms as a Function of Developmental Stage The impact of these symptoms on intimacy appears to be independent of age or gender. However, the way ­the  impact manifests itself does differ as a function ­of  whether or not the individual has been diagnosed with narcolepsy, and especially as a function of

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developmental stage. It is this latter progression that will be developed here. Young people: At this stage of development, early diagnosis, the psychological issue of separationindividuation, and the psychosocial issue of inclusion/ exclusion from a peer group are central. Diagnosis: There is a high probability that the young person with emerging narcolepsy may erroneously be diagnosed with depression, a personality disorder, a neurotic disorder, or an adjustment reaction [12]. Anecdotal data also suggest a high probability of an Attention Deficit Hyperactivity Disorder (ADHD) diagnosis. The result is that youngsters with undiagnosed narcolepsy, often treated for one of these other disorders, experience difficulties neither they, their parents, friends, teachers nor their health care professionals understand. The hypnagogic/hypnapompic hallucinations pose a particular problem with respect to diagnosis and potentially inappropriate treatment. Whether as yet diagnosed with narcolepsy or not, the child may be completely unwilling to confide in anyone about hallucinatory experiences for fear of being labeled “crazy.” Further compounding the problem and as pertinent in this context, available anecdotal data indicate that if the health care professional treating the young person is unaware of narcolepsy as a possibility and the child does describe hallucinations, a psychotic diagnosis can at least be entertained. The result can be erroneous (and ineffective) treatment with powerful psychopharmacological medications. Separation-Individuation: Although there is documentation of onset before the age of 10, the typical age of onset for narcolepsy is around the second decade of life. This timing of narcolepsy’s typical age of onset is especially significant since the pre-adolescent/early adolescent period corresponds to a stage of psychological developmental termed “second individuation” [13]. According to certain schools of psychological thought (e.g., object relations theory), it is the developmental stage during which the ability to establish intimate relationships with same-sex peers begins to emerge. The psychological construct of “second individuation” builds upon Mahler’s characterization [14] of the early childhood “separation-individuation” process. In Mahler’s terms, “separation and individuation” refers to the process by which the toddler emerges from a symbiotic relationship to his or her caregiver (separation) and embarks upon individual achievements defining his or her identify (individuation).

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“Second individuation” refers to a re-emergence of this process during adolescence. The ability to negotiate the “second individuation” developmental task of adolescence is understood to bear heavily upon whether or not a youngster is able to establish intimate relationships outside the family. For instance, one study [15] with adolescents found that the rate of emotional separation from parents predicted the rate at which an adolescent was able to develop intimacy with a same-sex friend. One of the necessary preconditions for this milestone period of individuation is that the youngster have the opportunity to separate and individuate; and that the child have the opportunity to make some of his or her own decisions and then to experience the consequences, be they positive or negative. A booklet published by the Narcolepsy Network, “Questions and answers by and for young persons who have narcolepsy” [16], addresses the particular obstacles a young person with diagnosed narcolepsy may face in developing his or her own independent sense of self. A chapter entitled “Why don’t my parents let me lead my own life?” first notes that this is a general complaint of young people. However, it then goes on to identify additional parental restrictions that may be placed on autonomous decision-making for young people with narcolepsy. The additional restrictions arise out of fear that certain activities may be risky because of the ever-present possibility of a cataplectic attack or uncontrollable sleep attack. The youngster may also self-impose these same limitations, and for the same reason. These restrictions, especially if severe, may inhibit the child from learning independently what can and cannot be done safely. She or he therefore remains dependent, unable to separate and individuate.

Case History: MAG MAG is a 25 year old woman with narcolepsy who has just learned to drive a car. She is still uncomfortable driving alone, so will go out in the car only if there is another trusted adult with her and only for short drives on very familiar streets. She has just moved into her own apartment, and that with a great deal of trepidation. The move was accompanied by her opening her own checking account for the first time. Although her apartment is just a few blocks from her parents’ home,

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her choice has been to see them infrequently. She describes that while she was growing up, her parents would not allow her to participate in any activities with peers unless they had completely vetted not only the friends, but also their parents and each specific activity. Humiliated by this, she began to decline social invitations. Once she graduated high school, her life was limited to the confines of her home. She did not get a job. She did not go to college. Her parents provided her with the basic needs of life. “I was afraid of the world, had no idea how to take care of myself, and it never really occurred to me that I could.” She describes that one day, very abruptly, she decided she needed to make her own life. This was triggered by her having read a succession of local articles about high school friends’ marriages, and then childbirths. “ The world was leaving me behind.” Poorly prepared to be out on her own, she nonetheless made the decision to do so, this with support from a counselor she was seeing. Her avoidance of her parents was akin to the moving away from one’s parents that normally would have occurred during one’s teen years. She is still shaky, but quite determined. Currently she is on disability, and fortunately lives in a state where numerous support systems are available through the program. Her great hope is that she will be able to learn enough life skills to be able to go to college, begin a career, go off disability, and eventually have her own family. Based upon what she has already accomplished, this is a realistic hope. Inclusion/exclusion from a peer group: If the youngster is able to separate from family and begin moving toward his or her peer group, the issue of acceptance by that peer group arises. This is especially true in contemporary American culture where pre-adolescents and young adolescents begin to place a higher value on relationships with peers than with family members. Finding a peer group where they “fit in” is of paramount importance. Yet, sleepiness and the ever-present possibility of a cataplectic episode when laughing at a joke can pose what may seem like insurmountable barriers to fitting in with peers. Defenses against these possibilities include learning to contain emotions to avoid cataplexy; and trying to hide pervasive sleepiness. One approach to hiding the sleepiness is to keep moving around, trying to stay awake, possibly the basis for young people with undiagnosed narcolepsy erroneously carrying the diagnosis of ADHD. Finally, as described above in a different context, ­having hypnagogic hallucinations is also a secret a

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young person with narcolepsy may keep, one more aspect of “self” which may not be disclosed to another peer. These hallucinations pose other psychosocial problems as well. Anecdotal reports indicate that some young people with narcolepsy at times were not believed when they described specific events to a parent. The report was discarded as “one of your hallucinations” rather than being dealt with appropriately. Perhaps even more insidious is that sometimes a young person with narcolepsy is him- or herself unsure whether or not a particular event occurred. In a similar vein, dreams may be remembered as real memories, creating another potential problem for the young person with narcolepsy1. Keeping secrets about themselves, containing emotions, at times being unsure of what is real and what is not – this set of defenses is antithetical to young people being able to become close to a peer or peer group, and even to themselves. The potential problem is further exacerbated if the diagnosis of narcolepsy has not yet been made. It is eased when the correct diagnosis is made and appropriate psychosocial support is available. Another section of the Narcolepsy Network booklet entitled “Who to tell about your narcolepsy?” focuses on trust and self-disclosure. Kids who stand out as atypical (e.g., “weird” or “odd”) are at risk for being rejected from evolving peer groups. It is unlikely that any child in this sub-culture wants to be perceived that way. A rational explanation to a hoped-for friend about narcolepsy may possibly defuse the “odd” label, allowing the desired inclusion with a peer or peer group. On the other hand, to share this with someone else means to allow oneself to be vulnerable – a key element of intimacy. Young people with narcolepsy may worry and ask themselves, “But what if the other child laughs?” or “What if my explanation of narcolepsy adds fuel to the “weird” fire?” So the questions of who to tell, determining who can and cannot be trusted, is often a concern for the young person with narcolepsy. The associated psychosocial support would minimally involve helping the youngster make the necessary discrimination between who can and cannot be trusted.

 This set of problems is true for adults with narcolepsy as well.

1

Case History: RIL RIL was 17 years old when he described his experiences prior to his narcolepsy diagnosis. Now happily looking forward to beginning college, he recalls how difficult things were for him from about age 12 or so, when he was just beginning middle school. He’d been a reasonably good student until that time, but then his grades started to fall. He realized part of his problem was note-taking. When he went home to study his notes, he saw that at some point in class he had started writing nonsense, his words “dribbling down and off the page” (automatic behavior). He also described that at times during the school day, it was as if he were seeing things under “stroboscopic light” (micro-sleeps). He’d see bits and pieces of events, but sometimes these just didn’t hold together. He eventually realized he was drifting in and out of sleep, but did not dare share that with anyone. He just kept fidgeting and moving around, mostly trying to stay awake. In the gym locker room, as his friends were starting to tell off-color jokes, he’d begin to feel a “dippy feeling” in his knees (partial cataplexy), and slowly learned to drift away when the jokes were told. He was therefore increasingly more separated from his peer group. At home, his parents told him to stop sleeping all the time and study, then maybe his grades would improve. As a product of all of this, the then 12  year old became more and more depressed. Eventually he was “coded” as having a learning disability and ADHD. He had begun seeing a psychiatrist for antidepressant medication (which, serendipitously seemed to help the skeletomuscular weakness – i.e. cataplexy), and was mortified to have to see a special education resource counselor. He was frankly thrilled when finally diagnosed with narcolepsy, the sleep work-up initiated by his resource counselor. For the first time he was able to understand what had been going on. But that did not happen until he was about 15 years old. With understanding came action on his part. Slowly, he found he was able to explain to a few chosen friends what had been going on, and began to find his place in his peer group. By age 17, he felt academically and socially prepared for college. Later adolescence and early adulthood: As later adolescence and then early adulthood begin, potential problems relating to dating become central. The question “who to tell” described for younger people continues to be an issue in later adolescence and early adulthood, but now can affect dating relationships.

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For instance, a young adult may become so sleepy during a date that the person’s companion can take it as boredom or rudeness. Should the relationship nonetheless continue and light sexuality become involved, there is the possibility that s/he may fall asleep with the onset of sexual activities. Perhaps the young adult with narcolepsy may deal with the situation by finding a way to end the relationship. Alternatively, he or she may choose to explain to the partner what is actually going on; revealing more as the partner also begins to share more personal things. It is a risk, of course. If the partner is able to be understanding and genuinely cares for the person with narcolepsy, this kind of disclosure can result in the couple becoming closer. On the other hand the disclosure can have the opposite effect, leading the partner to back off. Another variation on the theme encountered by young adults with narcolepsy whose cataplexy is incompletely controlled is that they might have a cataplectic attack as sexual excitement increases. Again, the question of appropriateness of self-disclosure arises as the adolescent questions who to tell and under what circumstances. Adulthood and non-sexual aspects of intimacy: Serious dating and then the formation of a long-term intimate relationship are often important milestones in adulthood. Serious dating: As young adulthood progresses and the possibility of committed long term relationships and marriage enter the picture, new obstacles are faced, especially if the symptoms are not wholly controlled. The possibility of an automatic behavior episode poses one potential obstacle to a young adult with narcolepsy. Understanding that behaviors can occur without awareness, the person with narcolepsy can entertain all manner of fears. The fears revolve around whether he or she might do something without being aware and which would be inappropriate or offensive to the prospective partner. Such fears may stand in the way of the person with narcolepsy even allowing the possibility of an intimate relationship. Or, dream material stored as “real” memories, can affect one’s ability to be intimate with another person. For instance, perhaps in waking life a woman with narcolepsy fears she may be taken advantage of by a man should the strong feelings he elicits trigger a cataplectic episode. Such a fear has a rational basis. Although studies have not been done to establish the prevalence rate of people with narcolepsy having been sexually

violated, raped or assaulted; and whether such incidents are sleep-related, there are published reports indicating that such abusive events do occur and are sleep related (see the Adulthood and sexual aspects of intimacy section below). Thus, a woman who begins to feel close to a man may fear this could happen to her, even in the absence of suggestive behavior on his part. This worry can be integrated into a dream in which her prospective mate does take advantage of her. If that dream material becomes stored as a “real” memory, it can negatively affect an incipient intimate relationship if this is not discussed.

Case History: PR PR is a newly married man. He awakened – or so he believed at the time – in the middle of the night and heard his wife say she didn’t love him anymore. He was devastated, especially since he never truly believed that a woman could love him. Weeks went by, during which he waited for his wife to bring this up during their waking time. But she said nothing. He did not understand how his wife could go about business as usual after this horrible admission. He finally confronted her, only to learn that she did very much still love him and had not told him during the night that she did not love him. Since he knew well that she did not talk in her sleep, it finally dawned on him that what he had experienced was a hallucination, or perhaps a dream disguising itself as a true memory – a trick of his own mind. Finally, if the person with narcolepsy has successfully entered into and maintained an intimate relationship to the point that marital plans are discussed, fear of what might happen once they are married can lead to a last minute decision to break an engagement. The person might become frightened that because of the narcolepsy the marriage might not work out. Marriage/committed long term relationship: Once a person with narcolepsy does enter into a committed long term relationship, other issues arise that need to be anticipated and managed. For instance, for many adults with or without narcolepsy, living a normal life includes the desire to have a family. The decision to have a child is based on a wide range of considerations for all couples. If one member of the couple has narcolepsy, additional

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considerations are present. A concern about genetic transmission of narcolepsy can play a prominent role in family planning. Pertinent here is that although in the canine model narcolepsy is known to be genetically transmitted [17], for humans it is not yet clear whether the same is true [18]. If the couple is highly concerned, fear of an unwanted pregnancy can interfere with intimacy. This fear needs to be made explicit and discussed. If the decision is made to have a child, potentially serious adverse effects of the pregnant woman’s narcolepsy medications on the developing fetus need also be taken into account. The prevailing medical practice is that before attempting to conceive, the woman should withdraw from those medications. This means that throughout her pregnancy, her pre-medication sleepiness, cataplexy and other narcoleptic symptoms are likely to re-emerge. A genuine concern for the couple can be whether or not the marriage or union is strong enough to sustain 9 months of her being sleepy most of the time, and of the increased likeliness that she will have a cataplectic episode in response to strong emotions (e.g., loving emotions, anger, joy). Even if the woman was very clear prior to their marriage about her narcolepsy and what the symptoms were like before diagnosis and pharmacological treatment, a possible fear is that her partner still may not be prepared when these symptoms actually occur. For this reason, too, there can be a fear of pregnancy with the potential of affecting intimacy. Persistent sleepiness (readiness to sleep) and tiredness (not sleepy, but just no energy) has the potential of dissolving an already established marital relationship even when pregnancy is not involved. If the partner poorly understands narcoleptic sleepiness, for instance, and the sleepiness is not effectively controlled by medication, it is possible the partner may call it “laziness” on occasion – a painful epithet and one that can create distance between the two people. Or, even worse, an epithet such as this may be used with such persistent frequency and intensity that it borders on emotional abuse. Even under the best of conditions, when the partner is aware and accepting of the person with narcolepsy’s incompletely controlled sleepiness, simply the rate at which it might occur can wear on the relationship. Cataplexy plays an important role in a context different from what was described above as well. Inevitably, in any relationship, there will be disagreements,

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conflicts and even anger. Conflict resolution, with a particular focus on communication, is a central issue in couples therapy [19]. Poor communication can occur if one member of the couple is unable or unwilling to communicate a troubling situation or issue to their partner, rendering conflict resolution impossible since one partner is unaware of the problem. A traditional intervention in couples therapy, therefore, is to teach each partner to express his or her concerns to the other, to stand up for him- or herself. When one partner in the relationship has narcolepsy, the process can be more complex because the anger a conflict might engender can be a powerful precipitant of cataplexy. As a consequence, some percentage of people with narcolepsy have learned to avoid even the possibility of confrontation or conflict, many shutting down entirely rather than addressing the issue at hand. The therapist working with a couple when narcolepsy is involved needs to be especially aware of this, and be able to help the couple recognize the accommodations each of them must make so that effective communication and peaceful conflict resolution become possible. Another challenge to a long term committed relationship revolves around the issue of psychiatric depression. One concern has to do with the issue of mis-diagnosis. If narcolepsy has not yet been diagnosed, the excessive daytime sleepiness of narcolepsy may be mistaken for the lethargy of depression. The consequence if the diagnostician does not include narcolepsy in the differential diagnosis is that an erroneous diagnosis of depression may in fact be made. Anecdotal reports indicate that some people whose narcolepsy was not diagnosed until adulthood were subjected to increasingly more aggressive treatments for “depression” because of apparent refractoriness to the just-prior treatment. Erroneous labeling of the adult with still undiagnosed narcolepsy as an intractable, severe depressive would significantly impair the person’s desirability as a continuing long-term committed partner. Even if narcolepsy has been correctly diagnosed, another consideration is that depression can be comorbid with it [12, 20, 21]. Often, the depression is secondary to frustration at being unable to do what used to be possible. Over time, unresolved symptoms of narcolepsy can result in job loss due to incremental difficulty carrying out the work. Under certain circumstances, the person with narcolepsy can pursue and

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obtain legal disability benefits [22], but being put on disability itself can further undermine a person’s selfesteem. Depression secondary to job loss and enforced disability status is more likely when narcolepsy develops late, after a person has already established herself or himself professionally since she or he may have lost a well-established career. The co-morbid depression can put additional stress on the relationship, loosening and possibly dissolving the relationship’s bonds. This is especially true if the person with narcolepsy who has co-morbid depression refuses to seek treatment for it.

Case History: Mrs. L. Mrs. L. was in her late 40s when her husband divorced here. Onset of narcolepsy symptoms for her was late, beginning at about 25 years old . She was not actually diagnosed until another 5 years had passed. By then, her first marriage had dissolved, in large part because she “was sleeping all the time.” However, she had the good fortune that a long time male friend and she began dating. The two had worked for the same company where they became friends. They subsequently married. Her husband entered the marriage with his eyes wide open, completely aware of all aspects of his wife’s narcolepsy, having seen it during all the years of their friendship. By the time they got married she had cycled through first reaching a high level of middle management, then becoming increasingly more symptomatic and slowly losing the team working under her, to finally being released from the company and put on disability. Despite her job loss, her husbandto-be was able financially to support both of them. He was highly empathic to her disability. In fact, he literally supported her as she began a cataplectic episode while they were walking down the aisle at their marriage ceremony. For the first several years of marriage, her husband increasingly took over functions in recognition of his wife’s difficulties. He was not, however, prepared for her to be in bed “almost all the time,” for her more and more often falling asleep on the couch and not sharing their marital bed. He was even less prepared for this formally vital, intellectually keen and resourceful woman to become overwhelmingly self-absorbed, “having almost constant pity parties.” Realizing that what he was seeing was incremental depression in his wife, he asked, and then

begged, her to seek psychotherapeutic help. After “too many years” of her refusing to do so, feeling tremendously sad, he finally asked her for a divorce. He rued the life he believed they could have had together, “growing old with each other.” Even under the best of circumstances, unresolved sleepiness of the narcoleptic partner can stress not only the relationship but the non-narcoleptic partner as well. That partner may genuinely love and be extremely supportive of the person with narcolepsy, but may also feel too guilty to acknowledge the partner’s chronic sleepiness as a significant stressor. If the partner without narcolepsy is a married woman, for instance, she may keep entirely to herself how often she feels as if she were single. She may not disclose how her husband is unable to be a true companion to her or to their friends. The woman may stoically accept all of the domestic, social and financial responsibilities that fall on her shoulders. However, the cumulative effect over the years of keeping these stresses to herself out of guilt can have a tremendous impact on her well-being. Once again, we see the detrimental effect of keeping secrets. With good communication and the personal decision not to keep this kind of secret, quite a different outcome is possible. When a wife, let us say, is able openly to acknowledge, talk about and work through the effects of her husband’s narcolepsy on her she will more wholeheartedly be able to support him. A potential result is that later in life, should she fall ill, her spouse will more likely be available to support her.

Case History: Mr. B. Mr. B. is a 79 year old man with narcolepsy, married for over 55 years to his high school sweetheart. They grew up in the same town. Their immediate and extended families not only knew each other but were social friends. He recalls that his symptoms of narcolepsy probably started around the time he and his now-wife began dating. However, in those years, there were no sleep disorders centers. Despite his tendency to fall asleep at awkward moments, and events which were probably the early stages of partial cataplexy, so close were the families that his symptoms were simply accepted as part of him. He described the trajectory of his and his wife’s many decades together,

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how wonderful and accepting his wife and both their families had been of him as his symptoms progressed; and what a relief it was when finally he had a sleep evaluation, was diagnosed with narcolepsy and pharmacological treatment initiated. He then described his experience as his wife became ill in her mid-70s, especially his sadness to see his lifelong companion becoming so very ill. But the strength of their marriage combined with strong family and community allowed him to emerge with the strength he needed to offer her the same kind of loving support she had offered him for so very many years. Critical variables in all the instances described are openness in communication; maturity; and effective, informed, appropriate psychosocial support. Adulthood and sexual aspects of intimacy: Marriage (or a committed relationship between two people) almost invariably involves sexual intimacy. The difficulties people with narcolepsy can have with sexual intimacy, therefore, need also to be considered. A textbook chapter by Karacan and his colleagues [23] describes sexual dysfunction in men with narcolepsy. The article provides case studies centering on loss of sexual interest in men because of sleepiness, cataplexy induced by sexual arousal, and erectile dysfunction induced especially by the stimulant medications intended to control sleepiness. Amphetamine, in particular, is identified as a drug whose chronic use can produce erectile failure, ejaculatory problems and decreased libido in men. If the person with narcolepsy is also depressed and psychopharmacological treatment is warranted, one possibility is that the antidepressant will be a selective serotonin reuptake inhibitor (SSRI). Possible sexual side-effects of SSRIs, including loss of libido and/or loss of ability to successfully engage in sex, are now well documented [24]. Thus, while the potential for interpersonal intimacy may increase as the depression lifts, with this class of medication the potential for sexual intimacy may decrease. On a positive note, effective antidepressant medications without sexual side-effects are becoming available. On quite a different note, a review paper [25] describes several case studies wherein the female patient either had hallucinations of being sexually abused or was actually sexually abused during an episode of cataplexy. In one case, the subject was described as having

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first been raped by a policeman, then several years later at a party given by her manager at work. In both situations, she described having been aware of what was happening, but because of her cataplectic paralysis was unable to fight either man off or to scream out for help. This kind of history can give a woman second thoughts about sexualized intimate contact with a man. Cataplexy can directly affect a woman’s sexual intimacy with her partner as well, even in the absence of a cataplexy-related sexual abuse history. For instance, a woman’s partner may be unaware during a sexually intimate occasion that she is in the midst of a cataplectic episode, continuing his sexual engagement with her despite the advent of her cataplectic attack. It is also possible that he actually may be aware but decides to proceed with sexual contact despite it. Either situation can raise a dilemma for the woman who will have been aware but unable to respond during the sexual encounter. Depending upon the solidity of interpersonal intimacy and communication between the two, she may be left trying to decide if she were being taken advantage of in a particularly distasteful way – or if her mate simply accepted her, cataplexy and all. Unresolved daytime sleepiness can also have an impact on sexual intimacy. The person with narcolepsy might find him- or herself often in a state of being neither truly awake nor truly asleep during the usual waketime hours. This would be equivalent to the experience any sleeper has when beginning to fall asleep, during the “hypnagogic period.” The hypnagogic period (Stage 1 non-REM sleep) is a time when one’s thoughts begin to drift. Experiential input from external stimuli (e.g., the sound of rain) is interspersed with dream-like cognitions and images. However, in the case of narcolepsy with unresolved sleepiness this state can be present throughout the daytime, not just at the interface between daytime wakefulness and nighttime sleep. A sleepy consciousness in a sexually charged situation can lead a person into some very unpredictable situations. Another theme that emerges revolves around the fact that for a very large percentage of the population, sex and sleep occur in the same place – in bed, when the couple is recumbent, and often at night. The ensuing sleepiness for a person with narcolepsy would directly interfere with sexual intimacy. One solution to this is that the couple set things up so that sexual intimacy is reserved for afternoons or mornings, not nighttime; and so that it occurs any place in the house but in their bed and bedroom.

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While not explicitly sexual, the closely related problem a person with narcolepsy may encounter in sharing a bed with his or her partner for purposes of sleeping is addressed here. Sharing the bed may, for one reason or another, lead to a less than restful night for the partner with narcolepsy. Impairment to the restfulness of nighttime sleep can, in turn, exacerbate daytime narcoleptic symptoms. This can pose a difficult choice for people with narcolepsy regarding intimacy. Sleeping together and cuddling, in the same bed, and waking up with that person in the morning is an expression of intimacy, such that choosing to sleep in separate beds might deprive the couple of it. On the other hand, if sleeping in the same bed also means she or he is less wakeful the next day, that can negatively impact on the person with narcolepsy’s ability to be intimate with his or her partner. The clinician working with the couple can help them to make this dilemma explicit, and then help them communicate about it until they reach a satisfactory resolution. Timing of intimate sexual relations relative to nighttime medication intake can also present a problem. For instance, if the person with narcolepsy is taking sodium oxybate (Xyrem®) at bedtime, sleepiness will quickly ensue2. It is therefore important that the couple keep this in mind, planning so that their initiation of intimate sexual contact occurs before the sodium oxybate bedtime dose is taken. But, as with all things involving the maintenance of intimate relationships, communication about this is necessary. Such communication means that certain obstacles need to be overcome. For instance, many people are hesitant to discuss intimate issues under any circumstances. Or, there may be the concern that this kind of planning runs counter to the desire for spontaneous sexual intimacy, such a concern potentially interfering with the willingness to discuss coordination between the timing of sexual intimacy and bedtime medication. Even if the willingness is there, external factors may interfere. If, as an example, both members of the couple work, the part of the couple with narcolepsy may be especially exhausted at the end of a work day. The result would be an insufficient amount of useful awake time available for that discussion at the end of the day. A solution would be to have

 Sodium oxybate, currently indicated for excessive daytime sleepiness and cataplexy in the context of narcolepsy, is taken in two doses: at bedtime, and 4 h later.

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this conversation before the work day begins – or on a non-work day. Concluding comments: The willingness first to enter into an intimate relationship, and then to establish and maintain it, can be difficult for many people. What has been described here are the additional obstacles to intimacy a person with narcolepsy may face. Each of the symptoms of narcolepsy, if not under control, can pose problems independent of age and gender. The ways such potential problems manifest themselves as a function of developmental stage in particular have been described. Not all people with narcolepsy experience these obstacles, but the clinician does need to be aware of the possibility. The following are key to whether or not narcolepsy’s symptoms will present such obstacles: (1) whether or not, and at what point in life, narcolepsy has been diagnosed; (2) the degree to which the symptom is under control, generally by pharmacological agents possibly complemented by psychosocial support; (3) the maturity of the person(s) with whom the person with narcolepsy care(s) to become intimate; (4) the acceptance by the person with narcolepsy that narcolepsy is a part of his or herself, and that it does not define who she or he is; (5) open communication between the person with narcolepsy and his or her prospective or actual intimate partners, and also with people who could be in a position to help (e.g., family, friends, work associates, therapists). A national organization, the Narcolepsy Network, has been a prominent catalyst for the recognition of this neurological disorder by the school, legal, healthcare and pharmaceutical communities. The organization is run by, and for the benefit of, people with narcolepsy. Details about the organization including the various types of support it offers can be found on its website: http://www.narcolepsynetwork.org. Whether or not, and at what point in life, narcolepsy has been diagnosed: One result of increasing awareness on the part of school systems and health care professionals is that narcolepsy is to some extent being identified far earlier in a person’s life. In the not-sodistant past it was not unusual for a diagnosis of narcolepsy to be delayed until a person was in their third or even fourth decade of life. Importantly, early recognition and early treatment can minimize or obviate the significant damage to self esteem, ability to establish intimate relationships with a peer group (and ultimately with a life partner), and the possibility of a youngster with narcolepsy being treated for the wrong

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diagnosis (e.g., ADHD or depression). Unfortunately, the general consensus is that narcolepsy continues to be under-diagnosed in school aged children. Continuing efforts are being made to rectify this. The degree to which symptoms are under control: With respect to pharmacological control of symptoms, new medications are now available for the most intrusive narcoleptic symptoms: excessive daytime sleepiness and cataplexy. Some of the obstacles to intimacy described above, therefore, can at least be mitigated pharmacologically. However the following caveats must be recognized: (1) Not all people have access to these medications; (2) Even when these medications are available to a person with narcolepsy, the medications do not invariably (if at all) wholly eliminate narcoleptic symptoms. Residual symptoms, if present, can present the obstacles to intimacy delineated above; (3) For various reasons, a person may need to discontinue their medications for a period of time. The discontinuation of medication during pregnancy has already been described. Also, some people with narcolepsy develop tolerance to stimulants very quickly, and must take a medication holiday every week-end in order to get the benefit of the stimulant during the following work week. These individuals often sleep away the entire weekend, depriving the family, partner and/or spouse of time together that can be critical to maintaining a healthy relationship; (4) The medication(s) may be ­discontinued entirely because of noxious side-effects. Maturity, self acceptance, open communication: Some form of psychosocial support, such as self-help groups, individual psychotherapy, couple therapy and/ or family therapy is often useful. Psychosocial support can, variously, focus on self-acceptance; appropriate disclosure of symptoms; and on assisting with open communication, problem solving and conflict resolution. The ability to be willing and able to enter an intimate relationship is an important aspect of an individual’s life in our culture. This chapter has been written in the hope that the health care professionals who treat people with narcolepsy will have a greater ability to assist in their care. Hopefully in the years to come, a chapter similar to this can be grounded in systematically collected empirical data. Acknowledgments  A warm thank you to Audrey Kindred, Ann Austin and Sharon D. Smith, who provided significant substantive and editorial input to this manuscript.

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18 Narcolepsy, Intimacy and Sexuality 20. Daniels E., King M.A., Smith I.E., Shneerson J.M. (2001) Health-related quality of life in narcolepsy. J Sleep Res 10, 75–81 21. Merritt S.L., Cohen F.L., Smith K.M. (1992) Depressive symptomatology in narcolepsy. In Goswami M., Pollak C.P., Cohen F.L., Thorpy M.J., Kavey N.B., Kutrscher A.H. (eds). Psychosocial Aspects of Narcolepsy, 53–59. Haworth Press, New York 22. Ingravallo F., Vignatelli L., Brini M., et al. (2008) Medicolegal assessment of disability in narcolepsy: an interobserver reliability study. J Sleep Res 17, 111–119 23. Karacan I., Gokcebay N., Hirshkowitz M., Ozmen M., Ozmen E., Williams R.L. (1992) Sexual dysfunction in men

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Chapter 19

Narcolepsy, Driving and Traffic Safety Claire EHM Donjacour, Monique AJ Mets, and Joris C Verster

Introduction Excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis and nocturnal sleep disturbances are the best-known symptoms of narcolepsy. Although less well described, but important in the context of driving, disturbed vigilance is also a very important symptom of narcolepsy [1]. About 4–12% of the general population suffers from EDS. Daytime sleepiness may result in reduced alertness and thus affects driving ability. The 2002 Gallup survey [2] revealed that 37% of drivers reported that they have nodded off or fallen asleep at least once in their driving career. The Sleep in America Poll [3] showed that 91% of respondents acknowledged that less sleep may increase the risk for injuries, but 51% of them reported that they did drive while sleepy. Powell and colleagues [4] reported that an increase of 1 unit on the Epworth Sleepiness Scale (ESS) was associated with a 4.4% increase of having at least one accident (P < 0.0001). Fulda and Schulz [5] reviewed the literature concerning cognitive functioning of patients with narcolepsy. A total of 14 studies revealed that narcolepsy is characterized by reduced alertness, poor performance on divided attention and tracking tasks, and reduced vigilance.

Narcolepsy and Accident Risk Broughton et  al. [6] performed a survey among 180 patients with narcolepsy. When compared to matched controls, patients reported more often falling asleep at C. EHM Donjacour () Neurology, Leiden University Medical Center, PO Box 9600 2300, RC Leiden, The Netherlands e-mail: [email protected]

the wheel (66%) and near or actual accidents (67%). Cataplexy (29%) and even sleep paralysis (12%) while driving were reported. These high numbers were gathered by subjective patient reports about their driving behavior. More recent studies also reported a significantly increased traffic accident risk for patients with narcolepsy [7].

Driving Performance of Untreated Narcolepsy Patients Findley et al. [8] examined driving performance of ten patients with untreated narcolepsy. In the Steer Clear, subjects observe a car driving on a two-lane drawn highway. Now and then during the 30 min task, obstacles (i.e. cartoon bulls) appear on the road. By pressing the space bar the car changes lane and a collision is avoided. When compared to matched controls, narcolepsy patients hit a higher percentage of obstacles. Poor performance on the Steer Clear was associated with a higher reported traffic accident rate in the patients with narcolepsy. Using the same computerized simple reaction time driving simulation task, Findley and colleagues [9] compared performance of 16 patients with narcolepsy with that of 31 untreated sleep apnea patients and 14 healthy controls. The number of collisions was measured in six 4-min periods of simulated driving. Narcolepsy and sleep apnea patients had significantly more collisions than healthy controls. Interestingly, the inter-subject variability in errors among the narcoleptic patients was fourfold that of the apnea patients, and 100-fold that of healthy volunteers; pointing at the great difference in impairment levels among narcoleptic patients.

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George and colleagues [10] compared performance of 21 patients with sleep apnea, 16 narcolepsy patients and 21 healthy controls. Using a simple driving simulator participants were tested for 20-min. Tracking error was much worse in narcolepsy patients when compared to controls. The relationship between multiple sleep latency test (MSLT) and tracking in either patient group was weak. Kotterba and colleagues [11] compared driving simulator performance and neuropsychological test results in narcolepsy in order to evaluate their predictive value regarding driving ability. Thirteen patients with narcolepsy and ten healthy control subjects performed a 60-min driving simulator test (Computer Aided Risk Simulator, CAR), including different weather and daytime conditions. Also, occasionally obstacles were present on the road. The number of accidents (crashes with other cars, pedestrians or obstacles on the road) was recorded. Concentration lapses (e.g., disregarding traffic lights or speed limit, driving at night with switched off headlights) were counted manually. Patients with narcolepsy had significantly more accidents than healthy controls. No differences were found on the number of concentration lapses.

Treatment Effects on Driving Performance Currently, gamma-hydroxybutyrate (sodium oxybate) is the first line treatment option for narcolepsy patients who suffer from both EDS and cataplexy. Modafinil is also often used to improve symptoms of EDS. Up to now, the effects of modafinil and sodium oxybate on driving performance of narcolepsy patients have not been examined. As yet only the effect on driving of the stimulant drug methamphetamine has been studied in narcolepsy patients [12]. Methamphetamine was administered daily to eight narcoleptic patients (0, 20 or 40–60 mg) and eight healthy controls (0, 5 or 10 mg) for 4 days for each dosage, separated by 3 days of washout (drug free). A test in the Steer Clear driving simulator was performed on the last day of each treatment condition. In addition, the MSLT was performed to determine sleep tendency. Sleep latency increased from 4.3 min (placebo) to 9.3  min (highest dose) in narcoleptic patients. In healthy controls sleep latency increased

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from 10.4 (placebo) to 17.1 min (highest dose). In line, error rate on the driving task decreased from 2.53% (placebo) to 0.33% (highest dose) for narcoleptic patients. In healthy controls, the error rate decreased from 0.22% (placebo) to 0.16% (highest dose). When taking the high dose of methamphetamine, performance of narcoleptic patients did not differ significantly from healthy controls receiving placebo. This study illustrates that stimulant drugs cause a dosedependent decrease in daytime sleep tendency and improvement in performance. Two healthy volunteer studies confirm improvement of driving performance after stimulant drug use. Ramaekers and colleagues [13] examined the effects of 3-4-methylendioxymethamphetamine (MDMA) (75  mg), methylphenidate (20  mg) and placebo on driving performance in 18 recreational MDMA users. On-the-road driving tests were performed 3–5 h after drug use, and the next day (27–29  h after intake) to examine possible withdrawal effects. The first driving test measured the weaving of the car while participants tried to maintain a steady lateral position within the right traffic lane and a constant speed. Primary parameter of the test is the Standard Deviation of Lateral Position (SDLP), i.e. the weaving of the car. A second driving task, also performed on a public highway in normal traffic, comprised following a lead car. Main parameters in this task were time to speed adaptation (TSA) and break reaction time (BRT). Both MDMA and methylphenidate significantly improved driving performance as indicated by reduced weaving. However, MDMA affected performance negatively in the car following test, whereas performance after using methylphenidate did not differ significantly from placebo. During withdrawal, no significant differences from placebo were found. Verster and colleagues [14] examined the effects of methylphenidate on driving performance in adults with attention deficit hyperactivity disorder (ADHD). After a training session and withdrawal of methylphenidate for at least 4 days, patients participated in a double blind trial and performed an on-the-road driving test after intake of placebo or their regular dose of methylphenidate. In line with Ramaekers’ findings, driving performance after using methylphenidate was significantly improved when compared to placebo. Given these findings, it can be expected that stimulant drugs will also improve driving in patients with narcolepsy.

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A recent study [15] showed that in sleep apnea patients who stopped their CPAP treatment and tested the following day, modafinil (200 mg) did not improve performance in the STISIM driving simulator.

Interpretation of Driving Simulator Results Various studies have shown that untreated narcolepsy patients have impaired cognitive functioning, especially on domains of attention and vigilance [5]. EDS impairs performance and successful treatment should diminish these symptoms. Besides the fact that the number of driving studies examining narcolepsy treatment is limited, there are some methodological issues that should be taken into account when interpreting the results and conclusions of these studies. First, although a relationship between daytime sleepiness and driving performance has been reported [16], the simple fact that successful treatment reduces daytime sleepiness does not automatically imply that driving is safe. Second, predicting actual driving from laboratory tests measuring attention, vigilance and other isolated psychological skills and abilities is often inaccurate [17]. Driving is an example of skilled but complex behavior in which various skills and abilities are integrated. These can be tested in isolation, but the results do not sum up in a predictive score of actual driving performance. Third, various driving simulators were used in the studies discussed in this chapter. Especially the older driving simulators such as the Steer Clear are in fact divided attention tasks. Subjects are seated behind a computer screen and use the computer keyboard to control a drawn car on the computer screen. These tests do not differ from other divided attention tests when it comes to predicting actual driving. The aim of the study by Kotterba and colleagues [11] was to see whether performance on a neuropsychological test battery correlates significantly with driving simulator performance in patient with narcolepsy. If this was the case, the extensive testing methods could be replaced by a simple and shorter driving simulator test. Unfortunately, there was no correlation between driving performance and neuropsychological test results. Also, there was no significant correlation between driving simulator performance and EDS. Surprisingly, Kotterba and colleagues conclude that

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the driving simulator is suitable to access fitness for driving and state that “On-road evaluation may be unnecessary especially in cases with ambiguous neuropsychological test results.” The obviously artificial environment of simple driving simulators is evident to participants of experiments, and this will affect their performance accordingly. In contrast to driving in real traffic, the tests are often experienced as a game. For example, accidents in driving simulators may be regarded as funny; in real life accidents may have serious consequences. Newer more advanced driving simulators such as the STISIM are more promising and try to make the driving test more realistic. Subjects are seated in a real car and a driving scene can be presented on a curved screen surrounding the front of the car. These newer driving simulators also include other traffic – an essential perquisite to test driving performance in a more realistic manner. Up to now, the on-the-road driving test is the gold standard to examine driving performance. Performing the test on a public highway in real traffic ensures its ecological validity. Taken together, although often claimed, there is little direct scientific evidence that treatment of narcolepsy improves driving performance. Future studies should be executed to examine driving performance of patients with narcolepsy, preferably using the on-theroad driving test during normal traffic.

Decisions on Fitness to Drive There is no standard list of criteria or assessment scale to assess fitness to drive in people with narcolepsy. Commonly, physician and psychiatrists rely on their own clinical experience and base their decision on the presence and severity of narcolepsy symptoms. Unfortunately, decisions whether a narcolepsy patient is suitable to drive a car are not always uniform, given the differences between physicians in interpretation of the assessment criteria. Ingravallo [18] reported that agreement on driving license decision ranged from 73 to 100%. The decision correlated significantly with age, number of daytime naps, sleepiness, cataplexy and quality of life. A recent survey among sleep specialists who attended the 2007 WorldSleep conference confirmed that there is disagreement about whether or not narcolepsy patients should drive a car, and that this

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220 "Drivers with confirmed untreated narcolepsy should not drive"

"Succesfully treated drivers with narcolepsy should be authorized to drive"

11.9% 21.4%

10.9% 7.1% 77.2%

71.4%

I Agree

I disagree

Depends on the amount of EDS

I Agree

I disagree

Depends on the amount of EDS

Fig.19.1  Results from a survey conducted among attendants of the 2007 WorldSleep conference in Cairns, Australia (N = 125). The majority of sleep experts concluded that untreated

narcolepsy patients are unfit to drive a car. After successful treatment patients are regarded fit to drive, depending on the presence and severity of excessive daytime sleepiness

depends greatly on the amount of daytime sleepiness experienced by patients (Fig. 19.1). Currently, most European countries do not include EDS among the specific medical conditions to be considered when judging whether or not a person is fit to drive. A unified European Directive seems desirable [19]. In addition, there is a need for a social awareness program to educate the public about the potential consequences of narcolepsy and EDS in order to reduce impaired driving and the number of traffic accidents [20]. The International Council on Alcohol, Drugs and Traffic Safety (ICADTS) states that the decision whether or not it is safe to drive (irrespective of the condition or treatment) should be based on the results of driving tests performed in real traffic, preferably combined with additional evidence from driving simulators and laboratory test results that examine drivingrelated skills and ability in isolation. From this chapter it is evident that untreated narcolepsy may significantly impair driving ability and may increase the risk of becoming involved in traffic accidents. More systematic epidemiological studies are needed to calculate the traffic accident risk of both treated and untreated patients with narcolepsy. Given the great variability in symptom severity between narcolepsy patients, this should be taken in account when determining whether narcolepsy patients are fit to drive or not.

References 1. Fronczek, R., Raymann, R.J.E.M., Romeijn, N., Overeem, S., Fischer, M., van Dijk, J.G., Lammers, G.J., van Someren, E.J.W. (2008) Manipulation of core body and skin temperature improves vigilance and maintenance of wakefulness in narcolepsy. Sleep 31:233–240 2. Gallup Organization. (2003) National Survey of Distracted and Drowsy Driving Attitudes and Behaviors. National Highway Traffic Safety Administration, Washington, USA 3. National Sleep Foundation. (2002) 2002 Sleep in America Poll. National Sleep Foundation, Washington, USA 4. Powell, N.B., Schechtman, K.B., Riley, R.W., Guilleminault, C., Chiang, R.P., Weaver, E.M. (2007) Sleepy driver near-misses may predict accident risks. Sleep 30:331–342 5. Fulda, S., Schulz, H. (2001) Cognitive dysfunction in sleep disorders. Sleep Med Rev 5:423–445 6. Broughton, R., Ghanem, Q., Hishikawa, Y., Sugita, Y., Nevsimalova, S., Roth, B. (1981) Life effects of narcolepsy in 180 patients from North America, Asia and Europe compared to matched controls. Can J Neurol Sci 8: 299–304 7. León-Muñoz, L., de la Calzada, M.D., Guitart, M. (2000) Accidents prevalence in a group of patients with the narcolepsy– cataplexy syndrome. Rev Neurol 30:596–598 8. Findley, L., Unverzagt, M., Guchu, R., Fabrizio, M., Buckner, J., Suratt, P. (1995) Vigilance and automobile accidents in patients with sleep apnea or narcolepsy. Chest 108:619–624 9. Findley, L.J., Suratt, P.M., Dinges, D.F. (1999) Time-on-task decrements in “steer clear” performance of patients with sleep apnea and narcolepsy. Sleep 22:804–809

19 Narcolepsy, Driving and Traffic Safety 10. George, C.F., Boudreau, A.C., Smiley, A. (1996) Comparison of simulated driving performance in narcolepsy and sleep apnea patients. Sleep 19:711–717 11. Kotterba, S., Mueller, N., Leidag, M., Widdig, W., Rasche, K., Malin, J.P., Schultze-Werninghaus, G., Orth, M. (2004) Comparison of driving simulator performance and neuropsychological testing in narcolepsy. Clin Neurol Neurosurg 106:275–279 12. Miller, M.M., Hajdukovic, R., Erman, M.K. (1993) Treatment of narcolepsy with methamphetamine. Sleep 16:306–317 13. Ramaekers, J.G., Kuypers, K.P.C., Samyn, N. (2006) Stimulant effects of 3-4-methylendioxymethamphetamine (MDMA) 75 mg and methylphenidate 20 mg on actual driving during intoxication and withdrawal. Addiction 101: 1614–1621 14. Verster, J.C., Bekker, E.M., De Roos, M., Minova, A., Eijken, E.J.E., Kooij, J.J.S., Buitelaar, J.K., Kenemans, J.L., Verbaten, M.N., Olivier, B., Volkerts, E.R. (2008) Methylphenidate and driving ability of adults with attentiondeficit hyperactivity disorder: a randomized crossover trial. J Psychopharmacol 22:230–239 15. Williams, S.C., Rogers, N.L., Marshall, N.S., Leung, S., Starmer, G.A., Grunstein, R.R. (2008) The effect of modafinil following acute CPAP withdrawal: a preliminary study. Sleep Breath 12:359–364

221 16. Ramaekers, J.G. (2003) Antidepressants and driving impairment: empirical evidence from a standard on-the-road test. J Clin Psychiatry 64:20–29 17. Verster, J.C. (2002) Measurement of the Effects of Psychoactive Drugs on Driving Ability and Related Psychological Processes. Utrecht, The Netherlands. ISBN 90-393-3132–3134 18. Ingravallo, F., Vignatelli, L., Brini, M., Brugaletta, C., Franceschini, C., Lugaresi, F., Manca, M.C., Garbarino, S., Montagna, P., Cicognani, A., Plazzi, G. (2008) Medico-legal assessment of disability in narcolepsy: an interobserver reliability study. J Sleep Res 17:111–119 19. Alonderis, A., Barbé, F., Bonsignore, M., Calverley, P., De Backer, W., Diefenbach, K., Donic, V., Fanfulla, F., Fietze, I., Franklin, K., Grote, L., Hedner, J., Jennum, P., Krieger, J., Levy, P., McNicholas, W., Montserrat, J., Parati, G., Pascu, M., Penzel, T., Riha, R., Rodenstein, D., Sanna, A., Schulz, R., Sforza, E., Sliwinski, P., Tomori, Z., Tonnesen, P., Varoneckas, G., Zielinski, J., Kostelidou, K.; COST Action B-26. (2008) Medico-legal implications of sleep apnoea syndrome: driving license regulations in Europe. Sleep Med 9:362–375 20. Pandi-Perumal, S.R., Verster, J.C., Kayumov, L., Lowe, A.D., Santana, M.G., Pires, M.L., Tufik, S., Mello, M.T. (2006) Sleep disorders, sleepiness and traffic safety: a public health menace. Braz J Med Biol Res 39:863–871

Chapter 20

Memory and Cognition in Narcolepsy Christian Bellebaum and Irene Daum

This chapter addresses the issue of cognitive deficits associated with the sleep disorder of narcolepsy. In the first section, the main symptoms and pathophysiological mechanisms in narcolepsy will be summarized and discussed in relation to the mechanisms which are relevant to the development or mediation of neuropsychological impairments accompanying narcolepsy. These impairments are outlined in more detail in the following section. In the final section of this chapter, the findings will be summarized and discussed in terms of the possible neurocognitive mechanisms which may underlie the neuropsychological impairments in narcoleptic patients.

Main Symptoms of Narcolepsy The most prominent symptom of narcolepsy is excessive daytime sleepiness [1]. During their normal everyday activities like working, eating, etc., most patients experience two or more sleep attacks during the day. Together with cataplexy and sleep paralysis accompanied by hallucinations, sleepiness forms part of the “narcoleptic tetrad” [2]. Cataplexy refers to a sudden reduction or complete loss of skeletal muscle tone, which can affect single body parts or even the whole body. These attacks are frequently triggered by emotional experiences and may last several minutes. The patients are fully conscious, and are unable to move. Similarly, the narcolepsy sufferer is awake and unable C. Bellebaum (*) Department of Neuropsychology, Institute of Cognitive Neuroscience, Ruhr-University of Bochum, Universitätsstraße 150, D-44780, Bochum, Germany e-mail: [email protected]

to move during sleep paralysis. But this symptom usually occurs only during periods of falling asleep or waking up. It can last up to 10 minutes and is often accompanied by visual hallucinations. Hallucinations, however, can also occur independently.

Dysfunction of the Hypocretin System in Narcolepsy Narcoleptic symptoms have consistently been associated with dysfunctions of the hypocretin system, with two hypocretin neuropeptides – hcrt-1 and hcrt-2 – being generated from a single precursor and synthesized by neurons in the lateral hypothalamus [3, 4]. In narcoleptic dogs, hcrt-2-mutations have been found to be responsible for low hypocretin levels. In human subjects, however, extensive screening revealed that mutations in hypocretin-related genes are rare. Nevertheless, up to 90% of narcoleptic patients show evidence of hypocretin deficiency, i.e. very low hcrt-1 levels. Post-mortem studies revealed a reduction of hypothalamic hypocretin neurons [5].

Neurotransmitter Dysfunction Cholinergic and monoaminergic neurotransmissions are involved in the regulation of normal sleep and there is evidence of disruption of both the systems in narcolepsy patients [5]. Drugs affecting cholinergic and monoaminergic systems also affect single symptoms of narcolepsy. For example, activation or blockade of the cholinergic system exacerbates or reduces cataplexy,

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and anticholinergic antidepressant medication is used to successfully treat cataplexy. In addition, findings of altered receptor binding in the amygdala, globus pallidus, putamen, and nucleus caudatus along with increased levels of monoaminergic metabolites also indicate neurotransmitter dysfunction in narcolepsy [5, 6], which may be linked to dysfunction of the hypocretin system [7].

Cognitive Deficits in Narcolepsy Memory Memory problems are among the most frequent complaints in self-reports of narcolepsy patients. In an early investigation, patients reported forgetfulness and problems in following conversations [8]. More systematic investigations in larger samples corroborated these first observations. Nearly 50% of 180 patients from different continents (Asia, Europe, and North America) complained about memory problems, predominantly affecting memory of recent events [9, 10]. In a large sample of 700 narcoleptic sufferers, approximately 40% of the patients reported at least mild memory problems [11]. In the light of these self-report data, it is surprising that memory assessment by standardized tests did not consistently yield significant impairments. Earlier studies did not find significant group differences on immediate and delayed recall for verbal and visual memory between narcoleptic patients and healthy control subjects [11, 12]. Mild memory deficits have been linked to impaired perceptual encoding [13]. Along similar lines, low performance on recall of a prose passage or word lists of patients compared to control subjects was observed at immediate recall, with no further loss across a 30-min retention period [14]. These findings also strongly indicate that memory deficits in narcoleptic patients may be attributed to impairments in encoding rather than deficits in storage of and/or access to memory contents. Interestingly, the results of the study by Naumann et al. [15] also suggest a modality specific effect, with more severe problems with retention of verbal memory compared to visual memory. In summary, although there is evidence of reduced memory performance in narcolepsy sufferers compared

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to healthy controls, the impairments tend to be mild which is in clear contrast to the subjective complaints of significant or severe forgetfulness. Patients may be able to enhance their cognitive function for brief periods of time by “investing” more attentional resources, leading to near-normal performance in memory tests in laboratory environments. In everyday life with its multiple distractions, however, subjects fail to keep up a higher level of arousal for an extended period of time, leading to fluctuations in memory and – in some circumstances – to severe retention problems. The most straightforward explanation for memory problems in narcoleptic patients is related to their excessive sleepiness. If sleepiness is the underlying cause of memory dysfunction in narcoleptics, similar impairments would be expected for other sleep disorders accompanied by daytime sleepiness such as obstructive sleep apnea (OSA) and insomnia. Similarly, experimentally induced sleep deprivation should lead to comparable deficits. The empirical evidence is as yet inconsistent. Nevertheless, it is interesting to note that memory problems are quite frequently observed in insomniac patients, although the general cognitive status is largely in the normal range. The memory problems of insomnia patients can, however, not unequivocally be linked to daytime sleepiness. First, objective measures such as the multiple sleep latency test (MSLT) seem to suggest that insomniacs are not particularly sleepy, as they do not fall asleep earlier than control subjects, when given the opportunity to sleep during the day [13]. Since difficulty with falling asleep is one of the core symptoms of insomnia, the MSLT may, however, not adequately reflect sleepiness in insomnia patients. Second, additional mechanisms might come into play in insomniac patients, since nocturnal sleep is necessary for memory consolidation. Although earlier studies yielded contradictory findings with respect to the role of sleep in memory consolidation, recent studies confirmed a critical role of sleep for memory for word pairs [16] or spatial information [17]. The precise mechanism remains to be fully explored, but hippocampal reactivations during sleep appear to play an important role, and different stages of sleep appear to facilitate the consolidation of different types of memories [14, 18]. Nocturnal sleep is clearly disrupted in narcolepsy sufferers. The patients often fall asleep easily, but they wake up again after a brief period and have difficulty falling asleep again. In a 24-h day, many patients do

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not sleep longer than healthy subjects [19]. REM sleep, which typically emerges after about 90 min of sleep in healthy subjects, is observed after 10 min in narcoleptic patients [20]. A possible explanation is that transitions between states of wakefulness and sleep, and transitions between different sleep states are disrupted in narcoleptics, with disruption of memory consolidation as a secondary effect. The pattern of memory problems, however, does not support the hypothesis of deficient memory consolidation, since impairments appear to be most pronounced immediately after encoding, before consolidation has been established.

Attention As mentioned above, daytime sleepiness is one of the most striking symptoms of narcolepsy. The patients experience the urgent need to nap, and they frequently fall asleep despite their efforts to stay awake. It is not surprising that around 40% of narcolepsy patients complain about concentration difficulties as a prominent cognitive impairment. In psychological terms, it is difficult to determine the nature of the problem that patients refer to as concentration problems. The term concentration, as used in everyday life, comprises a number of different processes and presumably matches the psychological term attention or sustained attention most closely. Attention is not a unitary concept, but involves several distinct subcomponents, such as alertness, vigilance, selective, or divided attention [21]. In contrast to memory, subjective reports of concentration problems tend to be corroborated, at least partly, by the results of standardized attention tests. Alertness refers to a subject’s ability to engage in and sustain a state of preparation for the detection of highly relevant stimuli. Vigilance shares similarities with alertness, but usually refers to the maintenance of alertness over an extended period of time. In narcoleptic patients, alertness/vigilance has frequently been assessed with the critical flicker fusion (CFF) test. This test provides a more indirect measure of attention. The CFF is the minimal frequency at which flickering lights induce the perception of a constantly flashing light. The higher the CFF, the more alert the subject is considered to be. Applying this measure, Levander and Sachs [16] reported lower alertness in narcolepsy patients than in healthy controls; alertness was enhanced by the administration

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of central stimulants. In a study by Rieger et al. [17], tonic alertness was assessed in terms of speed of responding to a target stimulus and phasic alertness was assessed in terms of forewarned reaction times (RT), i.e. the ability to increase the alertness level in expectation of the target stimulus. Narcolepsy patients showed slower RTs than controls, suggesting a general alertness deficit. Similar to healthy control subjects, however, narcoleptics responded faster in the phasic alertness condition, when the target was preceded by a warning stimulus. This result suggests that phasic alertness mechanisms are intact, while the general speed of information processing is slowed. Other studies, however, did not replicate the finding of longer RTs in the tonic alertness condition using the same task [14] or related alertness tasks [22]. While the data for alertness are contradictory, assessment of the ability to sustain attention across an extended time period (vigilance) yields a consistent impairment pattern in narcolepsy patients. In a study which applied the CFF test at 15  min intervals for a total duration of 10 h, general alertness levels did not differ between patients and controls, but patients showed a significant increase in the performance variability throughout the session [23]. This pattern was interpreted in terms of a high level of alertness fluctuations over time, a finding which was corroborated by several recent studies. Compared to patients with obstructive sleep apnea, narcoleptics perform poorer than controls on driving simulation tasks, with increasing problems with increasing duration of the assessment [24, 25]. Comparable vigilance impairments have been reported for a variety of other tasks, which required high levels of attention for up to one hour [26, 27]. Patients may be able to compensate alertness problems when performing short tasks in the range of seconds or a few minutes, but such compensatory mechanisms cannot be upheld for an extended time period, and performance differences between patients and controls increase with time during the duration of a task. In addition, performance on vigilance tasks tends to be more variable in narcolepsy patients, reflecting high alertness fluctuations [28]. Although the data basis is quite small to date, more demanding attention aspects, such as the ability to efficiently divide attentional resources between different tasks appear to be more severely affected than alertness. Two recent studies administered the same divided attention tasks, which required subjects to simultaneously

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monitor both visual and auditory stimuli, and to respond to target stimuli in both channels [15, 17]. In the earlier study [17], narcoleptic patients missed more targets and showed longer and more variable RTs than control subjects. Slow RTs also emerged during task conditions in which the patients had to respond to visual or auditory stimuli only and RT slowing was thus not specific to the divided attention condition. The reduced accuracy in the divided attention compared to the single stimulus condition, on the other hand, would support the hypothesis of a specific divided attention impairment. In the more recent study, there was evidence for a speed-accuracy trade-off in the patients, with intact accuracy scores being accompanied by prolonged RTs [15]. Other attention subcomponents such as focused or sustained attention have also been assessed in narcoleptic patients. Considerable between-study differences in the tasks used to assess attention do not allow a direct comparison of the results. The majority of the studies reported significant impairments in the patients. They scored lower than controls on the Digit Symbol Substitution Test under conditions of induced low arousal [28], and showed elevated perseverative errors on a cancellation task [11]. Visual search tasks yielded evidence of speed-accuracy trade-offs, with one study reporting reduced accuracy and normal RTs [22], while the other finding the opposite pattern: intact accuracy and prolonged RTs [17]. Similarly, Naumann et  al. observed slower performance speed of narcoleptics on a cancellation task, while performance accuracy did not differ from control subjects [15]. Taken together, the available evidence does not suggest a general impairment of attentional functions in narcoleptic patients. Attention appears to be particularly affected on tasks a) which require cognitive processing across an extended period of time , or b) which are characterized by increased information processing demands, e.g. which require the ability to focus or to divide attentional resources. In situations with relatively low demands, such as simple RT tasks, narcoleptic patients seem to be able to compensate for arousal fluctuations by phasic increases in alertness which can be upheld for a short period of time [7]. Similarly, patients might be able to cope with more demanding tasks, but the need to use effort to keep up high arousal levels leads to speed-accuracy trade-offs, with the patients either performing less accurately or more slowly than control subjects.

Executive Functions The term “executive functions” refers to superordinate cognitive control functions, which allow the efficient coordination of information processing and action control [29, 30]. Executive functions do not refer to a unitary process, but generally come into play when limited attentional resources have to be allocated to different sensory input channels or when different actions have to be coordinated during multitasking. Executive control is also necessary for the temporary inhibition of predominant, but currently inadequate response tendencies, e.g. in certain social situations. Executive functions have so far been rarely studied in narcolepsy patients. The assessment of working memory, i.e. the ability to hold and to process new information for a limited period of time, did not yield consistent group differences between narcoleptic patients and control subjects, at least when simple digit backward tasks were administered [11, 12, 15, 26]. Naumann et al. did, however, observe prolonged RTs in narcoleptic patients in an n-back task, while performance accuracy was intact. A comparable performance pattern was observed when the Sternberg task was administered to study working memory [31]. The results for verbal fluency as a measure of ruleguided cognitive search and flexibility are also inconsistent [14, 15], which may at least partly be related to methodological differences. In a comprehensive assessment of different executive function subcomponents, Naumann et  al. [15] reported a significant impairment of narcolepsy patients on the Hayling Sentence Completion Test, with narcoleptic patients needing longer time to retrieve suitable words from memory, but they also had difficulties in inhibiting a predominant, but in the current context unsuitable, response tendency [14]. Although the study by Rieger et al. [17] focused on attention, the results derived from a flexible attention task are also of interest for the executive function domain. In this task, subjects are presented two stimuli, a digit and a letter, each being presented on one side of the screen, left or right. Subjects have to indicate the location of the target stimulus by pressing either the left or right button, but the target – letter or digit – changes from trial to trial. Thus, performance on this task would reflect cognitive flexibility. Narcolepsy patients not only took longer to perform this task, but they also made

20 Memory and Cognition in Narcolepsy

more errors [17]. It remains to be clarified, however, whether this problem can be interpreted in terms of an increased susceptibility to interference [15]. Thus, the data basis for executive function assessments in narcoleptic patients is small, and further research is clearly needed, before firm conclusions can be drawn. Recent research seems to suggest that narcoleptic patients do suffer from some degree of executive control impairments. By definition, executive function tasks are demanding. It is conceivable that the mechanism of breakdown shares some similarities with the problems observed during the performance of demanding attention tasks. Narcoleptic patients may have to allocate a considerable proportion of their attentional and cognitive resources to the continuous maintenance of alertness. The resulting reduction of processing resources may not suffice to perform demanding tasks as fast and as accurately as control subjects.

Summary and Discussion Although the empirical data base on cognitive function in narcolepsy is sparse and there are considerable between-study inconsistencies, the general pattern does seem to indicate that the majority of narcoleptic patients suffer from cognitive problems. Attention appears to be the most affected cognitive domain. On the one hand, this finding complicates the interpretation of results from other cognitive domains, since adequate attentional functions are a prerequisite for successful performance of any kind of task. On the other hand, attentional impairments emerge only during the performance of demanding or longer lasting tasks, which led to the suggestion [14] that patients need to allocate a considerable proportion of their attentional resources to the maintenance of alertness (or to prevent them from falling asleep). The remaining resources are sufficient for the performance of short and simple, but not complex or demanding tasks. This hypothesis applies to attentional problems, and also to memory or executive dysfunction. It should be noted that cognitive impairments might be indirectly caused by elevated levels of sleepiness. In an attempt to control the effect of sleepiness, healthy subjects were sleep-deprived to the same level of sleepiness as narcolepsy patients, which was achieved after 36  h of sleep deprivation, i.e. the subjective

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sleepiness ratings were comparable [32]. Control subjects still outperformed the narcolepsy patients on an attention task. Although this result does seem to argue against sleepiness as the primary cause of cognitive problems in narcolepsy, it is possible that subjective ratings do not reflect the real level of sleepiness in narcoleptics. They may use a different reference frame than healthy controls, which might lead to underestimation of their sleepiness [33, 34]. Thus, it cannot be excluded that the performance differences in this study were caused by increased levels of sleepiness in the patients. In line with this assumption, more objective sleepiness measures such as the MSLT suggest that narcolepsy is accompanied by increased levels of sleepiness. As a diagnostic criterion, short sleep latencies of less than 8 min – as revealed by the MSLT – are used [1, 35]. Taken together, the neuropsychological profile of narcoleptic patients might be at least partly linked to the disruptive effects of sleepiness. In fact, sleepiness induced by sleep deprivation in healthy human subjects is associated with changes in task-related brain activity in distinct cortical regions. Increased activity in frontal and parietal brain regions in association with different types of tasks was interpreted in terms of “compensatory recruitment” [36–38]. In a recent study, Chee et al. [39] examined neural activity in rested and sleepy subjects on lapses of attention in a selective attention task. Compared to lapses after a normal night of sleep, lapses in sleep-deprived subjects were associated with decreased fronto-parietal, visual cortex and thalamic activity. Most interestingly, however, the neural responses associated with very fast correct responses did not differ between rested and sleep-deprived subjects. Compensatory recruitment thus leads – from time to time – to “normal” activations of task-related brain areas, enabling the subject to perform in the normal range. In summary, these findings show that in sleepdeprived subjects, brain regions related to cognitive control functions which are responsible for the allocation of attention, are recruited more strongly than in non-sleep-deprived states, yielding adequate cognitive performance. This mechanism can be upheld only for short time intervals. If the task at hand lasts longer, lapses of attention cannot be avoided, leading to performance decrements [39]. These insights from studies with sleep-deprived healthy subjects lend further support to the notion that cognitive problems in narcolepsy are at least partly caused by sleepiness. As outlined in the previous

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sections, narcoleptics have been shown to be impaired on more complex tasks and on tasks, which last longer than a few minutes. Under these conditions, the patients are no longer able to compensate for sleepiness effects, because a higher proportion of cognitive resources are recruited for the maintenance of alertness. Increased task-related activations in sleep-deprived subjects have been found during the performance of attention as well as memory tasks [38, 40, 41]. In addition, compensatory activations were found to be larger for more demanding and difficult tasks, indicating a link between task complexity and the degree of compensatory neuronal recruitment [42]. Narcolepsy patients have been reported to suffer from a reduction of hypocretin neurons in the lateral hypothalamus. This reduction may lead to structural changes, and this hypothesis has been supported by recent evidence of gray matter reductions in the temporal cortex and in different sub-regions of the frontal cortex [43, 44]. Another study, however, did not find structural differences between patients and controls [45], and further research is needed to clarify this issue [46]. There are very few data on functional brain activity in narcoleptic patients, with most studies not focusing on cognitive tasks, but, for example, on humor processing [47, 48]. Evidence from event-related potentials indicates that the patterns of brain processes in narcoleptics are altered. Increased P300 amplitudes as well as reduced mismatchnegativity-asymmetry over frontal brain areas appear to corroborate the assumption that activation changes are primarily observed in the frontal cortex [49]. It should be noted, however, that there are also reports of normal event-related potential data in narcolepsy [8]. To summarize, cognitive impairment in narcolepsy seems to be partly caused by neural mechanisms triggered by, and compensating for, sleepiness. It is, however, also possible that factors more directly related to the disorder and its pathology (such as neurotransmitter changes) might have a direct effect on cognitive function, which would be in line with – as yet to be corroborated – findings of structural and functional neurocognitive changes in narcoleptic patients. In support of this idea, the severity of cognitive dysfunction in patients is, on an average, more pronounced than in sleep-deprived healthy subjects. Future studies on the relationship between narcoleptic symptoms, cognitive profile and degree of pathophysiological changes in large samples of patients will hopefully shed more light on the mechanisms underlying cognitive dysfunction in narcoleptic patients.

References   1. American Academy of Sleep Medicine (2005) International classification of sleep disorders. Diagnostic and coding manual, 2nd Edition. Westchester: American Academy of Sleep Medicine.   2. Yoss, R.E., Daly, D.D. (1957) Criteria for the diagnosis of the narcoleptic syndrome. Proc Staff Meet Mayo Clin 32, 320–328.   3. Thannickal, T.C., Moore, R.Y., Nienhuis, R., Ramanathan, L., Gulyani, S., Aldrich, M., Cornford, M., Siegel, J.M. (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27, 469–474.   4. Peyron, C., Tighe, D.K., van den Pol, A.N., de Lecea, L., Heller, H.C., Sutcliffe, J.G., Kilduff, T.S. (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18, 9996–10015.   5. Kish, S.J., Mamelak, M., Slimovitch, C., Dixon, L.M., Lewis, A., Shannak, K., DiStefano, L., Chang, L.J., Hornykiewicz, O. (1992) Brain neurotransmitter changes in human narcolepsy. Neurology 42, 229–234.   6. Aldrich, M.S., Prokopowicz, G., Ockert, K., Hollingsworth, Z., Penney, J.B., Albin, R.L. (1994) Neurochemical studies of human narcolepsy: alpha-adrenergic receptor autoradiography of human narcoleptic brain and brainstem. Sleep 17, 598–608.   7. Naumann, A., Daum, I. (2003) Narcolepsy: pathophysiology and neuropsychological changes. Behav Neurol 14, 89–98.   8. Ganado, W. (1958) The narcolepsy syndrome. Neurology 8, 487–496.   9. Broughton, R., Ghanem, Q., Hishikawa, Y., Sugita, Y., Nevsimalova, S., Roth, B. (1983) Life effects of narcolepsy: relationships to geographic origin (North American, Asian or European) and to other patient and illness variables. Can J Neurol Sci 10, 100–104. 10. Broughton, R., Ghanem, Q., Hishikawa, Y., Sugita, Y., Nevsimalova, S., Roth, B. (1981) Life effects of narcolepsy in 180 patients from North America, Asia and Europe compared to matched controls. Can J Neurol Sci 8, 299–304. 11. Rogers, A.E., Rosenberg, R.S. (1990) Tests of memory in narcoleptics. Sleep 13, 42–52. 12. Aguirre, M., Broughton, R., Stuss, D. (1985) Does memory impairment exist in narcolepsy-cataplexy? J Clin Exp Neuropsychol 7, 14–24. 13. Riedel, B.W., Lichstein, K.L. (2000) Insomnia and daytime functioning. Sleep Med Rev 4, 277–298. 14. Marshall, L., Born, J. (2007) The contribution of sleep to hippocampus-dependent memory consolidation. Trends Cogn Sci 11, 442–450. 15. Naumann, A., Bellebaum, C., Daum, I. (2006) Cognitive deficits in narcolepsy. J Sleep Res 15, 329–338. 16. Levander, S., Sachs, C. (1985) Vigilance performance and autonomic function in narcolepsy: effects of central stimulants. Psychophysiology 22, 24–31. 17. Rieger, M., Mayer, G., Gauggel, S. (2003) Attention deficits in patients with narcolepsy. Sleep 26, 36–43. 18. Rasch, B., Born, J. (2007) Maintaining memories by reactivation. Curr Opin Neurobiol 17, 698–703. 19. Nishino, S. (2007) Clinical and neurobiological aspects of narcolepsy. Sleep Med 8, 373–399. 20. Dement, W., Rechtschaffen, A., Gulevich, G. (1966) The nature of the narcoleptic sleep attack. Neurology 16, 18–33.

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229 deprivation and the relationship with performance. Psychiatry Res 140, 211–223. 37. Drummond, S.P., Brown, G.G. (2001) The effects of total sleep deprivation on cerebral responses to cognitive performance. Neuropsychopharmacology 25, S68–S73. 38. Drummond, S.P., Bischoff-Grethe, A., Dinges, D.F., Ayalon, L., Mednick, S.C., Meloy, M.J. (2005) The neural basis of the psychomotor vigilance task. Sleep 28, 1059–1068. 39. Chee, M.W., Tan, J.C., Zheng, H., Parimal, S., Weissman, D.H., Zagorodnov, V., Dinges, D.F. (2008) Lapsing during sleep deprivation is associated with distributed changes in brain activation. J Neurosci 28, 5519–5528. 40. Drummond, S.P., Gillin, J.C., Brown, G.G. (2001) Increased cerebral response during a divided attention task following sleep deprivation. J Sleep Res 10, 85–92. 41. Drummond, S.P., Brown, G.G., Gillin, J.C., Stricker, J.L., Wong, E.C., Buxton, R.B. (2000) Altered brain response to verbal learning following sleep deprivation. Nature 403, 655–657. 42. Drummond, S.P., Brown, G.G., Salamat, J.S., Gillin, J.C. (2004) Increasing task difficulty facilitates the cerebral compensatory response to total sleep deprivation. Sleep 27, 445–451. 43. Brenneis, C., Brandauer, E., Frauscher, B., Schocke, M., Trieb, T., Poewe, W., Hogl, B. (2005) Voxel-based morphometry in narcolepsy. Sleep Med 6, 531–536. 44. Kaufmann, C., Schuld, A., Pollmacher, T., Auer, D.P. (2002) Reduced cortical gray matter in narcolepsy: preliminary findings with voxel-based morphometry. Neurology 58, 1852–1855. 45. Overeem, S., Steens, S.C., Good, C.D., Ferrari, M.D., Mignot, E., Frackowiak, R.S., van Buchem, M.A., Lammers, G.J. (2003) Voxel-based morphometry in hypocretin-deficient narcolepsy. Sleep 26, 44–46. 46. Dang-Vu, T.T., Desseilles, M., Petit, D., Mazza, S., Montplaisir, J., Maquet, P. (2007) Neuroimaging in sleep medicine. Sleep Med 8, 349–372. 47. Schwartz, S., Ponz, A., Poryazova, R., Werth, E., Boesiger, P., Khatami, R., Bassetti, C.L. (2008) Abnormal activity in hypothalamus and amygdala during humour processing in human narcolepsy with cataplexy. Brain 131, 514–522. 48. Reiss, A.L., Hoeft, F., Tenforde, A.S., Chen, W., Mobbs, D., Mignot, E.J. (2008) Anomalous hypothalamic responses to humor in cataplexy. PLoS ONE 3, e2225. 49. Naumann, A., Bierbrauer, J., Przuntek, H., Daum, I. (2001) Attentive and preattentive processing in narcolepsy as revealed by event-related potentials (ERPs). Neuroreport 12, 2807–2811.

Chapter 21

Medico-Legal Aspects of Disability in Narcolepsy Francesca Ingravallo and Giuseppe Plazzi

Introduction Narcolepsy is a severe, chronic, disabling disease affecting almost all personal and social activities. Sleep disorder specialists encounter the disabling burden of narcolepsy from their first approach to the patient. Diagnosis of narcolepsy is often established after many years of unrecognized evolution, misdiagnosis, and inappropriate treatments. The disease continues to be a burden throughout the patient’s life as pharmacological and behavioral treatments seldom control the ­variety of symptoms. Since people with narcolepsy experience a wide range of occupational problems, both clinicians and researchers are interested in finding means of helping their patients hold down a job, return to work, and, if necessary, receive benefits for work disability. However, an overview of disability in narcolepsy is difficult because “disability is a slippery and potentially expansive category: it is inherently subjective, ambiguous, fuzzy, elusive, and inevitably problematic to define and measure” [1]. In addition, national social disability programs differ substantially in the type of economic (invalidity pension, lump sum benefit, occupational benefits, etc.) and other (medical care, occupational or social rehabilitation, home help, etc.) disability benefits and in conditions governing eligibility, and the complementary or supplementary schemes of protections against work disability each have their own rules. Since any generalization of disability is impossible, this chapter considers only the medical aspects of work F. Ingravallo (*) Francesca Ingravallo, Section of Legal Medicine, Department of Medicine and Public Health, University of Bologna, Bologna, Italy e-mail: [email protected]

disability in narcolepsy. After a definition of work disability, we discuss the essential issues clinicians and researchers have to address in providing medical information to assist disability determination in people with narcolepsy. In conclusion, a work disability classification of narcolepsy is proposed.

Disability and Work Disability Research over the past several decades has clearly shown that “disability” is defined and conceptualized differently from one society to the next [2]. Different conceptual models of disability have influenced the definition of disability, and hence the identification of persons with disability. The medical model views disability as a characteristic or attribute of the person, whereas the social model views disability as a socially created problem. Beyond these definitions, disability can be construed in relation to an ability “norm,” or in terms of the ability to perform certain activities. The 1980 World Health Organization (WHO) International Classification of Impairments, Disabilities, and Handicaps [3] made distinctions for impairment as loss or abnormality of psychological, physiological, or anatomical structure or function; disability as any restriction or lack of ability (resulting from an impairment) to perform an activity in the manner or within the range considered normal; and handicap as a disadvantage for a given individual, resulting from an impairment or a disability, that prevents the fulfilment of a role that is considered normal (depending on age, sex, and social and cultural factors) for that individual. In 2001, WHO published a major revision of its disability classification: the International Classification of Functioning, Disability and Health (ICF) [4]. Based on

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a biopsychosocial model, the ICF uses disability as an umbrella term for impairments, activity limitations, and participation restrictions. Impairments are “problems in body function or structure such as significant deviation or loss”; activity limitations are “difficulties an individual may have in executing activities”; and participation restrictions are “problems an individual may experience in involvement in life situations” [4]. The ICF construes disability and functioning as outcomes of interactions between health conditions (diseases, disorders, and injuries) and contextual factors; among contextual factors are external environmental factors (for example, social attitudes, architectural characteristics, legal, and social structures, as well as climate, terrain, and so forth), and internal personal factors, which include gender, age, coping styles, social background, education, profession, past and current experience, overall behavior pattern, character, and other factors that influence how disability is experienced by the individual [5]. The definition of work disability also differs according to different disability models. The US Social Security Administration, for example, defines work disability in a way consistent with the medical model [6]. For our purposes, we can define work disability as the “inability to meet the demands of gainful activity, due to functional limitations, caused by impairment” [7]. Scheme  1 summarizes the causal chain leading from pathology to disability, taking a medical vocational point of view that coincides with the definition of disability under a disability insurance scheme [7]. Age, gender, lifestyle, health record, occupational hazards

pathology

recovery prospects impairment chronic impairments may be corrected by medicine, aids, or appliances functional limitations functional limitations may be corrected by offsetting capacities, job accommodation or vocal rehabilitation

work disability

Scheme 1  Etiology of work disability (reproduced from de Jong (2003) with permission from Ashgate)

This framework focuses on the role of the sleep disorder expert in the complex process of work disability assessment of people with narcolepsy: assessing the impairment remaining after therapy and rehabilitation efforts, and describing functional limitations.

Work Limitations in Narcolepsy Pioneer studies [8–11] clearly disclosed the psychosocial impact of narcolepsy: the disorder affects all aspects of everyday life: family, school, job, interpersonal relationships, and social activities. Broughton et al. [9, 12] suggested that this is “an integral part of the disease or of the human reactions to it.” More recent SF-36 studies describing the healthrelated quality of life in people with narcolepsy corroborate this hypothesis: a comparable quality of life impairment, that can be improved, but not restored, by medical treatment, was found in the USA [13], United Kingdom [14, 15], Italy [16], Norway [17], and Germany [18]. This quality of life impairment is extensive and similar to other chronic neurological diseases like Parkinson’s disease and multiple sclerosis [18]. The distribution of the narcolepsy economic burden also resembles that of other chronic neurological diseases: indirect costs are higher than direct costs, and the indirect costs include the costs of early retirement due to the disease [19]. The rate of early retirement in patients with narcolepsy is currently one of the few measures reflecting the dramatic impact of narcolepsy on patients’ occupational life, as well as the number of missed working days and the rate of unemployment, that in the study by Dodel et al. [19] reached 59%. The disorder-related work problems reported by people with narcolepsy included an inability to use their qualification, low productivity, reduced job performance, loss of promotion, decreased earnings, and fear of losing their job [9, 14, 15, 20, 21]. Moreover, between 37% [14] and 52% [15] of patients were reported to have lost or left a job because of the disease, and between 8.3% [11] and 15% [20] have a work disability status. The available data on the grounds of work problems [8, 21] showed that people with narcolepsy attributed their job difficulties mainly to sleep attacks and inability to concentrate. In addition, falling asleep at work was reported by up to 80% patients [10].

21 Medico-Legal Aspects of Disability in Narcolepsy

The detrimental effect of narcolepsy on patients’ working lives could therefore be severe and long-lasting. The problem is how to establish whether a patient with narcolepsy has a work disability and how to distinguish between full and partial disability.

Impairment Variability The impact of narcolepsy may vary widely with respect to work disability: not all narcoleptic patients have a work disability, and those that do may only have a partial disability. Even job satisfaction among people with narcolepsy varied widely in the survey by Alaia [20]. The author emphasized that several people reporting the highest levels of job satisfaction indicated that they had found jobs in which they were physically active, could take short naps, or arrange their schedules to coincide with their more alert periods of the day. In addition, people with narcolepsy showed a high inter-individual difference in driving simulator performance [22, 23], and Vignatelli et al. [16] found a variance in health-related quality of life, noting a sub-group without specific drug treatment and a satisfactory healthrelated quality of life among their cohort of 108 patients. This variability is mainly attributable not only to the broad narcolepsy spectrum, but also to the variety of impairment due to narcolepsy with cataplexy itself, which also has a broad clinical spectrum, and especially major interpersonal (and sometimes intrapersonal) variations of excessive daytime sleepiness (EDS) and cataplexy. EDS in narcolepsy with cataplexy is generally characterized by brief repeated episodes of daytime naps or lapses into sleep, often associated with dream experience mentation. However, EDS may manifest as a persistent feeling of being sleepy, or as an urgent need to sleep, only in boring or monotonous conditions or even in very active situations (such as walking or talking), and daytime naps may recur only at characteristic times (mid-morning or after lunch) or every 2–3 h, or do not occur at all during work time. Cataplexy also shows a similar broad spectrum of severity, patterns, and frequency: the loss of muscle tone ranges from a mild sensation of weakness to a complete loss of muscular tone, and may be limited to some facial muscles or be generalized. Cataplexy may occur rarely in a month or many times during a day, and even the inducing stimuli vary widely from patient to patient.

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Associated features, such as sleep paralysis, hypnagogic hallucinations, and nocturnal sleep disruption also vary in occurrence and severity. In addition, the efficacy and acceptance of medical and behavioral therapy vary and will also have an impact on narcolepsy-associated symptoms. The variety of narcolepsy impairment is also due to the different extent patients adjust to this disorder that could depend on the coping strategies the person engages to manage and counterbalance the negative effects of the disease. Thus, impairment assessment must address both disease severity, as modified by therapies, and the efficacy of a patient’s coping strategies in managing narcolepsy symptoms.

The Lack of a Clinical Severity Scale The assessment of impairment due to narcolepsy is further hampered by the lack of a clinical severity scale. None of the severity criteria provided by the previous edition of the International Classification of Sleep Disorders (ICSD-R) [24], including those for narcolepsy (Table 21.1), are listed in the current edition because “such criteria could not uniformly be applied in different areas of the world” [25]. Moreover, Ohayon et al. [26] had already emphasized that ICSD-R criteria for “mild severity” appeared like a catch-all category that cannot be used in epidemiology because it would overestimate the prevalence of the disease. An impairment classification of “sleep and arousal disorders” is present in the American Medical Association’s Guides to the evaluation of permanent impairment [27], in which impairment is defined as “a significant deviation, loss, or loss of use of any body structure or body function in an individual with a health condition, disorder, or disease”. However, this classification is only a generic reference, because it is not specific for narcolepsy, whereas in Germany there have been suggested criteria to rate the degree of disability in narcolepsy in relation to sleep attacks, accidents, and cognitive impairment [28–30]. In addition to the lack of a severity classification of narcolepsy, there is the greater problem of a lack of validated and consistent tools to assess and quantify narcolepsy symptoms, especially EDS. This issue is ­crucial in work disability assessment because persistent EDS is considered the main disabling symptom of

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234 Table 21.1  Severity criteria for narcolepsy and sleepiness [24] Severity criteria for narcolepsy Mild

Moderate

Severe

Mild sleepiness or rare cataplexy (less than once per week) Severity criteria for sleepiness Mild Sleepiness This term describes sleep episodes that are present only during times of rest or when little attention is required. Situations in which mild sleepiness may become evident include but are not limited to watching television, reading while lying down in a quiet room, or being a passenger in a moving vehicle. Mild sleepiness may not be present every day. The symptoms of mild sleepiness produce a minor impairment of social or occupational function. This degree of sleepiness is usually associated with a multiple sleep latency test (MSLT), with a mean sleep latency of 10–15 min.

Moderate sleepiness or infrequent cataplexy (less than daily)

Severe sleepiness or severe cataplexy (daily)

Moderate Sleepiness This term describes sleep episodes that are present daily and that occur during very mild physical activities requiring, at most, a moderate degree of attention. Examples of situations in which moderate sleepiness occur include during concerts, movies, theatre performances, group meetings and driving. The symptoms of moderate sleepiness produce a moderate impairment of social or occupational function. This degree of sleepiness is usually associated with an MSLT mean sleep latency of 5–10 min.

Severe Sleepiness This term describes sleep episodes that are present daily, and at times of physical activities that require mild to moderate attention. Situations in which severe sleepiness may occur include during eating, direct personal conversation, driving, walking, and physical activities. The symptoms of severe sleepiness produce a marked impairment of social or occupational function. This degree of sleepiness is usually associated with an MSLT mean sleep latency of less than 5 min.

narcolepsy [11, 31], and a significant correlation between sleep attacks and costs has been found [19]. Furthermore, simulation and dissimulation may occur in disability ascertainment so that the procedure must be based on methods which are as objective as possible. An overview of sleepiness measures is beyond the scope of this chapter, but it should be emphasized that at present no validated tools or direct biologic measures are appropriate for an objective quantification of sleepiness. The Multiple Sleep Latency Test reflects the physiological sleep tendency in the absence of alerting factors [32]. The test is indicated to confirm the diagnosis of narcolepsy, but does not reflect the severity of the sleepiness. The Maintenance of Wakefulness Test, developed to assess the ability to stay awake, could serve as an adjunct to clinical ­judgment in determining the improvement following treatments [33], and more data are needed to establish its value as a measure of EDS severity. Regarding the subjective measures, several studies have shown that the most commonly used Epworth Sleepiness Scale scores poorly correlate with the objective test [34–40], and that different subjective scales could reflect different aspects of subjective sleepiness, which seems to have different dimensions [41]. Lastly, there is some evidence that EDS is a complex phenomenon in relation to work disability and no

single scale or technique is currently appropriate to assess the disabling weight of sleepiness in narcolepsy and other hypersomnias [42].

The Contribution of Sleep Disorder Experts to Work Disability Determination Lacking objective measures to assess the impairment due to narcolepsy, the clinician’s contribution to work disability determination remains pivotal. Clinical assessment includes: (1) diagnosis, (2) information on the clinical severity of narcolepsy, and (3) a description of the patient’s functional limitations. Diagnosis is dealt with in the relative chapter. The question of narcolepsy severity must address both the severity of EDS and cataplexy, and the quality of life impairment. EDS should be described specifying: • The patient’s sleep propensity in active and passive situations • The number of daytime naps the patient needs and the personal daytime sleep schedule • Whether sleep attacks occur, and if they are sudden and without warning

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• Quality of sleep during the night • The occurrence of automatic behaviors, and their frequency Additional information could be given enclosing a copy of questionnaires (not just the final score) filled in by the patient, and the Maintenance of Wakeful Test results. Cataplexy should be described in pattern, frequency, and severity (how protracted are the attacks and whether the patient falls down). The most inducing stimuli also have to be reported, along with the strategies adopted by the person to avoid or control the cataplexy and their efficacy. Hypnagogic hallucinations, sleep paralysis, and REM behavior disorders should be reported, ­specifying their influence on the patient’s life, especially when they cause psychological problems and risk of accidents. The clinician should also detail therapies, their efficacy and side effects, and behavioral recommendations. Then, the functional limitations in a patient’s activities should be described. The major areas of everyday activities to be considered are: self-care, home care, family care, mobility (moving away from home alone on foot or by car), and physical and social activities, specifying whether the person has difficulties in living independently. Finally, a description of a patient’s work problems (or difficulties in finding and holding down a job), and of the risk of accidents and near accidents is also very important.

Conclusions It is notoriously difficult, in practice, to determine what constitutes disability and work incapacity, and to distinguish those who are able to work from those

who are not [43]. Disability assessment remains a difficult process, irrespective of how disability is defined and how national procedures are implemented, and inclusion and exclusion errors are common [44]: an average 35% of unemployed disabled persons are excluded from disability benefits whereas 33% of disability beneficiaries report being without disabilities [7]. Disability assessment in narcolepsy is further complicated by the lack of both objective tools to quantify EDS and standardized criteria to determine the medical impairment. In addition, various symptoms are in part paroxysmal and modulated by circumstances and emotions, so that most people suffering from narcolepsy could experience a kind of “intermittent disability”, often with an individual time-schedule of daytime sleep [42]. Two further aspects should be addressed in assessing work disability in narcolepsy [42]. Firstly, narcolepsy characteristically not only limits patients’ working capacity, but also restricts their range of occupations to jobs which do not entail periods of physical inactivity or boredom, or risk of sleep-related accidents. Secondly, people with narcolepsy are probably unfit for current “standard” work, consisting of an office job that is not appropriate for people with EDS, and they are not aided by the new technologies that may play a major role in integrating other disabled workers. Since the spectrum of narcolepsy symptoms is broad in terms of pattern, frequency, and severity, the disability assessment should be always highly tailored to the individual patient given the variability in patients’ adjustment to the disease. Table 21.2 outlines four classes of work disability in narcolepsy, based on EDS severity, cataplexy severity, therapy efficacy, and patient’s ability to manage symptoms.

Table 21.2  Classification of work disability in narcolepsy

Class 1: Mild narcolepsy with or without cataplexy Excessive daytime sleepiness and cataplexy well compensated by medical and/or behavioral therapy, no need of nap during the work time.

Class 2: Narcolepsy with or without cataplexy controlled by therapy Excessive daytime sleepiness and cataplexy responsive to medical and/or behavioral therapy; the patient is able to manage the cataplexy; need for scheduled naps during the work day.

Class 3: Narcolepsy with or without cataplexy scarcely controlled by therapy Excessive daytime sleepiness and cataplexy not well controlled by medical and/or behavioral therapy; the patient is not always able to manage the cataplexy, sleep attacks recur.

Class 4: Severe narcolepsy with cataplexy Excessive daytime sleepiness and cataplexy resistant to drugs; multi-daily sleep attacks and/or multi-daily uncontrolled cataplectic attacks; the person is unable to care for himself/herself.

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Further efforts are needed to devise and validate tools for the assessment of narcolepsy severity and disability.

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21 Medico-Legal Aspects of Disability in Narcolepsy ders and excessive daytime sleepiness. Somnologie 2, 89–95. 31. Dement, W. C. (1976) Daytime sleepiness and sleep “attaks.” In: Guilleminault, C., Dement, W., Passouant, P., and Weitzman, E. (eds.) Narcolepsy. Holliswood, NY: Spectrum, 17–34. 32. Carskadon, M. A., and Dement, W. C. (1982) The multiple sleep latency test: what does it measure? Sleep 5, S67–S72. 33. Littner, M. R., Kushida, C., Wise, M., Davila, D. G., Morgenthaler, T., Lee-Chiong, T., Hirshkowitz, M., Loube, D. L., Bailey, D., Berry, R. B., Kapen, S., and Kramer, M. (2005) Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 28, 113–21. 34. Briones, B., Adams, N., Strauss, M., Rosenberg, C., Whalen, C., Carskadon, M., Roebuck, T., Winters, M., and Redline, S. (1996) Relationship between sleepiness and general health status. Sleep 19, 583–8. 35. Chervin, R. D., Aldrich, M. S., Pickett, R., and Guilleminault, C. (1997) Comparison of the results of the Epworth sleepiness scale and the multiple sleep latency test. J Psychosom Res 42, 145–55. 36. Olson, L. G., Cole, M. F., and Ambrogetti, A. (1998) Correlations among Epworth sleepiness scale scores, multiple sleep latency tests and psychological symptoms. J Sleep Res 7, 248–53. 37. Sangal, R. B., Mitler, M. M., and Sangal, J. M. (1999) Subjective sleepiness ratings (Epworth sleepiness scale) do

237 not reflect the same parameter of sleepiness as objective sleepiness (maintenance of wakefulness test) in patients with narcolepsy. Clin Neurophysiol 110, 2131–5. 38. Benbadis, S. R., Mascha, E., Perry, M. C., Wolgamuth, B. R., Smolley, L. A., and Dinner, D. S. (1999) Association between the Epworth sleepiness scale and the multiple sleep latency test in a clinical population. Ann Intern Med 130, 289–92. 39. Chervin, R. D., and Aldrich, M. S. (1999) The Epworth sleepiness scale may not reflect objective measures of sleepiness or sleep apnea. Neurology 52, 125–31. 40. Blaivas, A. J., Patel, R., Hom, D., Antigua, K., and Ashtyani. H (2007) Quantifying microsleep to help assess subjective sleepiness. Sleep Med 8, 156–9. 41. Kim, H., and Young, T. (2005) Subjective daytime sleepiness: dimensions and correlates in the general population. Sleep 28, 625–34. 42. Ingravallo, F., Vignatelli, L., Brini, M., Brugaletta, C., Franceschini, C., Lugaresi, F., Manca, M. C., Garbarino, S., Montagna, P., Cicognani, A., and Plazzi, G. (2008) Medicolegal assessment of disability in narcolepsy: an interobserver reliability study. J Sleep Res 17, 111–9. 43. Stattin, M. (2005) Retirement on grounds of ill health. Occup Environ Med 62,135–40. 44. OECD (2003) Transforming disability into ability. Policies to promote work and income security for disabled people. Paris, France: OECD.

Chapter 22

Narcolepsy and Mental Health John Shneerson

Introduction Narcolepsy is generally considered to be characterised by a tetrad of symptoms, excessive daytime sleepiness, sleep paralysis, hypnagogic hallucinations and cataplexy, but their impact on mental health has hardly been recognised. This is all the more surprising given the considerable recent advances in understanding the neuropathology and physiology of narcolepsy and the influence of sleep disorders on loss of attention, depression, memory, interpersonal behaviour and quality of life. In this chapter these issues will be explored and the effects of treatment discussed.

Cognitive Function Methodological Issues Many of the studies of cognitive function have suffered from only including small numbers of subjects so that inconclusive results have emerged. Meta-analyses have not been carried out, partly because it is difficult to make comparisons when, for instance, different tests have been carried out to assess the same cognitive function. There are also specific problems with testing patients with a sleep disorder, particularly when the sleepiness varies according to the time of day so that results may vary considerably diurnally. There is also the learning effect of repeated testing, which is dependent on the J. Shneerson (*) Respiratory Support and Sleep Centre, Papworth Hospital, Papworth Everard, Cambridgeshire, CB23 8RE, UK e-mail: [email protected]

ability of the subject to learn from experience. Either frequent pre-test familiarisation with the investigation or sufficiently prolonged intervals between testing may overcome this problem, although even these measures are often ineffective [1, 2]. There is also usually an afternoon nadir in cognitive function testing which needs to be taken into account [3].

Attention The three main types of attention – focused, sustained and divided – can be assessed by different batteries of tests. Focused attention is characterised by attention to the identified stimulus while ignoring distracting information. Sustained attention is maintained over an extended period of time, whereas with divided attention more than one task or different aspects of the same task are attended to. Most tests of attention in narcolepsy have shown abnormalities. Results from auditory vigilance tasks and serial reaction time tasks were similar to those of healthy individuals after sleep deprivation, and those with narcolepsy were unable to maintain alertness during monotonous tasks [4]. There was more variation in the performance of a critical flicker fusion test than in healthy volunteers, suggesting that narcoleptic’s vigilance fluctuates considerably [5]. The effects of changes in arousal have been assessed through complex cognitive function tests such as the paced auditory serial addition tests (PASAT) [2]. In those with narcolepsy who were highly aroused, their results were similar to normal individuals, suggesting that they were able to increase their level of attention transiently. A deficit in attention, and also the ability to increase the level of attention for high priority stimuli

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has also been shown [6]. This abnormality may be corrected by stimulant medication [7]. There may also be an inability to sustain attention, as shown by the rapid deterioration in performance at the end of a 10  min alertness task [6, 8]. Those with narcolepsy also appeared to be slower at processing stimuli [7], particularly when a higher degree of executive control was needed.

The results suggest that those with narcolepsy have reduced self efficacy, increased anxiety about memory function and an increased perception of memory decline. These negative self evaluations of cognitive function were thought to be due to difficulties with psycho-social adjustment and that they, rather than any psychophysiological disorder of memory itself, may have been responsible for the patient’s complaints. The impact of the abnormal sleep architecture in narcolepsy on memory has not been investigated.

Memory This is the function whereby information is registered, retained and retrieved. With short-term memory both the amount of information is limited as is the period of time for which it is retained. Working memory however enables information to be manipulated during the performance of cognitive tasks such as comprehension, learning and reasoning, including spatial and language components. Long-term memory may be either explicit (declarative) when it is concerned with memorising facts, or implicit (procedural) in which skills are memorised. Studies of memory in narcolepsy have been inconclusive. Self-reported memory in a questionnaire study by [9] revealed that almost half of the subjects felt that their memory had deteriorated, particularly for recent events since the onset of their narcolepsy and that this was due to poor concentration, sleep attacks and easy distractibility. Similar results were obtained in a mail survey, but without control subjects [10]. A detailed assessment of short and long-term memory, however, did not show any difference between treated and untreated narcoleptics or a control group possibly because of a temporary ability of those with narcolepsy to perform well in a motivating situation [11]. No memory deficit was found in a separate study [12], but another investigation showed several defects in memory [13] and there is also a mild verbal memory deficit [7]. Differences in objective and subjective assessments of memory may be due to the unnatural laboratory setting of the test or that the standardised memory test did not detect the aspects of memory that the patients were aware of, or that their subjective complaints were unfounded. “Meta-memory” which assesses the knowledge about one’s own memory capabilities, as well as the memory itself has been investigated [14].

Executive Function Executive functions enable individuals to carry out independent purposeful behaviour and include planning, decision making, initiation, judgement and cognitive flexibility. Executive function requires a variety of cognitive processes to be intact, including working memory, and it is dependent particularly on frontal lobe function. There are very few data on executive function in narcolepsy [15, 16], but there appear to be consistent impairments, particularly in the ability to suppress habitual responses and in verbal fluency [7]. There may therefore be a generalised executive dysfunction in narcolepsy, but how this relates to any attention and memory deficit is uncertain.

Mood Disorders Anxiety and Depression Anxiety and depression leading to low self esteem and little confidence are common problems in narcolepsy. Depression and other emotional disturbances have frequently been identified even in children [17]. In one study using the Beck Depression Inventory 56.9% of adults had a degree of depression [18] and in a separate investigation using the Euroquol-5D questionnaire 41.1% of narcoleptics were found to be anxious or depressed [26]. Depression is common in adolescents [20] and using the Beck Depression Inventory it is significantly common in those aged up to 45 than in

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older subjects [21]. The cause of this is uncertain but it may be related to improvement in some symptoms of narcolepsy or to psychological adjustments in older subjects, particularly with, for instance, unrealistic expectations and ambitions. The influence of depression on other aspects of cognitive function, such as memory has not been studied, nor have the effects of depression on the quality of sleep in narcolepsy, and in particular, its effect on early morning awakening. Depression probably has a major impact on family, carers, friends and employment, as well as on the individual’s quality of life [27]. Antidepressants are commonly prescribed in narcolepsy for cataplexy, but there is no information on their effect in relieving depression.

Psychosis The vivid experiences of hypnagogic hallucinations, which often include people talking to the person with narcolepsy, have raised the question of whether narcolepsy is related to schizophrenia. In narcolepsy, however, the communications during hypnagogic hallucinations do not try to control the behaviour of the subject with narcolepsy, and the two conditions are completely independent [22]. Psychosis is very unusual in narcolepsy, except during treatment with amphetamines. The risk of psychosis appears to be dose-related [22], although it is likely that some subjects are more susceptible to this complication than others. Psychosis is usually predominantly paranoid.

Other Psychological Aspects Dreams and Hallucinations Dreams in narcolepsy are usually vivid and there is often good recall. Dreams occur at the onset of sleep and the most intense emotional experience during dreams is in the first REM sleep episode of the night, contrasting with the experience of normal subjects in which dreams later in the night are the most emotionally charged [23]. Dreams are often in colour with vivid sounds, as well

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as with taste, smell and pain. There is often a sensation of levitation, including flying. Dreams may occur shortly before sleep, (hypnagogic hallucinations) or shortly after waking (hypnopompic hallucinations) as well as during sleep. These represent partial intrusion of REM sleep into wakefulness. These dreams may merge into wakefulness and are often sufficiently realistic for the subject to be unsure whether they represent reality or not. There may be sounds of insects or voices, or an awareness of semi-formed images or people or animals. This transient loss of contact with reality can be embarrassing and lead to a loss of confidence. Narcolepsy is also associated with the REM sleep behaviour disorder, in which there are dreams with an aggressive or vigorous content which are physically enacted. Characteristically the dreams are of being chased or attacked by strangers or animals, or less commonly of attacking or chasing people [24]. The narcoleptic may retaliate and thereby injure him or herself or partner.

Pain Pain is not generally considered to be a symptom of narcolepsy, but several studies have shown that generalised bodily pain appears to be more frequent in those with narcolepsy than normal subjects [25–27]. This is particularly a feature in those with severe narcolepsy [27]. Whether this is due to physiological abnormalities in pain pathways or increased awareness of painful sensations or even to a recognised organic cause for the pain is uncertain.

Food Cravings Craving for salty and carbohydrate food has been reported in narcolepsy, particularly close to the onset of the first symptoms, both in adults and children. In normal subjects sleep deprivation leads to an increase in appetite, but this appears to be distinct from this. The intake of carbohydrate food, particularly with a high glycaemic index, promotes sleep in normal subjects and probably to an exaggerated degree in those with narcolepsy.

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Functional Impairment The functional impairment due to the symptoms of narcolepsy such as excessive sleepiness, poor nocturnal sleep, cataplexy, hypnagogic and hypnopompic hallucinations, sleep paralysis and vivid dreams have wide ranging effects on the quality of life. In general the quality of life as assessed by questionnaires, such as the SF36, shows a reduction, particularly in the domains of vitality and physical role [18, 25, 26, 28, 29] (Fig. 22.1). The main factors that appear to influence the effects of narcolepsy on the quality of life are

Age There is an age-related reduction in sleep efficiency in narcolepsy [30, 31]. In younger subjects the quality of sleep appears to be normal, but with age the duration of wakefulness after the onset of sleep increases due to more prolonged awakenings rather than to an increase in micro-arousals [31]. The number of periodic limb movements during sleep also increases with age [32, 33] and obstructive sleep apnoeas may also be more common in older patients. Conversely sleep paralysis and hypnagogic hallucinations may improve with age [34–36]. There does not appear to be any significant change in excessive daytime sleepiness or cataplexy,

Fig. 22.1  Reproduced with permission from [18] Median SF-36 scores of UKAN sample and age–sex matched normative data

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or any age-related change in REM sleep instability [30, 37]. In children with narcolepsy there are almost universally psycho-social difficulties, emotional problems, difficulty with school performance, restriction of leisure activities and a tendency to be socially withdrawn [20, 38, 39]. Irritability and impulsive behaviour with lack of attention may lead not only to poor school performance, but also to disciplinary problems and difficulty with interpersonal relationships. Difficulties in learning are also partly due to loss of attention and possibly to memory defects. Excessive sleepiness severely restricts social and recreational activities, and cataplexy, particularly with its unpredictable nature in social situations leads to loss of self esteem. The extent to which each of these various symptoms contributes to depression in children and adolescents is uncertain, but the inability to establish normal interpersonal relationships is usually a major problem in adolescents [20]. In young adults depression continues to be frequent, but becomes less prominent in those over the age of 45 [21]. There is one report of vitality improving after the age of 53 possibly due to resolution of some of the symptoms of narcolepsy, to psychological adjustments to the condition and to realistic limitations on activities and expectations [25]. The quality of life also improves with the duration of symptoms, possibly due to psychological adjustments [26, 28] (Fig. 22.2).

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to take part in many sports [38] often leads to a feeling of being different from other children.

Accidents

Fig. 22.2  Reproduced with permission from [26] Results of the EQ-5D VAS, depending on age in patients with narcolepsy and in the general population

Accidents may occur both at work and home, but particularly during driving, although the exact risk of this is uncertain. Most narcoleptics have sufficient warning of sleepiness to be able to pull over to the side of the road and cataplexy is infrequent while driving. Occasional patients have vivid hypnagogic hallucinations, such as of a flock of birds about to collide with the vehicle, which may lead to sudden and unpredictable swerving or braking.

Education Gender There is no difference between the quality of life in male or female narcoleptics in most studies, except that there may be a greater reduction in social activities in women [25].

The impairment in attention and concentration and the possible memory deficit reduce educational achievements [19, 39]. It is common for those with narcolepsy to fall asleep in class and during examinations.

Employment Social Activities Narcolepsy has a major impact on interpersonal relationships [29]. The fear of falling asleep or of cataplexy during excitement tends to lead to social activities being avoided. Alcohol may precipitate irresistible sleep attacks. The problems may arise during relationships if the partner does not have a full understanding of the difficulties arising from narcolepsy. Failure to adapt to these problems often leads to confusion and anger. Divorce is twice as frequent in those with narcolepsy as those in the general population [26, 40].

Recreational Activities The opportunities for recreational activities are restricted, both by the risk of accidents and because the emotional response may lead to cataplexy, which is embarrassing and occasionally dangerous. The inability

The unemployment rate in those with narcolepsy is approximately twice that of normal control subjects [26, 40]. Monotonous work may precipitate sleep, and computer and desk jobs may be particularly difficult to cope with. Working with moving machinery or at heights should be avoided because of the risk of injuries.

Treatment Explanation Explanation and reassurance about the nature of narcolepsy and its symptoms and outcomes is important for both the patient and also for others such as parents, partners, teachers and employers [39, 40]. Those with narcolepsy are often thought to be lazy, depressed or bored, and resentment, anger and occasionally guilt may be precipitated by their sleepiness and cataplexy.

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Lifestyle Aspects Regular sleep hygiene may help to cope with cognitive difficulties due to narcolepsy. Exercise and exposure to bright light during the day may promote wakefulness. Alcohol and large meals, particularly those containing carbohydrates, should be avoided. Regular planned naps may be of considerable help and increases performance in tests of vigilance [8]. The development of coping strategies in order to feel in control of the condition, to enjoy what can be achieved and to retain social contacts is beneficial. Patient satisfaction over the control of their narcolepsy with modern treatment appears to be high, but despite this the frequency, range and impact of their symptoms on mental and physical functioning and everyday activities is considerable [27]. Interestingly the impact of narcolepsy on these factors is underestimated considerably by the physicians caring for the patients, and to a lesser extent by the partners. Almost 60% of those with moderately severe or severe narcolepsy require one or more hours per day of care from a family member of close friend [27]. Psychological support from family and friends, and colleagues at work can significantly improve the quality of life [26, 40]

the introduction of modafinil or sodium oxybate showed that those on treatment had a lower quality of life than those not receiving treatment [18]. A separate study also showed that drug treatment did not improve any of the domains of quality of life on the SF-36 questionnaire [28] (Fig. 22.3).

Amphetamines There is little information about the effects of amphetamines on mental function in narcolepsy. In one study when most narcoleptic patients were receiving amphetamines and antidepressants, those on treatment had a worse quality of life than those without treatment [18]. This may have been because the dosage of these drugs was limited by side effects. No mental health changes have also been shown for dexamphetamine and methylphenidate with higher ratings for “figure – activity,” confidence, talkativeness and competitiveness, but reduced fatigue, inertia, depression, dejection and confusion/ bewilderment [41]. Amphetamines may also cause a paranoid psychosis [22].

Drugs

Modafinil

The early introduction of effective drug treatment may minimise the impact of narcolepsy on mood and physical function [25], although a study carried out largely before

Treatment with modafinil has been shown to increase mental flexibility in an uncontrolled study [42] and improvements in spatial planning and motor speed

Fig. 22.3  Reproduced with permission from [28] SF-36 scale results in the three subgroups of patients with narcolepsy – NDN, PDNt+, PDNt- – in comparison with the Italian norm. The mean on each scale for the normative population was set to 0. The results for each subgroup were plotted in terms of their difference in standard scores (z scores) from the norm. PDNt+, “past diagnosis narcolepsy” (subjects with previous diagnosis of narcolepsy)

with therapy; PDNt-, “past diagnosis narcolepsy” (subjects with previous diagnosis of epilepsy) without therapy; NDN, “new diagnosis narcolepsy” (subjects with diagnosis of narcolepsy at the moment of inclusion); PF, physical function; RP, role limitations related to physical problems; BP, bodily pain; GH, general health perception; VT, vitality; SF, social functioning; RE, role limitations due to emotional problems; MH, mental health

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have been recorded [43]. Improvements in attention and executive function have also been found [44]. Modafinil improves the quality of life as assessed by the SF-36 questionnaire, particularly in the vitality and physical role domains [29], as well as improving psychological well-being, productivity, attention, selfesteem and leading to fewer difficulties in performing usual activities and fewer interferences with social activities [29] (Fig.  22.4). A separate study showed that Modafinil reduced fatigue, increased vigour and cognition as assessed by the profile of mood states (POMS) [45]. Modafinil also influences the mood of

Fig. 22.4  Reproduced with permission from [29] Change Scores from Baseline to Double-Blind Endpoint Narcolepsy-Specific Scales

Fig. 22.5  Reproduced with permission from [48] Change in scores from baseline to double-blind end point. The mean change from baseline in Functional Outcomes of Sleep Questionnaire (FOSQ) subscale scores following intervention are presented for the placebo and sodium oxybate doses of 4.5, 6.0 and 9.0 g per day

those with narcolepsy with reductions in feelings of hostility and aggression [43].

Sodium Oxybate Sodium oxybate has been shown in several studies to improve daytime alertness in narcolepsy [46, 47]. In a dose of 6–9 g daily it improves the total functional outcomes of sleep questionnaire score (FOSQ) as well as activity level, general productivity, vigilance and social outcomes subscales [48] (Fig. 22.5). It has also

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been found to improve all the domains of the SF-36 scale, except for bodily pain, and to particularly improve the mental health score [49].

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J. Shneerson 20. Stores G, Montgomery P, Wiggs L. The psychosocial problems of children with narcolepsy and those with excessive daytime sleepiness of uncertain origin. Pediatrics 2006;e1116–e1123 21. Shneerson JM, Myers AJ, Morrish E. Factors determining quality of life in narcolepsy. In preparation 22. Vourdas A, Shneerson JM, Gregory CA, Smith IE, King MA, Morrish E, McKenna PJ. Narcolepsy and psychopathology: is there an association? Sleep Med 2002;3:353–360 23. Fosse R, Stickgold R, Hobson JA. Emotional experience during rapid-eye-movement sleep in narcolepsy. Sleep 2002;25:724–730 24. Schenck CH, Mahwold MW. REM sleep behavior disorder: Clinical, developmental and neuroscience perspectives 16  years after its formal identification in sleep. Sleep 2002;25:120–138 25. Ervik S, Abdelnoor M, Heier MS, Ramberg M, Strand G. Health-related quality of life in narcolepsy. Acta Neurol Scand 2006;e114:198–204 26. Dodel R, Peter H, Spottke A, Noelker C, Althaus A, Siebert U, Walbert T, Kesper K, Becker HF, Mayer G. Health-related quality of life in patients with narcolepsy. Sleep Med 2007;8:733–741 27. Shneerson JM, Dauvilliers Y, Garcia-Borreguero D, Plazzi G. The impact of narcolepsy and its treatment – a European Study. Eur J of Neurol 2008 submitted for publication 28. Vignatelli L, D’Alessandro R, Mosconi P, Ferini-Strambi L, Guidolin L, De Vincentiis A, Plazzi G. Health-related quality of life in Italian patients with narcolepsy: the SF-36 health survey. Sleep Med 2004;5:467–475 29. Beusterien KM, Rogers AE, Walsleben JA, et  al. Healthrelated quality of life effects of modafinil for treatment of narcolepsy. Sleep 1999;6:757–765 30. Lamphere J, Young D, Roehrs T, et  al. Fragmented sleep, daytime somnolence and age in narcolepsy. Clin Electroencephalogr 1989;20:49–54 31. Quinnell TQ, Smith IE, Shneerson JM. Impact of age on narcolepsy: evidence for an accelerated decline in nocturnal sleep quality. J Clin Sleep Med 2008 submitted for publication 32. Wittig R, Zorick F, Piccione P, Sicklesteel J, Roth T. Narcolepsy and disturbed nocturnal sleep. Clin Electroencephalogr 1983;14:130–134 33. Dauvilliers Y, Pennestri M-H, Petit D, Dang-Vu T, Lavigne G, Montplaisir J. Periodic leg movements during sleep and wakefulness in narcolepsy. J Sleep Res 2007;16:333–339 34. Billiard M, Besset A, Cadilhac J. The clinical and polygraphic development of narcolepsy. In: Guilleminault C, Lugaresi E, eds. Sleep/wake disorders: natural history, epidemiology, and long-term evolution. New York: Raven, 1983:171–185 35. Passouant P, Billiard M. The evolution of narcolepsy with age. In: Guilleminault C, Dement WC, Passouant P, eds. Narcolepsy. New York: Spectrum, 1976;176–196 36. Rosenthal LD, Merlotti L, Young DK, et al. Subjective and polysomnographic characteristics of patients diagnosed with narcolepsy. Gen Hosp Psychiatry 1990;191–197 37. Dauvilliers Y, Gosselin A, Paquet J, et al. Effect of age on MSLT results in patients with narcolepsy-cataplexy. Neurology 2004;61:46–50

22 Narcolepsy and Mental Health 38. Nevsimalova S, Vankova J, Pretl M, Bruck D. Narkolepsie v detsckem a adolescentnim veku-klinicke a psychosocialni aspekty. Ces a slov Neurol Neurochir 2002;3:169–174 39. Wise MS. Childhood narcolepsy. Neurology 1998;50: S37–S42 40. Goswami M. The influence of clinical symptoms on quality of life in patients with narcolepsy. Neurology 1998;50:S31–S36 41. Zwicker J, Bruck D, Parkes JD, et al. Acute mood improvement after amphetamine and methylphenidate in narcolepsy. J Sleep Res 1995;4:252–255 42. Schwartz JRL, Nelson MT, Schwartz ER, et  al. Effects of modafinil on wakefulness and executive function in patients with narcolepsy experiencing late-day sleepiness. Clin Neuropharmacol 2004;27:74–79 43. Shneerson J, Randall D, Cafferty F, et  al. Treatment with modafinil may have beneficial effects on planning ability and mood in patients with excessive daytime sleepiness: findings from a pilot study. J Sleep Res 2006;15:P029 44. Saletu M, Anderer P, Semlitsch HV, et  al. Low-resolution brain electromagnetic tomography (LORETA) identifies

247 brain regions linked to psychometric performance under modafinil in narcolepsy. Psychiatry Res 2007;154:69–84 45. Becker PM, Schwartz JRL, Feldman NT, Hughes RJ. Effect of modafinil on fatigue, mood, and health-related quality of life in patients with narcolepsy. Psychopharmacology 2004;171:133–139 46. The Xyrem® International Study Group. A double-blind, placebo-controlled study demonstrates sodium oxybate is effective for the treatment of excessive daytime sleepiness in narcolepsy. J Clin Sleep Med 2005;1:391–397 47. The US Xyrem® Multicenter Study Group. 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;25:42–49 48. Weaver TE, Cuellar N. A randomized trail evaluating the effectiveness of sodium oxybate therapy on quality of life in narcolepsy. Sleep 2006;29:1189–1194 49. Hayduk R, Mitler A. Sodium oxybate therapy improves the quality of life of narcolepsy patients. Sleep 2001;24:A326

Section IV

Management

Chapter 23

Overview of Management of Narcolepsy Seiji Nishino and Nozomu Kotorii

Introduction Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy, and other dissociated manifestations of rapid eye movement (REM) sleep (i.e., hypnagogic hallucinations and sleep paralysis). Non-pharmacological treatments (i.e., by behavioral modification) are often reported to be useful additions to the clinical management of narcoleptic patients. Regular napping usually relieves sleepiness (for 1–2 h) and is the treatment of choice for some patients, but this often has negative social and professional consequences. Exercising to avoid obesity, keeping a regular sleep–wake schedule, and having a supportive social environment (e.g., patient group organizations and support groups) are also helpful. In almost all cases (more than 90% of diagnosed patients), however, a pharmacological treatment is needed. The treatment for EDS includes the use of amphetamine-like central nervous system (CNS) stimulants and modafinil (and its r-enantiomer), which are new non-amphetamine wake-promoting compounds. Due to the high safety and low side effect profiles, modafinil rapidly became the first-line treatment of choice for EDS associated with narcolepsy. These compounds do not improve cataplexy and dissociated manifestation of REM sleep, and antidepressants (monoamine uptake inhibitors) are additionally used for the treatment of cataplexy and REM sleep abnormalities. Although anticataplectic medications do not improve EDS, some

S. Nishino (*) Sleep and Circadian Neurobiology Laboratory, Center for Narcolepsy, Stanford University School of Medicine, 1201 Welch Road, MSLS, P213, Palo Alto, CA, 94304, USA e-mail: [email protected]

monoaminergic uptake inhibitors with dopaminergic uptake inhibition are wake-promoting and are occasionally used for the treatment of EDS. Caffeine may also be used in patients with mild EDS or before diagnosis is made. Gamma-hydroxybutyrate (GHB, a short-acting sedative; Sodium oxybate is the approved formula in the USA) given at night improves EDS and cataplexy, and the number of patients treated with sodium oxybate is also increasing in the USA. The major pathophysiology of human narcolepsy has been revealed in association with the discovery of narcolepsy genes in animal models: about 90% of human narcolepsy-cataplexy has been found to be hypocretin/orexin ligand-deficient. This discovery directly led to the development of new diagnostic tests (i.e., CSF hypocretin-1 measures). Hypocretin replacement is also likely to be a new therapeutic option for hypocretin-deficient narcolepsy, but this is still unavailable for humans. In this review, we first describe clinical symptoms of narcolepsy, followed by an overview of the management of these symptoms. Both pharmacological and non-pharmacological treatments are discussed. We also discuss prospects of new treatments. The mechanisms of actions of these pharmacological compounds are detailed in the 2nd chapter.

Symptoms of Narcolepsy Narcolepsy is a syndrome of unknown etiology (prevalence = 1 in 2,000 [1, 2]) characterized by EDS that is often profound. About 95% of narcoleptic cases are sporadic, but it also occurs in familial forms. Narcolepsy usually occurs in association with cataplexy and other symptoms and signs, which

M. Goswami et al. (eds.), Narcolepsy: A Clinical Guide, DOI 10.1007/978-1-4419-0854-4_23, © Humana Press, a part of Springer Science + Business Media, LLC 2010

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commonly include hypnagogic or hypnopompic hallucinations, sleep paralysis, automatic behavior, and disrupted nocturnal sleep [3]. Symptoms most often begin during adolescence or young adulthood. However, narcolepsy may also occur earlier in childhood or not until the third or fourth decade of life. Quality of life studies suggest that the impact of narcolepsy is equal to that of Parkinson’s disease [4]. Although EDS is not specific for narcolepsy and is seen in other primary and secondary EDS disorders (such as sleep apnea syndrome), cataplexy is generally regarded as pathognomonic. Occurrence of cataplexy is tightly associated with loss of hypocretin neurotransmission [5], and it rarely occurs as an ­isolated symptom. Cataplexy occasionally occurs in conjunction with other neurological conditions such as Nieman-Pick Type C disease, but the pathophysological links in these neurological conditions with the hypocretin abnormalities are not well established yet [6].

Sleepiness or Excessive Daytime Sleepiness (EDS) As with the sleepiness of other sleep disorders, the EDS of narcolepsy presents itself with an increased propensity to fall asleep, nodding or easily dozing in relaxed or sedentary situations, or a need to exert extra effort to avoid sleeping in these situations [6]. Additionally, irresistible or overwhelming urges to sleep commonly occur from time to time during wakeful periods in untreated narcolepsy patients. These socalled “sleep attacks” are not instantaneous lapses into sleep, as is often thought by the general public, but represent the episodes of profound sleepiness experienced by those with marked sleep deprivation or other severe sleep disorders. In addition to frank sleepiness, EDS of narcolepsy (as in other sleep disorders) can cause related symptoms including poor memory, reduced concentration or attention, and irritability. Narcoleptic subjects feel refreshed after a short nap, but this does not last long and they become sleepy again within a few hours. Narcolepsy may therefore consist of an inability to maintain wakefulness combined with the intrusion of REM sleep associated ­phenomena (hallucinations, sleep paralysis, and ­possibly cataplexy, see below) into wakefulness.

Cataplexy Cataplexy is the partial or complete loss of bilateral muscle tone in response to a strong emotion [6]. Reduced muscle tone may be minimal, occurring in a few muscle groups and causing minimal symptoms such as bilateral ptosis, head drooping, slurred speech, or dropping things from the hand, or it may be so severe that total body paralysis occurs, resulting in complete collapse. Cataplectic events usually last from a few seconds to 2 or 3  min, but occasionally continue longer [7]. The patient is usually alert and oriented during the event despite their inability to respond. Positive emotions such as laughter more commonly trigger cataplexy than negative emotions; however, any strong emotion is a potential trigger [8]. Startling stimuli, stress, physical fatigue, or sleepiness may also be important triggers or factors that exacerbate cataplexy. The current international classification of sleep disorders (ICSD-2) [3] for narcolepsy does not require cataplexy for diagnosing narcolepsy if REM sleep abnormalities (i.e., sleep onset REM sleep periods [SOREMPs] during multiple sleep latency test [MSLT]) are objectively documented. According to epidemiologic studies, cataplexy is found in 60–100% of patients with narcolepsy. The percentage affected with cataplexy is reported to be in a large range because the definitions of narcolepsy vary among studies (and different diagnostic criteria are used). The onset of cataplexy is most frequently simultaneous with or within a few months of the onset of excessive daytime sleepiness, but in some cases, cataplexy may not develop until many years after the initial onset of excessive daytime sleepiness [7].

Hypnagogic or Hypnopompic Hallucinations These phenomena may be visual, tactile, auditory, or multi-sensory events, usually brief but occasionally continuing for a few minutes, that occur at transitions from wakefulness to sleep (hypnagogic) or from sleep to wakefulness (hypnopompic) [6]. Hallucinations may contain combined elements of dream sleep and consciousness and are often bizarre or disturbing to patients.

23 Overview of Management of Narcolepsy

Sleep Paralysis Sleep paralysis is the inability to move, lasting from a few seconds to a few minutes, during the transition from sleep to wakefulness or from wakefulness to sleep [6]. Episodes of sleep paralysis may alarm patients-particularly those who experience the sensation of being unable to breathe. Although accessory respiratory muscles may not be active during these episodes, diaphragmatic activity continues, and air exchange remains adequate. Other commonly reported symptoms include automatic behavior – “absent-minded” behavior or speech that is often nonsensical which the patient does not remember, and fragmented nocturnal sleep – frequent awakenings during the night. Hypnagogic hallucinations, sleep paralysis, and automatic behavior are nonspecific to narcolepsy and occur in other sleep disorders (as well as in healthy individuals); however, these symptoms are far more common and occur with much greater frequency in narcolepsy [6].

Treatments of Narcolepsy Pharmacological Treatment of Daytime Sleepiness with Amphetamine-Like Compounds Non-pharmacological treatments (i.e., behavioral modification such as regular napping and work accommodations) are often helpful (see [9–11] (Table 23.1). Regular napping usually relieves sleepiness for 1–2 h [10] and is the treatment of choice for some patients, but this often has negative social and professional consequences. Exercising to avoid obesity and keeping a regular sleepwake schedule are also helpful. Referral to patient support groups (e.g. narcolepsy network) and giving directives regarding driving and other potentially dangerous activities is critical until the patient achieves a better understanding and control over the disorder. Characteristics of other non-pharmacological treatments for narcolepsy are summarized in Table 23.1. However, in a survey by a patient group organization [12], 94% of all patients reported using pharmacological therapies, mostly stimulant medications. Sleepiness

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is usually treated using amphetamine-like CNS stimulants or modafinil, a novel wake-promoting compound unrelated to the amphetamines (Table 23.2). The most commonly used amphetamine-like compounds are methamphetamine, d-amphetamine, methylphenidate (all are schedule II compounds), pemoline, and mazindol (both are schedule IV compounds) (Table 23.2). The most important pharmacological property of amphetamine-like stimulants is their release of catecholamines, mostly dopamine and norepinephrine [13, 14] (see the next chapter). The clinical use of stimulants in narcolepsy has been the subject of American Academy of Sleep Medicine (AASM) (formerly, American Sleep Disorders Association [ASDA]) Standards of Practice publications [15, 16]. Typically, the patient is started on a low dose, which is then increased progressively, to obtain satisfactory results (Table 23.2). Studies have shown that subjectively, daytime sleepiness can be greatly improved, but that sleep variables are never completely normalized by stimulant treatments [17]. Low-efficacy compounds/ milder stimulants (such as modafinil, or more rarely nowadays, pemoline) are usually tried first. More effective amphetamine-like stimulants (i.e. methylphenidate, d-amphetamine and methamphetamine) are then used if needed. The final dose of stimulant medication used varies widely from patient to patient, depending on tolerance, personality, efficacy, and life style (from no stimulant treatment to very high doses). Patient input and work environment is very important. Some patients prefer to use high doses of long-acting, slow-release preparations to stay awake all day long, while others combine lower doses and short half-life derivatives (e.g. methylphenidate) with scheduled napping. Stimulant compounds are generally well tolerated in narcoleptic subjects. Minor side effects such as headaches, irritability, nervousness, tremors, anorexia, palpitations, sweating, and gastric discomfort are common (Table  23.2). Cardiovascular impact such as increased blood pressure is possible considering sympathomimetic effects of these classes of compounds established in animals but which have been remarkably difficult to document in human studies [18]. Surprisingly, tolerance rarely occurs in this patient population and “drug holidays” are not recommended by the American Academy of Sleep Medicine [15]. Stimulant abuse is rare for the well-defined narcolepsy subjects [19–22], and a compliance study had shown about half of patients who

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254 Table 23.1  Non-Pharmacological Approaches to the Treatment of Narcolepsy Management

Description

References

Structured nocturnal sleep Avoid deprivations and shifts in sleep schedule Regular timing of nocturnal sleep (e.g., 10:30 pm to 7 am) Relaxation techniques prior to nocturnal sleep [112] Avoidance of intense stimulation prior to nocturnal sleep

Maintain a structured bedtime and arising time, despite the quality or continuity of the nocturnal sleep. If you wake up during the night, and find it difficult to go back to sleep, you can take a short break and do a sedentary activity such as reading for a brief time. But you should return to bed and attempt to sleep. The time scheduled for nocturnal sleep should be 8 h or more.

[112]

Daytime sleep schedules Strategically timed naps   15-min naps at 12:30 pm and 17:00 pm are significant on MWT [114] Efficacy of nap: single long nap > multiple short naps > no nap [115] (single long nap: 24% of whole sleep; multiple short naps: 4.8% of whole sleep × 5; sleep per 24 h was held constant)   15-min and 30-min naps on the 1,600-h latency test are equally effective [11]   Narcoleptic persons have no significant sleep inertia effects [115] Planning napping strategies before using medications

Daytime naps provide a critical part of treatment for the daytime sleepiness associated with narcolepsy. Naps may range from 15 to 20 min to longer than 1 h. Many find short naps (<30 min) refreshing, but others require longer naps. Generally, narcoleptic persons have no significant sleep inertia effects whereas increased nap duration (>15 min) provided no additional benefits. At least one nap, and usually two, proves very beneficial for almost all persons with narcolepsy. Additionally, morning impairment (steady decline in performance from time of awakening) might be curtailed by addition of a single short morning nap).

[11, 114, 115]

Dietary practice Taking nonprescription stimulants(tea, coffee, mate, etc.) at scheduled times   The caffeine content of six cups of strong coffee has about the same stimulant effect as 5 mg of dexamphetamine [113] Morning and mid-day avoidance of sweets and carbohydrates Abstinence or minimal use of alcohol Avoidance of REM suppressants and drugs that increase daytime sleepiness

Little is known about the effects of diet on alertness and sleep with narcolepsy, but good dietary practices are useful in insuring good sleep hygiene. Some nonprescription stimulants such as tea and coffee are not considered as drugs, but these beverages should be prepared in a consistent manner. Use of the tablet form of caffeine permits more precise dosage monitoring.

[113]

Counseling or other assistance Counseling for reorganization of lifestyle Counseling for reconsideration of the type of work Individual or group psychotherapies [113] Assist scheduling of alertness-requiring activities Advocacy by a professional against employers

A recent study of more than 500 narcoleptics revealed that they suffer from decrease in quality-of-life measures similar to those experienced by patients with Parkinson’s disease. Most victims of narcolepsy will require special considerations at work or school. Most narcoleptics will find shift work or changes in work schedule extremely difficult. Daytime work is strongly recommended. There is also much need for counseling about the psychosocial impact so that patients can optimize their adaptation to the disease and be realistic in their expectation.

[114], p. 385

received stimulants to reduce or withdraw stimulant medications by themselves [23]. Exceptionally, psychotic complications may be observed, most often when the medications are used at high doses and chronically disrupt nocturnal sleep. Amphetamine was first used to treat narcolepsy in 1935 [24], only 8 years after it was initially synthesized

by Alles [25]. Both the l- and d- isomers have been used for the treatment of narcolepsy, either in isolation or as a racemic mixture (available in the United States). The d-isomer is a slightly more potent stimulant (see, [26, 27]) and is more generally used. l-amphetamine is occasionally used in some European countries (dose range 20–60 mg), (see [28]). It is well absorbed by the

23 Overview of Management of Narcolepsy

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Table 23.2  Current pharmacological treatment for EDS associated with human narcolepsy Compound Usual daily doses Half life (h) Side effects/notes Wake-promoting compounds for EDS Sympathomimetic stimulants d-amphetamine sulfate (II) 5–60 mg 16–30 Irritability, mood changes, headaches, palpitations, tremors, excessive sweating, insomnia Methylphenidate HCl (II) 10–60 mg ~3 Same as amphetamines, less reduction of appetite or increase in blood pressure Pemoline (IV) 20–115 mg 11–13 Less sympathomimetic effect, milder stimulant slower onset of action, occasionally produces liver toxicity Non-amphetamine wake-promoting compounds Modafinil (IV) 100–400 mg 9–14 No peripheral sympathomimetic action, headaches, nausea Armodafinil (IV) 100–300 mg 10–15 Similar to those of modafinil Compounds improving disturbed night-time sleep and EDS GHB (I), sodium oxybate (III) 20–40 mg/kg/ ~0.3 Overdoses (a single dose of 60–100 mg/kg) night induces dizziness, nausea, vomiting, confusion, agitation, epileptic seizures, and hallucinations and coma with bradycardia and respiratory depression evidence of withdrawal syndrome All compounds in the list are scheduled compounds and the class is listed in the parentheses The half-life of s-enantiomer of modafinil is short and 3–4 h, and thus the half-life of racemic modafinil mostly reflects the half-life of armodafinil (r-enantiomer)

gastrointestinal tract and is partially metabolized in the liver using aromatic and aliphatic hydroxylation. This process yields parahydroxyamphetamine and norephedrine, respectively, both of which are biologically active [29]. Amphetamine is metabolized into benzoic acid (23%), which is subsequently converted to hippuric acid or to parahydroxyamphetamine (2%). This in turn is converted to parahydroxynorephedrine (0.4%). Thirty-three percent of the oral dose is excreted unchanged in the urine. Importantly, urinary excretion of amphetamine and many amphetamine-like stimulants is greatly influenced by urinary pH. Amphetamine is a weak base and at the physiological pH, it exists mainly as a charged amine [RNH3]+, which is poorly reabsorbed in the renal tubules. Acidifying the urine thus favors the excretion of the charged form of the amine (see [30]), increases urinary excretion versus liver catabolism, and reduces the half-life. At a urinary pH of 5.0, the elimination half-life of amphetamine is very short (about 3–5 h) but at pH 7.3 it increases to 21 h [30]. Sodium bicarbonate will delay excretion of amphetamine and prolong its clinical effects, whereas ammonium chloride will shorten the duration of

amphetamine toxicity. Finally, d-amphetamine is available as a sulfate base derivative or as spansule (slow release) capsules. Methamphetamine is the most efficacious and most potent amphetamine derivative available. This compound is extremely useful in subjects with severe sleepiness who need high doses. The addition of a methyl group makes this derivative more lipophilic, thus increasing CNS penetration and providing a better central profile over a peripheral profile. The widespread misuse of methamphetamine has led to severe legal restrictions on its manufacturing, sales, and prescription in many countries (see [28]), but it is available in the United States. Methylphenidate was introduced for the treatment of narcolepsy by Yoss and Daly almost 50 years ago [31]. It is now the most commonly prescribed amphetamine, with 46% of narcoleptic patients are using the compound on a regular basis [12]. Part of its popularity is due to its relatively short duration of action (approximately 3–4  h). This property allows narcoleptic patients to use the compound on an “as needed” basis while still keeping the possibility of napping

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open. The compound is also reported to produce fewer psychotic complications at high doses [32]. A slow release formulation is available but less frequently used. Pemoline is generally better tolerated than methamphetamine or D-amphetamine but it is also less efficacious and less potent. Pemoline has been withdrawn from the market in several countries, including USA, because of liver toxicity. After taking a therapeutic dose of pemoline (40  mg), peak levels in serum are reached within 4–6  h. The half-life is 16–18  h. Pemoline is partially metabolized by the liver. Metabolites include pemoline conjugates, pemoline dione and mandelic acid. After oral administration of 40 mg of pemoline, 35–50% of the dose is excreted in the urine within 32  h, and only a minor fraction is present as metabolites [33]. The long duration of action of pemoline may be associated with better compliance in narcoleptic patients [23]. Pemoline most selectively blocks dopamine reuptake and only weakly stimulates dopamine release. Fatal hepatotoxicity has been reported and may be dose-related [34, 35]. Pemoline should thus not be prescribed to patients with impaired hepatic function, and hepatic function should be carefully monitored during chronic drug administration. The recent introduction of modafinil, a novel wakepromoting agent with a similar profile and fewer side effects, has greatly diminished the use of this compound in narcolepsy.

Modafinil and Armodafinil Racemic modafinil, a compound structurally distinct from amphetamines, was approved in the USA in 1998 (schedule IV compounds) for the treatment of EDS associated with narcolepsy. The compound has also been explored increasingly to treat other conditions, and clinical uses for residual sleepiness in treated obstructive sleep apnea syndrome (OSAS) and EDS associated with shift work sleep disorder (SWSD) were also approved by the FDA. Modafinil has been available in France since 1986, and long-term follow-ups suggest no remarkable side effect profile and show low abuse potential. Clinical trials in France and Canada have shown that 100– 300  mg of modafinil is effective for improving daytime sleepiness in narcoleptic and hypersomnolent

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subjects without interfering with nocturnal sleep. It has limited efficacy on cataplexy and the symptoms of abnormal REM sleep [36–38]. Recent double-blind trials on 283 narcoleptic subjects in 18 centers in the USA and 75 narcoleptic subjects in 11 centers in Canada revealed that 200 and 400  mg of modafinil significantly reduced sleepiness and improved patients’ overall clinical condition [39, 40]. However, it was also reported that patients who have previously been treated with methylphenidate may respond more poorly to modafinil [40]. Modafinil is well tolerated by these subjects, and adverse experiences with modafinil use occur at rates comparable to placebo [39, 40]. In humans, modafinil exhibits a linear pharmacokinetic profile for doses ranging from 50 to 400 mg, with a terminal elimination half-life (t1/2) of 9–14  h [41]. Modafinil is extensively metabolized into two major pharmacologically inactive metabolites, modafinil acid and modafinil sulfone, which are renally excreted. Less than 10% of the oral dose of modafinil is excreted unchanged, and 40–60% is excreted as the unconjugated acid in urine [41]. Armodafinil is the r-enantiomer of modafinil (racemic), with a considerably longer half-life of 10–15 h (verses 3–4 h for the s-enantiomer) [42–44]. Armodafinil was approved by the FDA in June 2007 for the treatment of EDS with narcolepsy, OSAS, and SWSD, for the same indications as those of modafinil. The exact mode of action of modafinil is still uncertain. Some of the actions proposed are detailed in the next chapter. Similarly, the modes of action of armodafinil are still uncertain. Several factors make modafinil an attractive alternative to amphetamine-like stimulants, and modafinil rapidly became the first-line treatment for EDS associated with narcolepsy. First, animal studies suggest that the compound does not affect blood pressure as much as amphetamines do [45] (potentially resulting from its lack of effects on adrenergic release or reuptake). This suggests that modafinil might be useful for patients with a heart condition or high blood pressure. Second, animal data suggest that there are no neurotoxic effects and little or no rebound hypersomnolence upon withdrawal. Third, data obtained to date suggest that tolerance and dependence for this compound is limited [36], although a recent animal study reports a cocainelike discriminative stimulus and reinforcing effects of

23 Overview of Management of Narcolepsy

modafinil in rats and monkeys, respectively [46]. Finally, clinical studies suggest that the alerting effect of modafinil might be qualitatively different from that of amphetamine [36]. In general, patients feel less irritable and/or agitated with modafinil than with the amphetamines [36]. In animal experiments, modafinil did not induce behavioral excitation, as measured by lack of locomotor activation [47]. The efficacy profile of armodafinil has demonstrated that it has longer wake promoting effects than modafinil. It should be noted that the elimination half-life of the racemic compound (9–14  h) is for the most part likely to be a function of armodafinil. Once-a-day treatment with modafinil may not be adequate in some patients who have not been able to maintain a sufficient level of wakefulness throughout the day. Lower doses of armodafinil, 150 and 250 mg, were used in a Phase III trial [48], whereas earlier modafinil trials used 200 and 400 mg. Armodafinil is available at lower doses than modafinil, indicating the potential for an improved safety profile.

Other Wake Promoting Agents Mazindol (2–8 mg daily), a sympathomimetic anorectic agent, is less frequently used due to its weaker stimulant activity (see [49]). At these doses, mazindol produces central stimulation, a reduction in appetite, and an increase in alertness, but has little or no effect on mood or the cardiovascular system. It is a weak releasing agent of dopamine, but it also blocks dopamine and norepinephrine reuptake with high affinity (see [50]). Mazindol is effective for both excessive daytime sleepiness and cataplexy [49]. Mazindol is absorbed quantitatively at a medium rate from the gastrointestinal tract, and the peak blood concentration is reached after 2–4  h. The half-life of clearance from blood was estimated to be 33–55 h [51]. Bupropion is a dopamine (DA) reuptake inhibitor that may be useful for the treatment of EDS associated with narcolepsy (100 mg t.i.d.) [52, 53]. It may be especially useful in cases associated with atypical depression [53]. Convulsion is a dose dependent risk of bupropion (0.1% at 100–300 mg, and 0.4% at 400 mg). Caffeine, a xanthine derivative, may be the most popular and widely consumed stimulant in the world. The average cup of coffee contains about 50–150 mg

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of caffeine. Tea (25–90  mg/5  oz), cola drinks (35– 55 mg/12 oz), chocolate (15–30 mg/1 oz), and cocoa (2–20  mg/5  oz) also contain significant amounts of caffeine. Taken orally, caffeine is rapidly absorbed, taking 47  min to reach maximum plasma concentration. The half-life of caffeine is about 3.5–5 h [54]. A slow-release soft gelatin caffeine capsule is also available with a mean delay in peak plasma concentration of 4 h [54]. The behavioral effects of caffeine include increased mental alertness, faster and clearer flow of thought, increased wakefulness, and restlessness [55]. Fatigue is reduced, and the need for sleep is delayed [55]. Physical effects of caffeine include palpitations, hypertension and increased secretion of gastric acid and increased urine output [55]. Heavy consumption (12 or more cups a day, or 1.5 g of caffeine) can cause agitation, anxiety, tremors, rapid breathing, and insomnia [55]. The mechanism of action of caffeine involves antagonism of an adenosine (non-specific) receptor and of adenosine-induced neuronal inhibition [55] (see details in the next chapter). Considering the fact that 100 mg of caffeine is roughly equivalent to one cup of coffee, caffeine does not possess the efficacy to counteract the pathological sleepiness seen in narcolepsy. Nevertheless, caffeine can be bought without a prescription in the form of tablets (No Doz®, 100-mg caffeine; Vivarin® 200-mg caffeine), and is used by many patients with narcolepsy prior to diagnosis.

Sodium Oxybate and Treatment of Disturbed Nocturnal Sleep Insomnia is a major complaint in narcoleptic subjects. Several studies reported that benzodiazepine hypnotics are effective in consolidating nighttime sleep in patients with narcolepsy [56]. GHB, a compound with remarkable REM- and SWS-inducing properties, has also been used for consolidating nighttime sleep, an effect that leads to decreased sleepiness and cataplexy the following day [57–60]. Due to its positive effects on mood and libido, its SWS-enhancing properties, and a subsequent increase in growth hormone release, the drug is widely abused by athletes and other populations [65, 66]. In addition, because of its euphorigenic, behavioral disinhibitive, and amnestic properties, coupled with simple administration (i.e. high solubility, colorlessness and tastelessness of drink), the abuse/misuse of

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GHB as a recreational substance and as a so-called “date-rape drug” has risen sharply in recent years, leading to an increased number of overdoses and intoxications for which no specific antidote exists [68, 69]. However, recent large-scale double-blind placebo controlled clinical trials in the United States led to reestablish Sodium oxybate (sodium salt of GHB) as a first line treatment for narcolepsy-cataplexy [61–64] (see also [16]). In the USA, sodium oxybate is the approved formula of GHB and is classified as a schedule III compound, while GHB itself is classified as a Schedule I drug that currently has no accepted medical use for treatment in the USA. The compound is especially useful in patients with severe insomnia and cataplexy who do not tolerate well the side effects of antidepressant medication on sexual potency. Although improvement in sleepiness occurs relatively quickly, anti-cataplectic effects appeared 1–2 weeks after the initiation of the treatment. The modes of actions of sodium oxybate on sleep and sleep-related symptoms are largely unknown (see the next chapter). The compound has also been reported to increase periodic leg movements in narcoleptic patients [67]. Sodium oxybate is absorbed 15–20 min after oral ingestion, and peak plasma concentration occurs at 60–120 min. The elimination half-life is 20 min [ [70], [71]]. Exogenous sodium oxybate is almost completely eliminated by oxidative biotransformation to carbon dioxide and water; less than 5% is detected unmetabolized in the urine [70, 71]. At low doses, sodium oxybate is an anxiolytic and myorelaxant. At intermediate doses, Sodium oxybate increases slow wave sleep and REM sleep [72]. However, due to the short half-life of the compound, its effects on sleep architecture are short-lasting (about 3–4 h) and administration thus has to be repeated 2–3 times during the night (20–40  mg/kg/night). Overdoses (a single dose of 60–100  mg/kg) induce dizziness, nausea, vomiting, confusion, agitation, epileptic seizures, hallucinations and coma with bradycardia and respiratory depression [73]. There was no evidence of rebound cataplexy upon discontinuation after long-term treatment [62]. There is little evidence of withdrawal syndrome after prescribed usage of sodium oxybate [74]; however, withdrawal symptoms following excessive use can be severe [75, 76].

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Antidepressants and the Pharmacological Treatment of Cataplexy Amphetamine stimulants and modafinil have little effect on cataplexy, and additional compounds are most often needed to control cataplexy if the symptom is severe enough to warrant treatment. Since the 1960s, it has been known that imipramine is very effective in reducing cataplexy [19]. Together with protriptyline and clomipramine, these tricyclic antidepressants are the most commonly used anticataplectic agents [12] (Table  23.3). Other antidepressant compounds of the tricyclic family have also been used with some success (Table 23.3). The use of tricyclic antidepressants in the treatment of cataplexy is, however, hampered by a number of problems. The first one is the relatively poor side effect profile of most tricyclic compounds. These are mostly due to their anticholinergic properties, leading to dry mouth (and associated dental problems), tachycardia, urinary retention, constipation, and blurred vision (see Table  23.3). Additional side effects are weight gain, sexual dysfunction (impotence and/or delayed orgasm), tremors, antihistaminergic effects leading to sedation, and occasionally orthostatic hypotension due to the alpha-1 adrenergic blockade effects of some compounds. In this respect, protriptyline is often preferred, due to its previously reported mild stimulant effect (see [77]). Nighttime sleep might also become more disturbed due to increased muscle tone and leg movements [78, 79]. The cardinal pharmacological property of tricyclic antidepressants is their ability to inhibit the reuptake of norepinephrine (and epinephrine) and serotonin (see [80]). The degree of uptake inhibition of norepinephrine and serotonin is quite variable depending on the compound and the existence of active metabolites (mostly active on adrenergic uptake) (see [80]). Additionally, some tricyclic compounds, such as protriptyline, are also weak DA reuptake inhibitors [80]. The introduction of newer antidepressants with selective serotonergic uptake inhibition properties (e.g. SSRIs) and no anticholinergic effects, such as fluoxetine, fluvoxamine, paroxetine, sertraline, zimelidine, and trazodone, has raised hope that control over cataplexy can be achieved with fewer side effects. In general, however, clinicians have been less impressed

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23 Overview of Management of Narcolepsy Table 23.3  Currently used anticataplectic agents Antidepressants compound Usual daily doses Tricyclics Imipramine 10–100 mg

Half-life (h)

Notes/side effects

5–30

Dry mouth, anorexia, sweating, constipation, drowsiness (NE>>5-HT>DA) a desmethyl metabolite of imipramine, effects and side effects similar to those of imipramine (NE>5-HT>DA) reported to improve vigilance measures. Anticholinergic effects (5-HT>NE>>DA) Digestive problem, dry mouth, sweating, tiredness, impotence. Anticholinergic effects. Desmethylclomipramine (NE>>5-HT>DA) is an active metabolite.

Desipramine

25–200 mg

10–30

Protriptyline

5–60 mg

55–200

Clomipramine

10–150 mg

15–60

SSRIs Fluoxetine

20–60 mg

24–72

Fluvoxamine

50–300 mg

15

SNRIs Venlafaxine

150–375 mg

4

Milnacipran

30–50 mg

8

NRI Atomoxetine

40–60 mga

5.2

20–40 mg/kg/ night

~0.3

Compounds improving disturbed night-time sleep and cataplexy GHB, sodium oxybate

No anticholinergic or antihistaminergic effects good anticataplectic effect but less potent than clomipramine. Active metabolite norfluoxetine has more adrenergic effects No active metabolite, pharmacological profile similar to fluoxetine. Less active than clomipramine, gastrointestinal side effects New serotonergic and adrenergic uptake blocker; no anticholinergic effects, effective on cataplexy and sleepiness, nausea New serotonergic and adrenergic uptake blocker; no anticholinergic or antihistaminergic effects, effective on cataplexy Normally indicated for Attention Deficit Hyperactivity Disorder (ADHD)

Overdoses (a single dose of 60–100 mg/kg) induce dizziness, nausea, vomiting, confusion, agitation, epileptic seizures, and hallucinations and coma with bradycardia and respiratory depression. No cataplexy rebound reported upon discontinuation SSRI selective serotonin reuptake blocker, SNRI norepinephrine/serotonin reuptake inhibitor, NRI norepinephrine reuptake inhibitor. Reboxetine is another NRI, but is not available in the USA a  Doses for treatments for ADHD are suggested to be lowered when starting anticataplectic treatment. Gamma hydroxybutyric acid is available as sodium oxybate in the USA and is classified as a Scheduled III compound

with the potency of the serotonergic compounds on cataplexy [81–83]. This experience ­parallels experiments in canine narcolepsy suggesting that adrenergic, and not serotonergic, uptake inhibition mediates the anticataplectic effects of most antidepressant medications [84, 85] (see the next chapter). Among the SSRIs, fluoxetine is a viable alternative to tricyclic compounds [81]. Fluoxetine has a good side effect profile and may induce less weight gain, a significant advan-

tage for some patients. Venlafaxine, a novel serotonergic and adrenergic reuptake blocker, has also been used recently with good success. Finally, the introduction of reboxetine, a specific adrenergic reuptake blocker, may offer a novel and more effective alternative to SSRIs and tricyclic antidepressants based on animal data. In addition to the antidepressants listed in Table 23.3, GHB (or sodium oxybate), a hypnotic compound

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discussed in greater detail in the section on disrupted nocturnal sleep, has been shown to alleviate cataplexy during long-term administration. MAOIs (monoamine oxidase inhibitors) are known to potently reduce REM sleep and are therefore excellent candidate anticataplectic agents. However, these compounds are less often used due to their poor safety profile. Selective or reversible MAOIs have recently become available, but largescale clinical trials on these compounds are still not available (see [6])

Treatment of Sleep Paralysis and Hypnagogic Hallucinations The treatment of these two symptoms is not well codified. Hypnagogic hallucinations can be quite bothersome, and often occur in patients who also suffer from frequent nightmares. As they are a manifestation of sleep onset REM sleep, the compounds that suppress REM sleep are usually helpful in alleviating this symptom, and tricyclic antidepressant treatment has been

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reported to have some beneficial effects [86]. Sleep paralysis only rarely requires treatment, but tricyclic antidepressants are also very effective for preventing this symptom. Recently, high doses (60 mg qd) of fluoxetine have been advocated as a very active treatment for isolated sleep paralysis [87]. GHB is also effective in suppressing hypnagogic hallucinations, sleep paralysis, and cataplexy [88].

Future Treatment Options Since a large majority of human narcolepsy patients are ligand-deficient, hypocretin replacement therapy may be a new therapeutic option. This may be effective for both sleepiness (i.e. fragmented sleep/wake pattern) and cataplexy. Animal experiments using ligand-deficient narcoleptic dogs suggest that stable and centrally active hypocretin analogs (possibly nonpeptide synthetic hypocretin ligands) will need to be developed in order to be peripherally effective [89, 90] (Table 23.4). This is also substantiated by a mice study that found normalization of sleep/wake patterns and behavioral arrest episodes (equivalent to cataplexy and

Table 23.4  Evaluations of hypocretin ligand replacement therapy in the animal model of narcolepsy Effect on Approaches Animal models Methods cataplexy Effects on sleep References Peptide replacement na [90] Ligand-deficient IV Very short lasting narcoleptic dog anticataplectic effect Ligand-deficient Intrathecal No effect na [91] narcoleptic dog Ligand-deficient ICV Improve Wake-promoting [92] mice Gene therapy Improve More [92] Ligand-deficient Diffuse expression of consolidated mice ligand (TG with beta-actin promoter) [116] Improve No effect on Ligand-deficient Transient expression sleep mice of ligand (with fragmentation HSV-1 vector) in the LH Cell Transplantation na na [117] Cells transplanted (LH from 10-day old rats) survive for a short period (up to 36 days). IV intravenous, ICV intracerebroventricular, HSV-1 herpes simplex virus-1, TG transgenic, LH lateral hypothalamus

23 Overview of Management of Narcolepsy

REM sleep onset) in hypocretin-deficient mice knockout models supplemented by central administration of hypocretin-1 [91] (Table 23.4). If exogenously administered hypocretin receptor agonists rescue the symptoms of narcolepsy, cell transplantations and gene therapy may be developed in the future (see Table 23.4). One of the concerns for this option is the receptor function in ligand-deficient narcolepsy. A significant degree of ligand deficiency is already evident at the disease onset. Life-long treatment of narcolepsy is required, and thus preserved receptor functions, many years after the loss of ligand, are essential for the replacement therapy. In order to evaluate changes in hypocretin receptors in hypocretin-deficient narcolepsy, Mishima et  al. [92] recently studied hypocretin receptor gene expressions of ligand-deficient narcolepsy in mice, dogs, and humans. Substantial decline (by 50–71%) in the expression of hypocretin receptor genes was observed in both ligand-deficient humans and dogs. The result in the mice study suggested that decline is progressive over age. However, about 50% of the original expression was still observed in old human subjects. It is not known if this is beneficial for the patients. However, since narcoleptic Dobermans heterozygous for hypocretin receptor 2 mutation (supposed to express 50% of hypocretin receptor 2 genes and normal levels of hypocretin [93]) are asymptomatic, it is likely that an adequate ligand supplement will prevent ­narcoleptic symptoms of hypocretin-deficient patients. Beside hypocretin replacement, preclinical and clinical trials for new classes of compounds are also in progress. Some histaminergic compounds may be used for wake-promotion. Histamine has long been implicated in the control of vigilance, and H1 antagonists are strongly sedative. The downstream effects of hypocretins on the histaminergic system (hcrtr2 excitatory effects) are likely to be important in mediating the wake-promoting properties of hypocretin [94]. In fact, brain histamine and CSF histamine contents are reduced in narcoleptic subjects [95]. Reduction of histamine contents is also observed in human narcolepsy and other hypersomnia of central origin [95, 96]. Although centrally injected histamine or histaminergic H1 agonists promote wakefulness, systemic administrations of these compounds induce various unacceptable side effects via peripheral H1 receptor stimulation. In contrast, the histaminergic H3 receptors

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are regarded as inhibitory autoreceptors and are enriched in the central nervous system. H3 antagonists enhance wakefulness in normal rats and cats [97] and in narcoleptic mice models [98]. Histaminergic H3 antagonists might be useful as wake-promoting compounds for the treatment of EDS or as cognitive enhancers and are under study by several pharmaceutical companies [99]. Another possible area that currently gathers less pharmaceutical interest is the use of thyrotropin releasing hormone (TRH) as direct or indirect agonists. TRH itself is a small peptide, which penetrates the blood brain barrier at very high doses. Small molecules with agonistic properties and increased blood brain barrier penetration (i.e., CG3703, CG3509 or TA0910) have been developed, partially thanks to the small nature of the starting peptide [100]. TRH (at the high dose of several mg/kg) and TRH agonists increase alertness and have been shown to be wake promoting and anticataplectic in the narcoleptic canine model [101, 102], and it has excitatory effects on motoneurons [103]. Initial studies had demonstrated that TRH enhances DA and NE neurotransmission [104, 105], and these properties may partially contribute to the wake-promoting and anti-cataplectic effects of TRH. Interestingly, recent studies have suggested that TRH may promote wakefulness by directly interacting with the thalamocortical network; TRH itself and TRH receptor type 2 are abundant in the reticular thalamic nucleus [106]. Local application of TRH in the thalamus abolishes spindle wave activity [107], and in the slice preparations, TRH depolarized thalamocortical and reticular/perigeniculate neurons by inhibition of leak K+ conductance [107]. Another recent in vitro electrophysiological studies demonstrated that TRH excite hypocretin [108] and histamine [109] neurons and argue the possibility that wake-promoting effects of TRH may also mediated by activations of these wake-promoting systems. Other pathways with possible applications in the development of novel stimulant medications include the adenosinergic system (more selective receptor antagonists than caffeine), the dopaminergic/adrenergic system (for example, DA/NE-reuptake inhibitors), the GABAergic system (for example, inverse benzodiazepine agonists) and the glutamatergic system (ampakines) (see [110]). It is also interesting to evaluate anti-cataplectic effects of D2/D3 antagonists in humans, since

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experiments in canine narcolepsy have suggested that dopamine D2/D3 receptor mechanisms may be more specifically involved in regulation of cataplexy (and sleep related motor control) than of REM sleep [111].

Conclusion Non-pharmacological treatments (i.e., behavioral modification such as regular napping and work accommodations) are often helpful. Nevertheless, over 90% of diagnosed narcoleptic patients are reported to take medications to control symptoms. Amphetamine-like stimulants have been used in the treatment of EDS in narcolepsy and various other conditions for decades. Amphetamines are sympathomimetic amines and induce various side effects. Amphetamines are also classified schedule II compounds. Racemic modafinil, a compound structurally distinct from amphetamines, was developed and approved for treatment for EDS associated with narcolepsy (in 1998 in the USA). Due to the high safety and low side effect profiles, modafinil rapidly became the first-line treatment choice for EDS associated with narcolepsy. The mode of action of the modafinil remains controversial and may involve dopaminergic and/or non-dopaminergic effects. Whatever its mode of action is, the compound is generally found to be safer and to have a lower abuse potential than amphetamine stimulants. Amphetamines and modafinil do not improve cataplexy and dissociated manifestation of REM sleep, and antidepressants (monoamine uptake inhibitors) are additionally used for the treatment of cataplexy and REM sleep abnormalities. Tricyclic antidepressants potently reduce REM sleep and have been used for treatments of cataplexy and other REM sleep abnormalities, but these classes of compounds induce various side effects (anticholinergic and antihistaminergic). The second-generation antidepressants, SSRIs, are also very commonly used as anti-cataplectics in humans. This is mostly due to their better side-effect profiles, but the anticataplectic effects of these compounds are rather modest. Recently, selective NE and NE/5-HT reuptake inhibitors were introduced, and evaluations of these are in progress and may bring profound beneficial insights.

GHB, a compound with remarkable REM- and SWS- inducing properties, has also been used for consolidating nighttime sleep, an effect that leads to decreased sleepiness and cataplexy the following day. Recent large-scale double-blind placebo controlled clinical trials in the United States led to the reestablishment of Sodium oxybate (sodium salt of GHB) as a first line treatment for narcolepsy-cataplexy. It should be noted that the therapeutic window for the compound is narrow, and overdose may induce fatal side effects. Other classes of compounds/systems with possible applications in the development of novel stimulant/ anti-cataplectic medications include the histamine system (especially H3 receptor antagonists), TRH system (TRH analogs), D2/3 antagonists (for cataplexy), reversible and selective MAOI, the adenosinergic system, the dopaminergic/adrenergic system (ex. some DA/NE-reuptake inhibitors), the GABAergic system (ex. inverse benzodiazepine agonists), and the glutamatergic system (ampakines). Finally, hypocretin replacement therapy may be more straightforward and efficient for the treatment of both cataplexy and sleepiness, but the development of small molecular weight peptide agonists is essential. If these are effective in humans, cell transplantation and/ or gene therapy may also be developed in the near future.

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264 activity in the rat. Can J Physiol Pharmacol 1994; 72(S1):362. 48. Harsh JR, Hayduk R, Rosenberg R, et al. The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy. Curr Med Res Opin 2006;22(4):761–74. 49. Iijima S, Sugita Y, Teshima Y, Hishikawa Y. Therapeutic effects of mazindol on narcolepsy. Sleep 1986;9(1, Part 2):265–8. 50. Nishino S, Mao J, Sampathkumaran R, Shelton J. Increased dopaminergic transmission mediates the wake-promoting effects of CNS stimulants. Sleep Res Online 1998;1(1): 49–61. 51. Hadler AJ. Mazindol, a new non-amphetamine anorexigenic agent. J Clin Pharmacol New Drugs 1972;12(11):453–8. 52. Nishino S, Mao J, Sampathkumaran R, Shelton J, Mignot E. Increased dopaminergic transmission mediates the wakepromoting effects of CNS stimulants. Sleep Research Online 1998;1:49–61. http://www.sro.org/1998/Nishino/49/. 53. Rye DB, Dihenia B, Bliwise DL. Reversal of atypical depression, sleepiness, and REM-sleep propensity in narcolepsy with bupropion. Depress Anxiety 1998;7(2):92–5. 54. Sicard BA, Perault MC, Enslen M, Chauffard F, Vandel B, Tachon P. The effects of 600 mg of slow release caffeine on mood and alertness. Aviat Space Environ Med 1996;67(9): 859–62. 55. Rall TR. Central nervous system stimulants. In: Gilman AG, Goodman LS, Rall TW, Murad F, eds. The pharmacological basis of therapeutics, 7th Ed. New York: Pergamon; 1985:345–82. 56. Thorpy MJ, Snyder M, Aloe FS, Ledereich PS, Starz KE. Short-term triazolam use improves nocturnal sleep of narcoleptics. Sleep 1992;15(3):212–6. 57. Scrima L, Johnson FH, Thomas EG, Hiller EE. The effects of gamma-hydroxybutyrate (GHB) on multiple sleep latency test (MSLT) in narcolepsy patients; a long term study. Sleep Res 1990;19:288. 58. Scrima L, Hartman PG, Johnson FH Jr, Hiller FC. Efficacy of gamma-hydroxybutyrate versus placebo in treating narcolepsy-cataplexy: double-blind subjective measures. Biol Psychiatry 1989;26(4):331–43. 59. Broughton R, Mamelak M. The treatment of narcolepsycataplexy with nocturnal gamma-hydroxybutyrate. Can J Neurol Sci 1979;6(1):1–6. 60. Broughton R, Mamelak M. Gamma-hydroxybutyrate in the treatment of compound narcolepsy: a preliminary report. In: Guilleminault C, Dement WC, Passouant P, eds. Narcolepsy. New York: Spectrum; 1976:59–67. 61. Group UXMS. Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Med 2004;5(2):119–23. 62. Group UXMS. A 12-month, open-label, multicenter extension trial of orally administered sodium oxybate for the treatment of narcolepsy. Sleep 2003;26(1):31–5. 63. Group USXMS. 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. 64. Group UXMS. A double-blind, placebo-controlled study demonstrates sodium oxybate is effective for the treatment of excessive daytime sleepiness in narcolepsy. J Clin Sleep Med 2005;1(4):391–7.

S. Nishino and N. Kotorii 65. Chin MY, Kreutzer RA, Dyer JE. Acute poisoning from gamma-hydroxybutyrate in California. West J Med 1992; 156(4):380–4. 66. Mack RB. Love potion number 8 1/2. Gammahydroxybutyrate poisoning. N C Med J 1993;54(5):232–3. 67. Bedard MA, Montplaisir J, Godbout R, Lapierre O. Nocturnal gamma-hydroxybutyrate. Effect on periodic leg movements and sleep organization of narcoleptic patients. Clin Neuropharmacol 1989;12(1):29–36. 68. Wong CG, Gibson KM, Snead OC III. From the street to the brain: neurobiology of the recreational drug gamma-hydroxybutyric acid. Trends Pharmacol Sci 2004;25(1): 29–34. 69. Nicholson KL, Balster RL. GHB: a new and novel drug of abuse. Drug Alcohol Depend 2001;63(1):1–22. 70. Palatini P, Tedeschi L, Frison G, et  al. Dose-dependent absorption and elimination of gamma-hydroxybutyric acid in healthy volunteers. Eur J Clin Pharmacol 1993;45(4): 353–6. 71. Vickers MD. Gammahydroxybutyric acid. Int Anesthesiol Clin 1969;7(1):75–89. 72. Lavie P, Peled R. Narcolepsy is a rare disease in Israel. Sleep 1987;10(6):608–9. 73. Li J, Stokes SA, Woeckener A. A tale of novel intoxication: seven cases of gamma-hydroxybutyric acid overdose. Ann Emerg Med 1998;31(6):723–8. 74. Group UXMS. The abrupt cessation of therapeutically administered sodium oxybate (GHB) does not cause withdrawal symptoms. J Toxicol Clin Toxicol 2003;41(2): 131–5. 75. Dyer JE, Roth B, Hyma BA. Gamma-hydroxybutyrate withdrawal syndrome. Ann Emerg Med 2001;37(2):147–53. 76. Perez E, Chu J, Bania T. Seven days of gamma-hydroxybutyrate (GHB) use produces severe withdrawal. Ann Emerg Med 2006;48(2):219–20. 77. Henry GK, Hart RP, Kwentus JA, Sicola MJ. Effects of protriptyline on vigilance and information processing in narcolepsy. Psychopharmacology (Berl) 1988;95(1):109–12. 78. Raynal D. Polygraphic aspects of narcolepsy. In: Guilemminault C, Dement WC, Passouant P, eds. Narcolepsy. New York: Spectrum; 1976:669–84. 79. Thorpy MJ, Goswami M. Treatment of narcolepsy. In: Thorpy MJ, ed. Handbook of sleep disorders. New York: Marcel Dekker; 1990:235–58. 80. Baldessarini RJ. How do antidepressants work? In: Davis JM, Mass JW, eds. The affective disorders. Wachington, DC: American Psychiatric Press; 1983:243–60. 81. Langdon N, Shindler J, Parkes JD, Bandak S. Fluoxetine in the treatment of cataplexy. Sleep 1986;9(2):371–3. 82. Montplaisir J, Godbout R. Serotoninergic reuptake mechanisms in the control of cataplexy. Sleep 1986;9(1, Part 2):280–4. 83. Schrader H, Kayed K, Bendixen Markset AC, Treidene HE. The treatment of accessory symptoms in narcolepsy: a double-blind cross-over study of a selective serotonin re-uptake inhibitor (femoxetine) versus placebo. Acta Neurol Scand 1986;74(4):297–303. 84. Mignot E, Renaud A, Nishino S, Arrigoni J, Guilleminault C, Dement WC. Canine cataplexy is preferentially controlled by adrenergic mechanisms: evidence using monoamine selective uptake inhibitors and release enhancers. Psycho­pharmacology (Berl) 1993;113(1):76–82.

23 Overview of Management of Narcolepsy 85. Nishino S, Arrigoni J, Shelton J, Dement WC, Mignot E. Desmethyl metabolites of serotonergic uptake inhibitors are more potent for suppressing canine cataplexy than their parent compounds. Sleep 1993;16(8):706–12. 86. Takahashi S. The action of tricyclics (alone or in combination with methylphenidate) upon several symptoms of narcolepsy. In: Guilleminault C, Dement WC, Passouant P, eds. Narcolepsy. New York: Spectrum Publication; 1976:625–38. 87. Koran LM, Raghavan S. Fluoxetine for isolated sleep paralysis. Psychosomatics 1993;34(2):184–7. 88. Mamelak M, Scharf MB, Woods M. Treatment of narcolepsy with gamma-hydroxybutyrate. A review of clinical and sleep laboratory findings. Sleep 1986;9(1, Part 2):285–9. 89. Fujiki N, Ripley B, Yoshida Y, Mignot E, Nishino S. Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin ligand deficient narcoleptic dog. Sleep 2003;6(8):953–9. 90. Schatzberg SJ, Barrett J, Cutter Kl, Ling L, Mignot E. Case study: effect of hypocretin replacement therapy in a 3-year-old Weimaraner with narcolepsy. J Vet Int Med 2004;18(4):586–8. 91. Mieda M, Willie JT, Hara J, Sinton CM, Sakurai T, Yanagisawa M. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci USA 2004;101(13):4649–54. 92. Mishima K, Fujiki N, Yoshida Y, et al. Hypocretin receptor expression in canine and murine narcolepsy models and in hypocretin-ligand deficient human narcolepsy. Sleep 2008;31(8):1119–26. 93. Ripley B, Fujiki N, Okura M, Mignot E, Nishino S. Hypocretin levels in sporadic and familial cases of canine narcolepsy. Neurobiol Dis 2001;8(3):525–34. 94. Nishino S, Sakurai E, Nevsimalova A, Yoshida Y, Watanabe T, Yanai K, Mignot E. Decreased CSF histamine in narcolepsy with and without low CSF hypocretin-1 in comparison to healthy controls. SLEEP 2009;32(2):175–180. 95. Kanbayashi T, Kodama T, Kondo H, Satoh S, Inoue Y, Chiba S, Shimizu T, Nishino S. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. SLEEP 2009;32(2):181–187. 96. Kanbayashi T, Kodama T, Hondo H, et al. CSF histamine and noradrenaline contents in narcolepsy and other sleep disorders. Sleep 2004;27(abstract supplement):A236. 97. Lin JS, Sakai K, Vanni-Mercier G, et  al. Involvement of histaminergic neurons in arousal mechanisms demonstrated with H3-receptor ligands in the cat. Brain Res 1990;523(2):325–30. 98. Shiba T, Fujiki N, Wisor J, Edgar D, Sakurai T, Nishino S. Wake promoting effects of thioperamide, a histamine H3 antagonist in orexin/ataxin-3 narcoleptic mice. Sleep 2004;27 (suppl):A241–A242. 99. Parmentier R, Anaclet C, Guhennec C, et  al. The brain H3-receptor as a novel therapeutic target for vigilance and sleepwake disorders. Biochem Pharmacol 2007;73(8): 1157–71. 100. Sharif NA, To ZP, Whiting RL. Analogs of thyrotropinreleasing hormone (TRH) : receptor affinities in brain, spinal cords, and pituitaries of different species. Neurochem Res 1991;16:95–103.

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Chapter 24

Modes of Action of Drugs Related to Narcolepsy: Pharmacology of Wake-Promoting Compounds and Anticataplectics Seiji Nishino

Introduction More than 90% of patients diagnosed with narcolepsy receive pharmacological treatments. The pharmacological treatments of excessive daytime sleepiness (EDS) include amphetamine-like central nervous system (CNS) stimulants and modafinil (and its R-enantiomer). Other less often used stimulants are compounds with dopamine uptake inhibitions. Caffeine is the most commonly consumed CNS stimulant in humans through coffee and various food and drinks containing products derived from the kola nut or from cacao, and may also be effective for mild EDS cases. These compounds do not improve cataplexy and other REM sleep abnormalities (hypnogogic hallucinations and sleep paralysis), and antidepressants (monoamine uptake inhibitors) are additionally used for the treatment of cataplexy and REM sleep abnormalities. Gamma-hydroxybutyrate (GHB, a short-acting sedative) given at night reduces both EDS and cataplexy. A series of pharmacological experiments, especially using the canine models of narcolepsy, revealed the major mode of wake-promoting action of amphetamines, amphetamine-like compounds and monoamine uptake inhibitors: wake-promoting effects of these compounds are mediated by presynaptic enhancement of dopaminergic neurotransmission. This mechanism may also be the major mode of action of modafinil, but this is still debated.

S. Nishino (*) Sleep and Circadian Neurobiology Laboratory & Center for Narcolepsy, Professor, Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 1201 Welch Road, MSLS P213, Palo Alto, CA, 94304, USA e-mail: [email protected]

Modes of action of anticataplectic compounds have also been revealed by animal experiments in the same way, and an enhancement of noradrenergic transmission is involved in the therapeutic action of monoamine uptake inhibitors. Mechanisms of actions of GHB, however, are largely unknown and remain to be studied. In this review, the modes of actions proposed for the therapeutic compounds for narcolepsy are discussed.

Neurobiology of Wakefulness and Modes of Action of Amphetamines and Modafinil on EDS Amphetamine was first synthesized in 1897, but its stimulant effect was not recognized until 1929, by Alles. In 1935, amphetamine was used for the first time for the treatment of narcolepsy. Narcolepsy was possibly the first condition for which amphetamine was used clinically. It revolutionized therapy for the condition, even though it was not a curative. The piperazine derivative of amphetamine, methylphenidate, was introduced for the treatment of narcolepsy in 1959 by Yoss and Daly; both compounds share similar pharmacological properties. Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide) is a chemically unique compound developed in France (Fig. 24.1). Modafinil has been available in France since 1984 on a compassionate mode and was approved in France in 1992. Modafinil (and its R-enantiomer) has recently been approved in the United States for the treatment of narcolepsy, shift-work disorder, and for the treatment of residual sleepiness in treated patients with sleep apnea syndrome.

M. Goswami et al. (eds.), Narcolepsy: A Clinical Guide, DOI 10.1007/978-1-4419-0854-4_24, © Humana Press, a part of Springer Science + Business Media, LLC 2010

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To understand how these compounds promote wake­ fulness, it is helpful to first review some of the basic anatomical and physiological pathways that promote wakefulness.

Neurobiology of Wakefulness Sleep/wake is a complex physiology regulated by brain activity, and multiple neurotransmitter systems such as monoamines, acetylcholine, excitatory, and inhibitory amino acids, peptides, purines, and neuronal and nonneuronal humoral modulators (i.e., cytokines and prostaglandins) are likely to be involved [1]. Monoamines are perhaps the first neurotransmitters recognized to be involved in wakefulness [2], and the monoaminergic ­systems had been the most common pharmacological targets for wake-promoting compounds in the past years.

On the other hand, most hypnotics target the gammaaminobutyric acid (GABA)nergic system, a main inhibitory neurotransmitter system in the brain [3]. Cholinergic neurons also play critical roles in cortical activation during wakefulness (and during REM sleep) [1]. Brainstem cholinergic neurons originating from the laterodorsal and pedunculopontine tegmental nuclei activate thalamocortical signaling, and cortex activation is further reinforced by direct cholinergic projections from the basal forebrain. However, currently no cholinergic compounds are used in sleep medicine, perhaps due to the complex nature of the systems and prominent peripheral side effects. Monoamine neurons, such as norepinephrine (NE) containing locus coeruleus (LC) neurons, serotonin (5-HT) containing raphe neurons, and histamine containing tuberomammillary neurons are wake-active and act directly on cortical and subcortical regions to promote wakefulness [1]. In contrast to the focus on these

24  Modes of Action of Drugs Related to Narcolepsy

wake-active monoaminergic systems, researchers have often underestimated the importance of dopamine (DA) in promoting wakefulness. Most likely, this is because firing rates of midbrain DA-producing neurons (ventral tegmental area [VTA] and substantia nigra (SN)) do not have an obvious variation according to behavioral states [4]. In addition, DA is produced by many different cell groups [5], and which of these promote wakefulness remains unde­termined. Nevertheless, DA release is greatest during wakefulness [6], and DA neurons increase discharge and tend to fire bursts of action potentials in association with significant sensory stimulation, purposive movement, or behavioral arousal [7]. Lesions that include the dopaminergic neurons of the VTA reduce behavioral arousal [8]. Recent work has also identified a small wake-active population of dopamineproducing neurons in the ventral periaqueductal gray that project to other arousal regions [9]. People with DA deficiency from Parkinson’s disease are often sleepy [10], and dopamine antagonists (or small doses of dopamine autoreceptor (D2/3) agonists are frequently sedating. These physiologic and clinical findings clearly demonstrate that DA also plays a role in wakefulness. Wakefulness (and physiology associated with wakefulness) is essential for the survival of creatures and, thus, is likely to be regulated by multiple systems, each having a distinct role. Some arousal systems may have essential roles for cortical activation, attention, cognition, or neuroplasticity during wakefulness while others may only be active during specific times to promote particular aspects of wakefulness. Some of the examples may be motivated behavioral wakefulness or wakefulness in emergency states. Wakefulness may thus likely be maintained by many systems with differential roles coordinating in line. Similarly, wake-promoting mechanism of some drugs may not be able to be explained by a single neurotransmitter system.

Modes of Action of Amphetamines Phenylisopropylamine (amphetamine) has a simple chemical structure resembling endogenous catecho­ lamines (Fig.  24.2). The pharmacological effects of most amphetamine derivatives are isomer-specific. d-Amphetamine for example, is a far more potent stimulant than the l-derivative. In EEG studies, d-amphetamine is four times more potent in inducing wakefulness than

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l-amphetamine [11]; not all effects are, however, isomer-specific. For example, both enantiomers are equipotent at suppressing REM sleep in humans and rats [11] and at producing amphetamine psychosis. The relative effects of d- and l-isomers of amphetamine on NE and DA transmission may explain some of these differences (for details, see the pharmacology section). Amphetamine-like compounds, such as methylphe­ nidate, pemoline, and fencamfamin, are structurally similar to amphetamines; all compounds include a benzene core with an ethylamine group side chain (Phenethylamine derivatives: Fig. 24.1). Both methylphenidate and pemoline were commonly used for the treatment of EDS in narcolepsy, but pemoline has been withdrawn from the market in several countries because of liver toxicity. The most commonly used commercially available form of methylphenidate is a racemic mixture of both the D- and L-enantiomers, but D-methylphenidate mainly contributes to clinical effects, especially after oral administration. This is due to the fact that L-methylphenidate, but not Dmethyl­phenidate, undergoes a significant first-pass metabolism (by de-esterification to L-ritalinic acid).

Molecular Targets of Amphetamine Action The molecular targets mediating amphetamine-like stimulant effects are complex and vary depending of the specific analog/isomer and the dose administered. Amphetamine per se increases catecholamine (DA and NE) release and inhibits reuptake. These effects are mediated by specific catecholamine transporters [12] (Fig.  24.3). The DA transporter [DAT] and the NE transporter [NET] have now been cloned and characterized. The DAT and NET proteins are about 620 amino-acid proteins with 12 putative membrane-spanning regions. Amphetamine derivatives inhibit the uptake and enhance the release of DA, NE, or both by interacting with these molecules. The DAT and NET normally move DA and NE, respectively, from the outside to the inside of the cell. This process is sodiumdependent; sodium and chloride bind to the DA/NE transporter to immobilize it at the extracellular surface and to alter the conformation of the DA/NE binding site, thereby facilitating substrate binding. Substrate binding induces movement of the carrier to the intracellular surface of the neuronal membrane, driven by sodium concentration gradients. Interestingly, in the

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Fig.  24.2  (a) Dopaminergic terminal neurotransmission in relation to mode of action of dopamine (DA) reuptake inhibitors and amphetamine; (b) Effects of dopamine reuptake inhibitors at the dopaminergic nerve terminal; (a) DA transporter (DAT) is one of the most important molecules located at the dopaminergic nerve terminals and regulate dopaminergic neurotransmission. (1) Amphetamine interacts with the DAT carrier to facilitate DA release from the cytoplasm through an exchange diffusion mechanism (c). At higher intracellular concentrations, amphetamine also (2) disrupts vesicular storage of DA, and (3) inhibits the Monoamine Oxidase (MAO). Both these actions increase cytoplasmic DA concentrations. (4) Amphetamine also inhibits DA uptake by virtue of its binding to and transport by the DAT. AADC aromatic acid decarboxylase; AC adenylyl cyclase; cAMP cyclic adenosine monophosphate; COMT catechol-O-methyltransferase; D1–D5 dopamine receptors 1–5; DA dopamine; DAT dopamine transporter; DOPA 3,4-dihydroxyphenylalanine; DOPAC dihydroxyphenylacetic acid; Gi, Go, and Gs protein subunits; HVA homovanillic acid;

MAO monoamine oxidase; TH tyrosine hydroxylase; VMAT vesicular monoamine transporter. (b) Sodium and chloride bind to the DAT to immobilize it at the extracellular surface. This alters the conformation of the DA binding site on the DAT to facilitate substrate (i.e., DA) binding. DAT reuptake inhibitors bind to DAT competitively and inhibit DA–DAT bindings, resulting increasing DA concentrations in the synaptic cleft. (c) Amphetamine, in competition with extracellular DA, binds to the transporter. Substrate binding allows the movement of the carrier to the intracellular surface of the neuronal membrane, driven by the sodium and amphetamine concentration gradients, resulting in a reversal of the flow of DA uptake. Amphetamine dissociates from the transporter, making the binding site available to cytoplasmic DA. DA binding to the transporter enables the movement of the transporter to the extracellular surface of the neuronal membrane, as driven by the favorable DA concentration gradient. DA dissociates from the transporter, making the transporter available for amphetamine, and thus another cycle

presence of some drugs such as amphetamine, the direction of transport appears to be reversed (Fig. 24.3). DA and NE are moved from the inside of the cell to the outside through a mechanism called exchange diffusion, which occurs at low doses (1–5 mg/kg) of amphetamine, and this mechanism is involved in the enhancement of catecholamine release by amphetamine. A recent in  vitro experiment has shown that amphetamine transportation causes an inward current, and intracellular sodium ion becomes more available,

thereby enhancing DAT-mediated reverse transport of DA [13, 14]. At higher doses, other effects are involved. Moderate to high doses of amphetamine (>5 mg/kg) interact with the vascular monoamine transporter 2 (VMAT2) (see [12]). The vesicularization of monoamines (DA, NE, serotonin, and histamine) in the central nervous system is dependent on VMAT2, and the VMAT2 regulates the size of the vesicular and cytosolic monoamine pools. Amphetamine is highly lipophilic and easily

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24  Modes of Action of Drugs Related to Narcolepsy

a Percent Change from Baseline Recording

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Desipramine Nisoxetine 0.4 mg/kg 0.5 mg/kg

Bupropion GBR-12909 Mazindol Amineptine Nomifensine 0.4 mg/kg 0.1 mg/kg 0.016 mg/kg 0.4 mg/kg 0.25 mg/kg

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Fig. 24.3  (a, b) Effects of various DA and NE uptake inhibitors, amphetamine and modafinil on the EEG arousal of narcoleptic dogs and (c) correlation between in  vivo EEG arousal effects and in vitro DA transporter binding affinities. (a, b) The effects of various compounds on daytime sleepiness were studied using 4 h daytime polygraphic recordings (10:00–14:00) in four to five narcoleptic animals. Two doses were studied for each compound. All DA uptake inhibitors and CNS stimulants dose-dependently increased EEG arousal and reduced SWS when compared to vehicle treatment. In contrast, nisoxetine and desipramine, two potent NE uptake inhibitors, had no significant effect on EEG arousal at doses that completely suppressed cataplexy. Compounds with both adrenergic and dopaminergic effects (nomifensine, mazindol, d-amphetamine) were active on both EEG arousal and cataplexy. The effects of the two doses studied for each stimulant were used to approximate a doseresponse curve; the drug dose that increased the time spent in wakefulness by 40% above baseline (vehicle session) was estimated for each compound. The order of potency of the com-

pounds obtained was: mazindol > (amphetamine) > nomifensine > GBR 12,909 > amineptine> (modafinil) > bupropion. (c) In vitro DAT binding was performed using [3H]-WIN 35,428 onto canine caudate membranes. Affinity for the various DA uptake inhibitors tested varied widely between 6.5 nM and 3.3 mM. In addition, it was also found that both amphetamine and modafinil have low, but significant affinity (same range as amineptine) for the DAT. A significant correlation between in vivo and in vitro effects was observed for all 5 DA uptake inhibitors and modafinil. Amphetamine, which had potent EEG arousal effects, has a relatively low DAT binding affinity, suggesting that other mechanisms, most probably monoamine releasing effects or monoamine oxidase inhibition, are also involved. In contrast, there was no significant correlation between in vivo EEG arousal effects and in vitro NE transporter binding affinities for DA and NE uptake inhibitors. These results suggest that presynaptic enhancement of DA transmission is the key pharmacological property mediating the EEG arousal effects of most wake-promoting CNS stimulants (Adapted from [17])

enters nerve terminals by diffusing across several membranes, which leads to a diffusion of the native monoamines out of the vesicles into the cytoplasm along a concentration gradient, and it acts as a physiological VMAT2 antagonist that releases the vascular DA/NE into the cytoplasm. These mechanisms, as well

as the reverse transport and the blocking of reuptake of DA/NE by amphetamine, all lead to an increase in NE and DA synaptic concentrations (see [12]). High doses (higher than a clinical dose) of amphetamines are also shown to inhibit monoamine oxidase (MAO) and prevent catecholamine metabolism.

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Various amphetamine derivatives have slightly different effects on all these systems. For example, methylphenidate also binds to the NET and DAT and weakly enhances catecholamine release, but has less effect on the VMAT granular storage site than amphetamine. Similarly, d-amphetamine has proportionally more releasing effect on the DA versus the NE system when compared to L-amphetamine. Of note, other antidepressant medications acting on catecholamines including both DA and NE (for example: bupropion or mazindol), tend to exert their actions by simply blocking the reuptake mechanism.

Dopaminergic Neurotransmission and EEG Arousal How amphetamines and other stimulants increase EEG arousal has been explored using a canine model of the narcolepsy, and DAT knockout mice models. Canine narcolepsy is a naturally occurring animal model of the human disorder [15]. Similarly to human patients, narcoleptic dogs are excessively sleepy (i.e., shorter sleep latency), have fragmented sleep patterns, and display cataplexy [15]. The pharmacological results demonstrated here are obtained mostly from the experiments using familial narcolepsy in Dobermans in which [16] hypocretin neurotransmission was disrupted by loss of function of hypocretin receptors (i.e., hypo­ cretin receptor 2). In contrast, sporadic (non-familial) form of narcoleptic dogs are found to be ligand deficient, similar to most human narcolepsy, but both forms of narcoleptic dogs exhibit similar symptoms and react to the pharmacological compounds in a similar way [15]. Although amphetamine-like compounds are known well to stimulate catecholaminergic transmission, the exact mechanism by which they promote EEG arousal is still uncertain. Stimulation of either adrenergic or dopaminergic transmission or both has been suggested to play a role. In order to address this question, the effects of ligands specific for the DA (GBR12909, bupropion and amineptine), NE (nisoxetine and desipramine), or both the DA and NE (mazindol and nomifensine) transporters, as well as amphetamine and a non-amphetamine stimulant, modafinil, were studied in narcoleptic and control Dobermans [17] (Fig.  24.3). DA uptake inhibitors such as GBR12909 and bupropion dosedependently increased EEG arousal in narcoleptic dogs,

S. Nishino

while nisoxetine and desipramine (two potent NE uptake inhibitors) had no effect on EEG arousal at doses which almost completely suppressed REM sleep and cataplexy (see [17]). Most strikingly, the EEG arousal potency of various DA uptake inhibitors correlated tightly with in  vitro DA transporter binding affinities (Fig.  24.3), while a reduction in REM sleep correlated with in vitro NET binding affinities [17]. These results strongly suggest that DA uptake inhibition is critical for the EEG arousal effects of these compounds. It should be noted that d-amphetamine has a relatively low DA transporter binding affinity but potently (i.e., need for a low mg/kg dose) promotes alertness (Fig. 24.3). It is also generally considered to be more efficacious (i.e., can produce more alertness at a higher dose) than pure DAT reuptake inhibitors in promoting wakefulness. However, as described earlier, d-amphetamine not only inhibits DA reuptake, but it also enhances DA release (at lower doses by exchange diffusion and at higher doses by antagonistic action against VMAT2) and inhibits monoamine oxidation to prevent DA meta­ bolism. The DA releasing effects of amphetamine are likely to explain the unusually high potency of amphetamine in promoting EEG arousal. The effects of various amphetamine analogs (D-amphe­ tamine, L-amphetamine, and L-methamphetamine) on EEG arousal and their in vivo effects on brain extracellular DA levels in narcoleptic dogs were compared [18], in order to further differentiate the DA and NE systems’ involvement in the mode of action of amphetamine derivatives. In vitro studies have demonstrated that the potency and selectivity for enhancing release or inhibiting uptake of DA and NE vary between amphetamine analogs and isomers [19]. Amphetamine derivatives thus offer a unique opportunity to study the pharmacological control of alertness in  vivo. Hartmann and Cravens previously reported that d-amphetamine is four times more potent in inducing EEG arousal than L-amphetamine, but that both enantiomers are equipotent at suppressing REM sleep in humans and rats [11]. Enantiomer-specific effects have also been reported with methamphetamine; L-methamphetamine is much less potent as a stimulant than either D-methamphetamine or D- or L-amphetamine (Fig.  24.4) (see [19]). Similarly, in canine narcolepsy, D-amphetamine is three times more potent than L-amphetamine and 12 times more potent than L-methamphetamine in increasing wakefulness and reducing Slow Wave Sleep [18].

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24  Modes of Action of Drugs Related to Narcolepsy

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Fig. 24.4  Effect of amphetamine derivatives on sleep parameters during 6  h EEG recording (a). Typical effects of amphetamine derivatives on sleep architecture in a narcoleptic dog (600 nmol/ kg i.v.). Representative hypnograms with and without drug treatment are shown. Recordings lasted for 6 h, beginning at approximately 10:00 am. Vigilance states are shown in the following order from top to bottom: cataplexy, wake, REM sleep, drowsy, LS and DS. The amount of time spent in each vigilance stage (expressed as % of recording time) is shown on the right side of each hypnogram. d-AMP was found to be more potent than 1-amphetamine (l-AMP), and 1-methyl-amphetamine (l-m-AMP) was found to be the least potent, while all isomers equipotently

reduced REM sleep. (b) Local perfusion of amphetamine derivatives: (a) effects on caudate DA and (b) Cortex NE levels. Local perfusion of 100 µM of d-amphetamine (d-AMP) raised DA levels eight times above baseline. l-AMP also increased DA levels up to seven times above baseline, but this level was obtained only at the end of the 60 min perfusion period. l-m-AMP did not change DA levels under these conditions. In contrast, all three amphetamine isomers had equipotent enhancements on NE release. These results suggest that the potency of these derivatives on EEG arousal correlated well with measurements of DA efflux in the caudate of narcoleptic dogs, while effects on NE release may be related to REM suppressant effects (Adapted from [91])

To further study what mediates these differences in potency, the effects of these amphetamine derivatives on DA release were examined in freely-moving animals using in vivo microdialysis. Amphetamine derivatives (100 µM) were perfused locally for 60  min. through the dialysis probe implanted in the caudate

of narcoleptic dogs (Fig. 24.4) [18]. The local perfusion of D-amphetamine raised DA levels nine times above baseline. L-amphetamine also increased DA levels by up to seven times, but peak DA release was only obtained at the end of the 60  min. perfusion period. L-methamphetamine did not change DA levels

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274

under these conditions. These results suggest that D-amphetamine is more potent than L-amphetamine in increasing caudate DA levels, while L-methamphetamine had the least effect; this is in agreement with data obtained in other species using the same technique [19]. NE was also measured in the frontal cortex during perfusion of D-amphetamine, L-amphetamine, and L-methamphetamine. Although all compounds increased NE efflux, no significant difference in potency was detected among the three analogs (Fig. 24.4.). The fact that the potency of amphetamine derivatives on EEG arousal correlates with effects on DA efflux in the caudate of narcoleptic dogs further suggests that the enhancement of DA transmission by presynaptic modulation mediates the wake-promoting effects of amphetamine analogs. This result is also consistent with data obtained with DA transporter blockers (see Fig. 24.3). Considering the fact that other amphetamine-like stimulants (such as methylphenidate and pemoline) also inhibit DA uptake and enhance release of DA, the presynaptic enhancement of DA transmission is likely to be the key pharmacological property mediating wake-promotion for all amphetamines and amphetamine-like stimulants. The role of the DA system in sleep regulation was further assessed using mice lacking the DAT gene. Consistent with a role of DA in the regulation of wakefulness, these animals have reduced non-REM sleep time and increased wakefulness consolidation (independently from locomotor effects) [20]. DAT knock-out mice have also proven to be a powerful tool to help dissect the molecular mechanisms mediating the effects of nonselective monoaminergic compounds. Using these animals, DAT was shown to be involved in mediating locomotor activation after amphetamine and cocaine administration. Indeed, no locomotor stimulation is observed in these mice after cocaine or amphetamine. Interestingly, NET knock-out mice are more sensitive to the locomotor stimulation of amphetamine, suggesting that NET may play a feedback control role on amphetamine-induced dopaminergic effects [21]. With regard to sleep, the most striking finding was that DAT knockout mice were completely unresponsive to the wake-promoting effects of methamphetamine, GBR12909 (a selective DAT blocker) and modafinil. These results further confirm the critical role of DAT in mediating the wake-promoting effects of amphetamines and modafinil (Fig. 24.3) [20] (see also modafinil section). Interestingly,

DAT knockout animals were also found to be more sensitive to caffeine [20], suggesting functional interactions between adenosine and DA systems in the control of sleep/wakefulness (see also caffeine/adenosine section).

Anatomical Substrates of Dopaminergic Effects Anatomical studies have demonstrated two major subdivisions of the ascending DA projections from mesencephalic DA nuclei (VTA, SN and retrorubral [A8]): (1) The mesostriatal system originates in the SN and retrorubral nucleus and terminates in the dorsal striatum (principally the caudate and putamen) [5]. (2) The mesolimbocortical DA system consists of the mesocortical and mesolimbic DA systems. The mesocortical system originates in the VTA and the medial SN and terminates in the limbic cortex (medial prefrontal, anterior cingulated, and entorhinal, cortices). Interestingly, DA re-uptake is of physiological importance for the elimination of DA in cortical hemispheres, limbic forebrain, and striatum, but not in midbrain DA neurons. It is thus possible that DA uptake inhibitors (and amphetamine and modafinil) act mostly on DA terminals of the cortical hemispheres, limbic forebrain, and striatum to induce wakefulness. Local perfusion experiments of DA compounds in rats and canine narcolepsy have suggested that the VTA, but not the SN, is critically involved in the regulation of EEG arousal [22]. DA terminals of the mesolimbocortical DA system may thus be important in mediating wakefulness after DA-related CNS stimulant co-administration.

Modes of Action of Modafinil/ Armodafinil The mechanism of action of modafinil/armodafinil is highly debated. There are limited numbers of studies addressing the mode of action of armodafinil, and this section mostly discusses the action of racemic modafinil. Modafinil/armodafinil has not been shown to bind to or inhibit any receptors or enzyme of known neurotransmitters [23, 24]. The list includes serotonin, dopamine, adenosine, galanin, melatonin, melanocortin, hypocretin/orexin, orphanin, benzodiazepines, trans­ porters for GABA, norepinephrine, choline, Catechol-­ O-methyl transferase, GABA transaminase, and tyrosine

24  Modes of Action of Drugs Related to Narcolepsy

hydroxylase [25–28] (see also [29] for a review). In vitro, modafinil/armodafinil binds to the dopamine transporter and inhibits dopamine reuptake [17, 23]. These binding inhibitory effects have been shown to be associated with increased extracellular dopamine levels in the striatum in rats and dog brain [20, 30]. Nevertheless, an interaction and/or involvement of adrenergic a-1 systems were initially suggested because of the ability of the a-1 antagonist, prazosin, to antagonize modafinil-induced increases in motor activity in mice [28] and wakefulness in cats [26]. However, modafinil does not bind to a-1 receptors in  vivo (Ki > 10−3 M, obtained from prazosin binding using canine cortex) (see [31]). Modafinil does produce smooth muscle contraction in a vas deferens preparation as for DA, 5-HT, or acetylcholine. The hyperlocomotion produced by amphetamine largely depends on the a1b receptor because mice lacking this receptor have much less hyperactivity. Modafinil in contrast, does not increase locomotor activity beyond that seen with normal wakefulness. Furthermore, previous studies in the canine model of narcolepsy have shown that adrenergic a-1 agonists are potent anticataplectic agents [32] and have significant acute hypertensive effect. Modafinil has no anticataplectic activity and lacks hypertensive effects, suggesting that its aler­ting properties are not derived from adrenergic a-1 stimulation. These preclinical observations generally argue against a direct effect of modafinil on adrenergic receptors. Clinical observations provide even stronger evidence that modafinil is neither a direct nor indirect sympathomimetic. Amphe­ tamine causes dilation of the pupils by increasing NE signaling, but modafinil has no effect on the pupils. Some studies have noted slight increases in heart rate or blood pressure with high doses of modafinil. However, these changes were small and the majority of clinical studies on modafinil, including a meta-analysis of seven large clinical trials of modafinil which is the most comprehensive study on this issue, have found no changes in heart rate or blood pressure. These clinical observations suggest that at the usual clinical doses, modafinil does not increase adrenergic signaling in humans. A serotonergic 5HT2 receptor-mediated change in GABAergic transmission was suggested next [25]. Modafinil increases 5HT metabolism in the striatum and reduces GABA flow to the cortex [25]. The effect on GABA release is blocked by ketanserin (a 5HT2 antagonist) but not by prazosin [25]. Furthermore, muscimol, a GABAergic agonist, blocks the effect of

275

modafinil on wakefulness in cats [26]. Although serotonergic/GABAergic interaction may be involved in the mode of action of modafinil, the effects described may be indirect and additional work is needed to substantiate this hypothesis. As for the 5HT2 receptor, modafinil does not bind serotoninergic receptors in vitro. Regarding the in vitro binding affinities of modafinil, a systematic receptor screening revealed that modafinil binds to the DA transporter (DAT) with IC50 of 10−6 M [23]. This binding affinity is low, but is not negligible since modafinil does not bind to any other known receptors and since clinical doses of modafinil are high (up to several mg/kg in human). With regard to modes of action of modafinil on sleep, the most striking finding was that DAT knockout mice were completely unresponsive to the wakepromoting effects of methamphetamine, GBR12909 (a selective DAT blocker), and modafinil. These results further confirm the critical role of DAT in mediating the wake-promoting effects of amphetamines and modafinil and that an intact DAT molecule is required for mediating the arousal effects of compounds [20]. It was recently shown that modafinil was effective in noradrenaline depleted (by DSP-4 administration) [33] and histamine decarboxylase (HDC) KO mice [34] (Fig.  24.5), also suggesting the importance of the dopaminergic system in wake-promotion of modafinil. Other investigators have shown, however, that modafinil can be distinguished pharmacologically from most other compounds by presynaptic dopaminergic activity. For example, modafinil does not produce stereotypic behavior at high doses. Additionally, agents that inhibit dopaminergic function such as D1 blockers, D2 blockers, and tyrosine hydroxylase blockers, have no effect on modafinil’s locomotor-enhancing effects in mice. Finally, an in vitro voltammetry study found that modafinil did not increase the catechol oxidation peak height (an indirect measure of dopaminergic activity), suggesting a lack of presynaptic dopaminergic involvement in modafinil activity. Ferraro et  al. [27], however, reported that systemic administration of modafinil (30–300 mg/kg) dose-dependently increased DA release in the nucleus accumbens of rats (as we also observed that modafinil enhance DA efflux in dogs [20]), but these authors initially claimed that the DA-releasing action of modafinil was most likely to be secondary to its ability to reduce local GABAergic transmission. It should also be noted that a recent brain slice experiment by Dopheide et al. [30] reported that

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276

Wake Change from Baseline (Min.)

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Fig.  24.5  Wake-promoting effects of modafinil on dopamine transporter (DAT) KO, and norepinephrine- and histamine-depleted mice. (a–c) Norepinephrine was depleted by an injection of DSP-4, while histamine decarboxylase (HDC), a synthetic enzyme for histamine knockout mice was used for histamine depleted mice. Wakepromoting effects of modafinil were completely abolished in DAT

KO mice, suggesting that intact DAT function is required for the mediation of wake-promoting effects of modafinil. The fact that the same wake-promotion was observed in norepinephrine- and histamine-depleted mice suggests that this system is not critically involved in wake-promoting effects of modafinil *p<0.05, **p<0.01, ***p<0.0001 (Adapted from [20, 33, 34])

modafinil (100–300 mM) evoked [(3)H] overflow from rat striatal slices preloaded with [(3)H]dopamine in a concentration-dependent manner , although modafinil was less potent and efficacious than amphetamine. Furthermore the DAT inhibitor nomifensine (10 mM) blocked modafinil-evoked [(3)H]overflow, suggesting that the DAT mediates modafinil’s effect. Korotkova et al. [35] recently evaluated modafinil action on dopaminergic and GABAergic neurons identified in the VTA and SN of rat brain slices and claimed that modafinil inhibits DA neurons (but not GABAnergic neurons) through D2 receptors (but not alpha 1 receptors) on DA neurons, independent from DAT inhibition. This finding is interesting, and may explain why pharmacological properties of modafinil are different from amphetamines and pure DA uptake inhibitors. However, the result is again paradoxical since modafinil had no significant binding affinity to D2 receptors. Furthermore, DAT plays significant functional roles at the DA terminals [36], and DAT is not enriched on VTA [37]. In addition, modafinil indeed increases DA efflux at the DA terminals [20, 27]. Therefore it is questionable if the D2 receptor mediated effects of modafinil observed in in vitro slices of the VTA plays essential roles for the modes of action of wake-promoting effects of modafinil.

Not only is the exact molecular target of modafinil action uncertain, but also there is much debate regarding modafinil’s neuroanatomical site of action. Anatomical studies coupled with functional markers of neuronal activity (i.e., the immediate early gene product, Fos) have been used to determine activation patterns induced by modafinil in comparison to other stimulants [38]. In cats, amphetamine and methylphenidate induce c-Fos throughout the cortex, striatum, and other brain regions. In contrast, modafinil induces a much more restricted pattern of neuronal activation, with marked expression of c-Fos in neurons of the anterior hypothalamus area and suprachiasmatic nuclei-brain regions implicated to regulate sleep and circadian cycle [38]. Modafinil also increases c-Fos expression in hypocretin cells [39, 40] and histaminergic cells of the tuberomammillary nucleus; these effects have been suggested to mediate the wake promoting effects of modafinil. At higher doses, the striatum and cingulate cortex are also activated [40]. Of note, however, it is likely that the stimulation of hypocretin cells is not essential to induce wakefulness since both hypocretin receptor-2 mutated canine narcolepsy and hypocretin-ligand deficient human narcolepsy (90% of narcolepsy–cataplexy patients) respond well to modafinil treatment. More likely, activation of these cell groups is secondary to the expression

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24  Modes of Action of Drugs Related to Narcolepsy

of increased wakefulness, as c-Fos expression in these cell groups increase in naturally occurring wakefulness. In anesthetized rats, it is also reported that modafinil (150 mg/kg) increases extracellular histamine concentrations by about 50%, but the rise occurred 3–4 h after the injection – much later than the usual onset of wakefulness by modafinil [41]. Gallopin et  al., recently reported that modafinil inhibits the sleep-active neurons of the ventrolateral preoptic nucleus (VLPO, a sleep promoting network of neurons), by facilitating adrenergic neurotrans­ mission [42]. In this study, modafinil potentiated the inhibitory effects of norepinephrine on VLPO neurons in a slice preparation. Surprisingly, modafinil did not potentiate the inhibitory effects of dopamine or serotonin on VLPO neurons. Nisoxetine, a potent NET inhibitor with low affinity to DAT [17], had a similar effect and the responses to the two drugs were not additive, suggesting they might work through the same biochemical pathways. Since modafinil does not bind to the NET in rats and dogs [17] and NE uptake inhibitors do not possess strong wake-promoting effects, modafinil may modulate norepinephrine/dopamine uptake mechanisms through novel mechanisms. In this case, modafinil may work on both the DA and NE system to promote wakefulness, and adrenergic/DAT interactions may be involved. Of note however, very high modafinil concentrations (generally 200 µM, the maximum that can be dissolved) were used in this study in vitro. It may also be that at this very high dose, small effects on adrenergic uptake, undetectable with the usual radio receptor binding assays, could occur. It is uncertain if these small in vitro activities are indeed important for the wake-promoting effects of the compounds, but may contribute to some of the pharmacological properties of modafinil. Interestingly, Madras et al. [43], recently reported by positron emission tomography imaging in rhesus monkey that modafinil (i.v.) occupied striatal DAT sites (5 mg/kg: 35%; 8 mg/kg: 54%). In the thalamus, modafinil occupied NET sites (5 mg/kg: 16%; 8 mg/ kg: 44%). The authors also showed that modafinil inhibited [3H] dopamine (IC50 6.4 M) five times and 80 times more potent than [3H] norepinephrine (IC50 35.6 M) and [3H] serotonin (IC50 500 M) transport, respectively, via the human DAT, NET, and serotonin transporter expressed cell lines. The data provide compelling evidence that modafinil occupies the DAT in living brain of rhesus monkeys, consistent with the

DAT hypothesis, but modafinil may also act on NET depending on the drug dose, brain structure, and other physiological conditions. Armodafinil, the R-enantiomer of racemic modafinil with longer half life was recently approved by the FDA for the EDS associated with narcolepsy, as well as residual sleepiness in treated with nasal continuous positive airway pressure (nCPAP) and sleepiness in shift work sleep disorder. The compound may act longer and merits some patients (sleepiness in later afternoon), but clinical data indicating this is still limited [44]. The modes of action of armodafinil are comparable to modafinil and are under debate [44].

Other Wake-Promoting Compounds This section describes the modes of action of less often used stimulants, mazindol, bupropion, and caffeine, for the treatment of narcolepsy. Mazindol is a weak releasing agent for DA that also blocks both DA and NE reuptake. Mazindol has a high affinity for the DA and NE transporters (see [17]), yet interestingly this compound has a low abuse potential. It is effective for the treatment of both EDS and cataplexy in humans [45] and in canine narcolepsy [46], possibly due to its dual dopaminergic and noradrenergic effects [17]. Bupropion is classified as a monocyclic phenylbutylamine of the aminoketone group. It selectively blocks DA uptake, and is six times more potent than imipramine, and 19 times more potent than amitriptyline in blocking DA reuptake. The selectivity of bupropion for the dopamine transporter is not absolute. Bupropion is a weak competitive inhibitor of NE reuptake (65-fold less potent than imipramine), and very limited serotonergic effects are also observed (200-fold less potent than imipramine). The mechanism of action of caffeine on wakefulness involves non-specific adenosine receptor antagonism. Adenosine is an endogenous sleep-promoting substance with neuronal inhibitory effects. In animals, sleep can be induced after administration of metabolically stable adenosine analogs with adenosine A1 receptors (A1R) or A2A receptors (A2AR) agonistic properties, such as N6-l-(phenylisopropyl)-adenosine, adenosine-5¢-Nethylcarboxamide, and cyclohexyladenosine [47]. Adenosine content is increased in the basal forebrain

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after sleep deprivation. Adenosine has thus been proposed to be a sleep-inducing substance accumulating in the brain during prolonged wakefulness [48]. Most studies in the area of sleep and adenosinergic effects have focused on A1R-mediated effects. The rationale for this focus is that A1R is widely distributed in the CNS, whereas A2AR is discretely localized in the striatum, nucleus accumbens, and olfactory bulb. Interestingly, sleep wake patterns and response to sleep deprivation were recently examined in adenosine receptor A1R knockout mice and found to be generally unaltered, suggesting that the constitutional lack of adenosine A1R does not prevent homeostatic regulation of sleep. In contrast, the sleep inhibitory effects of 8-cyclopentyltheophylline (a selective A1R antagonist) were abolished in these animals, indicating A1R mediation of stimulant effects with this compound. Huang et al. [49] recently reported that wake-promotion effects of caffeine is abolished in A2A receptor KO mice, while the effects were not altered and evident in A1R KO mice, arguing the A1R mediation of the wake-promoting effects of caffeine. However, it is not known if this result is indicative of other animal species, and further experiments are needed to address this question.

S. Nishino

of the cholinergic systems using the acetylcholinesterase inhibitor physostigmine also greatly exacerbates cataplexy in canine narcolepsy, with various side effects [15]. This cholinergic effect is mediated via muscarinic receptors since muscarinic stimulation aggravates cataplexy while its blockade suppresses it, and nicotinic stimulation or blockade has no effect [15]. Application of muscarinic antagonists in human narcolepsy is, however, hampered by its peripheral side effects. Monoaminergic transmission is also critical for the control of cataplexy. All therapeutic agents currently used to treat cataplexy (i.e., antidepressants or monoamine MAOIs), are known to act on these systems. Furthermore, whereas a subset of cholinergic neurons are activated during REM sleep, the firing rate of monoaminergic neurons in the brainstem (such as in the LC and the raphe magnus) are well known to be dramatically depressed during this sleep stage [51]. In contrast, dopaminergic neurons in the VTA and SN do not significantly change their activity during natural sleep cycles [51]. Using canine narcolepsy, it was demonstrated that adrenergic LC activity is also reduced during cataplexy [52]. It is also shown that histaminergic tuberomammillary neurons reduce their firing ­during REM sleep, but not during cataplexy in the canine model [53].

Mechanisms of Action of Tricyclic anti-Cataplectics

Preferential Involvement of Adrenergic Neurotransmission in the Control of As discussed in the stimulant section, neuropharmacological understandings of cataplexy also have been Canine Cataplexy greatly facilitated using the canine models [15]. Since cataplexy can be easily elicited by food or play and the severity of cataplexy can be quantified by a simple behavioral assay (i.e., Food Elicited Cataplexy Test), these animals have been intensively used for evaluating anti-cataplectic effects of various compounds [15]. Although the mechanism for the induction of cataplexy is not identical to that for REM sleep, both likely share common physiological and pharmacological mechanisms, especially for the executive systems for muscle atonia. Thus, the understanding of the pharmacological control of REM sleep is essential to the understanding of cataplexy. The importance of increased cholinergic activity in triggering REM sleep or REM sleep atonia is well established (see reference [50]). Similarly, activation

As mentioned above, tricyclic antidepressants have a complex pharmacological profile that includes monoamine reuptake inhibition, anticholinergic, alpha-1 adrenergic antagonistic, and antihistaminergic effects, making it difficult to conclude which one of these pharmacological properties is actually involved in their anti-cataplectic effects. In order to determine which property is most relevant, we studied the effects of a large number (a total of 17 compounds) of reuptake blockers/release enhancers specific for the adrenergic, serotonergic, or dopaminergic systems. Adrenergic reuptake inhibition was found to be the key property involved in the anti-cataplectic effect [54] (Table 24.1). Serotonergic reuptake blockers were only marginally effective at high doses and

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24  Modes of Action of Drugs Related to Narcolepsy Table 24.1  Effect of selective monoamine uptake inhibitors and release enhancers on canine cataplexy Drugs

Dose range (µg/kg i.v.)

Effect on cataplexy

ED 50 (µg)

NE selective compounds 1. NE uptake blockers   Desipramine 2–500 0 (p = 0.002) 20   Nisoxetine 1.58–100 0 (p = 0.004) 18   Nortriptyline 2–500 0 (p = 0.004) 28   Tomoxetine 16–1,000 0 (p = 0.002) 11   Viloxazine 8–2,000 0 (p = 0.002) 128 2. NE release enhancers   Amphetamine 2–128 0 (p = 0.02) 37 5-HT selective compounds 1. 5-HT uptake blockers   Fluoxetine 62–4,000 ± (p = 0.06)   Indalpine 62–4,000 = (ns)   Zimelidine 62–4,000 = (ns) 2. 5-HT release enhancers   Fenfluramine 62–4,000 ± (p = 0.05) DA selective compounds 1. DA uptake blockers   Amineptine 62–4,000 = (ns)   Bupropion 16–1,000 = (ns)   GBR 12909 16–1,000 = (ns) 2. DA release enhancers   Amfonelic acid 2–128 = (ns) “0” means that for higher doses there was a total suppression of cataplexy in all dogs. “±” means that there was a decreasing trend in cataplexy during the test, but without total suppression at the higher doses. “=” means that there was no change during the test

the dopaminergic reuptake blockers were completely ineffective. Interestingly, it was later found that these DA reuptake inhibitors had potent alerting effects in canine narcolepsy [15] (see also CNS stimulant section). We also compared the effects of several antidepressants with those of their demethylated metabolites. Many antidepressants (most typically tertiary amine tricyclics) are known to be hepatically first-pass metabolized into their demethylated metabolites that have longer half-lives and higher affinities to adrenergic reuptake sites [55]. During chronic drug administration, these demethylated metabolites accumulate [55] and can thus be involved in the drug’s therapeutic action. The effects of five available antidepressants (amitriptyline, imipramine, clomipramine, zimelidine, and fluoxetine) were compared with those of their respective demethylated metabolites (nortriptyline, desipramine, desmethylclomipramine, norzimelidine and norfluoxetine) [56]. In all cases, the demethylated metabolites were found to be more active on cataplexy than the parent compounds. We also found that the active dose of all anticataplectic compounds tested positively, correlating with the in vitro potency of each

compound to the adrenergic transporter but not with that of the serotonergic transporter [56]. In fact, the anti-cataplectic effects were negatively correlated with the in  vitro potency for serotonergic reuptake inhibition, but this may be biased since potent adrenergic reuptake inhibitors included in the study have a relatively low affinity to serotonergic reuptake sites. Although most of these results were obtained from inbred hcrtr 2-mutated narcoleptic Dobermans, similar findings (the preferential involvement of adrenergic system) have been also obtained in more diverse cases of sporadic canine narcolepsy, in various breeds donated to our colony (see reference [57]). The fact that serotonergic reuptake blockers, also known to have inhibitory effects on REM sleep, have less or no effect on cataplexy is surprising. Like adrenergic cells of the LC, serotonergic cells of the raphe nuclei dramatically decrease their activity during REM sleep [50]. This discrepancy could be explained by a preferential effect of serotonergic projections on REM sleep features other than atonia, for example, in the control of eye movements. In this model, adrenergic projections may be more important than serotonergic

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transmission in the regulation of REM sleep atonia and thus cataplexy [54]. In favor of this hypothesis, a pharmacological experiment has shown that serotonergic acti­vity does not decrease during cataplexy in narcoleptic canines [58].

Receptor Subtypes Involved in the Control of Cataplexy In order to dissect receptor subtypes that significantly modify cataplexy, more than 200 compounds with various pharmacological properties (cholinergics, adrenergics, dopaminergics, serotonergics, prostaglandins, opioids, benzodiazepines, GABA-ergics and adenosinergics) have also been studied in the narcoleptic canine model (see reference [15] for details). Although many compounds (such as M2 antagonists, alpha-1 agonists, alpha-2 antagonists, dopaminergic D2/D3 antagonists, 5HT1A agonists, TRH analogs, prostaglandin E2, and L-type Ca2+ channel blockers) reduce cataplexy, very few compounds significantly aggravate cataplexy (cataplexy aggravating effects are assumed to be more specific, since cataplexy can be non-specifically reduced by unpleasant drug side-effects) [15]. Among the monoaminergic receptors, blockade of the postsynaptic adrenergic alpha1B receptors [32] and stimulation of presynaptic alpha-2 autoreceptors [59] were also found to aggravate cataplexy, a result consistent with a primary adrenergic control of cataplexy. We also found that small doses of DA D2/D3 agonists significantly aggravated cataplexy and induced significant sleepiness in these animals [60, 61]. The cataplexy-inducing effects of D2/D3 agonists are, however, difficult to reconcile considering the fact that dopaminergic reup­ take blockers (in contrast to adrenergic reuptake inhibitors) have absolutely no effect on cataplexy [54] (see also CNS stimulant section). We also found recently that sulpiride (a D2/D3 antagonist) significantly suppresses cataplexy in the canine model but has no effect on REM sleep [62]. D2/D3 agonists are used clinically for the treatment of human periodic leg movements during sleep (PLMS). Incidence of PLMS is high in human narcolepsy, and it also occurs in the narcoleptic Doberman [63]. The dopaminergic system (i.e., D2/ D3 receptor mechanisms) may thus be specifically involved in sleep related motor control rather than REM sleep.

The sites of action of D2/D3 agonists were also investigated by local drug perfusion experiments, and a series of experiments identified acting sites for these compounds. These include dopaminergic nuclei or cell groups, such as the ventral tegmental area [61], the substantia nigra [22] and the A11 [64] (a diencephalic DA cell group that directly projects to the spinal ventral horn), suggesting a direct involvement of the DA cell groups and DA cell body autoreceptors in the regulation of cataplexy. The mechanism for emotional triggering for cataplexy remains to be studied, but it is possible that multiple brain sites and multiple functional and anatomical systems are involved.

MAOIs MAO inhibitors (MAOIs) are known to potently reduce REM sleep, and are therefore candidate anti-cataplectic agents. This has led several investigators to use MAOIs for the treatment of narcolepsy [65, 66]. The extracellular effect of naturally released catecholamine is terminated by either reuptake or enzymatic degradation, either by MAO and/or catechol-O-methyl transferase. MAO is a flavin-containing dominating enzyme located in the outer membranes of neural and glial mitochondria (see reference [67]). It exists in two forms: MAOA, blocked by clorgyline and having high affinity for noradrenaline and 5-HT, and MAO-B, insensitive to clorgyline and having high affinity for phenylethylamine and dopamine (see reference [67]). Even if these compounds are clearly active on narcolepsy [65, 66] and may be useful in cases refractory to more conventional treatment, the first generation of MAOIs have been rarely used in clinical practice to date due to their poor safety profile (e.g., the “cheese effect”) (see [68]). It is also dangerous to use other drugs with sympathomimetic effects (tricyclic antidepressants, amphetamine-like compounds or simply catecholaminergic cardiac stimulants) in patients treated with MAOIs due to the existence of interactions (sometimes fatal) that are impossible to predict (see reference [67]). Other side effects include edema, impotence, weight gain, insomnia, long-term hypertension, and psychological disturbances (see reference [67]). Drug withdrawal may lead to REM sleep rebound with exacerbation of the narcolepsy and the development of

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24  Modes of Action of Drugs Related to Narcolepsy

vivid nightmares [65]. In addition, the first generation of MAOI (irreversible MAOIs) has the unique property of binding covalently to the active site of the enzyme (“suicide substrate”), thus leading to long-term (up to several weeks) enzymatic inhibition even after a single dose (see reference [67]). A safer generation of MAOIs is now becoming available. These include compounds with selective MAO-A or MAO-B inhibition and/or a reversible enzymatic inhibition profile. In contrast to irreversible MAOIs, reversible MAOIs are substrates for the MAOs and compete with the endogenous monoamines (see reference [67]). Some of these new reversible MAOIs (brofaromine, moclobemide) are now being used in clinical trials in Europe and seem to be effective and safe for the treatment of human narcolepsy without noticeable side effects [69]. These compounds can be used with minimal dietary precautions. Selegiline is a potent irreversible MAO-B selective inhibitor used in the treatment of Parkinson’s disease. This compound is essentially a methamphetamine derivative and is metabolized to a significant extent into amphetamine and methamphetamine (9–30% and 20–60% are found in urine respectively); the use of low doses of selegiline does not require dietary restriction. A daily intake of 10 mg selegiline has no effect on

the symptoms of narcolepsy, but 20–30 mg improves alertness and mood and reduces cataplexy somewhat. This effect is comparable to amphetamine at the same dose [70]. Indeed, an experiment in canines also suggests that the anti-cataplectic effects of selegiline are likely to be explained by its active metabolites, l-amphetamine and l-methylamphetamine [71].

GHB GHB (also known as sodium oxybate), taken in the evening and once again during the night, reduces daytime sleepiness, cataplectic attacks, and other manifestations of REM sleep [72–77]. Although improvement in sleepiness occurs relatively quickly, anti-cataplectic effects appear 1–2 weeks after the initiation of the treatment. GHB was originally synthesized as a g-aminobutyric acid (GABA) analog that would readily cross the blood–brain barrier [78], and was later found to occur naturally in the brain [79] as a metabolite and, under certain conditions, as a precursor of GABA [80] (Fig. 24.6). Endogenous GHB has been suggested to act as a neurotransmitter/neuromodulator in a manner

Tricyclics Imipramine

Desipramine

N 2

2

CHCH CH N

N

CH3

3

2

2

CHCH CH N

CH3

Clomipramine

Protriptyline

CH

2

2

2

CH CH CH N

H

SSRI

N

H

CI 2

2

CHCH CH N

3

CH

3

CH

3

CH 3 CH

NRI

Fluoxetine

Fluvoxamine

3

CCH2CH2CH2CH2OCH3

3 FC

FC

N

O C

3

2

2

CHCH CH N

CH

OCH2CH2NH2

H

SNRI Venlafaxine

OH

HN2CH2

C H

O

Milnacipran

N(CH3)2

. HCI

CH

Atomoxetine H

3

HC

N H

O

. HCI CH3

C2H5 C2H5

H

H3CO

Fig. 24.6  Chemical structures for tricyclic, selective serotonin (SSRI), serotonin and norepinephrine (SNRI), and norepinephrine (NRI) antidepressants

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282

independent from that of the GABA systems [80]. GHB is believed to have its own high (and low) affinity binding sites in different species, including humans [80–82]. Its distribution and ontogeny differ from those of GABAA and GABAB receptors [80, 81]. Thus GHB has multiple mechanisms of action in the brain. Exogenously administered GHB induces a wide range of neuropharmacological actions, including sedation, memory impairment, an increase in sleep stages 3 and 4, seizures, dependence/abuse, and coma [83]. Experimentally, GHB-elicited absence seizures in the rat [83] are the best pharmacological model of human typical absence seizures [84]. It also has a limited use as an anesthetic [83] and for alcohol dependence/withdrawal [85]. By the use of potent and selective GABAB receptor antagonists, most of these actions of exogenous GHB have been shown to be mediated, either fully or in part, by GABAB receptors [80, 83, 86]. Notwithstanding its endogenous presence in the brain, its few experimentally and clinically significant uses, and the toxicity resulting from its abuse/misuse or its pathological increase (e.g., in human GHB aciduria [83]), the physiological significance of a brain GHB signaling pathway and the detailed mechanisms of many actions of exogenous GHB remain unclear. In 2003, however, the cloning of a putative GHBR has been reported [87]. Using the high-affinity ligand NCS-400 (a GBH structural

analog), a 512 amino acid protein (57 kDa) has been isolated that shows a predicted secondary structure indicative of seven-transmembrane-spanning regions (as for G-protein-coupled receptors [GPCRs]) and several phosphorylation sites. GHBR mRNA shows a brain distribution similar to that of native GHB binding sites, but with some differences, such as high density in the cerebellum where no or very few native GHB sites have been detected [80, 81, 83]. The pharmacological profile of the recombinant protein expressed in Chinese hamster ovarian cells is also similar to that of native GHB binding sites, but some discrepancies are also noted; it lacks NCS-382 (another putative GHB antagonist) binding and its link to a mixed cationic (Na+/K+) current (as opposed to a Ca2+ current in native brain GHB binding sites [88, 89]). These results and the presence of three mRNA bands are indicative of GHBR subtypes (Fig. 24.7). Despite these new findings, the physiological signi­ ficance of a brain GHB signaling pathway is still unknown, and there is an urgent need for a well-validated functional assay for GHBRs. Moreover, as GHB can also be metabolized to GABA, it remains to be seen whether the many GABAB receptor-mediated actions of GHB are caused by GHB itself acting directly on GABAB receptors or by a GHB-derived GABA pool (or both) (Fig. 24.6).

GHB

GABA

GABAB receptor Fig.  24.7   g-Hydroxybutyric acid (GHB) has multiple mechanisms of action in the brain. Physiologically relevant concentrations (1–4 mM) of GHB activate at least two subtypes of the GHB receptor. In addition to binding to the GHB receptor, at supraphysiological concentrations (high

GHB receptor micromolar to low millimolar), a sufficient quantity of GHB might be metabolized to GABA, which then activates the GABAB receptor. At supraphysiological levels, GHB itself might also bind to the GABAB receptor (Adapted from [92])

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24  Modes of Action of Drugs Related to Narcolepsy

Conclusion Over 90% of diagnosed narcoleptic patients are reported to take medications to control symptoms [90], and better understanding on the pharmacology of therapeutic compounds for narcolepsy are essential in the clinical practice. Amphetamine-like stimulants have been used in the treatment of EDS in narcolepsy and various other conditions for decades, yet only recently has the mode of action of these drugs on vigilance been characterized. In almost all cases, the effects on vigilance were found to be mediated via the effects on the DA transporter (DAT). This has generally led to the widely accepted hypothesis that wake-promoting effects will be impossible to differentiate from abuse potential effects of these compounds. Importantly however, the various medications available have differential effects and potency on the DAT, and on monoamine storage/release. It thus appears more likely that complex properties (for example, the ability to release DA rather than simply block reuptake, plus the combined effects on other monoamines [such as 5-HT]) may be important to explain the characteristic of the wake-promoting effect of each compound. The mode of action of modafinil remains controversial and may involve dopaminergic and/or nondopaminergic effects. Whatever its mode of action is, the compound is generally found to be safer and to have a lower abuse potential than amphetamine stimulants. Its favorable side effect profile has led to an increasing use outside the narcolepsy indication, most recently in the context of shift work disorder and residual sleepiness in treated sleep apnea patients, and the FDA approved these applications. This recent success exemplifies the need for developing novel and non-amphetamine wake-promoting compounds. A need for treating daytime sleepiness extends well beyond the relatively rare indication of narcolepsy–cataplexy. Caffeine is a nonselective adenosine receptor antagonist, and wake-promoting effects of caffeine may be mediated by A1 and A2a receptors. Cataplexy is currently treated with antidepressants, a class of compounds that enhance monoaminergic neurotransmission by inhibition of monoamine reuptake (NE, 5HT, DA). Most narcolepsy–cataplexy patients also take wake-promoting compounds, but these have little effect on cataplexy. Experiments in canine narcolepsy suggest a preferential involvement of NE rather

than 5HT reuptake inhibition in the anticataplectic properties of the drugs. DA reuptake inhibition does not reduce cataplexy, but does significantly enhance wakefulness. In humans, compounds with NE reuptake inhibition also reduce cataplexy. SSRIs are also very commonly used as anticataplectics in the human. This is mostly due to their better side-effect profiles, but the anticataplectics effects of these compounds are rather modest. Recently, selective NE and NE/5-HT (SNRI) reuptake inhibitors were introduced, and one of the SNRIs, venlafaxine, has become the first line of anticataplectic medications. MAOIs are another choice of anticataplectics medications, but use of classical, non-selective, irreversible MAOIs is hampered by various side effects, including hypertensive crisis. Reversible and selective MAOIs are available in some countries, and this may be useful for some severe or refractory cataplexy cases. Sodium oxybate (approved formula of GHB in the USA) given at night improves both EDS and cataplexy. Although improvement in sleepiness occurs relatively quickly, anticataplectic effects appear 1–2 weeks after the initiation of the treatment. Central actions of GHB may be mediated by direct actions on GHB and/or GABAB receptors or though its metabolite, GABA, but modes of actions of GHB on EDS and cataplexy are by and large unknown.

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Chapter 25

Modafinil/Armodafinil in the Treatment of Narcolepsy Michael Thorpy

The Introduction of Modafinil/ Armodafinil Modafinil has been used for the treatment of narcolepsy in France since 1992, and has been studied in other disorders of excessive sleepiness in that country, as well as for depression and “vigilance enhancement” [1, 2]. Preclinical and phase I studies on pharmacokinetics and on the mechanism of action of modafinil [3–5] that supplemented previous French research were initiated in the USA in 1993 to compare the abuse liability of modafinil with that of central nervous system (CNS) stimulants [23, 24]. Clinical studies were performed in narcolepsy that led to the approval of the medication for the treatment of excessive sleepiness since narcolepsy in 1988. In 2007 approval was obtained to use modafinil in the treatment of excessive sleepiness associated with obstructive sleep apnea syndrome and shift-work sleep disorder in 2004. By that time modafinil had been widely used off-label for the treatment of excessive sleepiness associated with other medical conditions such as Parkinson’s disease, myotonic dystrophy and multiple sclerosis. In 2007, a longer-acting form of modafinil, armodafinil, the r-enantiomer, was approved for the treatment of excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS) and shiftwork sleep disorder (SWSD) [6].

M. Thorpy (*) Sleep-Wake Disorders Center, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY, 10467, USA e-mail: [email protected]

Treatment of Narcolepsy by Modafinil Two double-blind, placebo-controlled studies of modafinil in narcolepsy evaluated both objective and subjective sleepiness, as well as overall clinical condition [7, 8]. Each trial (one conducted at 18 centers and one at 21 centers) used the Maintenance of Wakefulness Test (MWT), an objective measure of physiologic excessive sleepiness, as a primary end point. To assess subjective improvements in clinical condition and response or lack of response to modafinil, the Clinical Global Impression of Change (CGI-C) was also used as a primary end point. The objective physiological measure, the Multiple Sleep Latency Test (MSLT) and the subjective questionnaire, the Epworth Sleepiness Scale (ESS), were used as secondary end points. Each narcolepsy study was 9 weeks in duration, with clinic visits scheduled every 3 weeks (nocturnal polysomnography was performed the night before each clinic visit to assess sleep efficiency and changes in sleep architecture). The efficacy analyses used an intent-to-treat population (patients who received at least one dose of study drug and had at least one postbaseline assessment on both the MWT and CGI-C) [7, 8]. A total of 558 narcolepsy patients were randomized to placebo, modafinil 200  mg, or modafinil 400  mg. The majority of participants (81% in both studies combined) had cataplexy. Patients who could not discontinue anticataplectic medications safely for the trial periods were excluded from participation. The maximum mean MSLT sleep latency was 3.3 min in any of the six treatment groups, well below the diagnostic criterion for narcolepsy, at that time of 5  min [9]. The mean ESS scores ranged from 17.1 to 18.3. All patients except one were at least mildly ill on the Clinical

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Global Impression of Severity (CGI-S), with about one third considered markedly to extremely ill. The first study conducted, the 18-center study, used only a 1-day titration period for the 400-mg group (both groups received 200 mg on day 1). A higher percentage of patients in the 400-mg group withdrew due to adverse events compared with the 200 mg and placebo groups (12% vs. 1 and 0%, respectively) [7]. Therefore, the subsequent 21-center study used a stepup protocol, giving each treatment group 100  mg of modafinil on days 1 through 7 and 200 mg on day 8. On day 9 those patients in the 400-mg group were moved to the higher dose. Only 1% of patients in the 400-mg group withdrew due to adverse events; the lower incidence was likely (but not definitively) attributable to the longer titration schedule [8]. The 21-center study also included a 2-week discontinuation period to determine whether abrupt discontinuation of modafinil was associated with adverse events (especially those related to withdrawal from CNS stimulants, including fatigue, insomnia, increased appetite, and agitation). In this phase, those receiving placebo remained on placebo, while 80% of those in the modafinil groups switched over to placebo at the end of week 9. The remaining 20% continued on modafinil to serve as a comparator group [8]. The combined results of the two studies demonstrated a mean sleep latency on the MWT that increased by more than 2 min in each treatment group, compared with a decrease of 0.7  min in the placebo group (P < 0.001, change from baseline vs. placebo for both doses) [7, 8]. A significantly higher percentage of modafinil patients showed improvement in overall clinical condition on the CGI-C (61–66% vs. 37% for placebo; P < 0.001). Similar objective improvements were seen on the MSLT, and subjective improvements on the ESS [7, 8]. During the discontinuation period of the 21-center study, no symptoms consistent with tolerance or abrupt withdrawal were observed. However, improvements in wakefulness seen over the course of the study were lost on both subjective (ESS) and objective (MWT) measures in those who discontinued modafinil [8]. Polysomnographic recordings showed no significant changes in sleep efficiency (i.e., the time asleep as a percent of the total time in bed), time spent in REM sleep, or time spent in each non-REM sleep stage [7, 8]. The most common adverse event was headache (36–54% of patients), the majority of which occurred

M. Thorpy

in the first month of treatment and resolved within a few days. Modafinil was considered generally well tolerated in these studies. There was no difference in treatment response among those with or without cataplexy. The incidence of cataplexy as an adverse event ranged from 1 to 4%, with no difference between the treatment and placebo groups. However, as those who could not discontinue anticataplectic medications were excluded from the studies, it is likely that patients with severe cataplexy were underrepresented (a potential limitation of these studies). Although absolute changes from baseline on the MWT and MSLT may appear small, small increases in sleep latency (e.g., 1–2  min) can represent clinically significant improvements in wakefulness [10]. However, modafinil did not completely resolve sleepiness in these narcolepsy patients; the mean sleep latency, although significantly improved, was still considered to be in the mild to moderate range [7, 8]. A randomized, double-blind, placebo-controlled, 6-week trial that consisted of three 2-week crossover phases also showed significant improvements on the MWT and ESS. In this study, modafinil 200 mg and 400-mg doses were given twice daily in the morning and at noon [11]. The discontinuation results in the 21-center U.S. trial were also supported by similar results from a 16-week open-label extension of the Canadian study, which ended with a 2-week, double-blind, abrupt discontinuation period [12]. Together, the U.S. and Canadian studies formed the basis for recommending modafinil as a standard of care in a 2000 update to the American Academy of Sleep Medicine (AASM) guidelines for narcolepsy treatment and again in the recent 2007 AASM guidelines [13, 14]. The standardof-care designation (only assigned to modafinil) reflected the favorable risk/benefit profile of modafinil in these three studies, as well as several supporting studies conducted in the U.S. and France [15, 16]. Modafinil has now become the “first line” treatment for excessive sleepiness in most patients newly diagnosed with narcolepsy. Several U.S. studies have focused on determining optimal dosing protocols for modafinil in narcolepsy patients, including the use of doses higher than the recommended dose of 200 mg, as well as split dosing to achieve improvements in evening wakefulness. While no dose-response effect was seen for the 400-mg dose compared with 200 mg in the placebo-controlled

25 Modafinil Armodafinil in the Treatment of Narcolepsy

clinical studies, the first MWT nap opportunity was generally performed an hour after dosing of modafinil, too early for the agent to reach peak plasma concentrations. A study employing a modified version of the MWT that included evening test sessions demonstrated an improved response to the 400-mg dose compared with 200  mg, whether it was given as a single morning dose or a split dose in the morning and at noon. The greatest improvements in evening wakefulness were seen with the split-dose regimen [17]. A 600-mg split-dose regimen (400 mg in the morning and 200  mg in the early afternoon) was found to achieve more consistent wakefulness throughout the day (morning, afternoon, and evening) compared with 200 or 400 mg qAM or a 400 mg split-dose regimen [18]. Anecdotally, in clinical practice some physicians have reported increased favorable responses with doses up to 1,200 mg/day. This contrasts with research studies on fatigue, where significant improvements have not been seen consistently with doses higher than 200 mg/day [19]. Dosing studies have also addressed considerations involved in switching from CNS stimulants to modafinil. A recent study of 151 patients showed that modafinil can improve daytime wakefulness in patients who have used previous CNS stimulant therapy [20]. Additional data have shown that patients may be safely switched from methylphenidate both with and without a short washout or dose titration period [21]. European data, however, have shown greater difficulty in switching from amphetamine, with some cases of failure to withdraw [22].

Armodafinil Armodafinil is the r-enantiomer of modafinil and has a half-life of 10–14  h, whereas the s-enantiomer has a half-life of 3–4 h [26, 27]. Modafinil has equal amounts of r and s enantiomers however the s-enantiomer is eliminated three times faster than the r-enantiomer and therefore most of the circulating compound is armodafinil. Armodafinil is well absorbed and peak levels are obtained after 2 h [25]. Food will delay the peak concentration by 2–4 h. Metabolism is predominantly hepatic and therefore severe hepatic disease will cause elevated concentrations of armodafinil. The main pathway for metabolism is by amide hydrolysis, which

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is a non-CYP pathway [26, 27]. There is a small tendency for CYP inhibition and induction, but the only clinical interaction is predominantly CYP3A4/5 induction and CYP2C19 inhibition [27, 28].

Efficacy of Armodafinil in Narcolepsy Studies in healthy sleep-deprived individuals compared armodafinil with modafinil and placebo [29]. These studies showed longer MWT latencies and fewer PVT lapses during 6 to approximately 14 h compared with modafinil. From these studies and other modeling studies it was determined that the bioequivalent dose of 200 mg modafinil was 150-mg armodafinil, and the 400-mg modafinil was bioequivalent to 250-mg armodafinil. Subsequently these doses were used in the clinical placebo-controlled studies of disorders of excessive sleepiness. Studies in 196 patients with narcolepsy compared 150 mg and 250 mg of armodafinil with placebo [30]. The MWT was the main endpoint and the test was extended later into the day (09:00 – 15:00 h) to assess the longer duration of effect. Other tests included the ESS, the Brief fatigue Inventory (BFI) and a cognitive Drug Research (CDR) computerized battery of tests to assess attention and memory. The MWT mean sleep latency was significantly increased compared with placebo. The mean sleep latencies increased over baseline at final visit were 1.3  min for 150-mg armodafinil, 2.6 for 250-mg armodafinil and 1.9  min for combined groups of armodafinil, whereas placebo gave a decrease of 1.9  min (P < 0.01 for all comparisons). Significant improvements were seen at all time points for the 150 mg dose but statistical significance was not reached at 8 and 12 weeks for the 200-mg dose. The clinical global impression scale was improved at final visit for all groups, with proportions of 69, 73 and 71% for the 150 mg, 250 mg and combined armodafinil groups compared with 33% for placebo. The CDR and BFI showed statistically significant improvements in memory, attention and fatigue (P < 0.05). In summary, armodafinil showed improvements in wakefulness over the day, and improvements in overall clinical condition, memory and attention compared with placebo. Comparisons with modafinil were not made.

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Mode of Action of Modafinil/Armodafinil There are no known receptors that modafinil/ armodafinil bind to or inhibit [25, 31]. Evidence exists that modafinil in  vitro binds to the dopamine transporter (DAT) and inhibits dopamine reuptake [31]. DAT knockout mice are unresponsive to modafinil [31]. However, modafinil has activity that differs from other compounds that have presynaptic dopaminergic activity. Modafinil does not induce stereotypy at high doses and dopaminergic blockers do not effect modafinil’s locomotor activity. Although there has been the suggestion that modafinil interacts with adrenergic alpha-1 systems, studies in canine narcolepsy and hypertension suggest otherwise. Adrenergic alpha-1 stimulation exacerbates hypertension and inhibits cataplexy in canine narcolepsy, but modafinil does neither. Clinical evidence suggests that modafinil does not have adrenergic activity. Modafinil increase serotonin 5HT metabolism in the striatum and reduces GABA flow to the cortex, but these effects may be indirect and it is unlikely that these activities are involved in the action of modafinil [32]. Modafinil increases C-fos activity in the anterior hypothalamus, suprachiasmatic nucleus, hypocretin neurons, and tuberomammillary nucleus, and at higher doses the striatum and cingulated cortex [33–35]. It is likely that activation of these cell groups is secondary to increased wakefulness as c-fos expression occurs in these areas in normal wakefulness. Modafinil may modulate norepinephrine uptake mechanisms to promote wakefulness, as modafinil inhibits the sleep-inducing nucleus, the ventrolateral preoptic nucleus (VLPO) [36]. Modafinil works in a manner similar to nisoxetine, a potent norepinephrine transporter (NET) inhibitor [37]. So, modafinil may act on both DAT and NET enhancing norepinephrine/ dopamine systems.

Safety and Adverse Event Data with Modafinil/Armodafinil Substantial safety data on the use of modafinil has been compiled through a number of sources, including adverse event monitoring in the clinical trials, postmarketing adverse event reporting, preclinical studies

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on drug interactions, studies on abuse and dependence potential, and active postmarketing surveillance programs. Overall, modafinil exhibited a favorable adverse event profile in placebo-controlled studies [1, 7, 8, 38]. The most common adverse event was headache; most were mild or moderate in severity, appeared in the early stages of therapy, and resolved within several days. A dose-response relationship was seen with headache and anxiety. Armodafinil has been studied in over 1,000 patients and exhibits a similar safety profile to modafinil [25]. Its most common side effects are headache (17%), nausea (7%), dizziness (5%) and insomnia (5%). There have been some slight changes with armodafinil in the hepatic enzymes, gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) compared with placebo. Neither long-term, open-label studies nor postmarketing adverse event reporting for modafinil have revealed patterns of adverse events that differ from those in the double-blind, placebo-controlled studies. Patients in the narcolepsy studies were enrolled in an open-label extension study using flexible doses of 200–400-mg modafinil; results through 136 weeks have demonstrated continued improvement in wakefulness on the ESS, and expected treatment-emergent adverse events including headache, nervousness, and nausea [1, 39]. A total of 28.7% of patients discontinued treatment, for reasons that included “insufficient efficacy” (11.5%) and adverse events (9%). In clinical trials of modafinil, the incidence of rash resulting in discontinuation of modafinil was approximately 0.8% (13 per 1,585) in pediatric patients (age < 17 years); these rashes included 1 case of possible Stevens-Johnson Syndrome (SJS) and 1 case of apparent multi-organ hypersensitivity reaction. No serious skin rashes have been reported in adult clinical trials (0 per 4,264) of modafinil [40]. Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and children in worldwide post-marketing experience. The reporting rate of TEN and SJS associated with modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate. Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 and 2 cases per million-person years.

25 Modafinil Armodafinil in the Treatment of Narcolepsy

Most cases of serious rash associated with modafinil occurred within 1–5 weeks after treatment initiation and there are no factors that are known to predict the risk of occurrence or the severity of rash. As it is not possible to reliably predict which rashes will prove to be serious, modafinil should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug-related. One serious case of angioedema and one case of hypersensitivity (with rash, dysphagia, and bronchospasm), were observed among 1,595 patients treated with armodafinil. No such cases were observed in modafinil clinical trials. However, angioedema has been reported in postmarketing experience with modafinil. Patients should be advised to discontinue therapy and immediately report to their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes, lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness). Multi-organ hypersensitivity reactions, including at least one fatality in postmarketing experience, have occurred in close temporal association (median time to detection 13 days: range 4–33) to the initiation of modafinil. If a multi-organ hypersensitivity reaction is suspected, modafinil should be discontinued. Although there are no case reports to indicate cross-sensitivity with other drugs that produce this syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. Modafinil has been tested with a number of drugs that are metabolized by the hepatic cytochrome P450 enzyme system, including oral contraceptives, warfarin, and triazolam [41, 42]. In patients who are CYP2D6 deficient an elevation of clomipramine levels can occur. Blood levels of fluoxetine may be increased slightly by modafinil. Among the notable interactions was a decrease in the peak plasma concentrations of ethinylestradiol. As a result, the prescribing information contains a precaution advising women to seek alternative or additional methods of contraceptive while taking modafinil and for 1 month following discontinuation. Armodafinil is a moderate inducer of CYP3A4 and a moderate inhibitor of CYP2C19 in healthy subjects and therefore dosage adjustments may be required for drugs that are substrates of CYP3A4 (e.g., cyclosporin, triazolam)and CYP2C19 enzymes (e.g. diazepam, phenytoin) when administered with armodafinil [27].

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There are no drug interactions with medications taken concurrently for cataplexy. The anticataplectic medication, sodium oxybate, has been shown to provide additional benefit to daytime alertness when given with modafinil [43]. Modafinil and armodafinil are both Schedule IV medications of the Controlled Substances Act. Abuse potential is relatively low and may lead to limited physical or psychological dependence. Postmarketing surveillance of modafinil has not detected generalized interest in modafinil as a drug of abuse. However, there have been isolated cases of modafinil abuse reported through these methods of surveillance [44]. In addition, clinical studies in persons experienced with drugs of abuse have demonstrated the modafinil can produce mild psychoactive and euphoric effects consistent with those of CNS stimulants [45, 46]. In studies of obstructive sleep apnea syndrome, while mean systolic or diastolic blood pressure did not rise significantly in patients treated with modafinil, more patients taking modafinil in the placebo-controlled clinical studies required either an increase in dose or an additional prescription for an antihypertensive agent [38, 47]. Small but consistent changes in systolic and diastolic blood pressures have been seen in clinical trials with armodafinil. Analyses of electrocardiographic features such as QTc intervals have not revealed any evidence of detrimental effects. In clinical studies of modafiil, signs and symptoms including chest pain, palpitations, dyspnea and transient ischemic T-wave changes on ECG were observed in three subjects in association with mitral valve prolapse or left ventricular hypertrophy [25]. It is recommended that modafinil and armodafinil not be used in patients with left ventricular hypertrophy or in patients with mitral valve prolapse (MVP) who have experienced the MVP syndrome with other CNS stimulants. Modafinil and armodafinil have not been studied in patients with recent myocardial infarction or angina and it is recommended that caution should be exercised in such patients. The overall cardiovascular profile of modafinil and armodafinil is favorable compared with that of the stimulants. Psychiatric adverse experiences associated with the use of modafinil have included mania, delusions, hallucinations, and suicidal ideation, some resulting in hospitalization. Many patients had a prior psychiatric history. In the adult modafinil controlled trials database, psychiatric symptoms resulting in treatment

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discontinuation were anxiety (1%), nervousness (1%), insomnia (<1%), confusion (<1%), agitation (<1%), and depression (<1%). In the controlled trial armodafinil database, anxiety, agitation, nervousness, and irritability were reasons for treatment discontinuation more often in patients on armodafinil compared to placebo (armodafinil 1.2% and placebo 0.3%). In the armodafinil controlled studies, depression was also a reason for treatment discontinuation more often in patients on armodafinil compared to placebo (armodafinil 0.6% and placebo 0.2%) [25]. Caution should be exercised when modafinil/armodafinil is given to patients with a history of psychosis, depression, or mania. The medication should be stopped if there is the emergence or exacerbation of psychiatric symptoms. Modafinil and armodafinil are Category C for pregnancy. The general recommendation is for patients to avoid taking modafinil or armodafinil during pregnancy unless the risk-benefit ratio suggests otherwise.

Summary Modafinil is regarded as a first-line medication for the treatment of excessive sleepiness in narcolepsy. Although not the only medication recommended as a standard of treatment for the excessive sleepiness of narcolepsy by the AASM (sodium oxybate is also regarded as a standard of treatment) it is the most widely used medication. Despite there being common side effects of nausea and headache, these are usually self-limited and are only mild in severity. Since approval, modafinil has been found to have some serious adverse effects such as hypersensitivity reactions and skin rashes, however these are rare but the clinician needs to be aware that they might happen, and if so, stop the medication. In general, modafinil is safe and well tolerated by most patients. Modafinil is recommend as a single daily dose although many patients may require twice a day dosing to provide coverage in the late afternoon. Armodafanil is an effective medication for excessive sleepiness that is the isomeric form of modafinil. It has a longer duration of effect and has some of the same adverse effects as modafinil. As with modafinil the adverse effects are only mild and the medication is well tolerated. The dose of armodafinil required will be slightly less than for modafinil (250 vs. 400  mg,

respectively) which may be associated with fewer adverse effects. Armodafinil has a longer half-life and may be useful for those patients who need additional control of sleepiness in the late afternoon or early evening. Although FDA approved, but not yet available in pharmacies, the medication may be made available as early as 2009.

References   1. Thorpy M. (2006) Modafinil in the USA. In: Narcolepsy and Hypersomnia. Bassetti C, Billiard M, Mignot E, Eds. Informa Healthcare: New York.   2. Bastuji H, Jouvet M. (1988) Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. Prog Neuropsychopharmacol Biol Psychiatry; 12:695–700.   3. Robertson P Jr, Hellriegel ET. (2003) Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet; 42: 123–137.   4. Scammell TE, Estabrooke IV, McCarthy MT, Chemelli RM, Yanagisawa M, Miller MS, Saper CB. (2000) Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J Neurosci; 20:8620–8628.   5. Robertson P, Decory HH, Madan A, Parkinson A. (2000) In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. Drug Metab Dispos; 28:664–671.   6. In Y, Tomoo K, Ishida T, Sakamoto Y. (2004) Crystal and molecular structure of an (S)-(+)-enantiomer of modafinil, a novel wake-promoting agent. Chem Pharm Bull (Tokyo); 52(10):1186–1189.   7. U.S. Modafinil in Narcolepsy Multicenter Study Group. (1998) Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol; 43: 88–97.   8. U.S. Modafinil in Narcolepsy Multicenter Study Group. (2000) Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology; 54:1166–1175.   9. The International Classification of Sleep Disorders, Revised. (1997) Diagnostic and Coding Manual. Rochester, MN: American Sleep Disorders Association. 10. Patel SR, White DP, Malhotra A, Stanchina ML, Ayas NT. (2003) Continuous positive airway pressure therapy for treating sleepiness in a diverse population with obstructive sleep apnea: results of a meta-analysis. Arch Intern Med 163:565–571. 11. Broughton RJ, Fleming JAE, George CFP, Hill JD, Kryger MH, Moldofsky H, Montplaiser JY, Morehouse RL, Moscovitch A, Murphy WF. (1997) Randomized, doubleblind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology; 49:444–451. 12. Moldofsky H, Broughton RJ, Hill JD. (2000) A randomized trial of the long-term, continued efficacy and safety of modafinil in narcolepsy. Sleep Med; 1:109–116.

25 Modafinil Armodafinil in the Treatment of Narcolepsy 13. Littner M, Johnson SF, McCall WV, Anderson WM, Davila D, Hartse K, Kushida CA, Wise MS, Hirshkowitz M, Woodson BT, for the American Academy of Sleep Medicine Standards of Practice Committee. (2001) Practice parameters for the treatment of narcolepsy: an update for 2000. Sleep; 24:451–466. 14. Morgenthaler TI, Kapur VK, Brown T, Swick TJ, Alessi C, Aurora RN, Boehlecke B, Chesson AL Jr, Friedman L, Maganti R, Owens J, Pancer J, Zak R; Standards of Practice Committee of the American Academy of Sleep Medicine. (2007) Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep; 30(12):1705–1711. 15. Besset A, Chetrit M, Carlander B, Billiard M. (1996) Use of modafinil in the treatment of narcolepsy: a long term followup study. Neurophysiol Clin; 26:60–66. 16. Billiard M, Besset A, Montplaisir J, Laffont F, Goldenberg F, Weill JS, Lubin S. (1994) Modafinil: a double-blind multicentric study. Sleep; 17(8 Suppl):S107–S112. 17. Schwartz JRL, Feldman NT, Bogan RK, Nelson MT, Hughes RJ. (2003) Dosing regimen effects of narcolepsy for improving daytime wakefulness in patients with narcolepsy. Clin Neuropharmacol; 26:252–257. 18. Schwartz JRL, Feldman NT, Bogan RK. (2005) Dose response and dose regimen effects of modafinil in sustaining daytime wakefulness in narcolepsy patients with residual excessive sleepiness. J Neurol Clin Neurosci; 17(3):405–412. 19. Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN. (2002) Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry; 72:179. 20. Schwartz JRL, Feldman NT, Fry JM, Harsh J. (2003) Efficacy and safety of modafinil for improving daytime wakefulness in patients treated previously with psychostimulants. Sleep Med; 4:43–49. 21. Thorpy MJ, Schwartz JR, Kovacevic-Ristanovic R, Hayduk R. (2003) Initiating treatment with modafinil for control of excessive daytime sleepiness in patients switching from methylphenidate: an open-label safety study assessing three strategies. Psychopharmacology (Berl); 167:380–385. 22. Guilleminault C, Aftab FA, Karadeniz D, Philip P, Leger D. (2000) Problems associated with switch to modafinil – a novel alerting agent in narcolepsy. Eur J Neurol; 7:381–384. 23. Wong YN, Simcoe D, Hartman LN, Laughton WB, King SP, McCormick GC, Grebow PE. (1999) A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers. J Clin Pharmacol; 39(1):30–40. 24. Wong YN, King SP, Simcoe D, Gorman S, Laughton W, McCormick GC, Grebow P. (1999) Open-label, single-dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects. J Clin Pharmacol; 39(3):281–288. 25. NuvigilTM (armodafinil) Tablets prescribing information. (Tablets prescribing information) (2008) (cited; Available from http://www.cephalon.com/newsroom/assets/nuvigil_ prescribing_information.pdf). 26. Robertson P Jr, Hellriegel ET (2003) Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet; 42(2):123–137. 27. Darwish M, Kirby M, Robertson P Jr, Hellriegel ET. (2008) Interaction profile of armodafinil with medications metabolized by cytochrome P450 enzymes 1A2, 3A4 and 2C19 in healthy subjects. Clin Pharmacokinet; 47(1):61–74.

293 28. Robertson P Jr, Hellriegel ET, Arora S, Nelson M. (2002) Effect of modafinil at steady state on the single-dose pharmacokinetic profile of warfarin in healthy volunteers. J Clin Pharmacol; 42(2):205–214. 29. Dinges DF, Arora S, Darwish M, Niebler GE.(2006) Pharmacodynamic effects on alertness of single doses of armodafinil in healthy subjects during a nocturnal period of acute sleep loss. Curr Med Res Opin; 22(1):159–167. 30. Harsh JR, Hayduk R, Rosenberg R, Wesnes KA, Walsh JK, Arora S, Niebler GE, Roth T. (2006) The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy. Curr Med Res Opin; 22(4):761–774. 31. Mignot E, Nishino S, Guilleminault C, Dement WC. (1994) Modafinil binds to the dopamine uptake carrier site with low affinity. Sleep; 17:436–437. 32. Tanganelli S, Fuxe K, Ferraro L, Janson AM, Bianchi C. (1992) Inhibitory effects of the psychoactive drug modafinil on gamma-aminobutyric acid outflow from the cerebral cortex of the awake freely moving guinea pig. Arch Pharmacol; 345:461–465. 33. Lin JS, Hou Y, Jouvet M. (1996) Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinilinducedwakefulness,evidencedbyc-fosimmunocytochemistry in the cats. Proc Natl Acad Sci USA; 93:14128–14133. 34. 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. (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell; 98:437–451. 35. Scammell TE, Estabrooke IV, McCarthy MT, Chemelli RM, Yanagisawa M, Miller MS, Saper CB. (2000) Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J Neurosci,. 20(22): p. 8620–8628. 36. Gallopin T, Luppi PH, Rambert FA, Frydman A, Fort P. (2004) Effect of the wake-promoting agent modafinil on sleep-­ promoting neurons from the ventrolateral preoptic nuclueus: an in vitro pharmacologic study. Sleep; 27(1):19–25. 37. Nishino S, Mao J, Sampathkumaran R, Shelton J. (1998) Increased dopaminergic transmission mediates the wake-­ promoting effects of CNS stimulants. Sleep Res Online; 1:49– 61. http://www.sro.org/1998/Nishino/49/. 38. Roth T, Schwartz JR, Hirshkowitz M, Erman MK, Dayno JM, Arora S. (2007) Evaluation of the safety of modafinil for treatment of excessive sleepiness. J Clin Sleep Med; 3(6):595–602. 39. Mitler MM, Harsh J, Hirshkowitz M, Guilleminault C, for the U.S. Modafinil in Narcolepsy Multicenter Study Group. (2000) Long-term efficacy and safety of modafinil (PROVIGIL®) for the treatment of excessive daytime sleepiness associated with narcolepsy. Sleep Med; 1:231–243. 40. Citation: (2008) http://www.provigil.com/Media/PDFs/prescribing_info.pdf. 41. Robertson P Jr, Hellriegel ET, Arora S, Nelson M. (2002) Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers. Clin Pharmacol Ther; 71:46–56. 42. Robertson P Jr, Hellriegel ET, Arora S, Nelson M. (2002) Effect of modafinil at steady state on the single-dose pharmacokinetic profile of warfarin in healthy volunteers. J Clin Pharmacol; 42:205–214.

294 43. Black J, Houghton WC. (2006) Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep; 29(7):939–946. 44. Smith DE, Calhoun SR, Galloway GP, Romanoff SJ, Wolfe NE. (2004) Postmarketing surveillance of modafinil abuse and misuse (abstract). Sleep; 27(suppl):A57. 45. Rush CR, Kelly TH, Hays LR, Baker RW, Wooten AF. (2002) Acute behavioral and physiological effects of modafinil in drug abusers. Behav Pharmacol; 13:105–115.

M. Thorpy 46. Jasinski DR, Kovacevic-Ristanovic R. (2000) Evaluation of the abuse liability of modafinil and other drugs for excessive daytime sleepiness associated with narcolepsy. Clin Neuropharmacol; 23:149–156. 47. Schwartz JRL, Hirshkowitz M, Erman MK, Schmidt-Nowara W, for the U.S. Modafinil in Obstructive Sleep Apnea Study Group. (2003) Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea: a 12-week, open-label study. Chest; 24:2192–2199.

Chapter 26

Sodium Oxybate in the Treatment of Narcolepsy Geert Mayer

Conservative Treatment of Narcoleptic Symptoms Since 1934 medication has been available for the treatment of narcoleptic symptoms. With the fullblown symptomatology, patients had to be treated with two or three different substances: (1) excessive daytime sleepiness (EDS) with stimulants, (2) cataplexies with antidepressants, (3) fragmented night-time sleep with hypnotics. The majority of stimulants are amphetamines which act as dopaminergic agonists that can cause central stimulation, inhibition of sleepiness, improvement of cognition, concentration, and learning capacity, improvement of attention, reduction of appetite and thirst, increase of body temperature and blood pressure, vascular resistance, and energy metabolism of the brain. Because some of these substances have been on the market for 60  years, the available therapeutic studies often do not meet the criteria of modern evidence-based medicine. The available studies often have low evidence levels even though their clinical effects are beyond doubt. Modafinil introduced into the therapeutic spectrum in the 1980s was the first nonamphetamine-like stimulant. Its mode of action has not been sufficiently understood until recently [24]. However, it is the only stimulant that does not act via dopamine receptors but via GABA (reduction of extracellular concentrations) [8]. It is a postsynaptic a1-receptor agonist. Its few side effects are quite different from that of the amphetamines [9]. It has no potential for addiction. G. Mayer (*) Hephata Klinik, Schimmelpfengstr. 2, 34613 Schwalmstadt-Treysa, Germany e-mail: [email protected]

Cataplexies have been successfully treated for more than 60  years with tricyclic antidepressants. In recent years a growing number of selective and non-selective serotonine-, noradrenaline-, and catecholamine reuptake inhibitors have proved to be efficacious in studies with small patient numbers. However, the most potent anticataplectic medication is that with the highest noradrenaline reuptake inhibition. Studies on the treatment of fragmented night-time sleep are extremely scarce and comprise only very small patient numbers.

Gammahydroxybutyrate (GHB)/Sodium Oxybate (SO) In the 1960s, shortly after its discovery, GHB was used for the treatment of narcolepsy. The rationale was that it evokes sleep that resembles physiological sleep but comprises a higher amount of slow wave sleep, and consolidates REM sleep. Initial studies documented the improvement in sleep quality and a reduction of cataplexies [7, 11, 18, 19].

Pharmacology GHB is an endogenous fatty acid produced within the brain that is found in many other tissues [14]. It has specific receptors (GHB, GABAB) that are located within the central nervous system and to which it has a different affinity. Its binding to the GABAB receptor seems to be responsible for sleep induction. In the animal model, antagonizing GABAB inhibits sleep induced by

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SO whereas the genetic deletion of GABAB suppresses slow wave sleep. GHB applied in physiological doses has a modulating effect on gabaergic, dopaminergic, noradrenergic, and serotonergic neurons. The mechanisms by which SO enhances wakefulness over the daytime remain unclear. It is assumed that it shifts the relation of sleep–wake neurotransmission toward wakefulness by acting on the noradrenergic locus coeruleus.

Pharmacokinetics SO is rapidly absorbed after oral intake. Peak plasma concentrations are measured after 0.5–1.25 h. The halflife is 30–60  min. GHB-dehydrogenase metabolizes SO into succinic-semialdehyde which is converted into succinic acid that enters the Krebs cycle where it is converted to CO2 and water [20]. Five percent is eliminated unchanged in the urine. There is no induction of cytochrome P450 isoenzymes by SO [6, 17]. SO presented as a pharmaceutical preparation is a liquid. Due to its pharmacokinetics it should be administered in two equal doses directly prior to going to bed, and 2.5–4  h later [4]. Plasma concentrations increase disproportionally with dose [15]. Since food can reduce absorption of SO to quite an extent, it is recommended to administer the fluid at least 2 h after the last meal [5]. Due to enzyme saturation, plasma levels are increased after the second intake. The rationale for the twice nightly administration is the effect on sleep duration taken from the older pharmacological studies [7, 11, 18, 19]. Whether SO is efficacious after intake of one dose – which some patients would prefer – has not been studied.

Efficacy of SO in Treating Symptoms of Narcolepsy Cataplexy Safety and efficacy of SO was established in two doubleblind, randomized, placebo-controlled studies, and in one open-label extension study. In the first study, 136 patients who were allowed to maintain their stimu-

lants, were randomly exposed to 3, 6 or 9 g of SO in two equal doses per night, respectively. A significant dose-dependent reduction of cataplexies was found in 52% of patients treated with 6 g, and 62% treated with 9 g [27]. The results were confirmed in a group of 228 patients [22, 29]. In a 12-month study the initial dose of 6 g was up- or down-titrated every 2 weeks according to a defined protocol [26]. The most significant reductions in cataplexies were found after 4 weeks. The 90% reduction remained stable until month 12. An open label study in 55 patients with a treatment duration of 7–44 months (3–9 g) confirmed the results and showed a gradual return of cataplexies after withdrawal of SO [25]. None of the studies evidenced tolerance. After withdrawal of SO none of the patients reported rebound cataplexies.

Excessive Daytime Sleepiness Most of the studies for the investigation of cataplexies comprised an evaluation of daytime sleepiness by using the Maintenance of Wakefulness Test (MWT) and the Epworth Sleepiness Scale (ESS) [22]. In an 8-week double-blind, placebo-controlled study, 228 patients who, under controlled conditions, had been withdrawn from their antidepressants and maintained their stable doses of stimulants were randomly exposed to 4.5, 6, or 9 g of SO. Patients receiving 9  g had a significant reduction of the median ESS score from 17 to 12 points compared to placebo. The median changes for 4.5 and 6 g were 1 and 2 points, respectively. In the 9 g group, sleep latencies in the MWT increased significantly by 10 min, and median inadvertent naps decreased significantly in the 6 and 9 g groups. A detailed analysis attributed the changes to SO as additional effect to the concurrent stimulant treatment [22]. In the 12-month study, all doses of SO showed a significant improvement after 2 months when compared with placebo. In an 8-week randomized, placebo-controlled, doubleblind, double-dummy, controlled four arm study (placebo, placebo plus modafinil, placebo plus SO, SO plus modafinil, 228 patients) switching the patients from modafinil to SO did not result in any change of sleep latencies in the MWT. The combination of SO plus modafinil caused an increased extension of NREM sleep and reduction of nocturnal wake periods as compared to

26 Sodium Oxybate in the Treatment of Narcolepsy

SO alone as well as a significant increase in sleep latency (plus 2.7 min) compared to placebo. Apparently modafinil enhances the pharmacological effects of SO [21].

Sleep Increases of theta and delta activities in EEG recordings under administration of GHB have been known for more than 20 years [7]. In all GHB studies polysomnographies showed an increase of stages NREM 3 and 4 as well as of delta power [3]. SO consolidated sleep by a significant reduction of nocturnal wake episodes in the 6 and 9 g groups when compared to placebo. Total sleep time was extended significantly with 9 g [22]. In the MWT, sleep latency was significantly increased in the 9 g group. The number of inadvertent naps during daytime was significantly reduced in the 6 and 9 g groups from 18 to 12 and 14 to 8, respectively.

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hallucinations (76%), sleep paralysis (76%), daytime sleep attacks (76%), night-time awakenings (57%) and daytime sleepiness (76%), night-time sleep quality (81%), ability to concentrate (67%), and overall condition (81%) [12]. In a 6-month study with 140 narcoleptic patients, a statistically significant improvement (p < 0.05) was seen in seven of the eight domains measured by the SF-36 questionnaire, namely, physical functioning, limitations due to physical functioning, general health, vitality, social functioning, limitations due to emotional problems, and mental health [10]. The analysis of quality of life in one of the multicenter studies showed that SO 9  g produced a doserelated improvement in four out of five subscales of the FOSQ, with two subscales (activity and social outcome level) improving at the 6 g dose. No improvements were observed with sodium oxybate 4.5 g [28].

Adverse Events Quality of Life In a 10-week open-label, dose-escalating study patients reported changes of symptoms by a questionnaire: improvement of cataplectic attacks (86%), hypnagogic

In the muticenter international SO studies the overall incidence of adverse events 75% is given in Table 26.1. Most frequent adverse events were dizziness, nausea, headache, somnolence, enuresis, vomiting, sleep walking. In the own German [23] experience in more

Table 26.1  Overall incidence of adverse events in SO studies Sodium Oxybate g/day at onset Placebo Total 3 4.5 6 Number of patients N 260 781 111 543 631 Any AE N 156 674 68 277 388 % 60.0 86.3 61.3 51.0 61.5 Any related AE N 83 507 44 182 247 % 31.9 64.9 39.6 33.5 39.1 Any SAE N 5 79 4 13 22 % 1.9 10.1 3.6 2.4 3.5 Any related SAE N 1 20 0 2 6 % 0.4 2.6 0 0.4 1.0 Any severe AE N 15 165 5 36 67 % 5.8 21.1 4.5 6.6 10.6 Any related severe AE N 5 69 2 13 30 % 1.9 8.8 1.8 2.4 4.8 Discontinuation due to AE N 5 115 6 28 40 % 1.9 14.7 5.4 5.2 6.3 Discontinuation due to related AE N 3 82 6 18 29 % 1.2 10.5 5.4 3.3 4.6 data from [25, 26, 27, 29]

7.5 289 190 65.7 102 35.3 22 7.6 4 1.4 34 11.8 6 2.1 17 5.9 11 3.8

9 324 234 72.2 167 51.5 21 6.5 8 2.5 45 13.9 21 6.5 30 9.3 24 7.4

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than 80 patients (median intake 20 months) 12% had adverse events. Sweating was one of the major problems. Dizziness and somnolence were experienced when patients were getting up and walking around in the active phase of SO, or as “hangover” in the morning within the first days after intake. Enuresis occurred only twice in pharmacosensitive patients who had an enormous increase of slow wave sleep. Patients took two portions of 1.5  g each. Psychosis only occurred once in a patient who had a history of psychiatric disorder unknown to the investigators. In the long-term studies side, effects were similar to the 8-week studies. There were no treatment-related deaths in any of the studies. SO has the potential to induce respiratory depression. Apnea and respiratory depression have been observed in a fasting healthy subject after a single intake of 4.5 g at once (twice the recommended starting dose = 2 × 2.25 g). The potential effects of SO on respiratory measures during sleep were assessed as secondary endpoint in a 10-week, open-label, multicenter trial (4.5, 6, 7.5, and 9 g SO per night) on overnight polysomnographic measures. SO was not associated with a dose-effect on sleep-disordered breathing, or a decrease in mean oxygen saturation in patients in this study, including six patients with obstructive sleep apnea [2, 16]. However, patients should be asked and watched for signs of CNS or respiratory depression, and special monitoring should be warranted.

Contraindications SO treatment is not indicated for patients with sensitivity to one of its components, those with succinic semialdehyde dehydrogenase deficiency (a very rare disorder), patients treated with barbiturates or opioids, pregnant, or lactating women. Treatment of patients with sleep disordered breathing should only be performed under control of nocturnal breathing parameters. Patients consuming alcohol have to be instructed to skip the intake of SO which may potentiate its CNS effects. Infrequent psychiatric side effects (0.1–1%) are affective instability, crying, emotional disorder, euphoric mood, fear, auditory hallucinations, hypnagogic hallucinations, initial insomnia, altered mood, increased libido, insomnia, panic disorder, paranoia,

restlessness, sleep attacks, stress symptoms. SO prescription for patients with a history of psychiatric disorders should therefore be closely monitored (author’s remark). Experts do not recommend SO in patients who are on night duty, who have to attend new borns or young children, in elderly patients (due to the risk of falling when on SO) or patients living alone, and in patients with known heart failure, hypertension, or compromised renal function.

Treatment Recommendations In 2006, the European Federation of Neurological Societies (EFNS) published guidelines on the management of narcolepsy. For EDS, first-line treatment is modafinil (100–400  mg/day) at two doses, rarely 600  mg, second-line treatment is methylphenidate 10–60 mg, third-line treatment is SO (evidence level 1). For cataplexy, first-line treatment is SO, second-line are antidepressants, specifically clomipramine (10–75 mg). A combination with behavioral treatment (evidence level 2) is recommended [1]. In 2007, the American Association of Sleep Medicine (AASM) published practice parameters for the treatment of narcolepsy [13] stating that several large randomized, placebo-controlled studies indicate that modafinil and sodium oxybate are effective for treatment of hypersomnia associated with narcolepsy (evidence level 1): “The traditional stimulants amphetamine, methamphetamine, dextroamphetamine, and methylphenidate (evidence level 2) which are available in generic form and are less expensive, have a long history of use in clinical practice, but have limited high-level evidence from published studies.” For the treatment of cataplexies: “The recommendation for use of antidepressants (evidence level 2) for cataplexy is based largely on clinical experience and lower-evidence level clinical trials. Randomized controlled trials of these agents, particularly with comparison to sodium oxybate (evidence level 1), a more expensive medication that has high-level evidence of efficacy, are needed to assist the clinician in medication selection.” SO is indicated for the treatment of EDS, cataplexy, and disrupted sleep due to narcolepsy (evidence level 1).

26 Sodium Oxybate in the Treatment of Narcolepsy

Conclusion SO is a well tolerated, new compound for the treatment of the important narcoleptic symptoms such as EDS, cataplexy, and fragmented night-time sleep which does not cause symptom rebound after withdrawal. SO has few side effects and shows little interaction with other drugs: it should be considered for treatment in patients who do not respond well to conservative drugs, or those who display a combination of symptoms for which SO is efficacious. Due to its novelty and the absence of long-term observational data, SO should be administered by sleep specialists.

References 1. Billiard, M., Bassetti, C., Dauvilliers, Y., et al. (2006) EFNS guidelines on management of narcolepsy. Eur J Neurol 13, 1035–48 2. Black, J., et al. (2002) Effect of increasing doses of sodium oxybate on nocturnal oxygen saturation: preliminary findings. Sleep 25(suppl), A474–5 [Abstract] 3. Black, J., and Houghton, W. (2006) Sodium oxybate improver excessive day time sleepiness in narcolepsy. Sleep 9, 939–946 4. Borgen, L., Lane, E., Lai, A. (2000) Xyrem (sodium oxybate). A study of dose proportionality in healthy human subjects. J Clin Pharmacol 40, 1053 [Abstract] 5. Borgen, L. A., Okerholm, R., Morrison, D., Lai, A. (2003) The influence of gender and food on the pharmacokinetics of sodium oxybate oral solution in healthy subjects. J Clin Pharmacol 43, 59–65 6. Borgen, L. A., Okerholm, R. A., Scharf, M. B. (2004) The pharmacokinetics of sodium oxybate following acute and chronic administration to narcoleptic patients. J Clin Pharmacol 44, 253–257 7. Broughton, R., and Mamelak, M. (1980) Effects of nocturnal gamma-hydoxybutyrate on sleep/waking patterns in narcolepsy-cataplexy. Can J Neurol Sci 7, 23–31 8. Engber, T. M., Koury, E. J., Dennis, S. A., Miller, M. S., Contreras, P. C., Bhat, R.V. (1998) Differential patterns of regional c-Fos induction in the rat brain by amphetamine and the novel wakefulness-promoting agent modafinil. Neurosci Letter 241, 95–98 9. Ferraro, L., Tanganelli, S., O’Connor, W. T., et  al. (1996) The vigilance promoting drug modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus of the awake rat: possible involvement of the serotonergic 5-HT3 receptor. Neurosci Lett 220, 5–8 10. Hayduk, R., and Mitler, M. (2001) Sodium oxybate therapy improves the quality of life in narcoleptic patients. Sleep 24 (abstract), 571.K 11. Lammers, G. J., Arends, J., Declerck, A. C., Ferrari, M. D., Schouwink, G., Troost, J. (1993) Gammahydroxybutyrate and narcolepsy: a double-blind placebo-controlled study. Sleep 16, 216–220

299 12. Mamelak, M., Black, J., Montplaisir, J., Ristanovic, R. (2004) A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy. Sleep 27, 1327–34 13. Morgenthaler, T. I., Kapur, V. K., Brown, T., et  al. (2007) Standards of Practice Committee of the AASM. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 30, 1705–1711 14. Nelson, T., Kaufman, E., Kline, J., Sokoloff, L. (1981) The extramural distribution of g-hydroxybutyrate. J Neurochem 37, 1345–1348 15. Pardi, D., and Black, J. E. (2006) Sodium oxybate: neurobiology and clinical efficacy. Future Neurol 1(6), 721–35 16. Ristanovic, R., et  al. (2002) Analysis of dose-effects of sodium oxybate on nocturnal respiratory disturbances. Sleep 24(suppl), A473–474 [Abstract] 17. Scharf, M. B., Lai, A. A., Branigan, B., Stover, R., Berkowitz, D. B. (1998) Pharmacokinetics of gamma-hydroxybutyrate (GHB) in narcoleptic patients. Sleep 21, 507–514 18. Scrima, L., Hartman, P. G., Johnson, F. H. Jr., Hiller, F. C. (1989) Efficacy of gamma-hydroxybutyrate versus placebo in treating narcolepsy-cataplexy: double-blind subjective measures. Biol Psychiatry 26, 331–343 19. Scrima, L., Hartman, P. G., Johnson, F. H. Jr., Thomas, E. E., Hiller, F. C. (1990) The effects of gamma-hydroxybutyrate on the sleep of narcolepsy patients: a double-blind study. Sleep 13, 479–490 20. Snead, O. C., and Gibson, K. M. (2005) g-hydroxybutyric acid. N Engl J Med 352, 2721–2732 21. Black, J., and Houghton, W. (2006) Sodium oxybate improver excessive day time sleepiness in narcolepsy. Sleep 9, 939–946 22. The Xyrem International Multicenter Study Group (2005) A double-blind, placebo-controlled study demonstrates the nightly administration of sodium oxybate is effective for the treatment of excessive daytime sleepiness in narcolepsy. Journal of Clinical Sleep Medicine 1, 391–397 23. Thorpy, M.J., G. Mayer, J. Shneerson. (2008) Treatment of narcolepsy with cataplexy – an overview of the disease and a report on sodium oxybate dosage and prescribing information. European Neurological Review 3, 84–88 24. U.S. Modafinil in Narcolepsy Multicenter Study Group (2000) Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology 54, 1166–1175 25. U.S. Xyrem Multicenter Study Group (2004) Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Med 5, 119–123 26. U.S. Xyrem Multicenter Study Group (2003) A 12-month, openlabel, multicenter extension trial of orally administered sodium oxybate for the treatment of narcolepsy. Sleep 26, 31–35 27. U.S. Xyrem Multicenter Study Group (2002) 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 25, 42–49 28. Weaver, T. E., and Cuellar, N. (2006) A randomized trial evaluating the effectiveness of sodium oxybate therapy on quality of life in narcolepsy. Sleep 29, 1189–1194 29. Xyrem International Study Group (2005) Further evidence supporting the use of sodium oxybate for the treatment of cataplexy: a double-blind, placebo-controlled study in 228 patients. Sleep Medicine 6, 415–421

Chapter 27

Emerging Treatments for Narcolepsy Meredith Broderick and Christian Guilleminault

Introduction Treatment for narcolepsy is currently aimed at reducing two symptoms of narcolepsy–cataplexy associated with the most impairment in daytime functioning. In the case of narcolepsy–cataplexy, those symptoms are excessive sleepiness and cataplexy. In contrast, emerging therapies for narcolepsy are by medical advances unmasking the pathophysiology and neurobiology of the described neurological deficits in narcolepsy such that the underlying cause of narcolepsy is targeted. The shift has been fueled largely by the discovery of the strong relationship between decreased activities of hypocretin producing neurons and narcolepsy–cataplexy. Emerging therapies also include modifications of currently used therapies with the intention of fine tuning effectiveness, combinations of currently used medications, novel pharmacological agents developed in conjunction with discovery of pathophysiological mechanisms, or applications of treatment modalities used for other diseases which are hypothesized as having an application to narcolepsy. Although important advances have been made in narcolepsy research in the past few decades, treatment remains a challenge reflected in guidelines listing a 60% reduction in sleep latency as outcome measures [1]. Current treatment for narcolepsy is based on symptomatic treatment of excessive sleepiness (ES), cataplexy, and fragmented sleep and remains a limitation in clinical management. An ideal treatment would be effective in treating all of these symptoms with minimal side effects. The potential M. Broderick (*) Stanford University Sleep Medicine Program, 401 Quarry Rd suite 3301, Stanford, CA, 94305, USA e-mail: [email protected]

to combine each of these theoretical approaches for a potent treatment with minimal side effects is even more exciting. Future treatments can be divided into five broad categories, which will be described individually. Those five categories include hypocretin-based treatments, immunotherapy, thyrotrophin (TRH) analogs and promoters, histamine (H3) antagonists, combinations or variations of currently used therapies. Each category of therapies has theoretical mechanisms of actions based on our current understanding of the pathophysiology of narcolepsy, each with a unique set of limitations and barriers in development of an ideal treatment. These five categories will be reviewed in a stepwise fashion and discussed in this chapter. A miscellaneous category will be discussed at the end. A summary of these therapies is listed in Table 27.1.

Hypocretin-Based Treatments Mignot and Nishino speculated that one day the gold standard treatment for narcolepsy will be hypocretin replacement therapy [2]. Their statement reflects the many important discoveries made about the etiology of narcolepsy in the past decade. In 1999, Lin et  al. published a study demonstrating a mutation of the hypocretin 2 (Hcrtr2) gene which is responsible for canine narcolepsy [3]. The appearance of narcolepsy– cataplexy in hypocretin knockout mice was also demonstrated by Chemelli et  al. [4]. In humans, low or undetectable levels of hypocretin 1 have been reported in 95% of patients with narcolepsy and cataplexy [5, 6]. From this knowledge, it could be deduced that loss of function of the hypocretin neurons could be one

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302 Table 27.1  Categories of future treatments for narcolepsy Hypocretin-based treatments

Immunotherapies

Thyrotrophin (TRH) analogs Histamine (H3) antagonists Combinations or variations of existing treatments Others

Intranasal hypocretin Hypocretin cell transplantation Hypocretin gene therapy Stem cell transplantation Corticosteroids Plasmapheresis Intravenous immunoglobulins (IVIG) TRH Metallopeptidase inhibitors Histamine stimulation Duloxetine, reboxetine, atomoxetine, armodafinil Hypnotics, SWS stimulators

cause for manifestations of cataplexy and excessive sleepiness in narcolepsy–cataplexy. Hypocretin neurons have widespread projections to the areas of the brainstem linked to motor inhibition, including the locus coeruleus, raphe nuclei, laterodorsal tegmental nuclei, and ventral tegmental neurons [7]. Hypocretin 1 and hypocretin 2 are synthesized in the lateral hypothalamus after being cleaved from the single precursor preprohypocretin. They are both medium sized peptides important in the regulation of arousal, appetite, sleep architecture, neuroendocrine, and autonomic control. Hypocretin 1 is more stable than hypocretin 2 in the blood and in CSF and therefore has been applied more readily in pharmacological studies. Both peptides bind to two known seven transmembrane G protein coupled receptors named hypocretin receptor 1 (hcrtr1) and hypocretin receptor 2 (hcrtr2). Despite the fact that both peptides come from a single precursor, each has slightly different properties. Hypocretin 1 binds to hcrtr1 with two to three times greater affinity than hypocretin 2 [8]. Hypocretin 1 is a key modulator in the arousal state and locomotor activity through its actions on the locus coeruleus [9]. A comparison between the two ligands is in Table 27.2. Many researchers have begun investigating the potential of hypocretin supplementation as a treatment modality for narcolepsy–cataplexy. John et  al. published a study showing systemic administration of hypocretin 1 produces increases in activity levels, wake times, reduces sleep fragmentation, and has a dose dependent reduction in cataplexy in canines with narcolepsy [10]. Lee et  al. conducted a study in rats showing the discharge of hypocretin neurons correlates with the wake state associated with muscle tone and locomotion, whereas they are silent during sleep

Table 27.2  Comparison of hypocretin 1 to hypocretin 2 Hypocretin 1 Hypocretin 2 33 Amino acids 29 Amino acids More stable in vivo Less stable in vivo Higher binding affinity to hcrtr1 Higher binding affinity for hcrtr2

[11]. These are only some of the important studies suggesting the potential of hypocretin 1 replacement as an effective treatment for narcolepsy. One major barrier in the delivery of hypocretin 1 is that it has to cross the blood brain barrier by diffusion to reach the central nervous system. Studies have shown the permeability of hypocretin 1 through the blood brain barrier is low, limiting its bioavailability to the central nervous system when injected peripherally while hypocretin 2 does not pass through the blood brain barrier intact [12, 13]. Therefore, very high doses of hypocretin 1 would be required for therapy. This could be a limiting factor because with increasing systemic concentrations peripheral side effects are more likely. Requiring very high doses of hypocretin would also be limited by supply and cost. With this in mind, therapies exploring alternate modali­ ties of drug delivery are of more interest. The other potential possibilities for hypocretin replacement include intracerebroventricular (ICV) hypocretin replacement, intranasal hypocretin administration, hypocretin cell transplantation, hypocretin gene therapy, or hypocretin stem cell transplantation. ICV replacement of hypocretin 1 has been studied and observed as being effective in narcoleptic mice, but not in hcrtr2 mutated dobermans [12]. The presence of several neuropeptides in the cerebrospinal fluid after intranasal administration has been demonstrated suggesting intranasal delivery of hypocretin may be an effective method of treatment [8, 14]. Intranasal delivery of hypocretin bypasses the blood brain barrier with the added benefits of onset of action within minutes and fewer peripheral side effects [8]. Intranasal delivery works because of the connections between the central nervous system to the outside environment through the olfactory and trigeminal nerves. The mechanism of action is extracellular so there is no dependence on receptors or axonal transport for drug delivery. Hanson et al. conducted a study showing intranasal delivery of hypocretin in awake mice led to drug delivery to the brain and spinal cord [8]. Interestingly, they found that the

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concentrations were highest in the hypothalamus and the trigeminal nerve. Deadwyler et  al. recently conducted an important study in sleep-deprived rhesus monkeys comparing intravenous to intranasal administration of hypocretin 1 [15]. They found that intranasal administration of hypocretin 1 has a more profound effect on cognitive effects of sleep loss compared to the hypocretin 1 administered intravenously. In their study, intravenous hypocretin 1 had efficacy on sleepiness at high doses, but with the limitations of the high cost of administering such high doses. It will be exciting to see if this outcome can be replicated in a narcolepsy model. It is important to note that studies have shown the presence of diurnal fluctuations in hypocretin secretion, suggesting integration with circadian pacemaker. Therefore, any therapy may require timed administration [16]. Alternatively, the poor permeability of hypocretin 1 through the blood brain barrier could be overcome with the development of hypocretin peptide analogs. Ideally, these peptide analogs would have characteristics of greater stability in the blood and greater CNS penetration. An effective peptide analog should serve as a hypocretin agonist by selectively targeting hcrtr1 or hcrtr2 [6]. Asahi et  al. experimented with amino acid substitution in hypocretin 2 as a means of successfully increasing the selectivity for hcrtr2 [17]. In this process, they made an important discovery: They found that the entire hypocretin protein is not necessary for biological activity and selectivity for the receptors [18]. Instead it is the C-terminal of hypocretin 1 and hypocretin 2 that are important for these properties. Lang et  al. took this one step further and determined the minimal sequences needed for receptor activation by synthesizing different combinations of C-terminally and N-terminally truncated peptides in addition to fragments of central sequences of hypocretin 1 and hypocretin 2 [19]. In their study, only full sequences of hypocretin 1 were able to activate receptors while with hypocretin 2, fragments containing the C-terminus remained active as long as greater than 19 amino acids were active. They also reported several analogs that selectively activate hcrtr1. These analogs are exciting possibilities in the development of hypocretin agonists for the treatment of narcolepsy. Asahi et al. and Lang et al.’s findings constitute a foundation for the finely tuning peptide analogs to selectively activate hcrtr1 or hcrtr2. One of the barriers in developing these drugs is finding a peptide analog with the right

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combination of selective activation while minimizing peripheral side effects, and using it in the right patient. It is unknown whether hypocretin agonists would only be effective when used in patients with absent or low hypocretin 1 levels, that is, narcolepsy–cataplexy or if it would also be effective in treating narcolepsy patients without cataplexy. Exploration should also be done to determine whether sensitivity to these peptides or peptide analogs persists for a long time or if there is a limited time window to begin treatment due to possible disappearance and remodeling of a receptor if it is not stimulated for a long time.

Hypocretin Gene Therapy Another possible approach to hypocretin replacement is through gene therapy. Gene therapy aimed at stimulating the production of hypocretin could theoretically address the deficiency of hypocretin in narcolepsy– cataplexy. Mieda et  al. conducted a study examining the possibility of genetic rescue in mice with ablated hypocretin neurons [20]. They produced mice with over expression of a preprohypocretin transgene with a beta-actin/cytomegalovirus hybrid promoter and found that ectopic transgenic expression of hypocretin prevents cataplexy even in the setting of hypocretin neuron ablation. This study suggests that deficiency or absence of hypocretin 1 does not confer a permanent loss of function. Their study highlights hypocretin gene therapy with viral vectors as a potential future treatment for narcolepsy–cataplexy. Additional evidence examining the molecular genetics of narcolepsy has suggested a potential relationship between monoaminergic genes, immune-related genes, which could also serve as a target for gene therapy [21]. These combinations of genes could lend the clinician with useful predictive value in predetermining patients who would be responsive or unresponsive to specific or combinations of treatments.

Hypocretin Cell Transplants Hypocretin gene therapy extrapolated in another ­direction raises the possibility of hypocretin cell transplantation in the treatment of narcolepsy. If the ligands

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themselves cannot be supplemented, then the cells producing the ligands may be successful. There are an estimated 70,000 hypocretin neurons in normals. In narcolepsy–cataplexy, a estimated loss of 85–95% of hypocretin neurons is thought to produce symptoms, corresponding to CSF hypocretin 1 level of less than 30% of normal. Therefore, it is postulated that a minimum of 10% of the hypocretin producing cells would need to be replaced to obtain therapeutic effects [6, 22]. Transplantation techniques, such as those used in Parkinson’s disease for dopaminergic neurons, could be applied, although graft survival and immune reactions are current limiting factors [7]. To examine the survivability of grafted hypocretin neurons, AriasCarrion et  al. examined the survival of hypocretincontaining rats neurons to the pontine reticular formation [23]. Initial trials of transplantation were unsuccessful, but with enriched transplant medium, survival was extended to 36 days. Transplant of hypocretin grafts is limited by available supplies of hypocretin neurons and graft reactions. The current barrier in graft ­survivability confers the additional limit of cost effectiveness because the transplants need to be done on a continuous basis at various intervals.

Stem Cell Transplantation The barrier of graft survivability, graft reactions, and cost barriers could be reduced if genetically engineered cells or employing stem cell techniques were used instead. Further investigation is required to determine the possibility of these therapies but they remain a theoretical possibility.

Hypocretin-Receptor Agonists Our current concept of narcolepsy as destruction to the hypocretin neurons may evolve with increasing research such that known genetic mutations that could be screened for, identified, and targeted. If that is true, then hypocretin-receptor agonists may be a fruitful future target for pharmacotherapy. Also, evidence revealing that the entire hypocretin sequence is not required for agonist activity raises the possibility of abbreviated hypocretin peptide analogs that may be useful for drug

treatment if they could be targeted to hcrtr1 and hcrtr2, thus serving as hypocretin-receptor agonists [17]. Animal models of narcolepsy differ from the human model in that rather than destruction of hypocretin producing neurons, some are hypocretin receptor 2 deficient (hctr2). To investigate the polymorphisms of the hypocretin receptors in humans, Peyron et al. screened over 500 patients HLA-DQ1B*0602 negative patients and found 14 genetic polymorphisms in the hcrtr gene in a total of 192 patients (74 Caucasian and 118 ethnically matched controls) [24]. Even though the majority of patients in their study did not show a connection between these genetic polymorphisms and narcolepsy, they did report one patient with a point mutation in the hcrtr associated with narcolepsy–cataplexy at 6 months of age. Various genotypes and phenotypes of narcolepsy may exist, similar to what is observed in animal models. That is, hcrtr2 deficiency is responsible for the canine model of narcolepsy and hcrtr knockout mice [4, 25]. These findings allude to the possibility of narcolepsy as a heterogeneous disease, with variations in symptoms depending on the basic defect, and in turn, a need to tailor treatment based on these factors insofar as they impact disease severity, characteristics, and responsiveness to different treatments. Another study comparing HLA predispositions demonstrated the heterogeneity of narcolepsy in two different ethnic populations [26].

Immunotherapy An autoimmune process has been speculated as being one of the possible pathophysiological mechanisms for destruction of the hypocretin neurons in narcolepsy. The reasons for this hypothesis have to do with the association of narcolepsy–cataplexy with human leukocyte antigen HLA-DQB1*0602 in addition to the fact that it is sporadic and has been observed to have low concordance in homozygotic twins [18, 24]. The hypothesis of an autoimmune etiology has caused some investigators to explore immunotherapy as a treatment for narcolepsy such as corticosteroids, plasmapheresis, and intravenous immunoglobulin (IVIG) because of its application in the treatment of other autoimmune disorders. The results are mixed suggesting immunotherapy may not be effective at all or only effective in certain clinical scenarios or with very ­specific treatment regimens.

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A study in narcoleptic canines treated from birth with a combination of methylprednisolone, methotrexate, and azathioprine showed an initial delay in onset of symptoms with a 90% reduction in cataplexy [27]. Interestingly, they also found that canines treated later in life have a lesser response to therapy, suggesting immunotherapy must be instituted early in the disease course. In humans, there is a case report of an 8-yearold boy presented with a 2 month history of daytime sleepiness, undetectable levels of hypocretin, and was HLADQ1B*0602 positive treated with prednisone [28]. Treatment with prednisone did not have any noticeable benefit on the symptoms. Chen et  al. reported a 60-year-old woman with a 2 month history of cataplexy treated with plasmapheresis [29]. She experienced a temporary benefit from plasmapheresis but further treatments became limited by a severe catheter infection. This patient was then treated with azathioprine, but developed hepatitis and it had to be discontinued. She was then treated with IVIG which was also ineffective. Lecendreux et  al. reported a 10-year-old boy with cataplexy and excessive daytime sleepiness diagnosed with narcolepsy. He was treated with IVIG 1 g/kg for 2 days followed by 1.3 mg/kg of prednisolone for 3 weeks within 2 months of symptomatic onset [30]. Three days after treatment was instituted, an improvement was noted. He had no daytime sleepiness or cataplexy after 3 weeks. After 3 weeks, prednisolone was weaned to half the dose and symptoms remained improved. However, side effects such as weight gain and acne led to the eventual discontinuation of treatment. Dauvilliers et  al. reported four cases of hypocretin deficient narcolepsy, (three of four were treated within months of symptom onset) with IVIG 1 g/kg for 2 days and repeated at three times at 4 week intervals [31]. They found a lasting reduction in cataplexy, hypnagogic hallucinations, and sleep paralysis up to 7 months after treatment. After IVIG therapy, there was no change in the finding of low or undetectable levels of hypocretin. Zuberi et al. reported two cases of narcolepsy–cataplexy, one patient with a few months of symptoms and one with years of symptoms [32]. The patient with the more recent onset of symptoms experienced an improvement after treatment with IVIG. The patient with recent onset was an 8-year-old boy treated with IVIG 2 g/kg. Improvement in symptoms was observed beginning at 1 week post treatment and maximal at 4 weeks. He had a relapse of symptoms at 7 weeks post treatment and was retreated

with 1  g/kg of IVIG again with improvement in symptoms. In the second case, a 16-year-old girl with a 9 year history of cataplexy, there was no improvement noted after treatment with 1 g/kg of IVIG. The postulated mechanism of action for high doses of IVIG in narcolepsy involves down regulation of pathological T-cell functions and cytokine production which may lead to a reduction or reversal in the destruction of hypocretin producing neurons. The case studies reported with limited success and reduction of symptoms suggest that if a therapeutic benefit is obtained, it may be limited by the timing of treatment being at the onset of disease. Some postulate the reason for this is because the hypocretin deficiency that occurs in narcolepsy–cataplexy is due to an irreversible destruction of neurons, in which case it would be imperative that immunotherapy would only have effectiveness at the onset of disease. Others postulate that the destruction is reversible and the hypocretin producing cells are only inactivated, or that immunotherapy works through abatement of symptoms. In these cases, immunotherapy may have applications throughout the course of the disease. One of the important failures of the current report is that no long-term follow-up is available and when short-term follow-up is reported, there is no clear persistence of initial improvement and the important side effects of treatment lead to discontinuation. From analyses of these studies, one may conclude that immunosuppressants are not always effective, and effective therapy may be directly related to the timing of treatment, with only specific immunomodulating agents, or specifically outlined and studied dosing regimens being effective treatments, similar to what has been found in the treatment of another disease with autoimmune characteristics in its pathogenesis, multiple sclerosis. For example, in multiple sclerosis, prednisone given orally is not effective in treating exacerbatings while methylprednisolone intravenously is.

Thyrotrophin Releasing Hormone Agonists Thyrotrophin releasing hormone (TRH) is a tripeptidic hormone (l-pyroglutamyl-l-histidyl-l-prolineamide) distributed throughout the central nervous system. TRH functions to stimulate the release of thyroid

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s­ timulating hormone and prolactin. TRH receptor-1 is found predominantly in the hypothalamus while TRH receptor-2 is more widespread and located in the reticular nucleus of the thalamus [33]. Evidence has also demonstrated TRH may have stimulant, antidepressant, and neurotrophic effects thus making it a possible treatment modality for narcolepsy [34]. Nishino et al. tested three TRH analogs for effectiveness in treating excessive sleepiness and narcolepsy in the setting of canine narcolepsy [35]. All three compounds had a significant impact on the frequency of cataplexy, whereas only two of the three had benefit in excessive sleepiness. Free T3 and T4 levels were not altered and no significant side effects were noted. The most potent of these compounds, CG-3703 was investigated further in canine narcolepsy [34]. CG-3703 orally was active and at 2 weeks reduced cataplexy and sleepiness in a dose dependent manner. Most cataplexy was suppressed with maximum of 16 mg of drug lasting approximately 3–6 h at a time. The anticataplectic potency was described as being equal to doses of despiramine and clomipramine while the effective dose in producing wakefulness was similar to a reasonable dose of D-amphetamine. Similar to other currently used drugs there was a trend toward requiring increasing doses of CG-3703 with prolonged exposure needed to elicit the same therapeutic benefit. Riehl et  al. postulated that the anticataplectic effects of CG-3703 may be due to enhancement of norephinephrine (NE) release and postsynaptic alpha-1 stimulation while the alerting effect is due to enhancement of dopaminergic effects. In any case, their findings suggest that with fine tuning and further research, a potential application of TRH agonists exists in the treatment of humans with narcolepsy. In addition to TRH agonists, another potential approach to using TRH agonists is the inhibition of the breakdown of TRH, by blocking the TRH-degrading enzyme, described by Schomburg et al. [36].

Histamine 3 Receptor (H3) Antagonists Numerous studies have demonstrated the importance of histamine in sleep regulation. Histaminergic neurons project from the tuberomamillary nucleus in the hypothalamus diffusely to the cortex, playing a key role in facilitating wakefulness. The sedative effects of

M. Broderick and C. Guilleminault

H1-receptor blockers are one example of the properties of histaminergic neurons. Studies have also demonstrated decreased histamine levels in the CSF of patients with narcolepsy [2]. This background knowledge facilitated interest into the theoretical possibilities of treatments involving histamine transmission for future therapies in narcolepsy–cataplexy. There are four types of histamine receptors, all of which are G protein-coupled receptors. The H3 receptor is an autoreceptor with the highest density in the striatum, substantia nigra, and the cortex. The H3 receptor helps regulate neurotransmitters such as glutamate, histamine, norepinephrine, and acetylcholine, and H3 receptor antagonists increase the release of these neurotransmitters. Histaminergic activation leads to wakefulness whereas decreased activity leads to sleepiness and therefore H3 receptor antagonists activate histaminergic neurons, increasing histamine, and producing wakefulness [37]. Application of the existence of H3 antagonists or H3 inverse agonists may be useful in the treatment of narcolepsy. Barbier et al. tested JNJ-5207852, a diamine-based H3 antagonist in rodents with demonstrated potency and selectivity for H3 receptors which was also shown to have clear wake promoting properties [38]. It was also shown to increase wakefulness without rebound hypersomnolence or increasing locomotor activity, similar to the actions of modafinil. Similar findings have been demonstrated in other H3 receptor antagonists such as thioperamide, carboperamide, and ciproxifan in rats, mice, canines, and cats [37, 39–43]. Parmentier et al. conducted a study with two H3 receptor antagonists, thioperamide and ciproxifan, and both demonstrated an increase in wakefulness and cortical EEG fast activity without an increase in sleep rebound [42]. In cats, thioperamide has been studied which revealed a dose dependent enhancement in wakefulness [37]. H3 receptors antagonists are thought to exert their effect by increasing histamine release and thereby increasing H1 activation. The first clinical trial conducted with an H3 inverse agonist was conducted with tiprolisant or BF2.649 [37]. In rats, tiprolisant has been found to increase levels of dopaminergic, histaminergic, and acetylcholine in the prefrontal cortices. [44] This phase II study showed tiprolisant has an improvement on ES compared to placebo. The dose studied was 40 mg orally and the most frequent side effects were headache, nausea, insomnia, and a fainting

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sensation. This study did not examine the effect of tiprolisant on other ­symptoms of narcolepsy such as cataplexy.

Modified Current Medical Therapies Currently, modafinil is a first-line non-amphetamine alerting agent used in the treatment of narcolepsy. It is extremely effective in treating ES, but has a short halflife and in some cases must be taken twice daily. A newer drug armodafinil, which is derived from moda­ finil, is an improved version. The difference in the two drugs is that while modafinil contains 10% of the R-enantiomers and the 90% of the S-enantiomers, while armodafinil is the R-enantiomer of the racemic mixture. The chemical names of armodafinil are 2-[(R)­(diphenylmethyl)sulfinyl] acetamide and 2-(R-benzylhy­ drysulfinyl) acetamide [45]. Cephalon obtained FDA approved for armodafinil in 2007 for the treatment of narcolepsy, obstructive sleep apnea [46], shift work sleep disorder (SWD). The R-enantiomer of modafinil has a half-life of 10–14 h versus a half-life of 3–4 h for the S-enantiomer. The elimination half-life of the S-enantiomer is three times faster than the R-enantiomer and therefore armodafinil is a longer acting medi­ cation than modafinil [47]. Armodafinil has two metabolites, acid and sulfone, neither of which appears to have wake promoting activity. Typical oral doses of armodafinil range from 50 to 400 mg. After 7 days of dosing, steady state concentrations are 1.8 times what is measured after a single dose [47]. In addition, peak plasma concentrations are reached approximately 2 h after administration if taken in a fasting state. Even though the bioavailability is not affected by food intake, the absorption can be delayed by up to 2–4 h if taken with food. A comparison of the characteristics between modafinil and armodafinil can been seen in Table 27.3. Dinges et al. compared the effects of a single dose of armodafinil (100 mg, 150 mg, 200 mg, or 300 mg) to modafinil (200 mg) and placebo in 107 men using the Maintenance of Wakefulness Test (MWT) as the primary outcome measure [45]. Armodafinil was associated with longer MWT latencies and higher plasma concentrations 6–14 h after administration. It was generally well tolerated and the most commonly reported side effects were abdominal pain, headache, and

Table 27.3  Comparison of modafinil to armodafinil Chemical composition Elimination half-life Therapeutic dose Time to peak in serum Side effects

Modafinil

Armodafinil

Racemic mixture

E-enantiomer

S-enantiomer 10–14 hRenantiomer 3–4 h 200 mg 2–4 h

R-enantiomer 3–4 h

Headache, nausea, dry mouth

Abdominal pain, headache, nausea

150 mg 2–4 h

n­ ausea. In a multicenter double-blind study of 196, ­subjects were randomized to receive oral armodafinil 150 mg, armodafinil 200 mg, or placebo once per day for 12 weeks [48]. The primary outcome measure was the MWT. In this study, both doses of armodafinil increased the MWT mean sleep latency compared to placebo. Both doses also showed an improvement in memory, attention, and fatigue. Adverse events reported in this study were headache, dizziness, and nausea. Armodafinil is a moderate inducer of CYP3A4 and a moderate inhibitor of CYP2C19 and therefore dosing adjustments are needed in the setting of coadministration of triazolam, diazepam, or phenytoin [49]. The mechanism of actions of modafinil and armodafinil has some controversy but it most likely targets dopamine reuptake [2]. Although armodafinil is generally well tolerated, there are side effects. Headache (17%) is the most commonly reported side effect, followed by nausea (7%), dizziness (5%), and insomnia (5%) [47]. There have not been reports of Steven’s Johnson syndrome or multiorgan hypersensitivity reactions but since two cases have been reported in the setting of modafinil and there is a close connection between the two drugs, prescribing physicians should supervise for development of a rash. As in the case of modafinil, steroid contraceptives may have reduced effectiveness for up to 1 month after discontinuation.

Combination Therapies Antidepressants are well known to improve cataplexy through their properties of adrenergic, serotoninergic, and dopaminergic reuptake inhibition. However, not

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all antidepressants have a therapeutic effect on cataplexy and may only be useful in the treatment of ES. These variable effects depend on the selective receptor reuptake or combination of selective reuptake receptors for each antidepressant. Novel therapies are being developed to block two or even three neurotransmitters to capitalize on this feature of antidepressants. DOV 216,303 is an antidepressant that blocks norepinephrine, serotonin, and dopamine. Beer et al. tested DOV 216,303 in seven subjects demonstrating safety and tolerability in doses up to 100 mg per day for 10 days [50]. The observation that venlafaxine, a serotonin, and norephinephrine reuptake inhibitor (SNRI) improves cataplexy has led some investigators to develop and test other drugs with SNRI activity. Duloxetine, a novel SNRI, was examined in a pilot study by Izzi et al. [51]. In this study, three patients with narcolepsy–cataplexy were identified. One patient was successfully treated with a dose of duloxetine 60 mg by mouth each morning in conjunction with modafinil 200 mg by mouth twice daily. The two remaining patients were successfully treated with duloxetine monotherapy. Polysomnography and multiple sleep latency tests were conducted and showed REM sleep suppression, increase in REM latencies, and improvement in ES. These findings have also been shown in other studies examining the effects of duloxetine in the setting of depression. The studies of duloxetine in the treatment of depression also showed an increase in stage 3 sleep [52]. No tolerance or adverse events were observed in a 1-year follow-up period [51]. Another SNRI, reboxetine 10  mg by mouth was given to 12 patients in a pilot study [46]. After 2 weeks, a measurable improvement in ES as determined by the Epworth Sleepiness Scale (ESS) and MSLT was observed. There was also a measurable decrease in the frequency of cataplexy. The same rationale was employed in a case reported by Niederhofer et al. when they administered atomoxetine, another SNRI to a patient with newly diagnosed narcolepsy [53]. Atomoxetine 40 mg by mouth three times daily was given for 4 weeks. Improvement in ES and cataplexy was observed starting on day 6. This type of approach improves upon the current limitation of requiring separate agents to treat ES and cataplexy. Development of dual or triple monoamine uptake inhibitors may allow treatment of ES and cataplexy with one agent therefore improving compliance, side effects, and costs in the treatment of narcolepsy.

Others Although disturbed nocturnal sleep is not typically included in the tetrad of symptoms describing symptoms of narcolepsy, it is nonetheless an important and disabling aspect of the condition. Studies in orexin knockout mice have demonstrated that even though amounts of total sleep times are comparable to wildtype mice, the sleep is more fragmented. Sleep fragmentation is postulated as one possible cause of ES in narcolepsy such that treatment with hypnotics if they can consolidate sleep may improve ES [54]. Currently, sodium oxybate (GHB) is used successfully in the treatment of narcolepsy–cataplexy. Part of its effectiveness may be due to its ability to consolidate sleep and increase slow wave sleep. Its mode of action is thought to be related to effects on GABA-B and possibly GHB receptors [55]. GHB has also been shown to increase slow wave sleep, delta power, daytime sleep latency and to decrease nocturnal awakenings [56]. This overall improvement in sleep architecture translates into improvement in daytime functioning. However, GHB has a short half-life requiring dosing in the middle of the night, which is inconvenient to patients and may decrease compliance with using it. GHB has also been implicated as being used for nonmedical purposes necessitating strict prescribing, regulation, and distribution of the drug. The limitations of GHB call for the development of novel GABAergic agents with similar effects, but distinct modes of actions. Other GABAergic hypnotics that also increased slow wave sleep currently being studied include gaboxadol [57] and tiagabine [58]. A double-blind, placebocontrolled, multicenter study was conducted in Europe to evaluate the efficacy of ritanserin, a 5HT2-antagonist in improving sleep in narcoleptics [59]. One hundred thirty-four patients with narcolepsy were randomized to receive ritanserin 5 mg, ritanserin 10 mg, or placebo for 28 days. Both doses of ritanserin resulted in an increase in the quantities of slow wave sleep with a reduction in NREM stage 1 sleep. Landolt et al. studied SR 46349B, another 5-HT2 antagonist administered 3 h prior to bedtime. At a dose of 1 mg by mouth SR 46349B increased the amount of slow wave sleep while reducing the amount of stage 2 sleep [60]. These studies suggest that there is potential for use of hypnotics as supplemental therapy in narcolepsy patients with poor quality of sleep that have not responded to GHB. Two other compounds in development with hypocretin

27 Emerging Treatments for Narcolepsy

antagonist activity may also play a role in improving consolidation of sleep in patient with narcolepsy, SB649868 by Glaxo Smith Kline and ACT-078573 by Actelion. Other important issues to keep in mind in the development of future treatments for narcolepsy are the following. Responses to pharmacological agents can be variable based on individual differences. Factors such as sex, age, BMI, ethnic background, and more specific genetic factors play a role in drug metabolism. Dauvilliers et  al. conducted a study to determine if the gene for catechol-O-methyltransferase (COMT), the enzyme responsible for the catabolism of dopamine, is associated with response to modafinil [61]. The results of the study suggested the optimal dose of modafinil is 100  mg lower in women compared to men. Moreover, any narcoleptic with low COMT activity requires a lower dose for optimal activity. In the future genetic polymorphisms such as in COMT activity will serve as important factors in the management of narcolepsy. Other potential targets for reducing ES in narcolepsy may involve targeting novel neuropeptides and proteins such as circadian clock proteins, ion channels, prokineticin [62], or neuropeptide S [63]. Currently, non-pharmacological treatments are used in the treatment of narcolepsy. Education and support groups play a role in assisting patients maintain good sleep hygiene, encourage scheduled naps, and provide social support to patients with narcolepsy. With the growth of behavioral sleep medicine, a structured program designed to address the unique challenges for patients with narcolepsy could play a role in therapy for narcolepsy, especially since some of the emerging pharmacological agents could depend heavily on circadian factors for optimal efficacy. This could include behavioral techniques aimed at regulating the sleep– wake cycle, reinforcing sleep hygiene, light therapy, and scheduled naps.

Conclusions There is a clear paucity in randomized, double-blind, placebo-controlled trials evaluating the treatments in development for narcolepsy. However, advances in basic science, neurobiology, and neurogenetics are leading to an increase in knowledge that will guide

309

and facilitated both a better understanding of narcolepsy and more effective treatment modalities.

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27 Emerging Treatments for Narcolepsy cytochrome P450 enzymes 1A2, 3A4 and 2C19 in healthy subjects. Clin Pharmacokinet 2008;47:61–74. 50. Beer B, Stark J, Krieter P, et  al. DOV 216,303, a “triple” reuptake inhibitor: safety, tolerability, and pharmacokinetic profile. J Clin Pharmacol 2004;44:1360–7. 51. Izzi F, Placidi F, Marciani MG, et al. Effective treatment of narcolepsy-cataplexy with duloxetine: a report of three cases. Sleep Med 2009;10:153–4. 52. Kluge M, Schussler P, Steiger A. Duloxetine increases stage 3 sleep and suppresses rapid eye movement (REM) sleep in patients with major depression. Eur Neuropsychopharmacol 2007;17:527–31. 53. Niederhofer H. Atomoxetine also effective in patients suffering from narcolepsy? Sleep 2005;28:1189. 54. Mochizuki T, Crocker A, McCormack S, Yanagisawa M, Sakurai T, Scammell TE. Behavioral state instability in orexin knock-out mice. J Neurosci 2004;24:6291–300. 55. Arnulf I, Mignot E. Sodium oxybate for excessive daytime sleepiness in narcolepsy-cataplexy. Sleep 2004;27:1242–3. 56. Mamelak M, Black J, Montplaisir J, Ristanovic R. A pilot study on the effects of sodium oxybate on sleep architecture and daytime alertness in narcolepsy. Sleep 2004;27:1327–34.

311 57. Krogsgaard-Larsen P, Frolund B, Liljefors T, Ebert B. GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic. Biochem Pharmacol 2004;68:1573–80. 58. Mathias S, Wetter TC, Steiger A, Lancel M. The GABA uptake inhibitor tiagabine promotes slow wave sleep in normal elderly subjects. Neurobiol Aging 2001;22:247–53. 59. Mayer G. Ritanserin improves sleep quality in narcolepsy. Pharmacopsychiatry 2003;36:150–5. 60. Landolt HP, Meier V, Burgess HJ, et al. Serotonin-2 receptors and human sleep: effect of a selective antagonist on EEG power spectra. Neuropsychopharmacology 1999;21:455–66. 61. Dauvilliers Y, Neidhart E, Billiard M, Tafti M. Sexual dimorphism of the catechol-O-methyltransferase gene in narcolepsy is associated with response to modafinil. Pharmacogenomics J 2002;2:65–8. 62. Cheng MY, Bullock CM, Li C, et al. Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 2002;417:405–10. 63. Xu YL, Reinscheid RK, Huitron-Resendiz S, et  al. Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron 2004;43:487–97.

Chapter 28

Non-pharmacologic Treatments of Narcolepsy Renee Monderer, Shelby Freedman Harris, and Michael J. Thorpy

Introduction Narcolepsy is a disorder that affects 1 in 2,000 people and can have a significant impact on patients’ overall daily functioning [1]. Although pharmacological methods are considered the primary treatment for managing the symptoms of narcolepsy, behavioral methods play a large role in adjunctive treatment. Patients often have residual sleepiness that is not fully managed by pharmacological methods alone and may benefit from behavioral interventions. Excessive daytime sleepiness and cataplexy often interfere with time spent socializing with others as well as the patient’s ability to effectively complete tasks at work and at home. These difficulties may be disabling for some and can often lead to problems with employers, coworkers, family members and romantic partners. Behavioral interventions are designed to target the numerous psychosocial problems commonly experienced by patients with narcolepsy. Although these strategies are commonly employed in this population, a paucity of controlled studies exists to examine their efficacy. A limited number of behavioral intervention reviews and patient accounts have been published summarizing behavioral treatment options [2–6]. Despite a lack of published research for these methods, it is important to note that approximately 15% of patients in the United Kingdom have been found to solely and consistently use medications to manage their narcolepsy, with many patients relying upon behavioral methods as either an adjunctive or primary treatment option [7]. R. Monderer (*) Sleep-Wake Disorders Center, Montefiore Medical Center, 111 East 210th Street, Bronx, NY, 10467, USA e-mail: [email protected]

Since patients commonly report using and benefiting from these methods, behavioral interventions should be considered when generating an overall treatment plan for patients with narcolepsy. Patients with narcolepsy may report feeling helpless and lack a sense of control over their symptoms. These strategies may provide structure, guidance, and can improve the quality of life for patients with narcolepsy. This approach can also generate a sense of understanding of the illness for the friends, family and coworkers of the patient. This chapter will review behavioral approaches to the treatment of narcolepsy, including a brief review of the literature and specific methods that can be applied. In addition, detailed information will be provided regarding the importance of psychosocial support, education, counseling and recognition of and treatment options for psychiatric and cognitive co-morbidities.

Excessive Daytime Somnolence and Involuntary Sleep Episodes Excessive daytime sleepiness is often the first symptom of narcolepsy. It can have a significant impact on a patient’s quality of life limiting his or her ability to work, drive and participate in social activities. People with narcolepsy often report feeling fatigued and lacking energy to participate in daily activities. Additionally, patients with narcolepsy report brief episodes of involuntary sleep that occur many times throughout the day. These episodes may occur three to five times per day and typically last for 15–30  min [8]. Although patients tend to fall asleep during times of inactivity or boredom they also may do so during inappropriate or dangerous times such as during a business meeting, during conversation, in the middle of eating or while driving.

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After sleep episodes, these patients often feel refreshed until the next episode occurs. Many patients with narcolepsy use behavioral techniques to improve daytime alertness. Avoidance of sleep inducing situations such as sedentary activities, boredom, and excessive warmth, is advisable. For the same reasons, standing rather than sitting, being outdoors, and seeking cooler environments can be effective ways of promoting wakefulness. More specific behavioral techniques that patients have found to be helpful include driving a car with a manual transmission, chewing on ice, and increasing background noise levels. Other techniques often used include using an alarm clock while driving, inducing pain while driving, avoiding social situations, and smoking cigarettes. Such techniques can prove detrimental to patients and should be advised against.

Scheduled Naps and EDS Multiple studies have examined the role of napping in improving daytime alertness in narcolepsy. Many studies show that naps have a positive effect on alertness. Guilleminault et  al. studied narcolepsy patients off stimulant medication and found that two 15 min naps at 12:30 and 17:00 improved sleep latency on the Maintenance of Wakefulness Test (MWT) [9]. Rogers and Aldrich looked at the usefulness of regularly scheduled naps by comparing MWT data before and after narcolepsy patients followed a month long schedule of three daytime naps, each 15 min in duration at the patient’s own desired time. Mean sleep latency was increased significantly at post treatment assessments. However, there was no significant difference in the number of MWT periods without sleep. Additionally, the number of sleep attacks reported by sleep log did not decrease significantly after the 4 weeks of napping treatment [10]. Studies have analyzed the effects of nap duration on daytime sleepiness. Mullington and Broughton looked at the efficacy of different lengths of naps on daytime sleepiness in patients on stimulant medication [11]. Patients were assigned to either one single long nap, multiple short naps or no nap, with total sleep per 24 h. held constant. Total amount of sleep time was based on the average sleep time per day from at least 5 days of sleep logs. In the long nap group, where naps lasted an

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average of 129  min, nighttime sleep was reduced by 25% and that time was made into their daytime nap positioned 180° after the midpoint of nighttime sleep. In the short nap group, where naps lasted an average of 26 min, there was an identical reduction of total sleep time with five scheduled naps distributed equidistantly across the day, with 5% of the total sleep time assigned to each nap. Daytime sleepiness and performance was assessed using multiple tests including a fixed sequence of the descending subtraction test, a grammatical transformation test, and four choice reaction time tests. Results of this study showed that the single long nap improved sustained performance compared to the no nap condition. The greatest benefit for the long nap group was in the afternoon and evening time. There was no significant improvement in performance in the multiple short naps compared to the no nap group, except that the number of incorrect reaction time responses was significantly lower in the short nap group than in the no nap group. A second study of nap duration by Helmus and colleagues compared a single 120-min nap to a single 15-min nap both of which were scheduled to end at 12:00 noon. Patients then underwent a modified MSLT, which consisted of five naps in a 2-h period, at 12:15, 12:40, 13:05, 13:30 and 13:55 hours. The naps were terminated after 20 min of wakefulness or after the first epoch of any stage of sleep. The results found that the 120-min nap was more beneficial in a modified MSLT [12]. The 120-min nap more than doubled the mean sleep latency when compared to the 15  min nap in patients with narcolepsy (2.0 vs. 5.3; p < 0.01). However, this alerting effect was transient when tested 3 h later. Based on the above data, a single long nap taken around noontime may be the most efficacious strategy for patients with narcolepsy. Studies have shown that patients with narcolepsy tend to have a peak in daytime sleepiness at least 1 h earlier than the period of maximum afternoon sleep tendency seen in normal patients [9, 13]. This may suggest that a single long nap earlier in the day may be the most beneficial in improving daytime sleepiness. More recently, Rogers and colleagues compared three different sleep schedules for reducing daytime sleepiness in narcolepsy patients on stimulant medications [14]. Daytime sleep was objectively measured using ambulatory polysomnographic recordings. Twenty-nine subjects were randomly assigned to one

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of three treatment groups: an absolutely regular schedule for arising and retiring to nighttime sleep (chosen by the patient) with no naps, patient’s own habitual nighttime sleep patterns with two additional 15  min naps per day, and a combination of regular hours of nighttime sleep with two 15  min naps per day. Symptom severity was measured by the Narcolepsy Symptom Status Questionnaire (NSSQ) both at baseline and at the end of the 2-week treatment period. The best response was found in the group where both nighttime sleep was regularized and two 15-min naps were added. These patients reported less daytime sleepiness and had less daytime sleep. Regular schedules for nocturnal sleep reduced subjective symptom severity, but did not change the objective levels of daytime sleepiness. Subjects who added two 15-min naps to their usual nighttime schedule did not improve with their symptom severity or duration of unscheduled daytime sleep time. Interestingly, subjects with severe daytime sleepiness benefited the most from the addition of scheduled sleep periods (p = 0.028). Mean amounts of unscheduled daytime sleep decreased from 97.7 to 62.9  min. This finding is similar to that reported by Rogers and colleagues in an earlier study, which stated that subjects who had more severe sleepiness received greatest benefit from a 1-month program of three regularly scheduled naps [10]. Naps, while beneficial to the narcolepsy patient, can be difficult to incorporate into a patient’s daily routine given the constraints of work and other commitments. Nonetheless, studies suggest that one extended nap provides the maximum benefit for longer and more sustained wakefulness. Shorter naps taken at intervals throughout the day are also beneficial and may be a more feasible option for those who are not self-employed. It is therefore advisable that people with narcolepsy plan a sleep-wake schedule by tracking the times of maximal sleepiness and wakefulness. This regimen would allow patients to tailor a napping schedule to their own time constraints, thereby producing the best response.

Dietary Manipulation in Managing Excessive Daytime Sleepiness Although few studies exist that have investigated the relationship between diet and daytime sleepiness in

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narcolepsy, many patients alter their food intake to improve daytime alertness. Strategies such as avoiding lunch to be more alert in the afternoon, binge eating just before sleeping to decrease arousals, avoiding carbohydrates, increasing proteins and increasing caffeine intake are common among patients with narcolepsy [15, 16]. A study by Bruck and colleges looked at the effect on sleepiness of adding a 50 g glucose drink to lunch [17]. The two variables that were used to assess sleepiness included performance measures from the Wilkinson Auditory Vigilance Task (WAVT) and EEG sleep variables from a 45-min nap. They found that in narcolepsy patients, the glucose drink was associated with decreased wake duration, reduced sleep onset latency and more spontaneous and induced sleep stage changes during the WAVT. The nap portion of the study showed increased REM duration in the nap after glucose. This study implied that glucose increases sleepiness in patients with narcolepsy. Pollak and Green showed that patients with narcolepsy reported higher levels of alertness 90 min prior to eating [18]. The level of alertness peaked at the time of eating and then decreased quickly over the next 150 min after the meal. During the postprandial period, there was increased napping and decreased subjective alertness. Interestingly, there was no difference in the mean meal size, protein, carbohydrate and fat content between those episodes that were followed by a nap and those that were not followed by a nap. This led the authors to conclude that this decreased alertness was not secondary to the metabolic effects of the food. A more recent study by Hussain and colleges looked at the effect of diet therapy on daytime sleepiness in narcolepsy [19]. Sleepiness was measured at baseline and at weeks 2, 4 and 8 using the NSSQ, the Epworth Sleepiness Scale (ESS), and the Stanford Sleepiness Scale (SSS). They found that a low-carbohydrate, ketogenic diet significantly improved daytime sleepiness as measured by the NSSQ decreasing 18% from 161.9 to 133.5 at 8 weeks (p = 0.0019). In addition, there was a decrease in sleep attacks and sleep paralysis. The ESS and the SSS did not change significantly over the 8 weeks. It seems unclear from this study whether alertness improved from diet changes or from weight loss. Over 8 weeks the body weight decreased from 99.3 ± 20.7 to 92.2 ± 19.8  kg. The benefits of the diet were noted early in the study before the patients had substantial weight loss, implying that lessening

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the carbohydrate intake was a major factor in increasing alertness. Even though there is still conflicting data as to whether dietary alterations increase daytime alertness, patients with narcolepsy should be counseled on daily caloric intake. Honda and colleagues observed an increased frequency of Type II diabetes among Japanese patients with narcolepsy [20]. More recent studies have shown that patients with narcolepsy have a higher body mass index (BMI) than the general population [21, 22]. Dahmen et al. studied 129 Swiss and German narcolepsy patients and found that a third were obese compared to 5% in the general population. [22] This increase in BMI was uniform across those patients that were drug-naïve and those on pharmacological treatment. Children with narcolepsy have also been shown to have an increased BMI [23]. This higher prevalence of obesity was not as robustly seen in a study of 485 American patients with narcolepsy, but a significant BMI increase (+1  kg/m2) was still noted (p < 0.005) [24]. In this study, Asian and African American patients had more of a relative increase in BMI than Caucasians. Conflicting studies exist as to whether patients with narcolepsy eat more or less than controls. Early studies by Bell have shown that patients with narcolepsy consume more calories than controls [25]. A more recent study by Bruck also found that patients with narcolepsy had a higher carbohydrate and kilojoule consumption than controls. Narcoleptics had more snacking behavior and sweet consumption than controls [16]. Interestingly, this increased consumption occurred during meals rather than through snacks. Lammers, on the other hand, found that they had a lower kilojoule and carbohydrate intake (8.8 ± 2.3 kJ/ day) than controls (10.6 ± 3.1 kJ/day) [26]. An interesting study by Chabas and colleagues recently looked at 13 patients with narcolepsy (7 “typical” patients with HLA DQB1*0602 and cataplexy and 6 “atypical” patients who were HLA negative or without cataplexy) and 9 matched controls [27]. The patient’s energy balance was evaluated by obtaining BMI, rest energy expenditure using calorimetry, daily food and water intake, and eating behaviors. Patients with narcolepsy (typical and atypical) were found to have a higher BMI and a lower basal metabolic rate. Patients with typical narcolepsy ate less than controls, and those narcoleptics who were overweight ate half as much as patients with normal weights. Additionally,

patients with narcolepsy were more likely to have features of bulimia nervosa (46% of narcolepsy patients vs. 11% of controls) and other eating disorders. This study implies that lower metabolic rates, most likely due to hypocretin deficiency, and differences in eating habits could account for higher BMIs found in patients with narcolepsy. The authors suggested that making qualitative changes to eating habits (like eating less but more often) rather than quantitative changes (total calorie intake) may alter these patient’s weights. Caffeine found in coffee, sodas, teas and chocolate can have an alerting effect. Wright and colleagues found that caffeine consumption improved objective alertness in sleep deprived patients as measured on the MWT [28]. Caffeine has not been studied as a means of treating sleepiness in patients with narcolepsy. Most narcoleptics report that caffeine has minimal effect on daytime sleepiness and can fall asleep easily after ingestion [29]. Caffeine should be avoided in the evening as it may aggravate nocturnal sleep disturbances.

Exercise It is often difficult for narcolepsy patients with daytime sleepiness to motivate themselves to exercise. Patients, however, report feeling more alert when they are active. The alerting effects of physical activity in narcoleptics have not been studied. A recent study comparing orexin knockout (KO) mice and wild type (WT) mouse on spontaneous wheel running activity found that orexin KO mice ran significantly less than WT mice [30]. Orexin KO mice often had cataplexy or transitioned quickly into sleep after running. This difference was presumably due to sleepiness and resulting cataplexy. Notably, both orexin KO mice and WT mice had an increase in wakefulness after running. Further research needs to be done to study the effects of exercise on wakefulness.

Disrupted Nighttime Sleep Sleep maintenance insomnia is commonly seen in patients with narcolepsy. Patients usually begin to show symptoms of fragmented nighttime sleep within 5 years after the appearance of excessive daytime sleepiness [31].

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The appearance of insomnia is frequently linked with the appearance of sleep paralysis, cataplexy, and hypnagogic hallucinations. Behavioral strategies for improving nighttime sleep in patients with narcolepsy are similar to those recommended for patients suffering from insomnia. Basic sleep hygiene rules should be stressed to the patient with narcolepsy, including: (a) maintain a regular bedtime and waketime 7 days per week with 8  h in bed each night, (b) exercise regularly but not within 3 h of bedtime, (c) maintain a comfortable bedroom temperature during the nighttime, (d) avoid alcohol 2–3  h before bedtime, (e) avoid smoking, (f) avoid excessive nighttime liquid intake, (g) make sure the bedroom is very dark and quiet, (h) eat regular meals but no heavy meals within 2  h prior to bedtime, (i) limit caffeine intake after noon, and (j) avoid stressful activities before bedtime. Stimulus control instructions may also be provided to the patient [32]. These instructions include: (a) go to bed only when sleepy, (b) get out of bed if awake for 15–20 min at any point during the night (refrain from clock watching, just estimate), (c) sit somewhere outside of the bedroom until sleepy again, and return to bed only when sleepy, and (d) keep a fixed wake time every day regardless of how much sleep was obtained the night before. If the patient wakes up multiple times per night, the practitioner must stress that the process of leaving the bedroom and returning to bed may be repeated several times over the course of the night for the first week or two. Further, generating a specific list of relaxing activities that the patient can do in the middle of the night can be quite useful (e.g., read a magazine, wash dishes, and solve easy crossword puzzles or wordfinds). Although limited evidence is available to show significant improvement in sleep with these measures, teaching muscle relaxation strategies, diaphragmatic breathing, imagery, mindfulness and worry techniques may prove useful as additional measures to help with sleep maintenance insomnia.

Cataplexy Many patients use behavioral strategies to manage cataplexy. Techniques used include napping, obtaining sufficient nighttime sleep, and avoiding sweets because

sleepiness tends to increase cataplectic episodes. A particularly effective strategy has been managing stressful situations which are triggers for cataplectic events. Techniques such as planning, worry reduction, counseling, progressive muscle relaxation, and breathing exercises can help reduce and prevent stress and thereby decrease cataplexy. These skills can prove to be more productive than avoiding emotional situations altogether.

Sleep Paralysis There are very few behavioral techniques used to abort episodes of sleep paralysis. It is reported that touching or talking to a patient during an episode can terminate the paralysis. No studies have been done to confirm or refute this finding. Education about sleep paralysis is very useful to help the patient understand that the episodes will be limited in duration and will not progress to any serious condition. This in turn helps relieve the fear that accompanies these episodes of sleep paralysis and makes them more tolerable.

Hypnagogic Hallucinations and Nightmares Hypnagogic hallucinations and nightmares can be very distressing to patients. Currently, there are no studies investigating behavioral techniques for treating these symptoms in patients with narcolepsy. Brylowski reported one case in which cognitive intervention in the form of lucid dream training was helpful for a patient with nightmares [33]. There is anecdotal evidence that working through dream content may relieve some of the distress associated with nightmares. Further studies need to be done to assess the role of dream therapy in narcolepsy.

Cognitive Complaints Although nearly 50% of patients with narcolepsy report difficulties with memory, attention, vigilance and

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performance, studies using sensitive neuropsychological tests have failed to systematically find decrements in these areas in comparison to controls [34–36]. When such difficulties are apparent, especially with attention and vigilance, authors have suggested that these difficulties may be mainly due to sleepiness and variations in the circadian rhythm [37–39]. Naumann et al. suggests that difficulties found in executive functioning may be related to the narcolepsy patient’s need to allocate most resources to the domain of vigilance, thus providing fewer resources for overall executive capabilities [38]. Simple strategies such as keeping to-do lists, taking frequent breaks between and during tasks, and using alarms can be helpful. Since a great deal of the aforementioned difficulties appear to be related to sleepiness, behavioral strategies targeted at reducing excessive daytime sleepiness are likely to be the most helpful with cognitive complaints. Shortening times on executive functioning tasks and engaging in such behavioral strategies during the day when most alert can help improve cognitive functioning.

Psychiatric Co-morbidities and Management Despite pharmacological treatment of narcolepsy with either stimulant medication or an anti-cataplexy agent (or a combination of the two), many patients continue to report significant impairment in their quality of life, including difficulties with depression and low selfesteem [40]. Narcolepsy negatively impacts areas of the patient’s life that extend far beyond the sleep realm, affecting psychosocial areas such as self-esteem, work, education, sexuality, and interpersonal relations. Approximately 50% of all narcolepsy patients report deleterious effects of the illness on psychosocial functioning [4, 34, 41–45]. Studies investigating healthrelated quality of life using the SF-36 (a questionnaire that defines health in terms of what people can do, how they feel, and how they evaluate their health and future [46]) have often found decrements in mental wellbeing, social functioning, and role limitations due to emotional problems [7, 47, 48]. Depression has been found in patients with narcolepsy, with rates ranging from 17% to 70% [7, 49–54].

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Merritt and colleagues [51] report 49% of patients with narcolepsy were depressed, and that intact marriages and older age of onset are considered to be modest buffers against depressed mood. A number of studies have methodological limitations such as basing diagnosis on a survey or a review of case notes and such studies are not standardized with a patient’s interview based upon DSM-IV specific criteria for depression. Interestingly, studies that have used DSM-III or DSM-IV classifications of major depressive disorder found depression in 22% of patients with narcolepsy, rates that do not differ significantly from the control group [52, 54]. Kales et  al. [42] hypothesizes that the depression which is found in narcolepsy may be a reaction to the diagnosis itself. Broughton et al. [34] posit that a possible sleep-related pathophysiology between endogenous depression and narcolepsy may exist, as patients with either condition have repeatedly been found to have shortened sleep onset REM latency periods as opposed to controls. Patients with narcolepsy often report significant difficulty participating in leisure activities (e.g., going to the movies or theater, playing sports and taking holidays) as a result of the illness [50, 51]. Declines in participation in pleasant activities where a sense of accomplishment is obtained have been shown to contribute to depressive ideation [55]. Psychotherapy is routinely considered to be useful in helping patients adjust to various psychosocial limitations and psychiatric co-morbidities [56, 57]. Symptom-focused, present-centered treatments such as cognitive therapy or behavioral activation may be beneficial. Cognitive therapy is one of the most efficacious treatments for depression [58], and recent research has found behavioral activation (gradually increasing activities that are both rewarding and give the patient a sense of accomplishment) to be just as promising [55, 59]. Solution-oriented treatment for managing the social and emotional consequences of depression can help increase overall self-efficacy and provide validation and support for the patient [56]. Narcolepsy is often misdiagnosed as schizophrenia due to the hypnagogic hallucinations that many patients report in narcolepsy. A proper intake interview should be helpful in discerning between the two diagnoses. Although it is possible to have both narcolepsy and schizophrenia, the rates of schizophrenia within narcoleptic populations are the same as in the general public

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in the United Kingdom [60]. Key differences between the two disorders are evident in a few domains. In narcolepsy, hallucinations occur primarily when the patient is drowsy, whereas hallucinations in schizophrenia occur in a completely alert state. The hallucinations of narcoleptic patients are primarily visual, whereas in schizophrenia, hallucinations are sometimes visual but can also be auditory or olfactory. Finally, while thought disorder is often quite prominent in schizophrenia, it is absent in narcolepsy.

Interpersonal Difficulties and Limited Psychosocial Support Patients with narcolepsy often have severe limitations in interpersonal relationships and peer support [7, 61, 62]. Tiexeira et al. [40] indicated that 56% of narcoleptic patients in their sample reported relationship difficulties (increased arguments, difficulties with communication), with others finding that family discord was also quite common [42]. For many patients with narcolepsy, their family members do not understand or accept the disease, with many family members and friends attributing the illness instead to psychiatric problems or even laziness. This serves to create a family and social setting with limited validation of the patient’s experience, and therefore can further any low self-esteem and depressive ideation which may already be present [56]. Many patients with narcolepsy report that they have difficulty making friends and were often bullied as children [7]. Goswami [56] reports that 18% of her study population with narcolepsy was divorced. Kales et al. [42] indicates that roughly one-fifth of patients reported that narcolepsy caused separation or divorce. Although rarely discussed in the literature, a high number of patients with narcolepsy experience sexual problems – this includes impotence, sleepiness, low libido and cataplexy during intercourse [42]. Although the cause is not fully understood, it could be related to medications (especially antidepressant medications such as imipramine, desipramine and clomipramine), the narcolepsy itself, depression or a combination of the above [63]. Early education about narcolepsy and counseling (provided to both the individual and the family) is necessary to help prevent the cycle of misunderstanding

and miscommunication that often happens between patients, friends and families. Social support has been shown to buffer against depression and low self-esteem in numerous studies of patients undergoing chronic stress [64, 65]. As patients with narcolepsy are often accused of being lazy, proper orientation of the family to the patient’s illness and specific symptoms is warranted, with a particular focus on validation. Krishnan and colleagues [62] report that patients with supportive families had better adjustment to their illness. Social activities should be scheduled during times when the patient is most alert. In doing so, the patient may be less likely to avoid such activities and therefore less strain will be placed on interpersonal relationships and the individual’s overall self-esteem.

Work and Education Difficulties Numerous authors have found that approximately 50% of patients with narcolepsy report decrements in concentration and overall feelings of underachievement in classroom settings [34, 37, 39, 40]. However, it should be noted that many patients in these studies were not diagnosed with narcolepsy until after they were at least 21 years old, therefore delaying any proper treatments that may have been available to them if diagnosed earlier. Godbout et al. [37] reports that 90% of patients with narcolepsy (with or without cataplexy) in their sample reported difficulties at work. As many as 95% of patients report falling asleep at work, with nearly 50% having reduced earning capacity and 11% indicating forced disability leave. Additionally, up to 50% of narcolepsy patients report memory and concentration problems and 34% indicate being misunderstood by coworkers [34, 37, 40]. Daniels et al. [7] indicate 37% of patients with narcolepsy report having left a job or lost a job due to the disorder. Accidents at work are also often reported, but consistent accident data is spotty. Work-related accidents ranging from minor to severe have been reported in roughly 15% of patients [40]. Table 28.1 lists a number of suggestions that have been used to manage daytime sleepiness in school and work environments. Although many of the techniques mentioned are anecdotal in nature, patients with narcolepsy commonly practice these strategies and report them to be very helpful. Educating teachers about the

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320 Table  28.1  Behavioral strategies to help maximize alertness while at work or school

Table  28.2  Strategies to help combat excessive daytime sleepiness while driving

Sit in the front of the class to maximize attention Sit in a less comfortable seat Move around inconspicuously in your seat Take brief naps during breaks in between classes Get up and stretch every 2 h If possible, schedule classes during times of increased alertness Concentrate homework into shorter time periods during more alert moments Keep a regular sleep–wake schedule Schedule shifts during times of increased alertness Use heavy machinery only during times of peak alertness

Do not drive alone Use a manual shift car Take extra stimulant medication before driving Take frequent rest breaks Do not drive at night Stop for coffee and stretch Pull over at planned intervals and take a short nap

symptoms of narcolepsy can also be beneficial, provided the student and/or parent have given permission to do so. Although many patients are concerned of the stigma of narcolepsy and possible job loss, it may be helpful for the patient to discuss his or her illness with employers and to educate them about the symptoms. Engaging in a discussion with the employer regarding short nap times and scheduling shifts during times of increased alertness can also prove beneficial to both employee and employer.

Difficulties with Driving and Home Chores Numerous authors have reported increased accidents and driving problems in patients with narcolepsy. Broughton et al. [34] show that 66% of patients with narcolepsy had a history of falling asleep while driving, 37% had major accidents and 67% had near motor vehicle accidents. Although there are no widely accepted guidelines on driving for patients with narcolepsy, anecdotally, patients have adopted a number of strategies to help remain alert when they are behind the wheel. Table 28.2 lists a number of these widely used tactics. Patients with narcolepsy also report difficulties with completing usual home activities and chores [7]. Tiexeira et al. [40] reports nearly one-third of patients with narcolepsy had difficulties while caring for children and cooking, whereas 11% of patients had difficulties while ironing. Injuries such as being burnt while ironing or cooking, falling and even causing fires due to falling asleep while smoking have all been reported to occur frequently. Patients should be advised

to enlist family support with household chores and only engage in these activities when most alert. In addition, the patient should be advised against driving, bathing, swimming and using any heavy machinery or household appliances during times of sleepiness.

Conclusion Although research is limited on the use of behavioral management with patients diagnosed with narcolepsy, many report that the use of these strategies can make a significant impact on their daily functioning. Scheduling naps, optimizing work periods during times of maximal alertness, following sleep hygiene and stimulus control and knowing ones limitations can all benefit the patient. Education and counseling is paramount in treatment of narcolepsy, both for the patient and his or her family, friends and work environment. Psychotherapeutic strategies for the management of depression, anxiety and any other psychological issues are recommended. Future research is necessary to fully examine the effectiveness of these strategies.

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Index

A Adolescence. See also Older adults nacrolepsy, precaution, 184 psycho-socio impact, 181 Alzheimer’s disease, 152 American Academy of Sleep Medicine (AASM) excessive sleepiness, 288 narcolepsy treatment, 284, 294 stimulants, 249 American Narcolepsy Association, 191 Amphetamines, 242 dopaminergic neurotransmission and EEG arousal, 268–270 endogenous catecholamines, 265, 266 L and D isomers, 250 mental function, 242 methamphetamine, 251 methylphenidate, 251, 252, 265 molecular targets DAT and NET proteins, 267 VMAT2, 266 older adults, 73 pemoline, 252, 265 Antidepressants drug cataplexy pharmacological treatment, 254 hypersomnia causes, 170 Antiparkinsonian drug, 170 Anxiolytic drug, 169–170 Armodafinil action mode, 286 clinical manifestation, 283 EDS, 252–253 efficacy, 285 vs. modafinil, 303 safety and adverse event data clinical trials, 286 Controlled Substances Act, 287 discontinuation, treatment, 288 obstructive sleep apnea syndrome, 287 post-marketing experience, 286 psychiatric experience, 287 rash sign, 287 B Behaviorally induced insufficient sleep syndrome, 169 Body-mass index (BMI)

narcolepsy treatment, 305 obesity and comorbid eating disorders, 105–107 patient, narcolepsy, 312 Brain stem encephalitis, 150 C Canine narcolepsy genetics autosomal recessive inherited, 27, 28 major histocompatibility complex (MHC), 28 neurotransmitter differences and imbalances central norepinephrine (NE), 26 cholinergic agonist, 26, 27 mammalian brain schematic, 26 phenotype food-elicited cataplexy test (FECT), 25 REM sleep discriminatory index, 26 veterinarian, 24 Cataplexy. See also Narcolepsy–cataplexy (NC) adrenergic neurotransmission, 274–276 discriminative trigger, 116 dissociated REM Sleep, 78 laughter, 116–117 model implication, 121–122 positive emotions, 115 receptor subtypes, 276 REM sleep muscle atonia, 33 sodium oxybate efficacy, 292 techniques, 312 triggering mechanisms, 34 Catechol-O-methyltransferase (COMT), 11, 305 Central sleep apnoea syndrome (CSAS), 171 Cerebral tumors, 147–148 Cerebrospinal fluid (CSF) hypocretin-1, 48 Childhood behavioral strategies cataplexy pharmacotherapy, 63–64 daytime sleepiness pharmacotherapy, 62 disorder key features, 62 differential diagnosis idiopathic hypersomnia, 61 insufficient nocturnal sleep, 60 hypocretin deficiency, 58 physical examination

323

324 Childhood (cont.) evaluating sleepiness, 59 sleep laboratory testing, 59–60 pre-school-age children, 56 prevalence lag, 56 variation, 55 psycho-socio impact behaviour problem, school, 181 clinical assessment, 183 emotion and family, 181 medical services, 182–183 precaution, nacrolepsy, 184 social function, 181 REM-off, 58 school-age children attention deficit hyperactivity disorder (ADHD), 56 Conners’ rating scale, 58 excessive daytime sleepiness, 56 hypnagogic/hypnopompic hallucinations, 57 sleep laboratory testing drug-induced changes, 59 MSLT normal values, 60 two threshold hypothesis, 58–59 Clinical global impression of change (CGI-C), 283 Clomipramine, 73, 74 Cognition. See Memory and cognition Combination therapies, 303–304 Comorbid medical illnesses cognitive dysfunction, 110 diabetes mellitus, 107–108 eating disorder and obesity body-mass index (BMI), 105 conditions, 106 CSF-to-serum leptin ratios, 106, 107 hypocretin, 106 fibromyalgia, 109 migraines and other headaches, 109–110 psychiatric disorders, 108–109 psychosocial issues, 111 QOL, narcolepsy vs. neurologic disorder, 111 Controlled Substances Act, 287 Critical flicker fusion (CFF) test, 223 D Diabetes mellitus, 107–108 Diurnal sleep excessive daytime sleepiness (see Excessive daytime sleepiness) symptoms, 79 Driving and traffic safety accident risk, 215 decision, fitness, 217–218 difficulties, 316 interpretation, 217 treatment effects, 216–217 untreated patients performance, 215–216

Index E Encephalopathies brain stem encephalitis, 150 limbic, 149–150 Rasmussen’s syndrome, 149 Wernicke’s encephalopathy, 149 Epidemiology age onset, 49 cataplexy, 47 co-morbidities, 50 diagnosis criteria, 48 gender differences, 49–50 genetic and environmental link, 50–51 hypersomnia, 47 initial symptom screening, 49 lifestyle characteristics, 50 narcolepsy without cataplexy, 49–50 prevalence and incidence estimates, 48–49 public health implications, 52 rapid development, 51–52 sleep-onset REM sleep, 48 sleep paralysis, 47–48 standard sleep hygiene advice, 51 Epworth sleepiness scale (ESS) excessive daytime sleepiness, 292–293 subjective phsycological measurement, 283 European Federation of Neurological Societies (EFNS), 294 Excessive daytime sleepiness (EDS) awaken inability, 248 bupropion, 253 caffeine, 253 children, 55, 56, 59 dietary manipulation, 311–312 dissociated REM sleep symptoms cataplexy, 78 hypnagogic hallucinations, 78–79 sleep paralysis, 79 driving ability, 215 Epworth sleepiness scale (ESS), 292 exercise, 312 hypersomnia, 176 hypnagogic/hypnopompic hallucinations, 248 mazindol, 253 older adults, 73, 74 pharmacological treatment amphetamine, 249 antidepressants, 254–256 L and D isomers, 250 methamphetamine, 251 methylphenidate, 251, 252 pemoline, 252 phenotype narcoleptic patients, 78 sleep episodes, 77, 78 psychiatric disorder, 109 scheduled naps, 310–311 severity, 78 sodium oxybate (SO), 292–293 symptoms, narcolepsy, 247–248 work disability, 232, 233

Index F Fibromyalgia, 109 Functional outcomes of sleep questionnaire (FOSQ) health-related quality of life (HRQOL), 190 sodium oxybate, 243 G Gamma-aminobutyric acid (GABA) GHB, 277 receptors, 278 Gammahydroxybutyric (GHB) acid, 15, 51 narcolepy treatment, 304 pharmacokinetics, 292 pharmacology, 291–292 Genetic predisposition. See also Human leukocyte antigen (HLA); Hypocretin animal models narcoleptic Doberman, 4–6 rodent models, 5 catechol-O-methyltransferase (COMT) gene, 11 HLA narcolepsy susceptibility genes, 9–10 typing, clinical practice, 10–11 narcolepsy environmental factors, 6 human leukocyte antigen (HLA)-DR2, 8–9 secondary cases, 13–14 twin studies, 6 narcolepsy–cataplexy diagnostic tests, 4 familial aspects, 7 hypocretin (orexin) deficiency, 88 prevalence studies, 3 narcolepsy without cataplexy diagnostic tests, 4 prevalence studies, 3–4 single nucleotide polymorphisms, 12 Guillain–Barre’s syndrome, 158–159 H Headaches, 109–110 Head trauma, 152–153 Health-related quality of life (HRQoL), 72 fatigue, 193 functional outcomes of sleep questionnaire (FOSQ), 190 narcolepsy OSAHS, 193 patient adjusment, 194 people with narcolepsy (PWN), 192 social network, 195 social support, 194 support group vs. self help groups, 195 reliability and validity, measuring instruments, 190 short form 36 (SF-36), 189 sickness impact profile (SIP), 190 Histamine 3 receptor (H3), 302–303 Human leukocyte antigen (HLA), 8–9, 48, 105. See also Genetic predisposition

325 Humor process, narcolepsy-cataplexy (NC) anatomical finding, 117 emotion-triggers, 115–116 functional abnormalities, 118 hypocretin deficiency, 115 neural correlation fmri studies, 119 hypothalamus, 118 neuroimaging abnormal hypothalamic activity, 119–121 amygdala activity, 119–121 model implication, 121–122 weak with laughter, 116–117 Hungtington disease, 152 Hypersomnia, 47. See also Excessive daytime sleepiness antidepressants drug, 170 cerebral tumors, 147–148 daytime MSLT, 80 differential diagnosis analgesics, 170 behaviorally induced insufficient sleep syndrome, 169 brain imaging, 169 cardiovascular drugs, 170 central sleep apnoea syndrome (CSAS), 171 clinical approach, 167–168 drug/substance, 169 idiopathic, 172–173 infectious disease, 175 Kleine–Levin syndrome, 173–174 maintenance of wakefulness test (MWT), 168–169 metabolic and endocrine diseases, 175 multiple sleep latency test, 168 neurological diseases, 174–175 neurology, 170 obstructive sleep apnoea syndrome, 170–171 PLMS and excessive daytime sleepiness, 176 polysomnographic recording, 169 positive diagnosis, 167 post-trauma, 175–176 psychiatric, 176 psychometric/psychiatric evaluation, 169 psychotropic drugs, 169–170 dissociated sleep REM sleep atonia intrusion, 81, 82 REM sleep without atonia, 82, 83 encephalopathies, 149–150 excessive daytime sleepiness (EDS), 176 head trauma, 152–153 hypocretin/dopaminergic, 83 infarctions, 148–149 maintenance of wakefulness test (MWT), 168–169 multiple sleep latency test (MSLT), 168 neurodegenerative disorders, 151–152 nocturnal polysomnography, 83 obstructive sleep apnoea syndrome (OSAS), 170–171 sleep apnea/hypopnea syndrome, 82 sleep microstructure, 81 sleep structure nighttime PSG, 80 typical nighttime hypnogram, 80, 81

Index

326 Hypnagogic hallucinations, 89 AIM Model, 93 clinical features, 88 dissociated REM Sleep, 78–79 dreams dreamlike intrusions, 88 visual field and action, 89 drowsiness, 89 intimacy and sexuality, 206 narcolepsy symptoms, 248 neurobiology, 91–92 non-pharmacologic treatment, 313 psychological aspects, 239 schizophrenia, 89 treatment, 256 antidepressants, 95 sodium oxybate, 94–95 Hypnotics drug, 169–170 Hypocretin (Hcrt). See also Orexin animal model, 5 cell transplantation, 300–301 characteristics, 135 childhood, 58 CNS lesions, 144–145 CSF hypocretin-1, 12–13 CSF hypocretin-1 levels, 135 gene therapy, 299 hcrtr1 vs. hcrtr2, 298 human narcolepsy–cataplexy, 8 hypothalamus control, 6 ICV replacement, 298 inherited disorders myotonic dystrophy, 146–147 Niemann-Pick Type C disease, 146 Prader-Willi syndrome, 145–146 intranasal delivery, 298 intravenous vs. intranasal administration, 299 measurements, 137–143 monoaminergic and cholinergic interactions anticataplectic agents, 14–15 gammahydroxybutyric (GHB) acid, 15 hypersensitivity, 16 REM sleep, 15–16 stimulants, 15 narcolepsy–cataplexy, 115 narcolepsy without cataplexy, 4 receptors, 300 replacement therapy, 256–258 therapeutic targets, 16 I Idiopathic hypersomnia, 172–173 Immunotherapy, 300–301 International Classification of Functioning, Disability and Health (ICF), 230 International Council on Alcohol, Drugs and Traffic Safety (ICADTS), 218 Intimacy and sexuality adulthood, 207, 210 automatic behavior, 204

dating relationship, 207 hypnagogic hallucinations, 205–206 later adolescence and early adulthood, 206–207 marriage/committed long term relationship cataplexy, 208 psychiatric depression, 208–209 tiredness and persistent sleepiness, 208 narcolepsy, symptoms impact, 205–206 pharmacological control, 212 non-sexuality aspects, 207 relationship, spouse, 209 psychosocial support, 212 sexual aspects, 210–211 sleep paralysis, 204 timing of, 211 working disability, 203 K Kleine–Levin syndrome, 61, 173–174 L Limbic encephalopathy, 149–150 M Maintenance of wakefulness test (MWT) excessive daytime sleepiness, 292–293 hypersomnia, diagnosis, 168–169 modafinil, 283 scheduled naps, EDS, 310–311 MAO inhibitors (MAOIs), 276–277 Medical therapies, 303 Medico-legal aspects, disability assessment, 233 clinical severity scale, 231–232 definition, 229 determination, 232–233 impairment variability, 231 work classification, 233 definition and etiology, 230 limitations, 230–231 Memory and cognition alertness, 223 critical flicker fusion (CFF) test, 223 executive functions, 224 hypocretin system dysfunctions, 221 impairment, 225 insomniac patients, 222 multiple sleep latency test (MSLT), 225 neurotransmitter dysfunction, 221–222 nocturnal sleep, 222 patient neuropsychological profile, 225 reaction times (RT), 224 symptoms, 221 Mental health attention, 237–238

Index dreams and hallucinations, 239 drugs amphetamines, 242 modafinil, 242–243 sodium oxybate, 243–244 executive function, 238 food cravings, 239 functional impairment, 240–241 methodological issues, 237 mood disorders anxiety and depression, 238–239 psychosis, 239 pain, 239 treatment explanation, 241 lifestyle aspects, 242 Methamphetamine, 251 3-4-Methylendioxymethamphetamine (MDMA), 216 Methylphenidate, 73 Migraine, 109–110 Modafinil vs. armodafinil, 303 action mode, 286 adrenergic neurotransmission, 275–276 clinical assessment, 271 clinical manifestation, 283 compounds, 273–274 EDS treatment, 252–253 effects and dopaminergic system, 272 GHB, 277–278 5HT2 receptor, 271 MAO inhibitors (MAOIs), 276–277 mental health, 242–243 narcolepsy treatment, 242–243 CNS stimulants, 285 objective physiological measurement, 283 subjective physiological measurement, 284 older adults, 73 receptor subtypes, 276 safety and adverse event data clinical trials, 286 Controlled Substances Act, 287 discontinuation, treatment, 288 obstructive sleep apnea syndrome, 287 post-marketing experience, 286 psychiatric experience, 287 rash sign, 287 tricyclic anti-cataplectics, 274 Multiple sclerosis, 154–156 Multiple sleep latency test (MSLT) hypersomnia, diagnosis, 168 idiopathic hypersomnia, 172 insomnia, 222 modafinil, 283 objective sleepiness measurement, 225 sleep latency, 147 sleep tendency, 216 Muscarinic cholinergic receptors, 42 Myotonic Dystrophy, 146–147

327 N N-acetylaspartate (NAA), 117 Narcolepsy–cataplexy (NC). See also Genetic predisposition abnormal hypothalamic and amygdala activity hypothalamic activity, 121 neutral picturesequences, 120 nucleus accumbens (NAcc), 120 tumor response, 121 anatomical finding, 117 CNS lesions, 144–145 emotion-triggers, 115–116 functional abnormalities, 118 inherited disorders myotonic dystrophy, 146–147 Niemann-Pick type C disease, 146 Prader-Willi syndrome, 145–146 model implication, 121–122 neural correlation, 118–119 weak with laughter, 116–117 Neurodegenerative disorders Hungtington and Alzheimer’s disease, 152 Parkinson’s disease, 151 progressive supranuclear palsy, 151–152 Neuroimaging studies functional studies daytime sleep attacks, 39 sleep deprivation, 39, 40 total sleep deprivation (TSD), 40 muscarinic cholinergic receptors, 42 narcolepsy hypocretin system, 40 pharmacotherapy, 41–42 SPECT studies, 40–41 Neuroleptics, 170 Neuroscientific theory AIM theory, 133 bizarre dream definition, 132 Niemann-Pick Type C disease, 146 Nightmares, 313 lucid dreaming, 126 patient dream, 126 Nighttime sleep, 312–313 Nocturnal sleep clinical features, 79–80 daytime MSLT, 80 laboratory characteristics, 80 polysomnographical findings dissociated sleep, 81–83 obstructive sleep apnea/hypopnea syndrome (OSAHS), 82 periodic leg movements in sleep (PLMS), 81 sleep microstructure, 81 sleep structure, 80–81 Non-pharmacological treatment cataplexy, 313 characteristics, 250 cognitive complaints, 313–314 disrupted nighttime sleep, 312–313 driving difficulties, 316 education difficulties, 315–316 excessive daytime somnolence

328 Non-pharmacological treatment (cont.) dietary manipulation, 311–312 exercise, 312 scheduled naps, 310–311 home chores difficulties, 316 hypnagogic hallucinations, 313 interpersonal difficulties, 315 nightmares, 313 psychiatric co-morbidities and management, 314–315 psychosocial support limitation, 315 sleep paralysis, 313 work difficulties, 315–316 Norwegian Association for Sleep Disorder (NASD), 193 O Obesity and eating disorder body-mass index (BMI), 105 conditions, 106 CSF-to-serum leptin ratios, 106, 107 hypocretin, 106 Obstructive sleep apnea/hypopnea syndrome (OSAHS), 82, 193 Obstructive sleep apnea syndrome (OSAS) hypersomnia, 170–171 vs. nacrolepsy, 183 Older adults delayed diagnosis mean sleep latency, MSLT function, 70, 71 multiple sleep latency test (MSLT), 70 implications, 72–73 obstructive sleep apnea syndrome (OSAS), 74 onset after age 35 obstructive sleep apnea (OSA), 70 sporadic case reports, 69 secondary/symptomatic narcolepsy iatrogenic narcolepsy, 71, 72 modafinil, 73 Parkinson disease (PD), 71 symptoms after restarting venlafaxine, 72 therapeutic challenges, 72–73 Orexin, 115. See also Hypocretin highly-penetrant orexin-gene mutations, 33 paralyzed wakefulness, 34 REM sleep muscle atonia, 33, 34 P Paraneoplastic syndrome, 159 Patient dream definition, 125 nightmares, 126 recall frequency, 125 REM awakening process, 126 Pemoline, 252 People with narcolepsy (PWN), 192 Periodic leg movements in sleep (PLMS), 81 Periodic limb movement disorder (PLMD), 12 Pharmacology, wake-promoting compounds amphetamines dopaminergic neurotransmission and EEG arousal, 268–270

Index endogenous catecholamines, 265, 266 methylphenidate, 265 molecular targets, 266–268 pemoline, 265 modafinil adrenergic neurotransmission, 275–276 clinical assessment, 271 compounds, 273–274 effects and dopaminergic system, 272 GHB, 277–278 5HT2 receptor, 271 MAO inhibitors (MAOIs), 276–277 receptor subtypes, 276 tricyclic anti-cataplectics, 274 wakefulness neurobiology cholinergic neurons, 264 DA and monoamine neurons, 265 multiple neurotransmitter and brain activity, 264 Physostigmine cholinergic mechanisms, 27 Post-traumatic hypersomnia, 175–176 Prader-Willi syndrome, 145–146 Proton magnetic resonance spectroscopy (1HMRS), 117 Protriptyline, 73, 74 Psychiatric disorders, 108–109, 176 Psychoanalysis approaches, 129–130 bizarre dreams, 129 dream analysis, 130 sleeping concept, 130 narcolepsy neuroscientific theory, 132–133 REMS model, 130–131 Psychosocial impact adolescence precaution, nacrolepsy, 184 problems, 181 childhood behaviour problem, school, 181 clinical assessment, 183 emotion and family, 181 medical services, 182–183 precaution, nacrolepsy, 184 social function, 181 comorbid medical illnesses, 111 disadvantage, 182 vs. other sleep disorder, 183–184 quality of life (QOL) computerized neurocognitive function test, 192 functional outcomes of sleep questionnaire (FOSQ), 190 impact and economic costs, 191 men and women, adjustment problem, 192 psychopathology and depression, 191–192 reliability and validity, measuring instruments, 190 short form 36 (SF-36), 189 sickness impact profile (SIP), 190 standardised psychosocial assessment, 181–182 support group attendees and non-attendees, 197 benefits, 195–196 counseling, 197–198 employment, 198

329

Index management implication, 197 meeting, patient inability, 196–197 research implications, 198 transportation, 198 Psychotropic drugs, hypersomnias, 169–170 Q Quality of life (QOL) health status, 187–189 HRQOL functional outcomes of sleep questionnaire (FOSQ), 190 narcolepsy, 192–195 reliability and validity, measuring instruments, 190 short form 36 (SF-36), 189 sickness impact profile (SIP), 190 narcolepsy computerized neurocognitive function test, 192 impact and economic costs, 191 men and women, adjustment problem, 192 psychopathology and depression, 191–192 vs. neurologic disorder, 111 sodium oxybate efficacy, 293 R Rapid eye movement (REM), 23, 24, 39, 41 cataplexy, 121 comorbidities, 106 dissociated REM phenomena consciousness states, 92 physiological variations, 93 hypnagogic hallucinations, 204 MOI, 276 patient dream, 125–126 psychoanalysis, 131–132 serotonergic projections, 275 tricyclic antidepressants, 258 Rasmussen’s syndrome, 149 Reaction times (RT), 224 REM sleep behavior disorder (RBD), 71 atonia index, 101 clonazepam, 99, 100 diagnostic criteria chin EMG activity, 101 sleep stages, 100 electrolytic lesions, 99 narcoleptic patients melatonin, 102 occurrence, 101, 102 prevalence, 101 vs. idiopathic RBD, 101–102 neurological diseases, 99–101 Rodent narcolepsy. See also Vigilance state characterization, rodent narcolepsy intracerebroventricular (icv) injection orexin-A, 28 prepro-orexin mRNA, 28, 29 vigilance state characterization orexin/ataxin-3 transgenic mice and rats, 31–32 orexin-/- mouse, 29–30 orexin receptor null mice, 32

S Sexuality. See Intimacy and sexuality Sickness impact profile (SIP), 190 Sleep paralysis, 313 AIM model motor output, 93 schematic representation, 94 antidepressant medications serotonin reuptake inhibitors (SSRIs), 95 clinical features, 90 culturally determined interpretations isolated sleep paralysis, 90 nightmares, 91 dissociated REM Sleep, 79 narcolepsy symptoms, 248 neurobiology, 92 treatment, 256 antidepressants, 95 sodium oxybate, 94–95 Sleep-related breathing disorders (SRBD), 12 Sodium oxybate (SO), 73, 94, 243–244 adverse events, 293–294 amphetamines, 291 contraindications, 294 efficacy cataplexy, 292 excessive daytime sleepiness, 292–293 sleep, 293 gammahydroxybutyrate (GHB) pharmacokinetics, 292 pharmacology, 291–292 mental health, 243–244 narcolepsy–cataplexy, 253–254 quality of life, 293 treatment recommendations, 294 Stem cell transplantation, 300 Symptomatic narcolepsy. See also Hypersomnia; Hypocretin anatomical substrate, 143–144 CSF hypocretin-1 level, 135 definition, 136, 143 demyelinating diseases acute disseminated encephalomyelitis, 157–158 anti-AQP4 antibody, 156–157 Guillain-Barre’s syndrome, 158–159 multiple sclerosis, 154–156 neuromyelitis optica, 156–157 paraneoplastic syndrome, 159 hypocretin measurements, 137–143 hypocretin status CNS lesions, 144–145 inherited disorders, 145–147 idiopathic narcolepsy, 135 Synucleinopathies, 100 T Thyrotrophin releasing hormone (TRH), 301–302 Total sleep deprivation (TSD), 40

330 U United Kingdom Association of Narcolepsy (UKAN), 193 V Venlafaxine, 95 Vigilance state characterization, rodent narcolepsy orexin/ataxin-3 transgenic mice and rats concurrent video and EEG/EMG monitoring, 31, 32 dark phase infrared video monitoring, 31 orexin gene promoter, 31

Index spectral analysis, 32 orexin receptor emotional arousal and amelioration, 29, 30 NREM onset, 30 null mice, 32 severe phenotype, 32 W Wernicke’s encephalopathy, 149 World Health Organization (WHO), 187, 229 WorldSleep conference, 217, 218