Sleep Medicine

Sudhansu Chokroverty • Michel Billiard Editors

Sleep Medicine

A Comprehensive Guide to Its Development, Clinical Milestones, and Advances in Treatment

Editors

Sudhansu Chokroverty
Professor of Neuroscience, Seton Hall University, South Orange, NJ;
Clinical Professor of Neurology, Rutgers Robert Wood Johnson Medical School,
New Brunswick, NJ;
Director of Sleep Research & Co-Chair emeritus of Neurology,
JFK New Jersey Neuroscience Institute, Edison, NJ, US

Michel Billiard
Honorary Professor of Neurology School of Medicine
University Montpellier I Honorary Chair
Department of Neurology
Gui de Chauliac Hospital Montpellier, France

ISBN 978-1-4939-2088-4 ISBN 978-1-4939-2089-1 (eBook) DOI 10.1007/978-1-4939-2089-1

Library of Congress Control Number: 2015936923

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Preface

Sleep medicine is now accepted as an independent medical specialty. Therefore, it is important for sleep specialists practicing sleep medicine to know its roots and historical evolution. Despite a remarkable progress and development of the eld of sleep medicine there are no books whatsoever addressing the evolution of the development of this tremendous endeavor. In addition to the need for carefully documenting this fascinating evolution from the rudimentary concepts of the ancient prehistoric and the early classical periods to our contemporary knowledge, it is essential for young sleep clinicians and researchers entering the eld to have access to a comprehensive, highly read- able account of the evolution of sleep medicine, chosen by these aspiring physicians as their profes- sional career.

Within the past two decades there has been at least a tenfold increase of volume on sleep disorder textbooks. There are now many tens of thousands of individuals involved in clinical sleep medicine and sleep research in addition to an explosion of sleep laboratories and sleep centers worldwide spanning from East to the West and from North to the South along with the growth of national and international sleep societies. A new and rapidly emerging eld needs its own specialty journals and societies. Beginning with the rst in the eld, the journal Sleep followed by the Journal of Sleep Research and Sleep Medicine, now there are a signi cant number of journals exclusively devoted to sleep medicine and sleep research both as print and online versions.

Despite the exponential growth of the eld including the number of societies and participants

involved, there has been little documentation of its historical development and its challenges until recently. Some early books on sleep provide a good account of the historical aspects including the early French volumes “Le Sommeil et les Reves” by Alfred Maury (1861), “Le Probleme Physiologique du Sommeil” (1913) by Henri Pieron, “Le Sommeil” (see the last chapter) by Dr. J. Lhermitte (1931), and “Les Troubles du Sommeil: Hyersomnies, Insomnies and Parasomnies” by Henri Roger (1932). These were followed by “Sleep and Wakefulness” (1939 and 1963) by Nathaniel Kleitman, “Sleep and Waking” by Ian Oswald (1962), “Le Som- meil de Nuit Normal et Pathologique” edited by Henri Fischgold (1965) and “The Abnormali- ties of Sleep in Man” edited by Lugaresi et al. (1968). Much information of historical interest is also in the volume “Sleep and its Disorders” by J. David Parkes (1985). However, all these volumes are either on sleep or sleep disorders in general rather than on the overall historical development of the eld. There have been a number of historical articles on individual break- throughs in our understanding of the basic sleep–wake mechanism and discovering new sleep disorders but there are no books on the historical milestones in this fascinating eld. The time is now not only ripe but overdue to document the remarkable progress on a state approaching rapidly “At Day’s close” (nighttime sleep) in which we spend one third of our existence.

The purpose of this book is to provide a comprehensive, balanced, fair, and easily readable account of the history of developmental milestones of sleep medicine. The book will be of interest not only to individuals working in the eld but also the physicians in general. As such the book is directed at internists (especially those specializing in pulmonary, cardiovascular,

vi Preface

gastrointestinal, renal and endocrine medicine), neurologists, neurosurgeons, family physi- cians, psychiatrists, psychologists, otolaryngologists, dentists, pediatricians, neuroscientists, as well as those technologists, nurses, and other paraprofessionals with an interest in sleep and its disorders. We believe that this book could attract signi cant interest in the general public as well.

Sudhansu Chokroverty Michel Billiard

Acknowledgements

We thank all the contributors for their lucid, scholarly, informative, and eminently readable con- tributions. We also wish to thank all authors, editors, and publishers who granted us permission to reproduce illustrations that were published in other books and journals. We are particularly indebted to Gregory Sutorius, editor of Clinical Medicine at Springer Science, New York for his professional- ism, thoughtfulness, and for ef ciently moving forward various stages of production. We must also acknowledge with appreciation the valuable support of Jacob Gallay, developmental editor and all the other staff at the Springer production of ce for their dedication and care in the making of the book.

The editors would like to acknowledge Roger Broughton, MD (author of Chap. 29 and co-author of Chap. 11), for encouraging them to write a book on the historical developmental of sleep medicine and in fact some of his thoughts and justi cations have been incorporated in this preface. SC would also like to acknowledge the splendid help of Samantha Staab and Toni Bacala, editorial assistants to the journal Sleep Medicine for correspondence with the contributors and making appropriate track changes and also Jenny Rodriguez for typing some materials for the book.

Last but not the least the editors would like to thank their wives. Dr. Chokroverty expresses his love, appreciation, and gratitude to his wife, Manisha Chokroverty, MD, for inspiring and encouraging him during all stages of production of the book while he had been stealing pre- cious weekends from her for continuing to work in order to nish the book in a timely manner; Dr. Billiard expresses his appreciation for his wife, Annick Billiard, for tolerating long hours spent in reviewing all the chapters.

Sudhansu Chokroverty Michel Billiard

vii

Contents

1 Introduction ………………………………………………………………………………………………… 1 Sudhansu Chokroverty and Michel Billiard

Part I Evolution of Sleep Medicine by Historical Periods

. 2 Sleep in Ancient Egypt…………………………………………………………………………………. 13
Tarek Asaad

. 3 Sleep Medicine in the Arab Islamic Civilization ……………………………………………. 21 Shahira Loza

. 4 Sleep Medicine in Ancient and Traditional India ………………………………………….. 25 V. Mohan Kumar

. 5 Sleep Medicine in Ancient and Traditional China …………………………………………. 29 Liu Yanjiao, Wang Yuping, Wang Fang, Yan Xue, Hou Yue and Li Shasha

. 6 Sleep in the Biblical Period ………………………………………………………………………….. 35 Sonia Ancoli-Israel

. 7 Sleep in the New Testament………………………………………………………………………….. 43 Michel Billiard

. 8 The Greco-Roman Period ……………………………………………………………………………. 47 Joseph Barbera

. 9 The Aztec, Maya, and Inca Civilizations……………………………………………………….. 55 Edgar S. Osuna

Part II Sleep Medicine from the Medieval Period to the 19th Century
10 Sleep Medicine in the Middle Ages and the Renaissance ……………………………… 63

A. Roger Ekirch

11 Sleep in the Seventeenth and Eighteenth Centuries……………………………………… 69 Michael Thorpy

Contents

Part III The Early Evolution of Modern Sleep Medicine

The Evolution of Sleep Medicine in the Nineteenth
and the Early Twentieth Century ……………………………………………… 75 Hartmut Schulz and Piero Salzarulo

The History of Polysomnography: Tool of
Scientific Discovery………………………………………………………………….. 91 Max Hirshkowitz

Part IV Sleep Medicine Societies, Professional Societies, and Journals

A History Behind the Development of Sleep Medicine
and Sleep Societies……………………………………………………………………. 103 Brendon Richard Peters and Christian Guilleminault

Development of Sleep Medicine in Europe………………………………… 113 Michel Billiard

Evolution of Sleep Medicine in Japan……………………………………….. 125 Masako Okawa

History of Japanese Clinical Sleep Medicine……………………………… 129 Naoko Tachibana

Sleep Medicine Around the World (Beyond North
American and European Continents, and Japan) ……………………… 133

Sudhansu Chokroverty

Part V Sleep Disorders in Historic Diseases

Cholera ……………………………………………………………………………………. 143 Donatien Moukassa, Obengui and Jean-Rosaire Ibara

Encephalitis Lethargica……………………………………………………………. 149 David Parkes

African Sleeping Sickness…………………………………………………………. 159 Alain Buguet, Raymond Cespuglio and Bernard Bouteille

Sleep and HIV Disease……………………………………………………………… 167 Kenneth D. Phillips and Mary E. Gunther

Part VI Historical Milestones of Individual Sleep Disorders
23 Evolution of the Classification of Sleep Disorders ……………………… 183

Michael Thorpy

24 History of Epidemiological Research in Sleep Medicine…………….. 191 Markku Partinen

Contents xi

25 The Insomnias: Historical Evolution ………………………………………… 197 Suresh Kumar and Sudhansu Chokroverty

Part VII Neurological Sleep Disorders

Narcolepsy–Cataplexy Syndrome
and Symptomatic Hypersomnia ……………………………………………….. 205

Seiji Nishino, Masatoshi Sato, Mari Matsumura and Takashi Kanbayashi

Idiopathic Hypersomnia…………………………………………………………… 223 Sona Nevsimalova

Kleine–Levin Syndrome …………………………………………………………… 229 Michel Billiard

Movement Disorders in Sleep …………………………………………………… 237 Sudhansu Chokroverty and Sushanth Bhat

History of Restless Legs Syndrome, Recently
Named Willis–Ekbom Disease ………………………………………………….. 249

Richard P. Allen

Sleep and Stroke………………………………………………………………………. 255 Mark Eric Dyken, Kyoung Bin Im and George B. Richerson

Sleep in Neurodegenerative Diseases…………………………………………. 271 Alex Iranzo and Joan Santamaria

Sleep, Cognitive Dysfunction, and Dementia …………………………….. 285 Stuart J. McCarter, Erik K. St. Louis and Bradley F. Boeve

Fatal Familial Insomnia and Agrypnia Excitata:
Insights into Human Prion Disease Genetics and the Anatomo-Physiology of Wake and Sleep Behaviours …………………. 301 Elio Lugaresi and Federica Provini

Epilepsy and Sleep …………………………………………………………………… 309 Sándor Beniczky and Peter Wolf

Sleep Disorders after Traumatic Brain Injury:
Milestones in Perspective …………………………………………………………. 319

Richard J. Castriotta and Mark C. Wilde

Headache Syndromes and Sleep ……………………………………………….. 331 Munish Goyal, Niranjan Singh and Pradeep Sahota

Part VIII Psychiatric and Psychological Sleep Disorders

38 Depression……………………………………………………………………………….. 339 Michelle M. Primeau, Joshua Z. Tal and Ruth O’Hara

xii

Contents

Schizophrenia and Psychosis ……………………………………………………. 345 Brady A. Riedner, Fabio Ferrarelli and Ruth M. Benca

Bipolar Disorder………………………………………………………………………. 351 Sara Dallaspezia and Francesco Benedetti

Part IX Respiratory Diseases

A Short History of Obstructive Sleep Apnea Syndrome……………… 357 Brendon Richard Peters and Christian Guilleminault

Upper-Airway Resistance Syndrome: A Short History ………………. 365 Brandon Richard Peters and Christian Guilleminault

Restrictive and Obstructive Lung Diseases
and Sleep Disorders …………………………………………………………………. 367

Vipin Malik and Teofilo Lee-Chiong

NREM Arousal Parasomnias ……………………………………………………. 375 Mark R. Pressman and Roger Broughton

REM Sleep Behavior Disorder………………………………………………….. 391 Carlos H. Schenck

Chronobiology and Sleep …………………………………………………………. 407 Juergen Zulley and Scott S. Campbell

Part X Medical Disorders and Sleep

Cardiovascular Disease and Sleep Dysfunction …………………………. 415 Thomas Penzel and Carmen Garcia

Nonrestorative Sleep, Musculoskeletal Pain,
Fatigue in Rheumatic Disorders, and Allied
Syndromes: A Historical Perspective ………………………………………… 423 Harvey Moldofsky

Sleep and Pain: Milestones and Advances from Research ………….. 433 Carol A. Landis

Endocrine–Metabolic Disorders and Sleep Medicine…………………. 443 Rachel Leproult and Georges Copinschi

The Gut and Sleep……………………………………………………………………. 451 M. E. Estep and W. C. Orr

Impotence and Erectile Problems in Sleep Medicine …………………. 457 Markus H. Schmidt

Women’s Health and Sleep Disorders……………………………………….. 465 Kathryn A. Lee

Contents xiii

Part XI Miscellaneous Important Aspects

The Emergence of Pediatric Sleep Medicine ……………………………… 473 Oliviero Bruni and Raffaele Ferri

Sleep Disorders, Cognition, Accidents, and Performance…………… 487 Torbjörn Åkerstedt and Pierre Philip

Sleep Deprivation: Societal Impact
and Long-Term Consequences………………………………………………….. 495

Michael A. Grandner

Sleep Models……………………………………………………………………………. 511 Mitsuyuki Nakao, Akihiro Karashima and Norihiro Katayama

Part XII Evolution of Treatment and Investigative Approaches in Sleep Medicine

A History of Nonpharmacological Treatments for Insomnia ………. 519 Arthur J. Spielman and Paul B. Glovinsky

The Pharmacological Treatment of Sleep Disorders ………………….. 527 Jaime M. Monti

Psychological Treatment of Insomnia:
The Evolution of Behavior Therapy
and Cognitive Behavior Therapy………………………………………………. 533 María Montserrat Sánchez-Ortuño and Jack D. Edinger

Modafinil: Development and Use of the Compound ………………….. 541 Michel Billiard and Serge Lubin

Phylogeny in Sleep Medicine…………………………………………………….. 545 Kristyna M. Hartse

Gamma-Hydroxybutyrate (Sodium Oxybate):
From the Initial Synthesis to the Treatment
of Narcolepsy–Cataplexy and Beyond ………………………………………. 557 Roger Broughton

Development and Impact of Brain Imaging Techniques…………….. 573 Julien Q. M. Ly, Sarah L. Chellappa and Pierre Maquet

Index ………………………………………………………………………………………………. 581

Contributors

Torbjörn Åkerstedt Stockholm University, Stockholm, Sweden; Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden

Richard P. Allen Department of Neurology, Johns Hopkins University, Baltimore, MD, USA

Sonia Ancoli-Israel Departments of Psychiatry and Medicine, University of California, San Diego, CA, USA

Tarek Asaad Ain Shams University Hospital, Institute of Psychiatry-Psychophysiology & Sleep Research Unit, Nasr City, Cairo, Egypt

Joseph Barbera The Youthdale Child and Adolescent Sleep Centre, Toronto, ON, Canada
Ruth M. Benca Departments of Psychiatry and Psycology, Center for Sleep Medicine and Sleep Research,

University of Wisconsin-Madison, Madison, WI, USA

Francesco Benedetti Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milano, Italy

Sándor Beniczky Department of Clinical Neurophysiology, Danish Epilepsy Centre, Dianalund, Denmark; Department of Clinical Neurophysiology, Aarhus University, Aarhus, Denmark

Sushanth Bhat JFK New Jersey Neuroscience Institute, Edison, NJ, USA; Seton Hall University, South Orange, NJ, USA

Michel Billiard Department of Neurology, Gui de Chauliac Hospital, Montpellier Cedex 5, France; School of Medicine, University Montpellier I, Montpellier, France

Kyoung Bin Im Department of Neurology, Sleep Disorders Center, University of Iowa, Roy J and Lucille A Carver College of Medicine, Iowa, IA, USA

Bradley F. Boeve Mayo Center for Sleep Medicine, Department of Neurology, Mayo Clinic and Foundation, Rochester, MN, USA

Bernard Bouteille Laboratory of Parasitology, Dupuytren University Hospital of Limoges, Limoges, France Roger Broughton Division of Neurology, Department of Medicine, University of Ottawa, Ontario, Canada

Oliviero Bruni Department of Developmental and Social Psychology, Center for Pediatric Sleep Disorders, Sapienza University, Rome, Italy

Alain Buguet Polyclinic Marie-Louise Poto-Djembo, Pointe-Noire, Congo Scott S. Campbell Chappaqua, NY, USA

xvi Contributors

Richard J. Castriotta Division of Pulmonary and Sleep Medicine, University of Texas Medical School at Houston, Houston, TX, USA; Sleep Disorders Center, Memorial Hermann Hospital—Texas Medical Center, Houston, TX, USA

Raymond Cespuglio Centre de recherche en neuroscience de Lyon, University of Lyon, Lyon, France

Sarah L. Chellappa Cyclotron Research Centre, University of Liège, Liège, Belgium Sudhansu Chokroverty JFK New Jersey Neuroscience Institute, Edison, NJ, USA; Seton Hall

University, South Orange, NJ, USA

Georges Copinschi Laboratory of Physiology and Physiopathology, Université Libre de Bruxelles, Brussels, Belgium

Sara Dallaspezia Department of Clinical Neurosciences, Scientific Institute and University Vita-Salute San Raffaele, Milano, Italy

Mark Eric Dyken Sleep Disorders Center, University of Iowa Hospitals and Clinics, Iowa, IA, USA; University of Iowa, Roy J and Lucille A Carver College of Medicine, Iowa, IA, USA

Jack D. Edinger National Jewish Health, Denver, CO, USA

A. Roger Ekirch Department of History, Virginia Tech, Blacksburg, VA, USA

M. E. Estep Lynn Health Science Institute, Oklahoma City, OK, USA

Wang Fang Psychology Department (Sleep Medicine Clinic), Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China

Fabio Ferrarelli Department of Psychiatry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA

Raffaele Ferri Department of Neurology, Sleep Research Centre, I.C., Oasi Institute for Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy

Carmen Garcia Interdisciplinary Sleep Medicine Center, Charité—Universitätsmedizin Berlin, Berlin, Germany

Paul B. Glovinsky Department of Psychology, The City College of the City University of New York, New York, NY, USA; St. Peter’s Sleep Center, Albany, NY, USA

Munish Goyal Department of Neurology, University of Missouri Hospitals & Clinics, Columbia, MO, USA

Michael A. Grandner University of Pennsylvania, Philadelphia, PA, USA
Christian Guilleminault Sleep Medicine Division, Stanford University Outpatient Medical

Center, Redwood City, CA, USA

Mary E. Gunther The University of Tennessee, College of Nursing, Knoxville, TN, USA

Kristyna M. Hartse Sonno Sleep Centers, El Paso, TX, USA

Max Hirshkowitz Department of Medicine and Menninger, Baylor College of Medicine, Houston, USA; Department of Psychiatry, Baylor College of Medicine, Houston, USA; Sleep Disorders & Research Center, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA; Michael E. DeBakey Veterans Affairs Medical Center, Houston, Linkwood, TX, USA

Jean-Rosaire Ibara Department of Gastroenterology and Medicine, University Hospital of Brazzaville, Brazzaville, Congo

Contributors xvii

Alex Iranzo Neurology Service, Hospital Clínic de Barcelona, Barcelona, Spain; Institut d’Investigació Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Inves- tigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

Takashi Kanbayashi Department of Neuropsychiatry, Akita University, Akita, Japan
Akihiro Karashima Biomodeling Lab, Graduate School of Information Sciences, Tohoku

University, Sendai, Japan

Norihiro Katayama Biomodeling Lab, Graduate School of Information Sciences, Tohoku University, Sendai, Japan

V. Mohan Kumar SA, Heera Gate Apartments, Thiruvananthapuram, Kerala, India; Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram, Kerala, India

Suresh Kumar Department of Neurology, Sree Balajee Medical College and Hospital, Chennai, India; Chennai Sleep Disorders Centre, Chennai, India

Carol A. Landis Department of Biobehavioral Nursing and Health Systems, University of Washington, Seattle, WA, USA

Kathryn A. Lee Family Health Care Nursing, University of California, San Francisco, San Francisco, CA, USA

Teofilo Lee-Chiong Department of Medicine, National Jewish Health, University of Colorado Denver, Denver, CO, USA

Rachel Leproult Unité de Recherches en Neuropsychologie et Neuroimagerie Fonctionnelle (UR2NF), Université Libre de Bruxelles, Campus du Solbosch, Brussels, Belgium

Erik K. St. Louis Mayo Center for Sleep Medicine, Department of Neurology, Mayo Clinic and Foundation, Rochester, MN, USA

Shahira Loza Cairo Centre for Sleep Disorders, Mohandessin, Cairo, Egypt
Serge Lubin Former Medical Director of L. Lafon Laboratory, Maisons-Alfort, France

Elio Lugaresi Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

Julien Q. M. Ly Cyclotron Research Centre, University of Liège, Liège, Belgium
Vipin Malik Department of Medicine, National Jewish Health, University of Colorado Denver,

Denver, CO, USA

Pierre Maquet Cyclotron Research Centre, University of Liège, Liège, Belgium

Mari Matsumura Stanford University Sleep and Circadian Neurobiology Laboratory, Depart- ment of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA

Stuart J. McCarter Mayo Clinic and Foundation, Rochester, MN, USA

Harvey Moldofsky Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Toronto Psychiatric Research Foundation, North York, Canada; Centre for Sleep and Chronobiology Research, Toronto, ON, Canada

Jaime M. Monti Department of Pharmacology and Therapeutics, School of Medicine, Clinics Hospital, Montevideo, Uruguay

xviii Contributors

Donatien Moukassa Medical and Morphology Laboratory, Loandjili General Hospital, Pointe- Noire, Congo

Mitsuyuki Nakao Biomodeling Lab, Graduate School of Information Sciences, Tohoku Uni- versity, Sendai, Japan

Sona Nevsimalova Department of Neurology, 1st Faculty of Medicine, Charles University, Prague 2, Czech Republic

Seiji Nishino Stanford University Sleep and Circadian Neurobiology Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA

Obengui Department of Infectious Diseases, University Hospital of Brazzaville, Congo
Ruth O’Hara Department of Psychiatry and Behavioral Sciences, Stanford University, Stan-

ford, CA, USA; VA MIRECC Fellowship Program, VA Palo Alto, Palo Alto, CA, USA

Masako Okawa Department of Sleep Medicine, Shiga University of Medical Science, Otsu, Japan

W. C. Orr Lynn Health Science Institute, Oklahoma City, OK, USA

Edgar S. Osuna Department of Morphology, School of Medicine, National University of Colombia, Bogotá, Colombia; Department of Neurology, University Hospital Fundacion Santa Fe de Bogota, Bogotá, Colombia

David Parkes Clinical Neurology, The Maudsley Hospital and King’s College Hospital, London, UK

Markku Partinen Helsinki Sleep Clinic, VitalMed Research Centre, Helsinki, Finland; Department of Clinical Neurosciences, University of Helsinki, Helsinki, Finland

Thomas Penzel Interdisciplinary Sleep Medicine Center, Charité—Universitätsmedizin Berlin, Berlin, Germany

Brendon Richard Peters Stanford Sleep Medicine Center, Stanford School of Medicine, Redwood City, CA, USA

Pierre Philip Université de Bordeaux, Sommeil, Attention et Neuropsychatrie, Bordeaux, France

Kenneth D. Phillips The University of Tennessee, College of Nursing, Knoxville, TN, USA

Mark R. Pressman Sleep Medicine Services, Lankenau Medical Center/Lankenau Institute For Medical Research, Wynnewood, Pennsylvania, USA; Jefferson Medical College, Philadel- phia, Pennsylvania, USA; Lankenau Institute For Medical Research, Wynnewood, Pennsylva- nia, USA; Villanova School of Law, Villanova, Pennsylvania, USA

Michelle M. Primeau Department of Psychiatry and Behavioral Sciences, Stanford Univer- sity, Stanford, CA, USA; VA MIRECC Fellowship Program, VA Palo Alto, Palo Alto, CA, USA

Federica Provini IRCCS Istituto delle Scienze Neurologiche di Bologna, University of Bologna, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

George B. Richerson The Roy J. Carver Chair in Neuroscience, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa, IA, USA

Brady A. Riedner Psychiatric Institute, University of Wisconsin-Madison, Madison, WI, USA

Broughton Roger Division of Neurology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada

Contributors xix

Pradeep Sahota Department of Neurology, University of Missouri Hospitals & Clinics, Columbia, MO, USA

Piero Salzarulo Trento, Italy
María Montserrat Sánchez-Ortuño Facultad de Enfermería, Campus de Espinardo, Univer-

sidad de Murcia, Murcia, Spain

Joan Santamaria Neurology Service, Hospital Clínic de Barcelona, Barcelona, Spain; Institut d’Investigació Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Inves- tigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

Masatoshi Sato Stanford University Sleep and Circadian Neurobiology Laboratory, Depart- ment of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA

Carlos H. Schenck Minnesota Regional Sleep Disorders Center, Minneapolis, USA; Depart- ment of Psychiatry, Hennepin County Medical Center, Minneapolis, USA; Department of Psy- chiatry, University of Minnesota Medical School, Minneapolis, MN, USA

Markus H. Schmidt Ohio Sleep Medicine Institute, Dublin, OH, USA

Hartmut Schulz Erfurt, Germany

Li Shasha Information Institute, China Academy of Chinese Medical Sciences, Beijing, China

Niranjan Singh Department of Neurology, University of Missouri Hospitals & Clinics, Columbia, MO, USA

Arthur J. Spielman Department of Psychology, The City College of the City University of New York, New York, NY, USA; Center for Sleep Medicine, Weill Cornell Medical College, Cornel University, New York, NY, USA

Naoko Tachibana Center for Sleep-related Disorders, Kansai Electric Power Hospital, Fuku- shima, Osaka, Japan

Joshua Z. Tal Department of Psychiatry and Behavioral Sciences, Stanford University, Stan- ford, CA, USA; VA MIRECC Fellowship Program, VA Palo Alto, Palo Alto, CA, USA

Michael Thorpy The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA

Mark C. Wilde Department of Physical Medicine and Rehabilitation, University of Texas Medical School at Houston, Houston, TX, USA

Peter Wolf Department of Neurology, Danish Epilepsy Centre, Dianalund, Denmark
Yan Xue Psychology Department (Sleep Medicine Clinic), Guang’anmen Hospital, China

Academy of Chinese Medical Sciences, Beijing, China

Liu Yanjiao Psychology Department (Sleep Medicine Clinic), Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China

Hou Yue Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China

Wang Yuping Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China

Juergen Zulley Regensburg, Germany; Department of Psychology, University of Regensburg, Regensburg, Germany

Introduction 1

Sudhansu Chokroverty and Michel Billiard

The evolution of history of sleep medicine from the antiq- uity to modern time is a fascinating reading. Since the dawn of civilization, sleep has fascinated and inspired religious scholars, poets, philosophers, playwrights, artists, historians, and scientists as re ected in numerous mythological, poetic, dramatic, and scienti c writings [1].

Preserved Babylonian and Assyrian clay tablets, recording dreams and their interpretations, date back to 5000 BC Egyp- tians erected temples to Serapis, god of dreams, where peo- ple would sleep in the hope of inducing fortuitous dreams.

There are references to sleep and dream in Indian and Greek mythologies. For example, Upanishad (c. 1000 BC), the great ancient Indian textbook of philosophy sought to di- vide human existence into four states: the waking, the dream- ing, the deep dreamless sleep, and the super conscious (“the very self”) [2]. This description is a reminiscent of modern classification of sleep–wakefulness. In Greek mythology, one finds reference to famous sleeping characters, e.g., En- dymion falling asleep, forever, after receiving a kiss from the moon [3]. Nyx, the Greek god of night, has twin sons: Hypnos, the god of sleep; and Thanatos, the god of death.

One of the greatest Chinese (Taoist) philosophers (300 BC), Chuang-Tzu (Zhuangzi) stated [4]:

Everything is one;
During sleep the soul, undistracted, is absorbed into the unity; When awake, distracted
It sees the different beings.

The ancient Chinese believed in two basic principles of life: Yang, the active, light, and positive; and Yin, the passive,

S. Chokroverty ()
JFK New Jersey Neuroscience Institute, 65 James Street, Edison, NJ 08818, USA
e-mail: schok@att.net

M. Billiard
School of Medicine, University Montpellier I, Montpellier, France

Department of Neurology, Gui de Chauliac Hospital, 70 allée James Anderson, 34090 Montpellier, France

dark, and negative. The Yin–Yang concept, originated with Fu Hsi (c. 2900 BC), has since become the symbol for sleep and wakefulness [4].

There are many references to a close relationship between sleep and death in poetic, religious, and other writings, such as the following quotations: “There she (Aphrodite) met sleep, the brother of death” (Homer’s Iliad, c. 700 BC); “Sleep and death are similar…sleep is one sixtieth (i.e., one piece) of death (The Talmud, Berachoth 576)”; “The deepest sleep resembles death” (The Bible, I Samuel 26:12); “Each night, when I go to sleep, I die. And the next morning, when I wake up; I am reborn” (Mahatma Gandhi, the greatest pro- ponent of nonviolence and about whom Einstein stated that such a man will never again walk this planet in another cen- tury). The Islamic literature also indicates some similarities between sleep and death [5] as noted in this Qur’anic verse: “It is Allah who takes away the souls (Wafat) at the time of their death, and those that die not during their sleep” [39.42].

William Shakespeare, the great English literary figure in the Elizabethan era (seventeenth century) evoked themes about sleep throughout his writings. One referring to sleep and death appeared in Macbeth, Act II, Scene ii:

Sleep that knits up the ravell’d sleave of care, The death of each day’s life, sore labour’s bath, Balm of hurt minds, great nature’s second course, Chief nourisher in life’s feast.

There are many other memorable quotes from Shakespeare referring to sleep and dream. Iago after attempting to poison Othello’s mind about Desdemona stated:

Not poppy, nor mandragora,
Nor all the drowsy syrups of the World,
Shall ever medicine thee to that sweet sleep
Which thou owed’st yesterday. (William Shakespeare, Othello, Act iii, Scene 3)

It is interesting to note about opium and mandragora as sleeping aids (see Chap. 2) and the interpretation here is that despite using the best sleep medicine in the world, suspi- cious Othello will never again have a good night’s sleep.

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_1, 1 © Springer Science+Business Media, LLC 2015

S. Chokroverty and M. Billiard

Another famous Shakespearean quotation often used in sleep literature in reference to sleep, death, and dream is the following one:

To die: to sleep;
……………………….
…………………………
To Sleep: perchance to dream:ay, there’s the rub; For in that sleep of death what dreams may come When we have shuffled off this mortal coil, Must give us pause. (Hamlet, Act 3, Scene i)

The English romantic poet John Keats in his 1817 poem “sleep and poetry” touches on the soothing softer side of sleep as reflected in the following excerpt from that poem:

What is gentler than a wind in summer? ……………………………………………………………. What is more tranquil than a musk-rose blowing? ……………………………………………………………. What, but thee Sleep? Soft closer of our eyes! ………………………………………………………………. Thee for enlivening all the cheerful eyes
That glance so brightly at the new sun-rise.

In contrast, the contemporary English poet Lord Byron touches on the reality of sleep:

Sleep hath its own world,
And a wide realm of wild reality,
And dreams in their development have breath, And tears, and tortures, and the touch of joys.

Prior to the twentieth century, views about sleep were not based on solid scientific foundation. However, remarks by some of the astute physicians and scientists proved to be strikingly similar to the contemporary views about sleep. For example, the opinion of Paracelsus, a sixteenth-century phy- sician, that “natural” sleep lasted 6 h, and the suggestion that individuals should not sleep too much or too little are similar to modern thinking (see [1]). The nineteenth-century physi- cians like Humboldt and Pfluger began to use principles of physiology and chemistry to explain sleep. The observations of Ishimori from Japan, in 1909 [6], and Legendre and Pieron from France, in 1913 [7], of sleep-promoting substances in the cerebrospinal fluid of animals during prolonged wakeful- ness were the beginnings of scientific research in the twenti- eth century. The table (Table 1.1) lists some milestones in the history of sleep medicine and sleep research. The discovery of the electroencephalographic (EEG) activity in rabbits and dogs by the English physician Caton, from Liverpool, Eng- land, in 1875, and, finally, documentation of EEG activity from the surface of human brain by Hans Berger (Fig. 1.1), the German physician from Jena, in 1929 [8], provided the scientific framework for contemporary sleep research. It is notable that the nineteenth-century German physiologist, Kohlschutter, thought that sleep was deepest during the first few hours based on his construction of classical depth-of- sleep curve, using auditory thresholds at different hours of

the night [9]. Modern sleep laboratory studies have generally confirmed this observation.

The description of sleep staging (stages A–E) based on the EEG changes in 1937 by the American physiologist Loomis et al. [10] followed by the discovery of rapid eye movement (REM) sleep by Aserinsky and Kleitman [11] at the University of Chicago, in 1953, propelled sleep research to the forefront of neuroscience (Fig. 1.2). Later observa- tions of muscle atonia in cats by Jouvet (Fig. 1.2) and Mi- chel, from Lyon, France, in 1959 [12], and human laryngeal muscles by Berger, from the USA, in 1961 [13], completed the discovery of all major components of REM sleep. In ad- dition to phasic eye movements, later investigators observed other important phasic components of human REM sleep: middle ear muscle activity (MEMA) [14]; periorbital inte- grated potentials (PIPs) [15]; phasic tongue movements [16]; transient myoclonic muscle bursts; phasic penile erections; phasic blood pressure; heart rate variability. It is interest- ing to note that Griesinger, in 1868, observed REMs under closed eyelids concomitant with twitching movements of the body in sleeping humans, and he commented that these were connected to dreams [17]. In 1892, Ladd, a professor of Psychiatry at Yale University in the USA, distinguished between fixed eye position in dreamless sleep as opposed to moving eyes in dreaming sleep [18]. In 1930, Jacobson also observed eye movements during dreaming sleep [19]. Freud, in 1895, observed that body muscles became relaxed during dreaming [20]. These findings of seemingly paralyzed body, REMs, and transient body muscle twitching during dreaming sleep before the advent of polysomnographic recordings are remarkable and astute clinical observations. Another devel- opmental milestone in the history of sleep medicine research is the publication of a paper by Dement (Fig. 1.2) and Kleit- man [21] documenting cyclic variation of EEG during sleep in relation to eye movements, body motility, and dreaming. Subsequent production by Rechtschaffen and Kales [22], of the standard sleep scoring technique monograph, in 1968, remained the gold standard until the American Academy of Sleep Medicine published the Manual for the Scoring of Sleep and Associated Events in 2007 [23].

Before outlining further clinical milestones in the history of sleep medicine, we briefly mention about the progress and evolution of some basic science research in sleep medicine. As early as 1920, before the discovery of EEG, McWilliam observed changes in blood pressure (BP), heart rate (HR), respiration, and other autonomic changes (e.g., penile erec- tions) episodically during sleep [24]. He also distinguished between “disturbed” and “undisturbed” sleep by noting that during “disturbed” sleep there was an increase in BP and HR [25].

In the first quarter of the last century, Von Economo (see Fig. 20.1 an astute young Austrian neurologist, cleverly ob- served that those patients with encephalitis lethargica, suf-

1 Introduction 3

Table 1.1 Some milestones in the history of sleep medicine Willis T (AD 1672): Description of RLS like symptoms

de Mairan J-J D (AD 1729): Discovery of a circadian clock in plants
Parkinson J (AD 1817): Description of Parkinson’s disease with sleep dysfunction
Gelineau E. (AD 1880): Description of narcolepsy
Ishimori K (AD 1909) from Japan, and Legendre R and Pieron H (AD 1913) from France independently described sleep-inducing factors (“hypnotoxin”) in the brain of sleep-deprived dogs
Von Economo (AD 1926–1929): The concept of a wakefulness centre in the posterior and a hypnogenic centre in the anterior hypothalamus Hans Berger (AD 1929): First report of EEG activity on the surface of the scalp of human
Bremer F (AD 1935): Feline preparations of midbrain transection causing cerveau isole and spinomedullary transection causing encephale isole Loomis AL, Harvey EN, Hobart G (AD 1937): EEG Sleep staging A-E
Kleitman N (AD 1939): Considered “father of sleep medicine research” wrote “Sleep and Wakefulness,” a comprehensive tome on all past and present sleep research citing 4337 references
Hess WR (AD 1944): Sleep, a well-coordinated active process and induced sleep in animals by stimulating the thalamus
Ekbom KA (AD 1945): Modern description of RLS
Moruzzi G, Magoun H (AD 1949): Discovery of the ascending reticular activating system (ARAS) in the upper brain stem as an arousal system Aserinsky E, Kleitman N (AD 1953): Discovery of rapid eye movements
Burwell CS, et al. (1956): Pickwickian syndrome (obesity-hypoventilation syndrome)
Dement W, Kleitman N (AD 1957): Described cyclic variation of sleep body, and eye movements throughout the night
Jouvet M, Michel M (AD 1959): REM muscle atonia in cat
Oswald I (1959): Hypnic jerks at sleep onset
Aschoff J (1960): Discovery of circadian rhythms in human
Severinghaus JW, Mitchell RA (AD 1962): Described Ondine’s curse or central hypoventilation, syndrome
Jouvet M, Delorme JF (AD 1965): Animal model of RBD in cat
Jung R, Kuhlo W (AD 1965): Obstructive sleep apnea syndrome (OSAS) called Pickwickian syndrome in those days)
Gastaut H, et al. (AD 1965): First PSG recording in OSAS
Gastaut H, Tassinari C, Duron B (1965): Discovery of the site of obstruction in upper airway obstructive sleep apnea syndrome (OSAS) Lugaresi E, et al. (AD 1965): First Polygraphic recording in RLS
Broughton R (1968): Disorders of arousal (sleepwalking, sleep terror, confusional arousal)
Rechtschaffen A, Kales A (AD 1968): Sleep stage scoring techniques
Khulo W, Doll E, Franck MC (AD 1969): Tracheostomy for OSAS
Fujita S, et al. (AD 1981): Uvulopalatopharyngoplasty (UPPP) for OSAS
Lydic R, Schoene WC, Czeisler C, Moore-Ede MC (1980); Discovery of human circadian clock in the suprachiasmatic nucleus
Coleman RM (AD 1980): Periodic limb movements in sleep (PLMS)
Sullivan C, Issa F, Berthon-Jones, et al. (1981): Introduction of CPAP to reverse OSA
Honda Y (AD 1983): Association of HLA-DR2 in narcolepsy
Lugaresi E, et al. (AD 1986): Nocturnal paroxysmal dystonia (NPD)
Schenck C, Mahowald M (AD 1986): Description of human RBD
Lugaresi E, et al. (1986): Fatal familial insomnia
de Lecea L, Kilduff T, Peyron C, et al. (1998): Indentification of two neuropeptides independently (hypocretin 1 and 2)
Sakurai T, Amemiya A, Ishii M, et al. (1998): Indentification of two neuropeptides independently (orexin A and B)
Lin L, Faraco J, Li R, et al. (1999) Animal models of narcolepsy-cataplexy with mutation of hypocretin receptor 2 gene
Chemelly R, Willie J, Sinton C, et al. (1999): Prepro-orexin knockout mice causing narcolepsy-cataplexy phenotype
Allen R P, Barker P B, Wehrl F, Song HK, Earley CJ (2001): Identified decreased iron acquisition in substantia nigra and iron-dopamine con- nection in RLS (Willis–Ekbom Disease) patients
Winkelmann J, et al. (2007); Stefansson H, et al. (2007): Genome-wide association studies identified novel RLS susceptibility genes
RLS restless legs syndrome, EEG electroencephalography, PSG polysomnography, RBD REM sleep behavior disorder

fering from excessive sleepiness, had extensive lesions in the posterior hypothalamus at autopsy, whereas those having severe insomnia had prominent lesions in the anterior hy- pothalamus. Based on these observations, he predicted that sleep-and-wake-promoting neurons reside in the anterior and posterior hypothalamus, respectively [26]. These find- ings propelled further research into generating fundamental theories about sleep and wakefulness. It is interesting to note

that in 1809, Luigi Rolando produced a permanent state of sleepiness after removing the cerebral hemispheres in the birds, and Marie Jan Pierre Flourens, in 1822, repeated the same experiment in pigeons producing similar results. Ex- periments by Ranson, Hess, and Dikshit, during 1930-1934, and later, Nauta, in 1946, (see [27]) confirmed Economo’s conclusion of existence of sleep center in the anterior hy- pothalamus. However, the emphasis shifted toward passive

S. Chokroverty and M. Billiard

Fig. 1.1

Hans Berger

somnolence in the cerveau isole preparation. These observa- tions implied that structures at the mesopontime junctions between these two preparations (cerveau isole and midpon- tial pretrigeminal) are responsible for wakefulness. It has been demonstrated that cholinergic neurons in the pedunce- dupontine (PPT) and laterodorsal tegmental (LDT) nuclei in the mesopontine junction and their projections to cerebral hemispheres through thalamus and forebrain regions in ad- dition to ascending aminergic, hypocretinergic, and dopami- nergic neurons maintain alertness. There is clear scientific evidence, based on discrete lesion, ablation, stimulation, ex- tracellular and intracellular studies, as well as immunohisto- chemical studies using c-fos activation, that sleep is not just a passive but an active state. The contemporary theory for sleep includes both active and passive mechanisms. Hypo- thalamic sleep/wake switch theory proposed by Saper et al. in 2001 [31] is currently the most popular theory of nonrapid eye movement (NREM) sleep. Briefly, there is a reciprocal interaction between two groups of antagonistic GABAergic and galaninergic sleep-promoting neurons in the ventrolater- al preoptic (VLPO) region of the anterior hypothalamus and wake-promoting neurons in the tuberomammillary histamin- ergic neurons of the posterior hypothalamus, lateral hypotha- lamic hypocretinergic, basal forebrain, and mesopontine teg- mental clolinergic, dopaminergic and brain stem noradrener- gic and serotonergic neurons. Sleep–wake is thus self-rein- forcing; when one end of the switch is on (firing actively), the other end is “off” (disfaciliation). Disruption of one side of the switch will cause instability due to destabilization of

theory of sleep following publication by the Belgian physi- ologist Bremer [28] of two preparations in cats: Cerveau isole and encephale isole. Bremer (Fig. 1.3) found that mid- collicular transection (cerveau isole) produced somnolence in the acute stage and that transection at the spinomedullary junction (encephale isole) showed EEG fluctuations between wakefulness and sleep, indicating that, in cerveau isole prep- aration, all specific sensory stimuli were withdrawn from the brain facilitating sleep. This conclusion was modified later to reflect the role of nonspecific ascending reticular activat- ing system (ARAS) in maintenance of wakefulness, follow- ing the discovery by Moruzzi and Magoun [29], in 1949, of the existence of reticular formation in the center of the brain stem. The passive theory was subsequently challenged by the findings of persistent EEG and behavioral signs of alert- ness after midpontine pretrigeminal brain stem transection experiments by Batini et al. in 1959 [30]. This preparation was only a few millimeters below the section that produced

Fig. 1.2 From left, Michel Jouvet, William Dement, Nathaniel Kleitman, and Eugene Aserinsky

1 Introduction

Fig. 1.3

Frédéric Bremer

colorful descriptions of characters, seemingly having dis- tinctive symptoms of primary sleep disorders, before these entered the scientific literature. We cite the following exam- ples: The American novelist Edgar Alan Poe in Premature Burial describing narcoleptic-like symptoms in a character published in 1844 (36 years before Gelineau’s descriptions of narcolepsy); sleep paralysis of the character Ishmael in the American novelist Herman Melville’s Moby Dick [35] published in 1851 (25 years before the description of night palsy by Mitchell in 1876 [36]); sleep walking (somnam- bulism) of Lady Macbeth described by the famous English playwright William Shakespeare (c. 1603–1607) long before the description of this entity in the medical literature; REM sleep behavior disorder (RBD)-like symptoms in the Inge- nious Gentleman Don Quixote of La Mancha by the famous Spanish author Miguel de Cervantes Saavedra in 1605 [37], centuries before description of RBD, in 1986, by Schenck et al. [38]; vivid nightmares in Shakespeare’s Macbeth, A Midsummer Night’s Dream, and Richard III, Tolstoy’s War and Peace and Anna Karenina, and Dostoevsky’s Crime and Punishment and The Brothers Karamazou; and sleep paraly- sis and nightmare of the protagonist in The Horla written by one of the greatest short storytellers, Guy de Maupassant of France, in 1887. Perhaps, the most famous of all these fic- tional characters is “The fat boy Joe” (Fig. 1.4) in The Post- humous Papers of the Pickwick Club [39] written, in 1836, by the famous British novelist Charles Dickens (“The object that presented itself to the eyes of the astonished clerk, was a boy—a wonderfully fat boy—habited as a serving lad, stand- ing upright on the mat, with his eyes closed as if in sleep”). Joe was indeed fat, excessively sleepy, and snoring. One hundred and twenty years after Dickens’ description of the somnolent “fat boy Joe,” Burwel et al. [40] published a paper entitled “Extreme obesity associated with alveolar hypoven- tilation: A Pickwickian Syndrome.” As pointed out by Com- roe [41] and Lavie [42], this title created both literary and scientific errors. All members of Pickwick Club did not have this syndrome. There was also no evidence of apnea in Dick- ens’ description of Joe. Furthermore, Burwel and coworkers erroneously attributed their patient’s extreme somnolence to chronic hypercapnia related to hypoventilation. It is notable that, prior to Burwel et al.’s publications, Auchincloss et al. [43] and Siekert and coworkers [44] published similar cases in 1955. However, 50 years before Burwel et al.’s descrip- tion, Osler, in 1906 [45], referred to Dickens’ description of “the fat boy Joe”: “An extraordinary phenomenon in exces- sively fat young persons is an uncontrollable tendency to sleep–like the fat boy in Pickwick.” The first polygraphic re- cording of a Pickwickian patient was performed by Gerardy et al. [46] from Germany in 1960 showing repeated apneas during sleep, and the authors erred in attributing the patient’s daytime somnolence to carbon dioxide poisoning similar to that by Burwel et al. In 1962, Drachman and Gumnit [47] in

the switch. For REM sleep, currently, there are three models available. The earliest one proposed, in 1975, is the McCa- rley–Hobson model of reciprocal interaction between brain stem “REM-on” cholinergic and “REM-off” aminergic neu- rons initiated by GABAergic interneurons through pontine reticular formation (PRF) effector neurons [32]. This model stood the test of time until challenged by Saper’s group in 2006 [33] who proposed a “flip–flop” switch model, with sublaterodorsal (SLD) GABAergic neurons in the pons (“REM-on”), initiating REM sleep through glutamatergic mechanism, and, at the same time, inhibiting “REM-off” GABAergic neurons in the ventrolateral periaqueductal grey and lateral pontine tegmentum. Ventral SLD through glutamatergic neurons activates glycine–GABA interneu- rons causing motor neuron hyperpolarization and muscle atonia, whereas dorsal SLD-ascending glutamatergic system of neurons activates forebrain to cause EEG desynchroniza- tion. The latest model is that proposed by Luppi et al. [34] in which, during REM sleep, SLD glutamatergic “REM-on” neurons are activated with deactivation of “REM-off” GA- BAergic ventrolateral periaqueductal grey and mesopontine tegmentum. Ventral SLD glutamatergic neurons, using both a direct pathway to spinal cord and an indirect one through ventromedial medulla, activate glycinergic and GABAergic inhibitory interneurons, causing hyperpolarization of motor neurons and causing REM atonia, a hallmark of REM sleep state. The dorsal SLD glutamatergic neurons project upward to activate thalamocortical system and subsequent EEG de- synchronization. The spectacular advances in basic science research in sleep in the twentieth and twenty-first centuries stimulated tremendous growth of clinical sleep medicine, giving rise to “sleep disorders medicine” as a separate spe- cialty recognized by the American Medical Association, as such, in 1996. In the following sections, we summarize a part of this sleep medicine revolution.

Before elaborating on some clinical milestones in the evolution and history of sleep medicine, we should like to mention that famous novelists of the past centuries gave

S. Chokroverty and M. Billiard

Fig. 1.4 Joe, the fat boy

Bethesda, Maryland, USA, recorded repeated sleep-related apneas and awakenings from a Pickwickian patient, and, like Gerardy et al., attributed excessive sleepiness to carbon di- oxide poisoning. Two neurologists from Germany, Jung and Kuhlo [48] performed nighttime polygraphic sleep record- ings for the first time in Pickwickian patients demonstrat- ing recurrent sleep-related apneas and awakenings, and they correctly attributed their patients’ excessive daytime sleepi- ness to sleep fragmentation and not to carbon dioxide poi- soning, but they erred in ascribing the problem of breathing to disruption of brain stem respiratory center activity. It was, however, Gastaut (Fig. 1.5), Tassinari, and Duron, three neu- rologists from Marseilles, France [49], in 1965, who pointed out, for the first time, that the recurrent apneas and awaken- ings were related to upper airway obstruction during sleep. Lugaresi et al. [50], in a publication in the same year, con- firmed the astute observations and conclusions of Gastaut et al., and described three types of apneas: central, mixed, and obstructive. They also made a very important observation of periodic fall of BP during apnea and rise on resumption of breathing. The next milestone in the evolution of the story of sleep apnea syndrome was the demonstration of dramatic relief of symptoms in these patients following tracheostomy (which bypasses the upper airway obstruction) by Kuhlo et al. [51], in 1969. In a brief report, published in the Trans- actions of the American Neurological Association Journal, in 1969, Chokroverty et al. [52], from the USA, made the following important observations after polygraphic study in four patients with obesity hypoventilation syndrome: Recur- rent episodes of apneas–hypopneas associated with relative bradycardia followed by awakenings and relative tachycar- dia; systolic BP dropped by 20–30 mmHg during apnea–hy-

popnea; on many occasions EEG changes preceded respira- tory alterations; oxygen inhalation produced more prolonged and frequent episodes of apneas indicating the importance of peripheral chemoreceptor-driven hypoxemia causing respi- ratory stimulation and arousal in presence of chronic day- time hypercapnia (these findings were confirmed by Guil- leminault et al. [53] in a later publication). Another important observation was that in two patients, following weight loss of 100–150 pounds, symptoms improved, daytime arterial carbon dioxide tension normalized but apneas–hypopneas persisted, though these were less frequent (implying that obesity played a secondary aggravating and not a primary factor). Subsequently, numerous papers were published by Guilleminault et al. when he came to Stanford, California, USA, in 1972, and Guilleminault coined the term sleep apnea syndrome [53–55]. Then came the seminal paper by Sullivan et al. in 1981 [56] showing reversal of obstructive sleep apnea following continuous positive airway pressure (CPAP) delivered through the nose which revolutionized the treatment of this common condition associated with many adverse consequences to health. Subsequently, there was fur- ther development of positive pressure titration in terms of bi-level delivery (BiPAP), assisted servo ventilation (ASV), intermittent positive pressure ventilation (IPPV), and others. There was an explosion of growth in publication of papers on sleep apnea syndrome since 1990, and it is still continuing. The other developments in the continuing saga of evolution of sleep apnea syndrome include uvulopalatopharyngoplasty (UPPP) surgery by Fujita et al. [57], in 1981, and the use of dental appliance for treating upper airway obstructive sleep apnea. In 1962, in an abstract, Severinghaus and Mitchell [58] described two patients with failure of automatic control

1 Introduction

Fig. 1.5

Henri Gastaut

brought the entity to general recognition. Sleep paralysis was added to excessive sleepiness and cataplexy to symp- tom combination in this condition by Wilson in 1928, and this was later confirmed by Lhermitte and Daniels (see [61]). The fourth symptom “vivid hypnagogic hallucination” was added by Alajouaninine and Baruk, Redlich and Wendero- wic (see [61]), and finally, Yoss and Daly [62] from Mayo Clinic coined the term narcoleptic tetrad. In fact, two other common symptoms should be added coining narcoleptic hextad: automatic behavior related to microsleeps (see [61]) and disturbed night sleep with repeated spontaneous arous- als. Vogel, in 1960, described the characteristic sleep-onset REM periods (SOREMs) [63]. The multiple sleep latency test (MSLT) documenting pathologic sleepiness and SO- REMs were applied to the diagnosis of narcolepsy by Rich- ardson et al. in 1978 [64]. The discovery by Honda et al. of a strong association of narcolepsy–cataplexy with the histo- compatability antigen HLA-DR2 haplotype in both Asians and Caucasians [65] propelled narcolepsy research another step further toward autoimmune theory. Finally, the new and exciting era of sleep research began with the identification of two neuropeptides, in 1998, in the lateral hypothalamus and perifornical regions independently by two groups of neuro- scientists. De Lecea et al. [66], from California, named these hypocretin 1 and 2, whereas Sakurai et al. [67], from Texas, called the same peptides orexin A and B. Within one year of this discovery, Lin et al. [68] produced a canine model of a human narcolepsy phenotype by mutation of hypocretin 2 re- ceptors, and Chemelly et al. [69] created a similar phenotype in pre-prohyprocretin knockout mice. Shortly thereafter, Hara et al. [70] used transgenic mice to produce narcoleptic phenotype. Research progressed rapidly with documentation of the decreased hypocretin 1 in the cerebrospinal fluid of human narcolepsy–cataplexy syndrome followed by autopsy confirmation of the marked depletion of lateral hypothalamic orexin neurons in human narcolepsy patients [71, 72]. These findings confirm that human narcolepsy is a hypocretin de- ficiency disorder, thus providing proof for the prophetic pre- diction of young Austrian neurologist Von Economo made in 1930 that the cause for the disease described by Westphal and Gelineau resides in the lateral and posterior hypothalam- ic region [26]. The dramatic development and remarkable progress in basic and clinical research in sleep medicine are described in the following chapters of this book.

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Part I

Evolution of Sleep Medicine by Historical Periods

Introduction

What Is the Meaning (Concept) of Sleep in Ancient Egyptian Culture?

Ancient Egyptians believed each person has five bodies [4]: 1. ka = creative or divine power or the living physical body 2. ba = soul, able to travel beyond the physical body
3. akh or Shat=body of the deceased in the afterlife (the

corpse body) which means the union of the ka and ba
4. the name = living part of the person
5. the shadow = another living part of the person
This description of multidimensional levels of the self has something to do with sleep, as the ancient Egyptians believed in the ability of the ba (soul) to travel beyond the physical body during sleep. The ba was represented in hieroglyphics as a human-headed bird floating above the sleeping body. In that sense, sleep was viewed to be similar, in some aspect, to death, in which the person is in a different state or a differ- ent world. Being strong believers in the afterlife, sleep was considered as a way or outlet to that mysterious world and a means through which a person can communicate with the dead as well as his gods. For this reason, it is not surprising to find some rituals related to sleep to resemble what is ad- opted in preparation for death [5].

The headrests used for the act of sleeping during life were most probably of a symbolic nature and were essential re- quirement for funeral—to be kept with the dead in his burial chamber, acting as a pillow for eternal sleep, ensuring the head remained physically intact with the body in the afterlife (Fig. 2.1). Thus, if the tomb represented the home for the deceased, the burial chamber represented the bedroom [6].

The idea that the dead were sleeping or that they occupied another dimension not totally disconnected from the living is indicated in letters to the dead written on papyrus or ostraca, including Coffin Texts. These Coffin Texts functioned as ritually protective spells and instructions, intended to ensure safe passage to the afterlife. In Coffin Text (CT) 74, it was written “Oh sleeper, turn about in this place which you do not know, but I know it. Come that we may raise his head. Come that we may reassemble his bones” [6].

Sleep in Ancient Egypt 2

Tarek Asaad

Despite being the oldest civilization in history, there is still an increasing fascination for everything Egyptian, some- thing which was referred to as Egyptomania [1]. Regarding sleep medicine, the contribution of ancient Egypt dates back to 4000 BC and it tackles various aspects concerning the na- ture of sleep and dreaming, dream interpretation, use of sleep as therapy, description of sleep problems like insomnia, de- scription of treatments for sleep disorders, and others.

How Were the Words “Sleep” and “Dream” Expressed in Hieroglyphics (Ancient Egyptian Language)?

The ancient Egyptians used the word qed (symbolized by a bed) to denote sleep, and the word rswt or resut (depicted as an open eye) to refer to dream. The literal translation of rswt means to come awake; thus, a dream is expressed in hiero- glyphics by the symbol of bed, combined with the symbol of open eye. Such a combination makes the word dream to be read as awaken within sleep, which is an early description of the physiologic similarity of dreams to wakefulness, despite being asleep [2].

Dream=′′rswt′′(awaken)(openeye)+′′qed′′(sleep)(bed) This symbol may be pointing also to the state of conscious-

ness that we call today lucid dreaming [3].

T. Asaad ()
Ain Shams University Hospital, Institute of Psychiatry- Psychophysiology & Sleep Research Unit, 14 Aly El-Gendy Street, PO Box 11371, Nasr City, Cairo, Egypt
e-mail: dr.tarekasaad@yahoo.com

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_2, 13 © Springer Science+Business Media, LLC 2015

T. Asaad

Fig. 2.1 Two headrests from the tomb of Tutankhamun [6]

How Were Dreams Dealt with by Ancient Egyptians?

The Importance of Dreams

Like many ancient cultures, the Egyptians put quite a bit of emphasis on dreams. They believed the gods could show themselves in dreams, delivering messages that could guide them in their lives, i.e., the received messages might cure an illness or help them make important decisions, to the point of deciding where to build a new temple or when to wage a war.

The Egyptians also believed that their dreams could serve as a window to see the activities of the dead. However, they often feared these types of dreams, being afraid that this could bring about unwanted evil spirits [7].

Types of Dreams

The records list three main types of dreams [8]:

1. Those in which the gods would demand some pious act

2. Those that contained warnings (perhaps about illness) or
revelations

3. Those that came about through ritual

Dream Incubation

Like other Near Eastern people, the Egyptians believed that the dreams could serve as oracles, bringing messages from the gods. The best way to get the desired answer, especially in sickness, was to induce or “incubate” dreams (Incubate comes from the Latin incubare, meaning to lie down upon). To incubate dreams, Egyptians would travel to a sanctuary or shrine, where they slept overnight on a special dream bed in the hope of receiving divine advice, comfort, or healing from their dreams. There were dream or sleep temples built specifically for this reason. The temples were open to every- one who believed in the god the temple was dedicated to, as long as they were considered pure. To achieve this, the person often went through a ritual of cleansing that included

fasting and abstinence for several days prior to entering the temple to assure their purity. The name of the god the person hoped to contact at the temple was written on a piece of linen and that linen cloth was burned in a lamp while at the temple. To help call the god, the dreamer would often recite a special prayer to him or her. Once they visited the ancient Egyptian dream temple, the person would often go to a priest or dream interpreter for dream analysis [7].

Dream Analysis in Ancient Egypt (The Dream Book)

Because they put so much stock into dreams, it was important for Egyptians to be able to understand the significance and meaning of their dreams. Like many others, some Egyptians kept a dream book—a book that chronicled their dreams and the interpretation of them. One such dream book, written on papyrus, dates all the way back to approximately 1275 BC, during the reign of Ramesses II [9, 10] (Fig. 2.2).

It is believed that the ancient Egyptian dream book kept in the British Museum in London had many owners as it was passed down for more than a century. All in all, the dream book included 108 different dreams, which included such activities as weaving, stirring, seeing, eating, and drinking.

The dreams were categorized into good ( auspicious) dreams and bad ( inauspicious) dreams, with the bad dreams being written in red, a color of bad omens. In this book, there are hieratic signs that state such interpretations, as that it is good when a man dreams he sees himself looking out of a window. Even a man seeing himself dead was seen as a good sign, meaning that he would live a long life. However, if a man dreamed he saw his own face in a mirror it was a bad omen. Also, dreaming of putting your own face to the ground was seen as a bad omen. It was believed that that particular dream meant that the dead wanted something.

Qenherkhepshef’s dream book was a family affair; penned by his grandson, the scribe Amen-nakht, who was the son of Kha-em-nun, Qenherkhepshef’s oldest child. The texts allow insight, not only into the dreams of these ancient people but also into the everyday experiences of their lived lives.

2 Sleep in Ancient Egypt

Fig. 2.2 Qenherkhepshef’s dream book, BM 10683,3 [10]

Listing of Dreams in the Dream Book [9]:
The dream book is divided into lists of auspicious and inaus-

picious dreams:

a. Auspicious dreams (good dreams)

• If a man sees himself eating crocodile meat, it is good,
meaning that he becomes an official among his people.

• If a man sees himself burying an old man, it is good,
meaning prosperity.

• If a man sees himself sawing wood, it is good, meaning
his enemies are dead.

• If a man sees himself seeing the moon shining, it is good,
meaning a pardon from God.

• If a man sees himself in a dream slaying a hippopotamus,
it is good, meaning that a large meal from the palace will
follow.

• If a man sees himself in a dream plunging into the river, it
is good, meaning purification from all evil.

b. Inauspicious dreams (bad dreams)

• If a man sees himself in a dream seizing one of his lower
legs, it is bad, meaning a report about him by those who
are yonder (the dead).

• If a man sees himself measuring barley in a dream, it is
bad, meaning the rising of worlds against him.

• If a man sees himself bitten by a dog in a dream, it is bad,
meaning that he is touched by magic.

• If a man sees himself in a mirror in a dream, it is bad,
meaning that he will find another wife.

• If a man sees himself in a dream making love to a woman,
it is bad, because it means mourning.

• If a man sees himself in a dream looking at an ostrich, it

is bad, meaning that harm will befall him.

• If a man sees himself in a dream feeding cattle, it is bad,

because it means wandering the earth.

• If a man sees himself in a dream casting wood into water,

it is bad, meaning bringing suffering to his house.

• If a man sees himself removing the nails of his fingers,

it is bad, because this means removal of the work of his

hands.

• If a man sees the gods making cessation of tears for him

in a dream, it is bad, because it means fighting.
It is not known to what extent these interpretative guides were used in daily life. Few people would have had access to such texts; few people were literate and able to read them. There are indications that many villages may have had a priest, or a local scribe, or else who could interpret dreams in which deceased relatives or gods might appear. Some later New Kingdom Deir el Medina texts refer to “the wise woman” of the village who supplied advice. Such seers were consulted not only concerning dreams, but also on other is- sues affecting daily life including disputes with neighbors, or concerns over failing crops. Dreams could be powerful experiences and revelatory dreams in particular, were taken seriously [11].

Most Prevalent Dreams

Like today, the ancient Egyptians had some dreams that were more prevalent than others were. People often dreamed of breaking stones, which the Egyptians interpreted as having one’s teeth fall out. Dreaming of your teeth falling out is still a common dream today [11].

T. Asaad

Many often dreamed of drowning in the Nile or climbing to the top ship’s mast. However, some other common dreams seem to defy explanation. Dreaming that your face turned into a leopard was a common dream in ancient Egypt [11].

Reading Dreams in Different Ancient Cultures, Compared to Egypt

Dream interpretation differed in various ancient cultures. The symbolic meaning of items in a dream might even have contradictory explanations. Table 2.1 is an illustration of how four different common items are symbolically interpreted in the ancient Egyptian culture, compared to other ancient cul- tures, namely the Assyrian, the Greek, and the Hebrew [8].

How Did Ancient Egyptian Medicine Deal with Sleep Disorders?

The medicine of ancient Egypt is one of the oldest docu- mented scientific disciplines. It is said that, “If one had to be ill in ancient times, the best place to do so would probably have been in Egypt.”

The Egyptian priest–physicians served a number of im- portant functions, discovering and treating a lot of diseases, through some powerful magic (rituals, spells, incarnations, talismans, and amulets), deities, scripture, herbal medicine, and some other methods.

Unfortunately, only a few papyri have survived, from which one could learn about Egyptian Medicine [12]:
1. The Edwin Smith Papyrus describing surgical diagnosis

and treatments (Fig. 2.3)

Snake

Good omen, indicating that the dreamer would soon settle some dispute

Seizing a snake = protection from angels

Ill omen (illness, enemies)

Snakes = secure livelihood Snake bite = doubled income

Table 2.1

Item

Egyptian

Assyrian

Greek

Hebrew

Fig. 2.3

[12]

Dream symbols in different ancient cultures [8]

Pot

Filling a pot = bad omen
Beer poured from a pot = robbery

Empty pot = poverty
Full goblet = children and fame

Wine poured from pots = serenity Drinking a cup dry was lucky

Cooking pots = peace and domes- tic calm

Edwin Smith Papyrus

Tree

Sitting in a tree = troubles could be overcome

Cutting date palm
trees = solution of problems

Trees for making
ships = unlucky sign (except for carpenters and seamen)

Palm trees = punishment for past sins

Bird

Catching birds = loss of some- thing precious

Meeting a bird = return of lost property

Eagles = rulers
Wild pigeons = immoral women

Good omen, except owls (bad luck)

2 Sleep in Ancient Egypt

2. The Ebers Papyrus (dates from the sixteenth century B.C.) on ophthalmology, diseases of the digestive sys- tem, the head, the skin and specific maladies like aAa, which some think may have been a precursor of aids and others, perhaps more reasonably, consider to have been a disease of the urinary tract, a compilation of earlier works that contains a large number of prescriptions and recipes (Fig. 2.4)

3. The Kahun Gynaecological Papyrus

4. The Berlin Medical Papyrus

5. The London Medical Papyrus

6. The Hearst medical papyrus repeats many of the recipes
found in the Ebers papyrus

7. The Demotic Magical Papyrus of London and Leiden contains a number of spells for treating physical ailments

Insomnia

The Egyptian medical papyri mentioned for the first treat- ment in history that the ancient Egyptians described use of poppy seed ( opium) as hypnotic to relieve insomnia, head- ache, and also as an anesthetic [12].

Lavender, which is considered herbal sleep remedy, was used by the Egyptians to preserve their mummies, which has something to do with their belief about death as an eternal sleep [13].

Chamomile was considered a sacred plant by the ancient Egyptians, being offered to the gods. It was used for different purposes as a cosmetic treatment, anesthetic, and antiseptic. It was known to induce a state of quiet and serenity foreword for sleep [14].

Snoring

Ebers Papyrus mentioned that Thyme—a herb used by the Egyptians for embalming—was thought to be beneficial in reducing snoring [15].

An interesting story about snoring was mentioned in one of the famous myths about “Isis” (the mother of goddess of

ancient Egypt). According to this story, Isis found Ra ( the sun god), asleep one day, snoring loudly, and saliva drip- ping from his mouth. She collected the saliva and mixed it with earth to form poisonous serpent, which she later used to force Ra to disclose his secret name to her! [16]

Narcolepsy

The Edwin Smith Papyrus referred to epilepsy without clear description of narcolepsy, as described in the translated Bab- ylonian texts [17].

Hypnosis

The ancient civilizations of Egypt, China, and Tibet used hypnosis in one way or another, with reference to deep sleep. Sleep temples are regarded by some as an early instance of hypnosis, over 4000 years ago, under the influence of Imho- tep, who served as chancellor and high priest of the sun god Ra. Such sleep temples were like hospitals of sorts, healing a variety of ailments, perhaps many of them psychological in nature. The treatment involved chanting and placing the patient in a trancelike or hypnotic state, before analyzing his dreams, to determine the treatment [18].

Conclusion

As in any other field of science, the ancient Egyptians did have their own fingerprint in the area of sleep medicine. They linked sleep to death (and afterlife), and practiced dream interpretation in a rather systematized and construc- tive way. Their medical papyri included mentioning of some sleep disorders and their treatments. However, more research and studying are still needed to clarify some of the many undiscovered secrets of the miraculous Egyptian civilization regarding the mysterious world of sleep.

18 T. Asaad

Fig. 2.4 Ebers Papyrus [12]

2 Sleep in Ancient Egypt

References

1. Humbert JM, Pantazzi M, Ziegler C. Egyptomania: Egypt in West- ern art,1730–1930 (exhibition catalog). Paris: Musée du Louvre; 1994.

2. Allen J. Middle Egyptian: an introduction to the language and culture of hieroglyphs. Cambridge: Cambridge University Press; 2000.

3. Szpakowska K. Behind closed eyes: dreams and nightmares in ancient Egypt. Swansea: Classical Press of Wales; 2003.

4. Lucy G. And now a word from ancient Egypt—the lucid dream exchange. 2009. http://www.dreaminglucid.com/issues/LDE50.pdf

5. Assmann J. Death and salvation in ancient Egypt. Ithaca: Cornell
University Press; 2006.

6. Barbara O’Neill. Sleep and the sleeping in ancient Egypt. Pub-
lished on magazine articles on egyptological. 2012. http://www. egyptological.com/2012/04/sleep-and-the-sleeping-in-ancient- egypt-8146. Accessed 3 April 2012.

7. Gotthard GT. Dreams as a constitutive cultural determinant—the example of ancient Egypt. Int J Dream Res. 2011:4(1):24–30.

8. Diagram Visual Information Limited. Understanding dreams. Col-
lins: HarperCollins; 2005. pp. 220–23 (1).

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12. 13. 14. 15. 16. 17. 18.

Gardiner AH, Litt D, editors. Hieratic papyri in the British museum, 3rd series: Chester Beatty gift (Vol. I. Text, pp. 7–23; No. III (Brit.Mus.10683), Plates 5–12a, Recto, The Dream Book). London: British Museum;1935.

British Museum. The dream book. http://www.britishmuseum.org/ search_results.aspx?searchText=Dream+book.
Libby Pelham BA. Ancient Egypt and dream analysis. Updated 16 Aug 2012. http://www.analysedreams.co.uk/ancient-egypt-dream- analysis.html. Aug 2012.

Ancient Egyptian medicine—smith papyrus—ebers papyrus. http://www.crystalinks.com/egyptmedicine.html.
An herbal sleep remedy for Egyptians. http://www.sleeppassport. com/herbal-sleep-remedy.html.

Ancient Egypt. Herbal secrets. Chamomile. http://:www.angel re.

com/ut2/egyptherb/chamomille.html.
Sleep and snoring—non-drug and non-surgical approaches. http:// http://www.breathing.com/articles/sleeping-snoring.htm.
Isis–Myth encyclopedia. http://www.mythencyclopedia.com/ Ho-Iv/Isis.html.
A brief history of sleep medicine. http://www.talkaboutsleep.com/ sleep-disorders/archives/history.htm.
Ancient hypnosis—hypnosis in history. https://hypnosisinhistory. com/ancient-hypnosis.

Sleep Medicine in the Arab Islamic 3 Civilization

Shahira Loza

Medicine is a science from which one learns the states of human body with respect to what is healthy and what is not, in order to preserve good health when exists and restore it when it is lack- ing. (Ibn Sina Avicenne Canon 1.3, 1025 AD) [1]

Islamic civilization covers a time frame between the seventh century and the fifteenth century spreading to a vast area from Spain in the West, to China in the East and encom- passing the whole of northern Africa including Egypt as well as Syria, Palestine, Transjordan, Central Asia, and parts of western India. Later, it was spread by Muslim merchants to the Far East: Malaysia and Indonesia [2].

The two sources of Islamic jurisprudence are the Quran and Hadith. The Holy Quran is the basis of Islamic religion and Hadith the teachings of Prophet Muhammad (Peace be upon him, PBUH) as recorded by his followers. Among Ha- diths are rules pertaining to personal hygiene, bathing, drink- ing, marriage, circumcision, sanitation, and sleep posture [3].

Muslim medicine has an important theological basis, with reference to taking care of the body, a religious obligation for the Muslims. Quranic verses and Hadith played an impor- tant role in creating the Islamic frame of mind of the future physicians.

Sleep specifically is mentioned in the Quran as a miracle and a sign of Allah.

And among His Signs is the sleep that ye take by night and by day, and the quest that ye (make for livelihood) out of His Bounty: verily in that are signs for those who listen.

S. Loza ()
Cairo Centre for Sleep Disorders, 55 Abdel Moneim Riad, Mohandes- sin, Cairo, Egypt

“And He it is Who makes the Night as a covering for you, and Sleep as Repose, and makes the Day (as it were) a Res- urrection.”

With the rise of the Abbasid dynasty during AD 750–1158 known as the Islamic golden age, a great deal of develop- ment occurred in science, philosophy, and medicine. Physi- cians occupied a high social position in the Arab culture [4]. Prominent physicians served as ministers or judges and were appointed as royal physicians, not only to Caliphs but also in foreign courts. Khubilai, the founder of the Yuan dynasty in China, appointed a Moslem physician [5]. The title of “Hakim” was bestowed upon physicians, which translates to “wise” as they were acknowledged for their great wisdom as well as their medical knowledge. This title is still used today in most Arab countries.

During the reign of caliph Haroun Al Rashid AD 830, “Bait ul Hikma” or the House of Wisdom was built repre- senting an educational institute devoted to translation and re- search [6]. Hunayn Ibn Ishaq d.c. AD 873–877, Yuhanna Ibn Masawyh AD 777–857, and Al Kindi were among the most famous translators of the period [2]. It is through these Ara- bic translations that medieval Europe rediscovered Greek medicine. Specifically, some works of Galen that had been lost in Greek medicine were only found in Arabic transla- tions [2, 7].

Among many physicians who contributed to medicine in Islamic civilization is Avicenna or Abu Ali Al Hussain Bin Ali Ibn Sina AD 980–1037. He is considered to be the most legendary physician of the Middle Ages [8]. His Canon of Medicine (Kitab Al Qanun fi al tibb), an encyclopedia of medicine in five books, completed in AD 1025 and consid- ered to be one of the most famous books in the history of medicine, presents the medical knowledge of the time. It supports the ancient theory of four humors and four tem- peraments and extended it to encompass emotional aspect,

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_3, 21 © Springer Science+Business Media, LLC 2015

S. Loza

Fig. 3.1 Text and painting, Avicenne’s Canon of Medicine, 1632 AD

mental capacity, moral attitudes, self-awareness, move- ments, and dreams. He dedicated a chapter in this book to sleep and vigilance (Chap. 9 in the first book) [1]. (Fig. 3.1)

Avicenna describes several aspects of sleep and its ben- efits in this chapter. He states that sleep in moderation as- sists and renews bodily functions and comforts the psyche. “Sleep arrests the dissipation of breath,” which he considers to be the vital power. The effects of sleep are recognized as restoring the equilibrium in quantity and quality of humors. He mentions that sleep also remedies the weakness due to dispersal of breath attributed to bodily fatigue, coitus, anger, or violent disturbance (Fig. 3.2).

Another interesting aspect mentioned in the Canon is the subject of sleep and the elderly; that sleep provides a hu- mectant and warm action which is specially advantageous to those advanced in age. Galen is quoted in the Canon saying “I am now careful to obtain sleep as I am an old man, the hu- midity which sleep brings is beneficiary to me” and that he consumes every evening lettuce leaves with aromatics—the lettuce to help him sleep; the aromatics to rectify the cold- ness of the lettuce.

In the same chapter, there is a description of how to obtain sleep: “A bath taken after the digestion of a meal, plenty of hot water poured over the head.” He also makes a note of the possibility of using more potent treatments, the details of which, he specifies, would be in the section of the book under medicaments. He therefore had a behavioral as well as a pharmacological approach to treat insomnia. The tim- ing of sleep is also mentioned: the good qualities of night

sleep, as it is deep and continuous. He also mentioned that if one is used to sleeping during daytime, the change to night sleep should be gradual and not abrupt. This is an example of a behavioral approach to circadian rhythm problems, a rule that is used today. He also suggests sleep hygiene rules: “Healthy persons should pay attention to sleep. It must be moderate, properly timed, and excess must be avoided. They must avoid remaining awake too long, that might result in in- juring mental faculty.” He therefore associated lack of sleep and insomnia to mental health. He gives a description of the best sleep being “the deep sleep after the passage of food from the stomach and after ridding off flatulences and eruc- tations, for to sleep on this is detrimental in many ways; it keeps the person turning from side to side, bringing harm to the person. Thus a walk before sleeping to ensure digestion is recommended. It is also bad to go to sleep on an empty stomach.” Today, we know that hunger will interfere with sleep, that sleeping after a heavy meal could lead to gastro- esophageal reflux and disturb sleep.

An interesting part of this chapter is the description of daytime sleepiness as related to illnesses: “Depending on humidity and catarrhal states resulting in bad color of health, heavy spleen, nerves losing their tone, lethargy, lack of li- bido, and leading to tumors and inflammatory conditions.” Avicenna explains that among reasons for these injurious ef- fects is the sudden interruption of sleep causing natural fac- ulties to be dulled. This description could well be symptoms of obstructive sleep apnea syndrome.

3 Sleep Medicine in the Arab Islamic Civilization

Fig. 3.2

Nervous system, Avicenne’s Canon of Medicine, 1632 AD

in his time. One of the important symptoms he discusses is dyspnea during sleep that leads to awakening [11].

Many other physicians contributed to medicine during the Middle Ages. Contributions of a few might be indirectly re- lated to the science of Sleep Medicine.

Ali Ibn al Tabary AD 838–870 wrote “The Paradise of Wisdom” with nine discourses including diseases and condi- tions affecting the head and nervous diseases. Abu Bakr al Razi (Razes) AD 865–925 mentioned and counseled against over prescribing Hashish [12].

Ali Ibn Abbas al Majusi (Haly Abbas) AD 949–983 wrote “The Complete Art of Medicine” (Kitab Kamel As Sinaa al Tibbiya) and “Royal Book” (Kitab al Maliki). His writ- ings deal with medical ethics, scientific research method- ology, neuroscience, and psychology [13]. Al Zahrawi AD 936–1013 used gold and silver tubes to overcome laryngeal obstruction and keep the upper airway patent. He surgically removed laryngeal tumors and performed tonsillectomies. He used opium and hashish as anesthetics [14]. Ibn al Nafis AD 1213–1288 was the first to discover the pulmonary cir- culation (the lesser circulation) [7].

Abu Marwan Ibn Zohr (Avenzoar) AD 1091–1161, an Arab physician born in Seville, wrote on preparation of drugs, reported on tracheotomy, and gave an accurate de- scription of neurological disorders including meningitis and intracranial thrombophlebitis [2].

Another important contribution to medicine is the devel- opment of hospitals or Bimaristans. The word Bimaristan is Persian in origin; Bimar is a disease and Stan is a place. A large number of hospitals were developed in the Islamic world in the eighth century, an institutional place for the car- ing of the sick as opposed to the areas attached to temples where patients were attended by priests, and they attended a therapy which consisted of prayers and sacrifices [6].

The first Bimaristan was built in Damascus by Caliph Al Walid bin Abdel Malik circa AD 707 [14]. According to Ibn Batuta, a fourteenth-century traveler from Tangier to China, there were 34 hospitals in the east; some can still be vis- ited in Baghdad, Aleppo, and Cairo. These establishments were divided into quarters for the insane, pharmacy, library, mosque, and Quranic school. Construction of these estab- lishments was regarded as holy work. Caliph al Mugtadir made preliminary examination compulsory before practicing medicine and gave one of his doctors the task of organiz- ing the tests, making them into an early model of teaching hospitals [4].

The most renowned of Medieval Islamic hospitals is Al Mansouri hospital built in Cairo AD 1284–85 by Sultan Al Mansour Qalawun. There were specialized wards for general medicine, surgery, and those dealing with fractures, fever, eye diseases, and with separate sections for males and fe- males. Admission to the Bimaristan was regardless of race, color, or religion and there was no limited time for inpatient

Finally, Avicenna recommends that the posture of sleep is best if started on the right and then turning to the left. This, in the author’s view, is according to medical and Islamic law, probably on account of earlier Prophetic Hadith. He contin- ues by explaining that the prone position helps digestion but considers sleeping on the back or supine position bad practice that leads to stroke, paralysis, and nightmares. He attributes the problem to accumulation of excreted matter in the tissues of the back preventing them from entering the natural chan- nels like the nostrils and the palate. He considered the supine position to be a weakness due to weakness of the muscles and the limbs; they are unable to support themselves on ei- ther side, as the back is stronger. The consequence is that such individuals sleep with their mouth open as the muscles, which keep the jaws closed, are too weak to maintain them in the open position. Again he describes mouth breathing in individuals with upper airway obstruction [9, 10].

Avicenna also discusses respiratory diseases in volume three of the Canon of Medicine covering the functional anat- omy and pathophysiology of the pulmonary diseases known

S. Loza

treatment. Patient stayed till they fully recovered, when they were able to eat a full chicken [2, 6, 14]. Special care is noted in the archives of Sultan Qualawun trust: points pertaining to cleanliness, food, and music therapy to help patients fall asleep. Also, there is a description of the teaching facility and notably the time shifts of caregivers [14].

Medieval Islamic medicine emerged as an intense cross- pollination with other cultures, by translation, trade, and travel. The Arab Islamic period formed an important link in the chain of scientific advancement between the Greek civi- lization and late medieval and renaissance Europe. Unfortu- nately, much of this rich culture has been lost as a result of the Mongol invasion in AD1258 [15]. Ibn el Nadim’s Fihrist (Catalogue), AD 938, lists many of those works and gives an indication of the losses sustained [6, 7, 15]. It has been estimated that less than one in thousand books listed has sur- vived. It is remarkable that in the eleventh century, a chapter in the medical textbook, the Canon, considered a reference, which was dedicated to sleep covering topics for many cen- turies that are still being researched today.

References

1. Wikipedia Contributors. Wikipedia, the free encyclopedia. [Online].
2012. http://en.wikipedia.org/w//index.php?title=The_Canon_of_
Medicine&oldid=511971595. Accessed 20 Aug 2012.

2. Lyons AS, Petrucelli RJ. Medicine under Islam Arabic medicine. In: Rawls W, editor. Medicine an illustrated history. New York:
Abrams; 1987. pp. 294–317.

3. Bukhari HS. Abu Abdallah Mohamed bin Ismail el Bukhari 854 AD. Riyadh K.S.A: Risalah Press; 2009.

4. Sournia JC. The muslem digression. In: Sournia JC, editor. The illustrated hisotry of medicine. England: Harold Starke; 1992. pp. 122–37.

5. Clements J. A brief history of Khubilai Khan, Lord of Xanadu Emperor of China. Philadelphia, Pennsylvania: Running Press; 2010.

6. Nagamia HF. Islamic medicine history and current practice. Interna- tional Institute of Islamic Medicine (IIIM). 1995 April 30.

7. Pormann PE, Savage-Smith E. The emergence of Islamic medicine in medieval Islamic medicine. Edinburgh: Edinburgh University Press; 2007.

8. Abdel Rehim S. Al Tibb Al Nafsi Fi Al Islam (Psychiatry in Islam). Damascus: Al Faraby; 1997.

9. Ibn Sina AHA. Al Qanun Fi Al Tibb (Avicenna Canon of Medicine). Beirut Lebanon (arabic): Ezz el Din Press; 1987. pp. 980–1037. 10. Gruner OC. Chapter 9 in the Second Thesis, The regimen proper

for the physically matured, in Part 3 Preservation of health. In: A treatise on the Canon of Medicine of Avicenna—incorporating a translation of the rst book. London: Luzak; 1930. pp. 417–9.

11. Hashemi SM, Raza M. Science Daily. [Online]. 2009. http://www.

sciencedaily.com/releases. Accessed 19 Aug 2012.
12. Nahas GG. Hashish in Islam. Bulletin NY Academy of Medicine.

1982 December. pp. 814–30.

13. Wikipedia Contributors. Wikipedia, the free encyclopedia. [Online].

2012. http://en.wikipedia.org/w/index.php?title=%27Ali_ibn_al-

%27Abbas_al-Majusi&oldid=511933070. Accessed 21 Aug 2012.

14. El Haddad MHI. Al Mogmal Fi Al Athar We Al Hadara Al Islamia (Comprehensive text in antiquities and civilization). Egypt: Zahran
Al Shark; 2006.

15. Prioreschi PA. A history of medicine: byzantine and Islamic medi-
cine, 2nd edn. Omaha: Horatius; 2001.

Sleep Medicine in Ancient and Tradi- 4 tional India

V. Mohan Kumar

Many centuries before the advent of the Aryans into India,

the Indus Valley civilization ourished in this region as is

evident from the excavations at Mohenjo-Daro and Harappa. Most of these regions are now in Pakistan. The knowledge of the original inhabitants about body function and medicine must have been based on magical, religious, and empirical practices [1]. When the Aryans entered the Indus Valley, they brought with them their knowledge of gods, medicine, and physiology. The chief sources of their culture and knowl- edge were the four Vedas. Four Vedas (books of knowl- edge), twelve Upanishadas (brief catechistical treatises) and various Smritis (canons of law) are the principal sources of knowledge of ancient Indian Philosophy. Though these scriptures are believed to have been brought to India by the Aryans, there is de nitive evidence to assume that many ele- ments of the Indus Valley civilization were assimilated by the Aryans [1].

According to traditional Indian belief (or Hindu religious belief) the Vedas were told to the sages by Brahma, the cre- ator of man, probably about 6000 years before Christ. But according to most scholars, even the Rig Veda, which is the oldest among Vedas, is not older than 2000 years before Christ [1]. The four Vedas are Rig Veda, Sama Veda, Yajur Veda, and Atharva Veda. They contain hymns and prayers addressed to different deities. Even in these purely religious texts we find a reflection of anatomical, physiological, psy- chological, pathological, and therapeutic views, which may have some symbolic origin and which had found their re- flection in the traditional Indian medicine, called Ayurveda. The meaning of the term Ayurveda is knowledge of life [2, 3, 4]. Though the word Ayurveda sounds as if it is related

V. M. Kumar ()
8A, Heera Gate Apartments, D.P.I. Junction, Jagathy, 695014 Thiruva- nanthapuram, Kerala, India
e-mail: wfsrs2005@rediffmail.com

V. M. Kumar

Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram, Kerala, India
e-mail: wfsrs2005@rediffmail.com

to the Vedic period, it was derived much later. According to traditional Indian belief, Brahma, the creator, also provided the knowledge contained in the Ayurveda. Unfortunately, Ayurveda in its original form is not available now, but most of its contents are revealed in the Samhitas (encyclopedia) written by Charaka and Sushruta in 1000 BC [5, 6].

Charaka has dealt with sleep and sleep disorders in more detail. Charaka Samhita gives details about his approach to sleep. According to Ayurveda, there are three Dhatus (basic factors) which decide the health or ill health of an individ- ual. They are called Vata, Kapha, and Pitta. They cannot be translated into any other language, as they do not have any equivalent terminology either in modern physics or in physiology and medicine. When they are in their natural state they provide the individual with strength, happiness, and long life. On the other hand, if these Dhatus are altered they bring about health problems. According to Ayurvedic concepts nidradhikya (excessive sleep) is caused by distur- bance in Kapha, and asvapna (sleeplessness) is caused by disturbance in Vata.

According to Charaka Samhita “When the mind gets tired, when the senses get dulled and incapable, the man goes to sleep.” In Ayurveda sleep is classified into seven types on the basis of its causative factors. Sleep can be either physi- ological or pathological [2, 1]. Thus seven types of sleep are produced as a result (or consequence) of night time (physi- ological sleep), tamas (ignorance), kapha (one of the basic factors or Dhatus), mental exertion, physical exertion, bad prognosis of disease or as a side effect of disease (e.g. fever). The night sleep is considered good, and it is described as that which “nurses all the living beings.” The sleep which is caused by tamas is considered as “the root cause of sinful acts.”

Proper or improper sleep would decide whether you are happy, miserable, obese, emaciated, strong, weak, virile, sterile, knowledgeable or ignorant, long-lived, or short- lived. The Charaka Samhita goes on to say that if the sleep is proper it brings about happiness and longevity. The con- sequences of both deficient and excess sleep will be just the

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_4, 25 © Springer Science+Business Media, LLC 2015

V. M. Kumar

opposite. Sleeping during the day time, in all seasons, is ad- vocated for the young, weak, tired, and those suffering from various diseases. During summer season (when nights be- come shorter) some sleep during the day is advocated for all. In other seasons, daytime sleep is not advocated. Although any comfortable position of the body may be regarded as suitable for sleep, sleeping on one’s right side (daksirasana) is considered the most favorable position for sleep. Accord- ing to them sleeping in sitting posture does not produce any harm. Keeping awake during night causes roughness in the body. Obesity and emaciation are specially mentioned as two conditions caused by improper sleep and diet.

For some reason, if one does not get sleep, it can be achieved by massage, bath or by consuming milk, rice with curd, alcohol, meat soup or by listening to some agreeable music [2, 4]. In addition, the following medicinal prepara- tions are suggested for curing insomnia [2]:

1. Root of kaka jangha (Peristrope bicalyoulata) tied onto the head produces sleep.

2. Application of til oil (gingelly oil) and sour fermented drink called kanjika on the head, legs, and heels produce sleep.

3. Powder of pippali mula ( Piper longum) boiled with guda (jaggery) can be used as linctus to cure even chronic sleeplessness.

4. Soup of Sali parni( Oryga sativa), bala ( Sida Cordifolia), Eranda ( Ricnus communis), yava ( Solanum melongeva), and mudga parni ( Phaseolus mungo) produce instanta- neous sleep.

5. Vrntaka ( Solanum melongeva) boiled at night and mixed with honey when consumed produces immediate sleep.

On the other hand, excess sleep can be dealt with by elimi-

nating dosas from the body and head through various means like purgation, emesis, etc. Application of paste prepared from nilotpala ( Nymphaea stlellata), seeds of sigru ( Mo- ringa oleifera), and naga kesara ( Masua ferrea) prevents excessive sleep [2].

Sushruta had devoted one complete chapter on the analy- sis of dreams. He considered them as omens. According to him, a favorable or unfavorable termination of a disease could be predicted from the dreams. Though Charaka fully recog- nized the lack of meaning in most of our dreams, Charaka Samhita deals, at length, with the theories of dream. Chara- ka, Sushruta, and Vagbhatta, the great medical scientists of ancient India, did believe that the dreams are produced when the vital equilibrium between the three dhatus is disturbed. These are seven types of significant dreams [7]. They are dreams about objects seen earlier, things which we have heard earlier, past experience, wish fulfillment, imagination, premonition, and morbid things.

Ayurveda does recognize prayer as one form of treatment. The goddess of sleep Nidra devi is invoked to get sleep for

the patient suffering from insomnia [2]. The following man- tra should be chanted:

“Om shuddhe yu yogini maha nidre svaha.” Along with chanting of this mantra, white tila should be put on the body of the patient. By this procedure he is expected to get sleep.

The subsequent writings like the Yoga Sutras of Patanjali (second century BC) give an account of the manner in which a healthy body can be prepared for higher states of mental function like Samadhi (meditation) [8]. Though Ayurveda and Yoga are still practiced in India, the scripts on Yoga pro- vided the most interesting information regarding the func- tioning of brain, consciousness, and sleep [9].

Yoga is popularly considered as a physical exercise (Asana), the practice of which maintains a healthy body. But traditional Indian philosophy considers physical exer- cise as only a step towards that mystical experience, which is achieved by physical and mental practice. Various treatises on Tantric Yoga shed some light on the supposed neural basis of many of these Yogic phenomena [10]. According to this, there are six to eight nerve centers located at different levels in the human body. These are called Chakras (or centers).

The lowest one, which is located at the level of the anus and sex organs, is the Muladhara chakra. This center con- trols the sexual activities. Similarly, different chakras are assigned various functions. The biological energy which resides at the level of the chakra has been referred to as Kundalini Shakti (Serpent power). The practitioner of yoga successfully channels his Kundalini Shakti through the suc- cessive chakras (nerve centers) till he can activate the chakra of the highest level. Once he learns, by practice, to control the chakras he can not only control all the autonomic func- tions but he can also acquire skills and powers, which are super normal. In order to understand the concept of sleep and wakefulness in Yogic terminology, one has to understand or appreciate the concept of consciousness in Yoga.

In modern understanding, consciousness is considered as a by-product of the proper functioning of the brain, and it ceases to exist with death or with damage to the brain, but according to Yogic concept consciousness is an expression of God and it is within every human being. In fact, every- thing in the universe is derived from and is the expression of God. So, the consciousness, mind, and matter are the three basic derivatives of God (or the Ultimate Reality). These three basic derivatives of reality exist in many subtleties and they also function at different levels. What we know of these derivatives of reality on the physical plane is their crudest expression at the lowest level. It is claimed that conscious- ness, through various intermediary states gives rise to the five elements ( Panchabhutas) [11]. These elements, under the influence of the three gunas (or energies), bring into exis- tence the universe and all its constituents including man him- self. The three gunas are the sattava, rajas, and tamas. The

4 Sleep Medicine in Ancient and Traditional India

sattava represents intelligence, knowledge, cognition, etc. whereas rajas represents energy, activity, change, etc. The tamas stands for inertia, ignorance, etc. These three energies are symbolized in the Puranas as three goddesses namely Saraswati, Lakshmi, and Kali, respectively [12]. Depending on the permutations and combinations of the influence of these three energies man goes into states of sleep, dreaming, and waking.

After appreciating a bit about the concept of conscious- ness in Yogic philosophy, we can try to understand the four states of consciousness. The four states are termed and in- terpreted differently by different authors. When they are de- scribed as different stages through which a yogi passes dur- ing his meditation, it is given one type of interpretation. It has been dealt with in some detail in the Mandukya Upanishad. According to them the four states of consciousness are Jag- rat, Svapna, Sushupti, and Turiya [13]. Jagrat is the waking state in which consciousness is in touch with objects around. Though the word meaning of Svapna is dream, it is consid- ered as that state in which there is some mental image as a re- sult of recall of memory or imagination. In this state he is not asleep. The state of Sushupti resembles dreamless sleep, but it is considered as totally different from sleep. In this state there is no mental image, and his mind is totally blank. A yogin is said to derive great pleasure after going through this state while practicing meditation. The yogin passes from Ja- grat through Svapna and Sushupti before reaching the fourth and final state called Turiya. The word meaning of Turiya is “fourth.” This is the highest spiritual state of consciousness, where one is in union with the ultimate reality. During this state an individual is said to be oblivious of the internal and external world. A voluntary control over thought process is essential for obtaining this state of consciousness.

According to a more radical interpretation, sleep and dreaming are two different states of consciousness [14]. In this interpretation Jagrat (or Vaisvanara) is the waking state, whereas Svapna (or Taijasa) is the dreaming state. In India, as in other countries, people have shown deep inter- est in the interpretation of dreams. The Puranas have nu- merous stories of dreams and dreamers. One of the slokas on Yoga when translated into English, states that “man sees his waking desires fulfilled while asleep.” The statement is very close to the theory of Freud. The Sushupti (or Prajana) is the dreamless sleep, equivalent to slow wave sleep. Ac- cording to Chhandogya Upanishad, man gets united with the pure Being during sleep [15]. In other words, people go to Brahma during sleep, though they do not realize it. One can always find the emphasis laid on deep sleep throughout the ancient literature.

According to Sushruta Samhita ten nerves control the various functions of the body. Man goes to sleep by using two of them and with the help of two others he wakes up. Curiously enough, at many places in the ancient literature it

is mentioned that one dreams when the nerve center “Svap- navha nadi” is functioning.

Several studies were undertaken during the last several years to understand and analyze scientifically the various claims made on yogic achievements. The first scientifically documented investigation on Yoga was initiated in 1924 at Lonavala (Poona, India) by a yogin named Swami Kuvalay- ananda. He and his colleagues studied many psycho-phys- iological functions during yogic practices [16]. Then came a period during which scientific proofs were provided for many of the claims by yogins like stopping the heart. These findings by some Western and Indian scientists were later proved incorrect [22]. But systematic scientific research showed that the yogin does possess the ability to control his autonomic nervous system, in a remarkable way. It is claimed that the fall in respiration, blood pressure, and heart rate, during yogic relaxation postures, are nearly 10 % more than that achieved during deep sleep. Das and Gastaut [17] were possibly the first to study the electroencephalographic (EEG) changes during meditation. They observed high volt- age, high frequency waves during the early stages of medita- tion, and sleep-like EEG in the later stages. But their sub- jects were those who had practiced meditation for a short period only. Several studies were undertaken on renowned yogins at All India Institute of Medical Sciences in 1960’s by Anand, Chhina, and Baldev Singh [18, 18–21]. The infer- ences arrived at by them, by and large, remain valid even today, in spite of studies undertaken in various laboratories of the world during the past several years. It can be summa- rized that during the practice of Yoga and also as a result of this practice, there is an increase in the amplitude of alpha activity, more synchronization and spread of synchronized waves to the anterior regions of the brain. There were dif- ferences in the EEG pattern observed in different individu- als during the later stages of meditation. Some yogins had predominant theta waves, and some others showed spurts, of short EEG desynchronizations in between [11]. The EEG pattern observed during meditation is less prone to alteration by external stimuli. In this state, sound and other peripheral stimuli do not produce desynchronization of the EEG. It does produce EEG desynchronization, in the same subject, when he is not doing meditation.

Many of the statements regarding Yoga and its effect on sleep need confirmation, particularly the relationship be- tween the state of meditation and sleep. Can meditation in any way compensate for normal sleep? There is some sug- gestive evidence which has shown the absence of compensa- tory increase of sleep in the sleep-deprived yogi. More sys- tematic research is required in this field. It is claimed that yogins can exercise a control over all states of consciousness including sleep. They are said to be capable of eliminating the dream phase of sleep (a claim which needs substantiation by scientific studies). It is also claimed that a Yogi passes

V. M. Kumar

through a special kind of sleep called yogic sleep ( Yog-ni- dra), and he is capable of controlling its progress, including elimination of dreams.

After having taken the liberty of looking into the yogic practice from a scientific angle, we should be also prepared to listen to what the yogins have to say about scientific in- vestigations. They really do not think very highly of the scientific investigation. According to them, consciousness, which is the penultimate reality of existence, and the source of mind and matter, cannot be investigated with a physical apparatus, however elaborate and imposing it may be. A yogin living in the foothills of Himalayas was approached by a team of scientists who wanted to investigate him dur- ing his meditation. He subjected himself to their tests. They did their tests and thanked him profusely before leaving the place. The yogin was never told about the results of their test, nor was he interested in knowing about it. He did not want to offend the scientists by telling it to their faces. According to him the ultimate secrets of existence cannot be investigated using physical means. Only physical data can be verified by physical means.

Though the scientific approach in various ancient beliefs has not proved all the claims, it is certainly worth looking into these aspects as seen by the ancient people. Thomas Henry Huxley said in 1881 “It is easy to sneer at our ances- tors—but it is much more profitable to try to discover why they, who were really not one whit less sensible persons than our own excellent selves, should have been led to entertain views which strike us as absurd.” It is in this spirit that we should build a borderless mind, which connects the past with the present. The idea is not to “recreate” the past but “under- stand” the past by using new science.

References

1. Anand BK. Yoga and medical sciences. Ind J Physiol Pharmacol. 1991;35:84–7.

2. Keswani NH. Medical heritage of India. In: Keswani NH, editor. The science of medicine and physiological concepts in ancient and medieval India. New Delhi: National Book Trust; 1974. pp. 3–52.

3. Dash VB, Kashyap VL. Diagnosis and treatment of diseases in ayurveda. New Delhi: Concept; 1981. p. 626.

4. Kurup PNV, Raghunathan K. Human physiology in Ayurveda. In: Keswani NH, editor. The science of medicine and physiological concepts in ancient and medieval India. New Delhi: National Book Trust; 1974. pp. 67–78.

5.Sharma RK, Dash VB. Agnivesa’s Charak Samhita. Varanasi: Chowkhamba Sanskrit Series office; 1976. p. 619.

6. Bhishagratna KKL. The Sushruta Samhita—an English translation based on original texts. Calcutta: Kaviraj Kunja Lal Bhishagratna; 1916. (Year Printed By M. Bhattacharyya, At The Bharat Mihir Press, 25, Roy Bag An Street).

7. Kaviratna, AC, Sharma P. The Charaka Samhita 5 vols., Indian medical science series. Delhi: Sri Satguru; 1997.

8. Bagchi AK. Concept of neurophysiology in ancient India. In: Kes- wani NH, editor. The science of medicine and physiological con- cepts in ancient and medieval India. New Delhi: National Book Trust; 1974. pp. 99–106.

9. Wood E. Practical yoga, ancient and modern. Being a new, inde- pendent translation of Patañjali’s yoga aphorisms, interpreted in the light of ancient and modern psychological knowledge and practical experience. London: Rider; 1951.

10. Kumar VM. Ancient concept of sleep in India. In: Liu S, Inoue S, editors. Sleep: ancient and modern. Shanghai: The Shanghai Scien- tific and Technological Literature; 1995. pp. 25–33.

11. Manchanda SK, Keswani NH. The yoga and the scientist. In: Kes- wani NH, editor. The science of medicine and physiological con- cepts in ancient and medieval India. New Delhi: National Book Trust; 1974. pp. 107–18.

12. Singh B, Chhina GS. Changing concepts of human consciousness from ancient to modern times. In: Kothari DS, Brahmachari D, Joshi SK, Chhina GS, Kurup PNB, editors. Seminar on yoga, sci- ence and man. New Delhi: Central Council for Research in Indian Medicine and Homoeopathy; 1976. pp. 284–9.

13.Pal K. Yoga and psycho-analysis. New Delhi: Bhagavan Das Memorial Trust; 1966. p. 180.

14. Taimni IK. Glimpses into the psychology of yoga. Madras: Theo- sophical Publishing House; 1976. p. 409.

15.Chhina GS, Singh B. Whither scienti c research on yoga. In:

Kothari DS, Brahmachar D, Joshi SK, Chhina GS, Kurup PNV, editors. Seminar on yoga, science and man. New Delhi: Central Council for Research in Indian Medicine and Homoeopathy; 1976. pp. 290–302.

16. Krishnananda S. Chhandogya Upanishad. Rishikesh: The Divine Life Society, Sivananda Ashram; 1984.

17. Das NN, Gastaut H. Variations de l’activité du coeur, de la médi- tation et de l’extase yoguique. Electroenceph Clin Neurophysiol. 1955;Suppl 6:211–9.

18. Singh B, Chhina GS. Some re ections on ancient Indian physiol- ogy. In: Keswani NH, editor. The science of medicine and physio- logical concepts in ancient and medieval India. New Delhi: National Book Trust; 1974. pp. 79–98.

19. Anand BK, Chhina GS. Investigations on yogis claiming to stop their heart beats. Ind J Med Res. 1961;49:90–4.

20. Anand BK, Chhina GS, Singh B. Studies on Shri Ramanand Yogi during his stay in an airtight box. Ind J Med Res. 1961a;49:82–9.

21. Anand BK, Chhina GS, Singh B. Some aspects of electroencepha- lographic studies in yogis. Electroencephalogr Clin Neurophysiol.
1961b;13:454–6.

22. Wenger MA, Bagchi BK, Anand BK. Experiment in India on “volun-
tary” control of the heart and pulse. Circulation. 1961;24:1319–25.

Sleep Medicine in Ancient and 5 Traditional China

Liu Yanjiao, Wang Yuping, Wang Fang, Yan Xue, Hou Yue and Li Shasha

The Discovery and Understanding of Circadian Rhythm, Sleep, and Sleep Disorders in TCM in Ancient China

The Theory and Practice of Circadian Rhythm of TCM

Deeply affected by Chinese traditional ancient philosophy, traditional Chinese sleep medicine (TCM) has placed great importance on the relations between nature and humans. It looks at the changes of human body from the standpoint of changes of “yin–yang”. Thus, a unique understanding of cir- cadian rhythm of TCM has formed. From the view point of ancient philosophy, sleep is not only a physiological phe- nomenon but also a kind of nature treatment or therapy.

The Discovery of Circadian Rhythm in TCM and Chinese Philosophy
In ancient China, through observing the changes in nature, such as the contradiction between earth and sky, day and night, sun and moon, cloudy and clear, cold and hot, water and fire, men and women, etc., people realized the char- acteristics of “yin–yang” changes and summed them up to form certain theories [1]. At the end of the Western Zhou Dynasty (AD eleventh century–771 BC), the concept of yin– yang was gradually concluded from contradictions in nature. People explained the reason for causing things to change by

W. Yuping () · H. Yue
Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
e-mail: wangyupi@public.bta.net.cn, ywang@xidian.edu.cn

L. Yanjiao · W. Fang · Y. Xue
Psychology Department (Sleep Medicine Clinic), Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China

L. Shasha
Information Institute, China Academy of Chinese Medical Sciences, Beijing, China

“yin–yang” changes. Laozi 《( 老子》) said, though yin and yang was mutually contradictory, they were actually in unity. The contradiction between yin and yang exists everywhere in the world. Yizhuan 《( 易传》) first put forward that Tao means the combination of yin and yang, which means that yin–yang plays the most important part in Chinese Philoso- phy. On the one hand, yin–yang emphasizes the differences and opposites between contradiction in movements; on the other hand, it emphasizes the combination and unification in the formation of objects. Yin and yang achieve relative bal- ance in alternations. On the basis of traditional philosophy, TCM developed the theory of circadian rhythm.

Suwen 《( 素问》), which is one of the most important books in TCM, said yin–yang is the principle of nature, the routine of all things, the source of changes, and the begin- ning of growth. TCM associates all kinds of human life ac- tivities with the natural phenomena and also correlates them to the physiological functions of viscera. Then the rhythm of viscera, diseases, cure, acupuncture, and so on were formed.

According to the theory of TCM, the changes of viscera rhythm follow the changes of yang in nature. The changes of human body follow the alternation of day and night. Suwen– Shengqi Tongtian Lun 《( 素问·生气通天论》) said “yang qi hosts the exterior in day time, beginning ascending at dawn, being prosperous at noon and being weak at sunset.”

The ancients used 12 Earthly Branches (di-zhi地支) for timing. The 12 Earthly Branches divide a day and a night together into 12 sections, which are also called 12 double- hour (Shichen 时辰). Qi and blood flowed through the 12 regular channels into 5 zang viscera and 6 fu viscera accord- ing to certain sequence from 3 a.m. (Yinshi 寅时). When the functions of zang viscera or fu viscera were poured by qi and blood, it reached its functional peak period. So the functional peak period of 5 zang viscera and 6 fu viscera was determined as follows: 11 p.m.–1 a.m. (Zishi 子时) to 1–3 a.m. (Choushi 丑时) for liver and gallbladder, 3–5 a.m. (Yinshi 寅时) to 5–7 a.m. (Moushi 卯时) for lung and large intestine, 7–9 a.m. (Chenshi辰时) to 9–11 a.m. (Sishi 巳时) for stomach and spleen,11 a.m. to –1 p.m. (Wushi午时) to

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_5, 29 © Springer Science+Business Media, LLC 2015

L. Yanjiao et al.

1–3 p.m. (Weishi 未时) for heart and small intestine,3–5 p.m. (Shenshi申时) to 5–7 p.m. (Youshi 酉时) for bladder and kidney, 7–9 p.m. (Wushi戊时) to 9–11 pm (Haishi亥时) for pericardium and sanjiao.

The Practice of Circadian Rhythm of TCM

Circadian rhythm greatly affects our work and life. The rhythm of time has been put to use in TCM. In Suwen–Sanbu Jiuhou Lun 《( 素问·三部九候论》), Huangdi asked “winter belongs to yin and summer belongs to yang, how does pulse correspond to this?” Qibo answered “if the pulses of nine sub-parts are all deep and thready, and being much different than normal, the patient will die at midnight. Winter belongs to yin. Midnight which corresponds to winter for a day also belongs to yin.” “If the pulses of nine sub-parts are all large and fast, and patient can hardly breathe and being restless, he or she will die at noon. Summer belongs to yang. Noon which corresponds to summer for a day also belongs to yang. Patient suffering from illness with dramatic alternation be- tween cold and hot syndrome will die at dawn, which cor- responds to the time yin and yang make alternation…” The above examples demonstrate how to judge the prognosis of diseases or time of death by pulse according to certain cir- cadian rhythm.

The relationship between the rhythm of time and occur- rence, and development of diseases are also mentioned in some books of TCM, such as Beiji Qianjin Yao Fang 《( 备急千金要方》) which said the following: “If the position of disease locates in liver, it will improve at dawn and get better at midnight.” “If there is food retention in the small intestine, patient will get fever at night and get better the next day.” “If the position of disease locates in spleen, it will improve at dusk, get serious at noon and get better at night.” “If the position of disease locates in kidney, it will improve at mid- night, get serious at daytime and get better in the afternoon.” Yizong Jinjian–Sizhen Xinfa Yao Jue 《( 医宗金鉴·四诊心法要诀》) said the disease was stable at daytime, improved at dawn, got serious at dusk, and critical at night. Spirit plays an important role in the recovery of disease when the vital— qi and pathogenic factors are fighting with each other. The rhythm of time for different diseases also differs from each other, some of which have been proved by the western and Chinese clinical medicine, some of which also need to be further proved.

In terms of the relationship between disease and sea- son, Zhouli·Tianguan·Zhongzai 《( 周礼·天官·冢宰》) said, “the epidemic disease can occur in all seasons, headache in spring, skin disease in summer, malaria in autumn, and cough in winter.”

In Tang Dynasty (AD 618—907), people treated epilepsy and anxiety by improving sleep. They helped insomnia pa- tients to regain natural sleep by taking herbs. This treatment is called sleep therapy, which is one of the most important therapies of TCM psychology.

The Application of Rhythm of Time in TCM Practice

In TCM, there are three theories about sleep including yin– yang sleep theory, nourishing-defensive sleep theory and soul-inferior spirit sleep theory, summarized from the book of Huangdi Neijing 《( 黄帝内经》). The brain theory of sleep in TCM was formed at the end of Ming Dynasty (AD 1368– 1644) and Qing Dynasty (AD 1616–1911). Taking yawn for example, Lingshu-Kouwen《( 灵枢·口问》) said “yin and yang host night and daytime respectively. Yang is related to ascent and is pertaining to above. Yin is related to descent and pertaining to below. When people go to sleep at night, yin qi will accumulate below; yang qi will go down and enter into the yin portion gradually. The still running up yang qi and going down yin qi cause yawn.” So, yawn is the result of crisscross between yin and yang, which is the signal of the shift of sleep and wake.

Moreover, it says, in TCM, that yang qi is on a rise from morning to 2:00 p.m., and then falls to the lowest point at midnight. Based on this theory, patients suffering from in- somnia are asked to take drug twice everyday, an hour after lunch and an hour after supper, to improve the clinical cura- tive.

In brief, the theory of circadian rhythm in TCM has the characteristics of Chinese philosophy which directly influ- enced the development of TCM. Today, when we study the related theories of sleep medicine in TCM, we have to con- firm them through modern measurements. Maybe we can find more useful knowledge to guide study and treatment in the near future.

Application and Development of Sleep Medicine in Ancient TCM

There has been a long history of TCM research in sleep and sleep disorders. Thirty kinds of treatment methods were re- corded in ancient TCM books to treat sleep disorders. China may be the first country in the world to give an account of sleepwalking. The dream analysis of TCM had become the important part of TCM clinic. The explanations of dream can be found early in Huangdi Neijing 《( 黄帝内经》), which had been an important reference to diagnose and treat diseases. Sleep health science originated in Tang dynasties. It obtained

5 Sleep Medicine in Ancient and Traditional China

good effect to use sleep therapy to treat epilepsy disease dur- ing that period. TCM prescriptions created by ancient doc- tors in past dynasties are still widely used in clinic.
Sleep disorders recorded in Huangdi Neijing 《( 黄帝内经》) ( 403 BC–AD 220) were relatively rich, such as insomnia, somnolence, and different kinds of dream diseases, such as dream fly, dream fall, dream diet, night terror. The sleep theories include Ying and Wei theory, Yin and Yang theory, which have an important influence in the realization of TCM to sleep disorders.

Insomnia in elders and its mechanism as well as somno- lence were recorded early in the book of Nan Jing (407–310 BC).

Shang Han Lun (Treatise on Febrile Diseases), written by Zhang Zhongjing (AD 150–219), recorded snore dur- ing sleep, such as “insomnia caused by febrile disease” and “sleepiness caused by febrile disease.” Jinkui Yaolue, writ- ten by Zhang Zhongjing (AD 150–219), recorded insomnia caused by consumptive disease and dysphoria, as well as Baihe disease accompanied with insomnia.

Huatuo Shenfang, may be written by Hua Tuo (AD 145– 208), recorded sleep disorders which include dream sexual intercourse, night sweet, insomnia, dream spermatorrhea, child night cry, and so on. (The author of this book is not clear). The sleep disorders recorded in Zhong Zang Jing (AD 145–208) included insomnia, pavor nocturnus during sleep and dream disorder related with deficiency and excess of Zang and Fu.

Zhenjiu Jiayi Jing (A-B Classic of Acupuncture and Mox- ibustion; AD 259) recorded the acupuncture treatment for in- somnia and the prescription of moxibustion to treat lethargy.

Sleep disorders in Zhu Bing Yuan Hou Lun ( General Treatise on the Cause and Symptoms of Diseases), written by Cao Yuanfang (AD 610), included insomnia caused by consumptive disease, insomnia due to serious illness, dream- iness caused by consumptive disease, insomnia caused by febrile disease, temper and insomnia due to cholera, somno- lence, night terror, and night cry.

Sleep disorders recorded in Prescriptions Worth Thou- sand Gold for Emergencies, written by Sun Simiao (AD 652), included insomnia, dream terror, dream cry, night- mare, dream fear, dream pavor, dream singing, dream waist soreness, and so on. Sleep disorders recorded in Qian Jin Yi Fang (AD 682) included dream pavor, dream supernatural beings, insomnia, sleepiness and their relative prescriptions, and herbs.

Shi Zhai Zhi Fang, written by Shi Kan (AD 1127–1279) recorded women with insomnia which was diagnosed through pulse.

Sleep disorders recorded in Sheng Ji Zong Lu, written by Zhao Zhe (AD 1117), included insomnia caused by febrile disease, insomnia due to cholera, sleepiness due to heat in gall-bladder, sleep lack, sleep terror, and restless sleep due

to cold in gall-bladder, and insomnia caused by consumptive disease.

Sleep disorders recorded in Taiping Huimin Heji Ju Fang, written by the government of Song dynasty (AD 1078–1085), included sleep disorder due to different causes, such as strange dream accompanied by lack of vigor dur- ing day time, dream terror, sleepiness, nightmare, restless sleep accompanied by spermatorrhea, dream pavor, restless sleep accompanied by dream dangerous experience, and so on, and their different prescriptions and herbs have also been recorded.

Pujing Benshi Fang, written by Xu Shuwei (AD 1132), recorded the manifestations of night terror which included being terrified, unable to sleep alone, worrying about being arrested, and head discomfort.

Ji Sheng Fang, written by Yan Yonghe (AD 1253), re- corded dream terror, many strange dreams during the night, dream pavor, sleeplessness during the night, restless sleep and dream, restlessness and sleeplessness, and so on. The causes and relative diseases of these sleep disorders have also been mentioned.

Su Wen Xuan Ji Yuan Bing Shi, written by Liu Hejian (AD 1152), first put forward sleep talking.

Pi Wei Lun, written by Li Dongyuan (AD 1249), put for- ward somnolence diseases related with spleen and stomach such as sleepiness, sleepiness after eating, and so on. Yi Xue Fa Ming recorded sweat during sleep, sleep terror, and feel- ing hot during sleep.

Zhang Cong Zheng (AD 1156–1228) who learned from Liu Wan Su, corrected the current malpractice of warming and tonifying therapy. He, guided by Nei Jing and Nan Jing, and by using the sweating, vomiting, and purgative method made by Zhang Zhongjing, created the theory which took attacking evil as the core and took insomnia as one kind of disease alone. Based on generation and restriction theory in Nei Jing, he used psychotherapy to treat different kinds of emotion diseases such as insomnia.

Shi Yi De Xiao Fang, written by Wei Yilin (AD 1345), has recorded sleeplessness during night, nightmare, dreaming ominous things, and sleeplessness due to dysphoria.

Ben Cao Gang Mu, written by Li Shizhen (AD 1590) recorded sleeplessness, sleepiness, hallucination, night cry, dream talking and their relative prescriptions, and herbs. It has also put forward the important theory that brain is the fu-viscera of mental activity.

Ming Yi Zhi Zhang, written by Huang Puzhong (AD 1368–1644), has put forward that phlegm stagnating in me- ridian could result in restless sleep and strange dream.

Dong Yi Bao Jian, written by Xu Jun (Korea, AD 1610) recorded “mind pillow method,” dream ejaculation, murki- ness and sleepiness, sleepless due to dysphoria, restless sleep, feeling heaviness in body and sleepiness, night sweat, drowsiness after eating, nightmare, night cry, night teeth

L. Yanjiao et al.

chattering, grinding of teeth, and so on. The book has also mentioned about the theory of sleep physiology such as dream, “Yang Qi is the key of sleep and wake,” “differences between elder and youth,” sleep method and “Yin, Yang, de- ficiency and excess differentiations of sleep.”

Qi Fang Lei Bian, written by Wu Shichang (AD 1644– 1911), has mentioned the therapy to suddenly falling asleep without natural waking as biting the patient’s foot thumb and spitting on his face; if the patient is still not waking, filling Chinese chive in the patient’s nose. The therapy for sleep paralysis has also been suggested, such as using the powder mixed with Xiong Huang, Niu Huang, Zhu Sha to burn under the bed, and then pouring warm wine into patient’s mouth.

Yi Xue Yuan Shi, written by Wang Honghan (AD 1692), is the book which had relatively more descriptions of sleep such as in the chapter “wake and sleep.” It stated the rela- tionship between wake and sleep, dream, “positive dream,” “drunken person without dream,” nightmare, “dreaming is the soul getting out of the body,” and so on, which had not been mentioned before.

Chang Sheng Mi Jue, written by Shi Chengjin (AD 1697), had mentioned that a drunken person should not sleep outdoors, if suffering from apoplexia, tinea, and rheumatism caused by the deficiency of Zheng Qi and suffering from Xie Qi.

Zun Sheng Dao Yang Bian, written by Zhang Yinhan (AD 1823), put forward the recuperate method for insomnia in elders. “Elders are susceptive to sleepless. At that time, it is best to sit up and action, calm thoughts, and keep unobstruc- tive of blood circulation.”

Yang Sheng Mi Zhi (AD 1644–1911), emphasized the method to keep essence was that sleep as a cat, essence would not run away; sleep as a dog, essence would not go away. It is a method important to keep Yuan Qi.

Lu Di Xian Jing, written by Ma Qi (AD 1644–1911), has put forward three sleep postures which help to calm, such as sickness dragon sleep, fist of the knee; sleep as ape, embrace of the knee; and sleep as turtle, bend of the hand and foot.

After the ending of feudal society in China (AD 1911), the medicine development laid particular stress on the pre- vention and treatment of epidemical diseases, which are the results of many factors such as war and so on. A hundred years passed since then, and Chinese economical situation also changed greatly, the incidence of sleep disorders gradu- ally increased following the development of economy.

The Development of Sleep Medicine of TCM in Modern China

The China Academy of Chinese Medical Science did the ini- tial work for the development of sleep medicine using TCM. It has been in a leading position in this field. The research

group and center for sleep medicine of TCM founded here is the earliest one in modern China.

Research on Sleep Medicine in TCM

In AD 1994, researchers from the Theoretical Research Insti- tute of China Academy of Chinese Medical Sciences first put forward the idea to carry out researches on sleep medicine in TCM. Sleep medicine specialty clinic was founded there. The first seminar of sleep medicine in TCM was held during that time. Until now, this seminar has been held five times. The scientific research cooperation network to preventing and treating sleep disorders was founded in Shanghai. Since AD 2005, the research direction of China Academy of Chi- nese Medical Sciences has been changed from theoretical in- vestigation to clinical practice. The sleep medicine specialty clinic, which has sleep monitoring rooms and related equip- ments, has become one of the typical clinical research cen- ters. It promotes the development of sleep medicine in TCM.

Academic Organizations of Sleep Medicine in TCM

In AD 2008, Traditional Chinese Medicine Committee, Chinese Sleep Research Society was founded in Shanghai. Sleep Medicine Specialty Committee, World Federation of Chinese Medicine Societies was founded in Beijing. These two typical organizations of sleep medicine of TCM aim at integrating the professionals in the field of traditional and modern sleep medicine together and to prompt the develop- ment of sleep medicine in China.

Academic Works of Sleep Medicine in TCM

Through 5 years’ hard work, the first academic book of sleep medicine in TCM, Sleep Medicine in Traditional Chinese Medicine, edited by Professor Liu Yanjiao and Professor Gao Ronglin from Guang’anmen Hospital, China Academy of Chinese Medical Sciences, was published in AD 2003. This book systematically presents the basic theories and clinical treatment of sleep medicine in TCM. It promoted the establishment of the discipline of sleep medicine of TCM and won the third prize for academic works of Chinese As- sociation of Chinese Medicine.

In AD 2012, Professor Wang Weidong, Professor Liu Yanjiao, and Professor Ci Shuping wrote Experimental and Clinical Diagnosis and Treatment for Sleep Disorders by Combination of TCM and Western Medicine, which pro- vided the basic theories and direction for clinical practice of

5 Sleep Medicine in Ancient and Traditional China

sleep medicine using the combination of TCM and Western medicine.

Professor Wang Qiaochu from Shanghai Traditional Chi- nese Medicine Hospital conducted a series of basic research- es along with Professor Huang Zhili from Shanghai Medici- nal College of Fudan University on using the leaf of peanut to treat insomnia, which has certain influence in China.

With the support of the World Health Organization, ex- perts from China Academy of Chinese Medical Sciences compiled the Clinical Guideline for Insomnia based on the evidence-based medicine. This guideline first spread the dif- ferentiation of TCM abroad and received high praise world- wide.

The Professional Training and Popularization for Sleep Medicine of TCM

The professional training for sleep medicine of TCM is focused on internal medicine, psychology, and otorhinolar-

yngology of TCM, etc. Most of the students were awarded a professional degree. China Academy of Chinese Medicine is the first admission unit to enroll students for sleep medi- cine of TCM. It has cultivated more than 40 graduates and students for advanced study. Twelve training classes have been held and more than 1700 trainees were enrolled in. On World Sleep Day on March 21, doctors from sleep medicine and psychology department of Guang’anmen Hospital go into the local community to publicize knowledge about sleep medicine and conduct epidemiological survey. Through or- ganizing international academic conferences, more and more people from all over the world have begun to pay attention to the development of sleep medicine in TCM.

Reference

1. Liu Y, Gao R. Sleep medicine in traditional Chinese medicine. Bei- jing: People’s Medical Publishing House; 2002.

Sleep in the Biblical Period 6

Sonia Ancoli-Israel

At the start of the universe, when God was creating the world, it became clear that the rhythm of dark and light was neces- sary even before the creation of man, creatures, and plants:

God said, “Let there be light”; and there was light. God saw that the light was good, and God separated the light from the darkness. God called the light Day, and the darkness He called Night. And there was evening and there was morning, a rst day. (Genesis, 1:1–5)

Today it is known that light is the strongest zeitgeber (cue) for strong circadian rhythms just as we know that periods of darkness are also necessary. If circadian rhythms are present at the very start of the Bible, it is likely that other information about sleep and sleep disorders may also be found in those pages. This chapter reviews what the Bible and Talmud (a record of rabbinic discussions about Jewish law, ethics, phi- losophy, customs, and history) say about sleep.

Sleep as a Vulnerable Period and as a Gift from God

Sleep is rarely the focus of any discussion in the Bible but rather occurs as part of a larger discussion of other topics. Sleep can be a gift from God. (“He provides as much for His loved ones while they sleep” Psalms, 127:2). Sleep can be a time of vulnerability as that is a time when enemies would attack. Therefore, many prayers ask God for safety during the night and assurance of waking up in the morning.

Parts of the paper were previously published in: Ancoli-Israel S. Sleep is not tangible or what the Hebrew tradition had to say about sleep. Psychosom Med. 63:778–787, 2001 and in Ancoli-Israel, S. Sleep in the Hebrew Bible. The Jewish Bible Quarterly, 31:143–152, 2003.

S. Ancoli-Israel ()
Departments of Psychiatry and Medicine, University of California, 9500 Gilman Drive, # 0733, 92093–0733 La Jolla, CA, USA e-mail: sancoliisrael@ucsd.edu

Examples of this include the story in Judges when Delilah cut Samson’s hair while he was sleeping and thus destroyed his strength. (“And she made him sleep on her knees; and she called for a man, and she caused him to shave off the seven locks of his head: … and his strength went from him” Judges 16:19). Another instance of vulnerability during sleep occurs in Samuel I (I Sam 26:7–12) in the story of David and Saul. David comes upon Saul sleeping and has the opportunity to kill him, but only takes away Saul’s water and spear. (“So David…approached the troops by night, and found Saul fast asleep…But David said…” Don’t do him violence!… Just take the spear and the water jar at his head and let’s be off…all remained asleep; a deep sleep from the Lord had fallen upon them” I Sam 26:7–12) [1]. In yet a third ex- ample, also in Judges, Sisera, a cruel Canaanite leader who ruled over the Israelites for 20 years was defeated by the Israelite surprise attack led by the prophetess and Israelite leader Deborah along with Barak. Sisera escaped the battle and sought refuge in the tent of the Jael, wife of Heber the Kenite. Jael invites Sisera into her tent, “…and she covered him with a blanket… Then Yael wife of Heber took a tent pin and grasped the mallet. When he was fast asleep from exhaustion, she approached him stealthily and drove the pin through his temple till it went down to the ground. Thus he died” (Judges 4:17–21).

Sabbath prayers ask God to protect us from this vulner- able period. On Friday night, the prayer says, “Grant that we lie down in peace, secure in Thy protecting love, and shelter us beneath Thy wings to keep us safe throughout the night. On the morrow raise us up in perfect peace to life, O God” [2]. Each morning the service continues with the prayer thanking God for the gift of waking up: “Blessed art thou, Lord our God, King of the universe, who removes sleep from my eyes and slumber from my eyelids” [3, 4].

In the book of Jeremiah, God says, “I will satisfy the weary soul and…every soul I will replenish” (Jer 31: 25). “Thereupon I [Jeremiah] awoke and looked about and my sleep had been pleasant to me” (Jer 31:26). In addition, al- most every prayer service ends with the singing of the prayer,

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_6, 35 © Springer Science+Business Media, LLC 2015

S. Ancoli-Israel

Adon Olam, part of which states, “To Him I entrust my spirit when I sleep and when I wake…” [3].

Sleep Stages

Today we understand that sleep is composed of different lev- els. There is the state of rapid eye movement (R) sleep (where most dreams take place) and non-rapid eye movement (N) sleep which is further divided into three stages: N1 (the very lightest level), N2, and N3 (deep or slow-wave sleep). These levels of sleep were first identified in the modern world in the 1950s [5, 6]. However, the rabbis believed that sleep is not one continuous state. There is a rather accurate descrip- tion of stage 1 sleep in the Talmud when Rabbi Yosi dis- cusses when on Passover it is permissible to eat: “If they fell into a light sleep, they may eat; if they fell fast asleep, they must not eat. What is meant by ‘a light sleep’?—Said R. Ashi: A sleep which is not sleep, a wakefulness which is not wakefulness, e.g., if he answers when called, cannot make a reasoned statement, yet recollect when reminded” (Talmud Pesahim 120b).

There are different Hebrew words used to describe sleep in different parts of the Bible, and these correspond to what are labeled as stages of sleep today [7, 8, 9]. The word te- numah is often used to mean drowsy or what is now called N1 sleep (e.g., Isa 5:27, Ps 76:6). Yashen and shenah are used to refer to conscious thought which becomes uncon- scious and involuntary, a good description of N2 (e.g., Gen 28:16). Radum implies a heavy or deep sleep or N3. (“Jo- nah’s sleep was so deep, though a storm howled, the Captain had to awaken him” Jonah 1:5–6). R sleep is also represented by the word tardemah, which refers to a period where the flow of thoughts continue in dreams or in revelation (e.g., Gen 15:12).

Function of Sleep

The true function of sleep is not yet known, although there are many theories including that it is physiologically restor- ative and provides for energy conservation [10]. The Bible and Talmud also suggest that the purpose of sleep is to re- plenish and heal the body. “What did the Holy One, blessed be He, do? He created the sleep of life, so that man lies down and sleeps whilst He sustains him and heals him and [gives] him life and repose” (Pirqe D’Rabbi Eliezer 12:7–8).

Sleep is also part of the two-process model composed of the homeostatic process and the circadian rhythm compo- nent [11, 12]. The Talmud also suggests a homeostatic pro- cess when it is explained that a wise person finds the balance between sleep and wakefulness (activity) [1]. “Rabbi Sime- on ben Eleazar said: ‘And, behold, it was very good’ means,

and, behold, sleep was good. Is there any sleep which is very good! Did we not learn thus:…a man sometimes sleeps a little and arises and toils much in the study of Torah” (Gen. R. 9:6). In this quote, the rabbis implied that sleep at night is very good because it allows the student to be alert enough to study throughout the day [8], i.e., like the homoeostatic theo- ry which suggests that the drive for sleep builds up during the waking state and is alleviated by sleep, or in other words, the more we sleep, the more alert we are the next day [12, 13].

A second function of sleep, healing, is also found in the teachings of the rabbis. “Sleep is like food and medicine to the sick” (Pirkei de Rabbi Eliezer) [14]. “Sleep is the best medicine. It strengthens the natural forces and diminishes the injurious fluids” (Sefer Shaashu’im 9) [14]. The Talmud lists six actions which can heal, including sleep. When a sick person sleeps, he gets well (Talmud Berachot 57b) [15]. “I should have slept; then had I been at rest” (Job 3:13). Sleep is so important when one is ill, that, although usually it is a sin to turn off a light on the Sabbath, it is not a sin when the light is turned off to help the sick person sleep. In addition, a sleeping patient should never be disturbed (Rosh al Hato- rah, Vayeira), reinforcing that nothing else is as important as sleep for the healing process [16].

The relationship between sleeping and healing has been endorsed by the studies of endocrine function [17, 18, 19, 20]. Glucose tolerance and thyrotropin concentrations are lower, evening cortisol concentrations higher, and sympa- thetic nervous system activity is increased in a sleep debt condition compared to a fully rested condition.

Sleep Deprivation

In addition to the relationship with health, sleep deprivation, whether caused by difficulty sleeping or by insufficient time in bed, has also been shown to result in impaired concen- tration, memory, and performance as well as problems with social, business, and personal relationships, and overall de- creased quality of life [19]. Although they likely did not un- derstand why, the rabbis were aware that there were negative effects of sleep deprivation. The absolute importance of sleep was emphasized and abstaining from sleep was considered a sin. “He that stays awake at night imperils his own life” (Tal- mud Avot 3:4–5), “because sleep is enforced by nature” (Tal- mud Tamid 28a) (17). The discussion continues with Rabbi Judah explaining that the “night was only created for sleep” and Rabbi Nachman bar Isaac stating that “humans were meant to work during the day” (Talmud Eruvin 65a). For this reason, “If someone swears not to sleep for three days, he is flogged….” (Proverbs, 6:10–11). This verse is interpreted to mean that not only is sleep absolutely necessary but also the person must be lying as the rabbis believed it would be impossible to remain awake for 3 days [16]. Scientific data

6 Sleep in the Biblical Period

support this belief that it is impossible to stay awake for too long. A study of rats sleep-deprived for 2 weeks resulted in temperature changes, heat-seeking behavior, and increased food intake but weight loss, increased metabolic rate, and in- creased plasma norepinephrine. The sleep-deprived rats also showed stereotypic ulcerative and hyperkeratotic lesions lo- calized to the tail and plantar surfaces of the paws, and all died within a matter of weeks [21].

Insomnia

Not only was excessive sleepiness discussed but also insom- nia was described. Being awakened too early in the morn- ing, particularly by noise, was seen as a problem, such as in Proverbs, “He who greets his fellow loudly early in the morning shall have it reckoned to him as a curse” (Proverbs 27:14), and “If a man desires to open a shop in a courtyard, his neighbour may prevent him on the ground that he will not be able to sleep through the noise of people coming and going” (Talmud Baba Bathra 21a). Samuel said, “Sleep at the break of dawn is as important as tempering is for iron” (Berachot 62b) [14].

Insomnia, or sleeplessness as it is called, was used in the Bible to stress the severity of whatever was wrong with the person. Loneliness is a common experience for insomniacs as they are alone and awake while everyone else is asleep. “I lie awake, I am like a lonely bird” (Psalms 102.8). In the book of Esther, a guilty conscience led to insomnia. “Sleep deserted the king [Ahasuerus]” when he realized he had not rewarded his wife’s uncle, Mordecai, after Mordecai had saved his (the king’s) life (Esther 6:1), while in the book of Daniel, King Darius’ “sleep fled from him” after he threw Daniel into the den of lions (Daniel 6:19) [15].

Anxiety and stress are also associated with insomnia in the Bible (e.g., Ps 127.2, Proverbs 4.16, 5:11, 8:16–17). “At night I yearn for You with all my being, I seek You with all the spirit within me” (Isaiah 26:9), “I am weary with groaning; every night I drench my bed, I melt my couch in tears” (Ps 6:7–8), “I call on God to mind, I moan, I complain, my spirit fails, You have held my eyelids open; I am overwrought, I cannot speak” (Ps 77:4–7), “Anxiety on his part, he cannot sleep at night” (Talmud Sanhedrin 100b), “All his days his thoughts are grief and heartache, and even at night his mind has no respite” (Ecclesiastes 2:23), “For I have set my mind to learn wisdom and to observe the business that goes on in the world—even to the extent of going without sleep day and night…” (Ecclesiastes 8:16). Job (7:3–4) complained of “nights of misery” where “when I lie down, I think, when shall I rise? Night drags on and I am sated with tossings till morning twilight.” Many patients with insomnia have the same complaint of worry at night keeping them awake.

Job has other references to difficulty sleeping, includ- ing pain causing insomnia (30:17), “By night my bones feel gnawed; my sinews never rest.” Another translation is, “… my arteries pulsate so strongly that I cannot sleep” [15]. There are other references to illness and sleeplessness in other books of the Bible. “Only from daybreak to nightfall was I kept whole, then it was as though a lion were break- ing all my bones; I cried out until morning. I piped like a swift or a swallow, I moaned like a dove, as my eyes, all worn, looked to heaven: ‘My Lord, I am in straits; Be my surety!’ What can I say? He promised me and He it is who has wrought it. All my sleep had fled because of the bitter- ness of my soul” (Isa 38:12–15). “For my days have van- ished like smoke and my bones are charred like a hearth. My body is stricken and withered like grass; too wasted to eat my food; on account of my vehement groaning my bones show through my skin. I am like a great owl in the wilderness, an owl among the ruins. I lie awake; I am like a lone bird upon a roof” (Ps 102:4–8).

Treatment of Insomnia

There are also treatments for insomnia mentioned, although a bit different from treatments used today. One of the first “steps towards sleep” is placing a hand on the forehead (Tal- mud Pesachim 112a) [15]. Perhaps this lifts the ribs to make it easier to breath, or perhaps it is an attempt to raise periph- eral body temperature. Sleep is induced by a drop in core body temperature which results in peripheral body tempera- ture rising [22]. Placing a hand on the forehead may dissipate the heat more swiftly thus accelerating core body tempera- ture drop, thus inducing sleep.

In Talmud Sabbath (67a–67b), it suggests, “One may go out with…a fox’s tooth, which is worn on account of sleep; a living [fox’s] for one who sleeps [too much], a dead [fox’s] for him who cannot sleep.” Physical activity is also sug- gested as a cure. In Ecclesiastes, we are told, “Sweet is the sleep of a labouring man, whether he eats little or much…but the rich man’s abundance doesn’t let him sleep” (Eccl 5:11). Interpretations of this passage include that the rich man wor- ries about losing his riches, and thus also loses sleep [16], or that sleep is a blessing set upon the laborer by God, thus to soften his difficult life [23, 24]. A more current interpretation may be that the laboring man who is physically active will likely sleep better than the rich man who spends his time counting his money, as exercise is known to help sleep [25].

There are also other suggestions for the treatment of insomnia. The Talmud suggests turning out the light (Tal- mud Sabbath 2:5) [15]. Today this would be understood as providing the darkness needed to stimulate the secretion of melatonin which induces sleep [26]. There is also a detailed

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description of how to create the soft sound of dripping water by raising water into the air from a container with a spout which had a double siphon, and allowing the water to slow- ly trickle out from the other siphon (Talmud Eruvin 104a; Tosefta Sabbath 2:8) [15]. This would be equivalent to white noise generators. Even hypnotics were not unknown as a sleeping potion was given to Rabbi Eleazar for abdominal surgery (for obesity; Talmud Baba Metzia 83b–84a) [15].

Sleep Hygiene

In 2005, the National Institute of Health convened a state of the science conference on insomnia and concluded that the most effective treatment for insomnia was behavior change [11]. A part of the behavioral treatment is teaching good sleep habits, or good sleep hygiene, including information on sleep duration and optimizing sleep [27]. Our forefathers and foremothers also refer to some of the same sleep hygiene rules that sleep medicine health professionals recommend. These include not spending too much time in bed, getting up at the same time every day, keeping the environment com- fortable (not too hot and cold) and dark, avoiding alcohol and limiting, if not avoiding, naps [28].

Sleep duration: One of the greatest Jewish philosophers as well as a physician, and considered by some to be the greatest Talmudic authority of the Middle Ages, Maimonides, said,

A day and night are twenty-four hours. It is suf cient if you

sleep one-third of that, i.e., eight hours…You should not sleep

face down or face up, only on your side. The rst part of the

night you should lie on your left side, the latter part of the night on your right side. Don’t sleep immediately after eating; wait about three or four hours before going to sleep. And don’t sleep in the daytime. (Hilchot De’ot 4:4–5) [15–16]

Post-Talmudic writers determined that although 8 h of sleep were needed, there could be individual differences [15]. In modern times, the recommended amount of sleep is 7–8 h. Timing of sleep: Writings in the Talmud advise on the best timing of sleep and wake. “Eight hours of sleep, terminating at dawn…” (Maimonides, Hilchot De’ot, 4:4–5). In several verses of the Psalms, it says: “Awake, O my soul! Awake, O harp and lyre! I will wake the dawn” (Ps 57:9 and 108:3), suggesting that the right time to arise is with the dawn. “Rab Judah observed: night was created for naught but sleep” (Talmud Eruvin 65a). Time to sleep was governed by the timing of prayer, specifically, for the reciting of the Shema (one of the oldest and most important of the Hebrew prayers which affirms Israel’s faith), first thing in the morning and last thing at the end of the day. “Rabbi Dosa ben Harkinas says: Morning sleep, and midday wine…drive a man out of the world” (Avot 3:14) [29]. Another source had a rabbi commenting, “Sleeping away the morning hours and indulg-

ing in strong drink dull the mind” (Talmud Aboth 3:10) [15, 16]. The interpretation of this advice was that “man should not wilfully sleep late” so that the time of reciting the Shema passes. Perhaps, as we know today, they understood that it is important to get up at the same time each day in order to keep the circadian clock synchronized. Environment: The Bible refers to the need for a comfortable temperature in order to have proper sleep at several different points. Jacob, during his travels through the desert, complains of extreme temper- atures robbing him of sleep: “Often scorching heat ravaged me by day and frost by night; and sleep fled from my eyes” (Gen 31:30), and again in similar words in Deuteronomy (24:12–13), God commands that “If you take your neigh- bor’s garment in pledge, you must return it to him before the sun sets, it is his only clothing, the sole covering for his skin. In what else shall he sleep?” (Ex 22:25–26). Yet another reference to keeping warm and comfortable during sleep is found when, as part of an analogy, the rabbis use an example of a physician telling a patient not to drink anything cold and not to sleep in a damp place [15] or to “rub his temples with oil and sleep in the sun” (Talmud Sabbath 129a).

Alcohol and food: While people with insomnia often use alcohol to fall asleep faster, it is known that later in the night, the alcohol results in insomnia [30]. In the Bible, there are also references to wine and difficulty sleeping: “Rami b. Abba stated: A mile’s walk or a little sleep removes the effects of wine.” The Rabbi replied: “This applies only to one who has drunk one quarter of a log [a Hebrew measure], but if one has drunk more than a quarter, a walk would only cause him more fatigue and sleep would produce more intox- ication” (Talmud Eruvin 64b, Talmud Ta’anith 17b, Talmud Sanhedrin 22b).

The effect of specific foods on sleep is also noted, in par- ticular, among other foods, milk, fishbrine, and wine should be avoided [15]. This advice is repeated in Talmud Moed Katan, where it is advised that “after eating fish, cress and milk, occupy your body [i.e., go for a walk] and not your bed” (Talmud Moed Katan 11a) [15].

Earlier in this chapter, under the discussion of vulnerabili- ty during sleep, we discussed the story of Yael and Sisera. As described, Sisera escaped the battle and sought refuge in the tent of the Jael, wife of Heber the Kenite. Jael invites Sisera into her tent, and after she covers him with a blanket he says, “Please let me have some water for I am thirsty.” But Yael instead “opened a skin of milk and gave him some to drink… When he was fast asleep from exhaustion, she approached him stealthily and drove a pin through his temple till it went down to the ground. Thus he died” (Judges 4:17–21). Yael must have known that milk would make him sleepy; as we know today, milk and fish contain tryptophan, an amino acid known to have sleep-promoting properties [31].

6 Sleep in the Biblical Period

Napping: Sleep is controlled by core body temperature which takes a dip in the afternoon, explaining why people get sleepy after lunch. This is their normal time to want to nap. However, sleeping too long in the afternoon can in- terfere with nighttime sleep. In the Talmud, napping is not recommended. Maimonides wrote, “don’t sleep in the day- time” (Hilchot Dei’ot 4:4, 5) [16]. Studies have shown that blood pressure declines during afternoon naps and this is an independent predictor of mortality [32, 33]. The Talmud, in general, is against naps on all days but the Sabbath, since daytime is a time for study, not sleep. In the Talmud, Rabbi Eliezer and Rabbi Yochanan ben Zakkai are both praised for only dozing off in the house of study on the Sabbath, but never on any other day (Talmud Sukkah 28a) [15]. Sleeping on the Sabbath, the day of rest, is considered a joy.

There are also situations in the Bible where people are found to nap, particularly when it is warm. For example, Abraham, David, and Ishboseth all sleep in the afternoon. “He [Abraham] was sitting at the entrance of the tent [sleep- ing] as the day grew hot” (Gen 18:1). [Although we are not told that Abraham was sleeping, we are told that it was hot and it was afternoon, and Abraham continues on to tell the visitors, “bathe your feet and recline under tree” (Gen 18:4). One interpretation therefore, is that since Abraham invites his visitors to recline, he too has been taking a nap.] “Late one afternoon, David rose from his couch and strolled on the roof of the royal palaces…” (II Sam 11:2). “And they reached the home of Ishboseth at the heat of the day, when he was taking his midday rest” (II Sam 4:5). Even animals rest at noon, “Tell me, you whom I love so well; where do you pasture your sheep: Where do you rest them at noon?” (Songs of Songs, 1:7).

There is also a discussion about how long the nap should last if one does nap. “A man may indulge in casual sleep while wearing his tefillin, but not in regular sleep” (Talmud Sukkah 26a–26b). The discussion continues, “What con- stitutes casual sleep? [Sleeping during the time] it takes to walk one hundred cubits” They continue, “It is forbidden for a man to sleep by day [when it is one’s duty to study the Torah] more than the sleep of a horse. And what is the sleep of a horse? Sixty respirations.”

In one commentary, 60 respirations take about one-half hour [15]. Good sleep hygiene rules today advise trying to avoid naps, but if you do nap, limit the length of naps to half an hour, since longer naps adversely affect the ability to sleep at night.

Excessive Daytime Sleepiness

The Talmud also discusses excessive sleepiness. Eight things were listed as being harmful in excess, but beneficial in small amounts including wine, work, sleep, wealth, business

affairs, hot water, cohabitation, and bloodletting (Midrash Lev. Rabbah 4:3) [16, 15]. In fact, it actually says: “Too much sleep is inadvisable” (Talmud, Gittin 70) [14]. Al- though the rabbis could not have known it, excessive sleepi- ness is often a sign of insufficient sleep at night, whether due to self-enforced sleep deprivation or sleep deprivation secondary to specific sleep disorders.

The Talmud also suggests that excessive sleepiness is caused in part by food. Being tired after a meal was well known (Talmud Yoma 18a): “The stomach when full induces sleep” (Talmud Berachot 61b) [15]. On holidays when the high priest was not allowed to sleep, he was not allowed to eat a large meal either, so that he would not get tired and be tempted to sleep.

In the Bible and Talmud, excessive sleep often is de- scribed as being synonymous with laziness and sloth. “How long will you lie there, lazybones; When will you wake from your sleep? A bit more sleep, a bit more slumber, a bit more hugging yourself in bed, and poverty will come calling upon you…” (Proverbs 6:9–11) and, “laziness induces sleep” (Proverbs 19:15). And if one becomes obligated to another, “Give your eyes no sleep, your pupils no slumber” (Proverbs 6:4) until your obligation is fulfilled (Proverbs 6:9–11, 10:5, 19:15, 20:13, 24:33–34, 26:14).

The ability to work is affected when a person is drowsy [34]. In Proverbs it says, “Drowsiness shall clothe a man with rags” (Proverbs 23:21).

Treatment of Excessive Sleepiness

The rabbis not only described the problems associated with excessive sleepiness but they suggested how to treat the problem. “If he sought to slumber, young priests would snap their middle finger before him and say: Sir High Priest, arise and drive the sleep away. Thus once on the pavement, they would keep him amused until the time for the slaughtering [of the daily morning offering] would approach” (Talmud Yoma 20a).

It is explained that “some of the worthiest of Jerusalem did not go to sleep all the night in order that the high priest might hear the reverberating noise [of the people awake around him, singing and amusing him] and so that sleep should not overcome him suddenly.” Priests used to prick themselves with a thorn to stay awake (Talmud Gittin 84a) or walk about on the cold marble floor (Talmud Yoma 1:7) [15]. This explanation is similar to masking which occurs when the environment is stimulating enough to fool (mask) people into thinking they are alert, i.e., keeping them awake even when they are excessively sleepy. When the situation is unmasked and the environment is no longer stimulating, then the person is overcome by sleep.

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Sleep Apnea

The Bible and Talmud do not refer specifically to snoring, sleep apnea, or breathing during sleep; however, there are some statements that suggest that perhaps they were aware of this phenomenon. In Talmud Berakhot, it says,

…the maw [stomach] brings sleep and the nose awakens. If the

awakener sleeps or the sleeper rouses (i.e.., if the nose induces sleep or the maw awakens), a man pines away. A Tanna taught: If both induce sleep or both awaken, a man dies forthwith. (Talmud Berakhot 61b)

The rabbis are suggesting that there is some enzyme in the stomach that helps one fall asleep. One group of rabbis con- siders the work of the stomach to be mechanical, just grat- ing and grinding. Another group believes that the action of the stomach is a chemical one, such that vapors from the stomach ascend and accumulate in the head and thus induce sleep [15]. However, there is no interpretation of the “nose awakening” in the commentaries. Are they suggesting that the “nose awakens” because when a person cannot breathe, they wake up, such as in the case of sleep apnea? “If the nose does not awaken, then one dies.” This might also refer to sleep apnea since patients with sleep apnea who are un- treated have a higher mortality rate and more often die dur- ing sleep [35, 36].

The closest reference to snoring is: “But did not Rabbi Joshua ben Levi curse anyone who slept lying on his back? In reply it was said: To sleeping thus, if he turns over a lit- tle on his side, there is no objection, but to read the Shema [prayer] thus is forbidden even if he turns over somewhat” (Talmud Berakhot 13b). Why does he object to having one sleep on his back? Perhaps because the person will be too noisy because he snores loudly on his back and the noise interferes with the sacred prayer.

Nightmares

Nightmares are very prevalent in the Bible. Job not only has difficulty sleeping because of pain but also suffers from nightmares: “When I think, ‘My bed will comfort me, my couch will share my sorrow,’ you frighten me with dreams and terrify me with visions” (Job 7:13–14).

Treatment of nightmares can also be found in the Talmud, which states that dreams can cause distress (Berachot 55b), which will only subside if the dream is interpreted immedi- ately [37]. As explained by Askenasy and Hackett [37], these anxiety dreams, or nightmares, are divided in the Talmud into three levels of severity, each of which is treated differ- ently. For the lightest level of nightmare, a special prayer is recited in front of the priests in the synagogue. For the mid- dle level of nightmare, i.e., one where the dreamer becomes depressed, verses from the Bible are recited in front of three

people, including, “You turned my lament into dancing, you undid my sackcloth and girded me with joy…” (Ps 30:12). For the most severe of nightmares, one must fast on the day following nightmare, since the dream may be a warning and fasting, which is a form of repentance, allows one to reflect and make amends for whatever he is being warned about.

Circadian Rhythms

One of the morning prayers includes, “Blessed art thou, Lord our God, King of the universe, who hast given the cock intel- ligence to distinguish between day and night” (Talmud Be- rakhot 60b). Sleep in the Bible is governed by the rising and the setting of the sun as well as by temperature. People rise when it is light and go to sleep when it is dark and when it is hot:

He made the moon to mark the seasons; the sun knows when to set. You bring on darkness and it is night, when all the beasts of the forests stir…When the sun rises, they come home and couch in their dens. Man then goes out to his work, to his labor until the evening. (Ps 104:19–23)

This confirms that man is diurnal, rising with the light and going to sleep with the dark, while some animals are noctur- nal, rising at night and going to sleep with the light. This also points out that there is a rhythm to life and that sleep is part of the rhythm, i.e., circadian rhythms.

As mentioned above, sleep is controlled in part by our core body temperature rhythm, which as it drops at night causes us to fall asleep and as it rises in the morning causes us to wake up [38]. In Talmud Sabbath, we are told, “Lend me your robe and I will sleep in it. He singed it, wrapped himself therein and slept. As he became heated through and got up, it fell away from him bit by bit” (Talmud Sabbath 110b). Temperature, particularly keeping warm during sleep, is also seen having healing properties. The Talmud suggests that an ill person “wraps himself in his cloak and sleep, and he must not be disturbed till he wakes himself. When he wakes he must remove his cloak otherwise the illness will return” (Talmud Gittin 70a). In both examples, a person needs to wrap himself up at night to keep warm as his body temperature drops, but needs to unwrap to stay cool as body temperature rises.

Sections of the commentaries also refer to circadian rhythm shifts. Research and clinical work in the area of cir- cadian rhythms has shown that it is easier to delay ones cir- cadian rhythm than to advance it and thus it is easier to travel west than east [39]. Talmud Yoma clearly says, “…it is easier to postpone the hour of sleep than to rise from sleep early in the morning” (Talmud Yoma 22a). These statements are in total agreement with what we know today about phase shifts.

6 Sleep in the Biblical Period

Aging

The Hebrew Bible often refers to reduced sleep quality with old age [8]. Old age is described as a time “when one rises up at the voice of the bird” (Ecclesiastes 12:4). With age comes lighter sleep such that even the song of the birds can awaken an older person (Talmud Sabbath 152a) [15, 16]. This is con- sistent with what we know about changes in sleep architec- ture that occur with age, particularly decreases in deep sleep which results in most of the night being spent in lighter lev- els of sleep [40]. Another aspect of the statement is that older people wake up early, even as the early bird begins to sing. This would suggest advanced sleep phase, a situation where the biological clock is out of synchrony with the environ- mental clock and the older person gets sleepy earlier in the evening and wakes earlier in the morning, a condition that is very common in older adults [41].

But not all older people have difficulty sleeping in the Bible or Talmud. When asked to what they attribute their longevity, the rabbis reply, “nor did I ever sleep in the Beth Hamidrash [house of learning] in which one spends the day and night…” (Megillah 28a) [15]. Here is an old man who does not need to nap, implying that he is sleeping sufficiently at night. This is confirmed by data from Foley et al. which suggested that elderly individuals who are healthy have no complaints of sleep and no difficulty sleeping [42].

Conclusion

Scientists today consider their discoveries to be landmarks. Yet thousands of years ago, there was already a tremendous amount of knowledge about sleep. In the Bible, sleep is gen- erally viewed as both pleasant and necessary [1]. There are references to sleep that can be directly interpreted by what we know today about sleep disorders. Our forefathers and foremothers were aware that sleep was not one continuous stage. They refer to the function of sleep as being restor- ative. They deplored sleep deprivation, believing that it impairs life. They felt that excessive sleepiness is harmful. They understood that insomnia could be caused by stress and anxiety and by excessive alcohol, and that physical activ- ity (exercise) and drinking milk could improve sleep. They suggested cures for insomnia, including some of the ideas included in today’s sleep hygiene rules. They understood that there is a rhythm or timing to sleep. They often took naps in the afternoon, but suggested just how long that nap should last—about one-half hour. And they knew that with age, sleep is advanced, but that healthy elderly do not have difficulty sleeping.

Although we think we have discovered many new fea- tures about sleep disorders, most of what we have done is match scientific data to ideas documented in the Bible and

Talmud. Our modern scientific knowledge about sleep is not new and existed even in biblical times. This wisdom is also mentioned in the Bible: “…what has been is what will be, and what has been done is what will be done; and there is nothing new under the sun” (Eccle 1:9).

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Michel Billiard

Abbreviations of Books of the New Testament

circadian rhythm sleep disorders, parasomnias, and sleep related movement disorders. On the other hand there are al- lusions to drowsiness and deep sleep, to the homeostatic pro- cess of sleep, to the alternation of day and night or night and day, to wakefulness and vigilance, to dreams, and in a single case, to a deadly consequence of excessive daytime sleepi- ness. Worth noting is that the word sleep often has a double meaning, one that is literal, which we shall consider, and one that is symbolic where sleep may mean lack of commitment, lack of faith, or even death.

Sleep Stages

Sleep stages are not figured out in the New Testament. How- ever, drowsiness and sleep are contrasted 5 “they all became drowsy and fell asleep” (Mt 25:5) and there are three reports of deep sleep, one in the synoptic gospels and two in the Acts of the Apostles. The first one is in Mark, Matthew, and Luke: 36 “Leaving the crowd, they took him (Jesus) with them in the boat just as he was. And other boats were with him. 37A vio- lent squall came up and waves were breaking over the boat, so that it was already filling up. 38 Jesus was in the stern, asleep on a cushion. They woke him and said to him, “Teach- er, do you not care that we are perishing?”” (Mk 4:36–38). The second one is during Herod’s persecution of the Chris- tians: 6“On the very night before Herod was to bring him to trial, Peter, secured by double chains, was sleeping between two soldiers” (Acts 12:6) and the third one shows a young man 9“sinking into a deep sleep as Paul talked on and on” (Acts 20:9)

The Homeostatic Process of Sleep

In Borbely and Achermann’s two-process model of sleep, process S is a homeostatic process increasing exponentially during wakefulness and decreasing exponentially during sleep [1].

Mt Mk Lk
Jn Acts
1 Thes 2 Thes 1 Tm 2 Tm Rv

Matthew
Mark
Luke
John
Acts of the Apostles 1 Thessalonicians

2 Thessalonicians 1 Timothy
2 Timothy Revelation to John

Sleep in the New Testament 7

Before being anything else the Hebrew Bible is a story in which people learn about God through the events of their lives, and the Talmud, a record of rabbinic discussions about Jewish law, ethics, philosophy, customs, history, theology, and other topics. The rst one is composed of 24 books. It was written from the sixth to fth century before Christ onward. The second one has two components, the Mishnah written during the second century after Christ and the Gemara writ- ten from the fourth to the sixth century after Christ.

In comparison, the New Testament, including the three synoptic gospels by Matthew, Mark, and Luke, the Gospel by John, the Acts of the Apostles, the 20 letters of Paul, James, Peter, John, and the Revelation to John, is the presentation of Jesus’s life, teaching, passion, death and resurrection, and of the lives of first Christian communities. The New Testa- ment was written from the 50s to the beginning of the second century after Christ.

Thus, it is no surprise that what the New Testament writes about sleep is different from what the Hebrew Bible and the Talmud write. In particular, although there are references to sleep in the New Testament, there is almost nothing about Sleep Medicine. There is nothing about insomnia, sleep- related breathing disorders, hypersomnias of central origin,

M. Billiard ()
Department of Neurology, Gui de Chauliac Hospital, 80 Avenue Augustin Fliche, 34295 Montpellier Cedex 5, France

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_7, 43 © Springer Science+Business Media, LLC 2015

M. Billiard

This process is exemplified in several sections of the New Testament.

The first one is on the occasion of the transfiguration of Christ, that is a transient change of his physical appearance, to reveal his divine nature, when Peter and his compan- ions are struck by sleep: 29“While he was praying his face changed in appearance and his clothing became dazzling white. 30 And, behold, two men were conversing with him, Moses and Elijah, 31 who appeared in glory and spoke of the exodus that he was going to accomplish in Jerusalem. 32Peter and his companions had been overcome by sleep.” (Lk 9: 29–32). However, the time of the day is not indicated, and this sleep may not reflect natural sleep but a state of sid- eration related to this divine event.

The second example is found in the discourse on the final age and judgment (Mt 24:1 to 25:46), in the parable of the ten virgins: 5“Since the bridegroom was long delayed and they all became drowsy and fell asleep” (Mt 25:5).

The third and main example appears in Christ’s Passion (Mt 26: 38–43, Mk 14, 37–41, Lk 22, 45–46). Following the Institution of the Eucharist in the evening in Jerusalem, Jesus goes with his disciples to the Mount of Olives, in a place called Gethsemane. 38Then he said to them, “My soul is sor- rowful even to death. Remain and keep watch with me”. He advanced a little and fell prostrate in prayer… 40When he returned to his disciples, he found them asleep, and 42with- drawing a second time, he prayed again…43Then he re- turned once more and found them asleep, for they could not keep their eyes open” (Mt 26: 38–43). This shows that, even in a dramatic situation, the evening pressure to sleep is so strong that the disciples cannot resist it.

The Alternation of Day and Night

A reference to night and day or to day and night is found repeatedly in the New Testament, three times in Matthew, twice in Mark, three times in Luke, twice in John, three times in the Acts of the Apostles, nine times in letters of Paul and seven times in the Revelation to John, that is 29 times in total.

In John it is clearly indicated that 4“We have to do the works of the one who sent me while it is day. Night is com- ing when no one can work (Jn 9, 4) and that 9 “If one walks during the day, he does not stumble, while if one walks at night he stumbles, because the light is not in him” (Jn 11, 9). In Luke, during the last days before Passion, 37 “During the day, Jesus was teaching in the temple area, but at night he would leave and stay at the place called the Mount of Olives.” (Lk 21, 37)

On the other hand, in the Acts of Apostles, in the letter by Paul and in the Revelation to John, the circadian rhythm of sleep and wakefulness seems to be ignored by the authors,

when they refer to tribes, widows, elders or Paul himself praying day and night (Acts 26:7; I Thes 3:10; I Tm 5:5; II Tm 1:3; Rv 4:8; 7:15), to Paul working day and night (I Thes 2:9; II Thes 3:8), to Paul admonishing disciples day and night (Acts 20:31) and to “demons” being tormented day and night (Rv 14:11; 20:10).

Wakefulness Versus Vigilance

The three synoptic evangelists, Matthew, Mark, Luke, and Paul use the expressions: stay awake (four times), keep watch or be watchful (15 times), be alert (once), and be vigilant (four times) corresponding to two verbs in the original Greek text, γρηγορέω, watch, and άγρυπνέω, be vigilant. Thus, al- ready in the New Testament, a distinction is made between what can be called “active wakefulness or full alertness,” a physiological concept, and what can be called “readiness to adopt the appropriate behavior in a given situation” [2], a cognitive concept.

Dreaming

The New Testament quotes far fewer dreams than the Old Testament. All of them appear in Matthew, probably a Greek-speaking Jewish convert to Christianity, speaking to Jews familiar with God speaking through dreams.

Six dreams are reported in the New Testament. Five are around Jesus’s birth and one a few hours before his death. Of the first five dreams, four are from Joseph, Mary’s husband and the other one from the Magi.

18Mary was betrothed to Joseph, but before they lived together, she was found with child through the holy Spirit. 19Joseph her husband, since he was a righteous man, yet unwilling to expose her to shame, decided to divorce her quietly. 20 Such was his intention when, behold, the angel of the Lord appeared to Joseph in a dream and said “Joseph, son of David, do not be afraid to take Mary your wife into your home. For it is through the holy Spirit that this child has been conceived. (Mt 1:18–20)

The second dream is a warning made to the Magi who had come from the east to do homage to Jesus: 12“And having been warned in a dream not to return to Herod, they departed for their country by another way.” (Mt 2:12; Fig. 7.1)

The three other dreams are warnings made to Joseph:

13When they had departed, behold, the angel of the Lord appeared to Joseph in a dream and said, “Rise, take the child and his mother, flee to Egypt, and stay there until I tell you. Herod is going to search for the child to destroy him” (Mt 2:13),

19When Herod had died, behold, the angel of the Lord appeared in a dream to Joseph in Egypt 20and said “Rise, take the child and his mother and go to the land of Israel, for those who sought the child’s life are dead” (Mt 2:19–20),

7 Sleep in the New Testament

Fig. 7.1 Papyrus 1 ( verso) designated by β1. This is a papyrus manu- script of the Gospel of Matthew, dating paleographically to the early 3rd century. It was discovered in Oxyrhynchus (Egypt) and is cur- rently housed at the University of Pennsylvania Museum. The surviv- ing text are versus 1:1–9 ( recto) and versus 12–13, 14–20 ( verso). Parts between square brackets are missing. The words are written continuously without separation. Accents and breathings are absent

22But when he heard that Archelaus was ruling over Judea in place of his father Herod, he was afraid to go back there. And because he had been warned in a dream, he departed for the region of Galilee. 23He went and dwelt in a town called Nazareth. (Mt 2: 22–23)

All these dreams are message dreams and all of them have been fulfilled. On the other hand the last reported dream in Matthew, a dream from Pilate’s wife, is a symbolic dream: 19“While he was still seated on the bench, his wife sent him a message, have nothing to do with this righteous man. I suffered much in a dream today because of him” (Mt 27:19), and in this case the advice in the dream is not followed, and Jesus is crucified.

There is a last reference to dreaming in the New Testa- ment, not in Matthew but in the Acts of the Apostles (Acts 2:17), not a dream but a quote of the prophet Joel (Jl 3:1) by the Apostle Peter

17God says, that I will pour out a portion of my spirit upon all flesh.

Your sons and your daughters shall prophesy, Your young men shall see visions
Your old men shall dream dreams

simply meaning that all people, whoever they are, will have part in the spirit of God.

20Ί]δου αγ[γελο]ς KY [κ]α[ο]ναρ [εφανη αυ]τω [λεγων] ίως[η]φ υίος] δ[αυίδ] μ[η] φο[βηθη]ς παρ[αλαβ]ει=[μ]αριαν [την] γυναι[κα σου] 20The angel of the lord appeared in a dream and said Joseph son of David do not be afraid to take into your home. Mary your wife

A Deadly Example of an Accident Due to Excessive Daytime Sleepiness

The Acts of the Apostles provide us with a clear example of excessive daytime sleepiness facilitated by the young age of a man, the time of the day, midnight, and listening to a man keeping up teaching at night.

7“Paul spoke to them because he was going to leave on the next day, and he kept up speaking until midnight. 8There were many lamps in the upstairs room where we gathered, 9 and a young man named Eutychus who was sitting on the window sill was sinking into a deep sleep as Paul talked on and on. Once over- come by sleep, he fell down from the third story and when he was picked up, he was dead. (Acts 20:7–9)

Conclusion

Although sleep is not considered from a medical point of view in the New Testament, there are many references to it. Sleep can be deep even in inappropriate situations. The drive to sleep builds up during the waking state, to the point

M. Billiard

that it may be impossible in the evening to stay awake even when it would be appropriate to do so. The alternation of day and night is continuously emphasized in the New Tes- tament. However, Jesus’s disciples take some liberty with this rhythm when they do not respect it or even recommend not respecting it. Wakefulness and vigilance, two frequently confounded concepts in the sleep literature are differentiated in the New Testament. Most dreams of the New Testament cannot be considered as true dreams but a way of communi- cation between God and humans, often in critical situations.

Finally, one accident due to excessive daytime sleepiness is alluded to in the New Testament.

References

1. Borbély AA, Achermann P. Sleep homeostasis and models of sleep regulation. J Biol Rhythms. 1999;14:557–68.

2. Koella WP. Vigilance – a concept and its neurophysiological and biochemical implications. Adv Biosci 1978;21:171–78.

Introduction

nificance of sleep in the ancient mind, however, took a back- stage to the significance of the dreams that accompanied this state. Beginning with the Iliad, dream narratives were ex- pounded in a number of literary, historical, cultic, and philo- sophical works spanning the whole of the Greco-Roman era, and such narratives provide us with important insights into how dreams were conceptualized in the ancient world. In such narratives, it is apparent that the ancient Greeks and Romans viewed dreams as an objective phenomenon, in- dependent of the dreamer who experiences the dream as a passive recipient. As Dodds (1951) [4] states, the ancient Greeks never spoke of having a dream, but always of seeing a dream. Prior to Plato, the word dream is generally used in its nominal form as opposed to a verb [5]. The notion that dreams were a product of the dreamer’s mind did not exist in the traditional view of dream in Greco-Roman culture. This objective reality of dreams is most prevalent in archetypal “message dreams” that are frequently described in ancient literary accounts [1]. In such dreams, the dreamer is visited by a dream figure, be they gods, the messengers of the gods, or deceased individuals. In the Odyssey, for example, Athene sends Penelope a dream messenger which takes on the form of her sister, Iphthime. The dream messenger is described as slipping past the bolt of Penelope’s room and coming to stand by her head to speak to her. Such message dreams find a prominent place in both literary and historical accounts.

Message dreams, as well as “symbolic dreams” [1], which contained more enigmatic imagery, were clearly seen by the ancients as being supernatural in origin. In the Iliad [3], dreams are explicitly stated as being sent by Zeus (I.60– 64). In the Odyssey [6], dreams are said to be the product of two gates located in the underworld: The Gate of Horn, which is responsible for prophetic dreams, and the Gate of Ivory, which is responsible for unfulfilled dreams. This view was reiterated by Plato ( Charmides 173) [7] and also finds a place in the Aeneid (6.890–900) [8]. The godsent dream, or oneiros, was sometimes even portrayed as a black-winged creature which could take on various forms as needed [4, 5]. Ovid, in his Metamorphosis [9], vividly personifies these

The Greco-Roman Period 8

Joseph Barbera

To the ancient Greeks and Romans, sleep was a state akin to death, and as such a liminal state between the waking world and the afterlife. Not surprisingly, they attributed great sig- nificance to the nocturnal visions that accompanied this state, believing dreams to be communications from the gods (or the dead), and attributing to them the power of prophecy. The belief in the divine and veridical power of dreams is one that the Greeks and Romans shared with the ancient Mes- opotamians and Egyptians before them [1, 2]. The Greeks and Romans, however, took this belief in the supernatural etiology of dreams to its ultimate extent. Dreams, in the Greco-Roman world, found a significant place in literary, religious, and historical accounts; and even in the daily life of citizens from slaves to emperors who sought out dream interpreters and dream oracles. At the same time, it is also in this period that we begin to see in Greek and Roman writ- ings the first naturalistic and rationalistic accounts of both sleep and dreaming, paralleling advances in philosophy and natural science. This chapter reviews both the traditional and rationalistic accounts of sleep and dreaming in the classical world, and what “sleep medicine” may have meant in both these perspectives.

Sleep and Dreams in the Greco-Roman World: The Traditional View

In the Iliad of Homer [3], Sleep, or Hypnos (Fig. 8.1), is personified in the form of a deity, who is referred to sev- eral times as the twin brother of Death (or Thanatos). Vari- ous other literary and philosophical references support this ancient view that sleep was a state akin to death. The sig-

J. Barbera ()
The Youthdale Child and Adolescent Sleep Centre, 227 Victoria St., M5B 1T8 Toronto, ON, Canada
e-mail: joseph.barbera@utoronto.ca

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_8, 47 © Springer Science+Business Media, LLC 2015,

J. Barbera

Fig. 8.1

Hypnos, the Greek god of sleep

Paralleling the work of such dream interpreters were the establishment of various dream incubation cults or oracles, wherein supplicants fell asleep in temples or other sacred places in an attempt to induce a divine dream from a deity. Such cults included that of Trophonius in Lebadeia, Am- phiaros in Oropos, and Isis and Sarapis from Egypt. The most widespread and influential of such cults, however, was that of the cult of Ascleipius, the God of Medicine [5, 15, 16].

Dreams and the Cult of Asclepius

Asclepius (Fig. 8.2), according to myth, was the son of the god Apollo and the mortal woman Coronos. He was initially revered as a hero and physician of great skill and by the end of the sixth century BC would be elevated to the status of the God of Medicine. His descendents, who carried on the medi- cal arts that he perfected, were known as Asclepiads, a term that would come to refer to all physicians [17]. The Rod of

Fig. 8.2 Asclepius, the Greek god of healing. In this statue, he is de- picted holding the “Rod of Asclepius,” a staff encircled by a single ser- pent, which continues to be used as a symbol of medicine to this day. (Image courtesy of http://www.HolyLandPhotos.org)

entities as Morpheus, Icelos, and Phantasos; all of whom were the sons of Hypnos (XI 573–709).

Later accounts view dream visions as the result of the soul being liberated from the body during sleep and undergoing otherworldly journeys [4, 5]. This view was expressed by Plato (427–347 BCE) in the Republic (571–572) [10] and the Neoplatonist Synesius of Cyrene (c. 365–414 AD) in his treatise On Dreams [11]. In some accounts, these two per- spectives—the dream being sent by a god to the dreamer, and the dreamer’s soul entering the dream world—may not be mutually exclusive. For example, in the Odyssey, the dream figure of Iphthime is portrayed as entering Penelope’s bed- room, but Penelope herself is also said to be sound asleep at the “Gate of Dreams” (4.811) [6]. It is as such that sleep, for the ancient Greeks and Romans, may be seen as representing a liminal state between the waking world and the afterlife.

Finally, it is evident in ancient writings that the Greeks and Romans believed in the veridical power of dreams— the ability of dreams to predict the future as well as provide knowledge of the present not immediately available to the dreamer. This is most notable in historical accounts where historical figures, no less than Xerxes [12] and Alexander the Great [13], are said to have been influenced in their actions by dreams they experienced. In practice, the belief in the ve- ridical power of dreams seems to have given rise to the pro- fession of the dream interpreter, or oneirocritic, as well as a proliferation of dream interpretation manuals. References to such manuals date back to at least the fifth century BCE with Antiphon the Athenian [11] and reached their zenith with the Oneirocritica of Artemidorus [14] in the second century AD. In five books, Artemidorus pours over a variety of dream imagery and indicates their meaning, taking into account the dreamer’s personal characteristics in a manner that presages Freud’s psychoanalytic perspective.

8 The Greco-Roman Period

Asclepius, represented by a staff entwined by a single snake, continues to be used as a symbol of medicine to this day1 [18], appearing most notably in the logos of the American Academy of Sleep Medicine (http://www.aasmnet.org/) and the American Board of Sleep Medicine (http://www.absm. org/).

The cult of Asclepius would prove to be one of the most widespread and enduring in the Greco-Roman world. From its origins in Epidaurus, the cult disseminated widely from the fifth century BCE onward, with Asclepieion sanctuaries, or Ascelpieia, being established in an embassy-like fashion throughout the Greco-Roman world [17]. The total number of such sanctuaries has been estimated at up to 513 [18], and it is likely that an Ascleipieoion was a standard institution in any Greco-Roman city or large town. These sanctuaries functioned well into the sixth century AD [17].

The sanctuaries of Asclepius functioned as modern-day spas, if not the precursors to modern-day hospitals. In gen- eral, attempts were made to locate Asclepieia in scenic lo- cations, or on sites of religious significance, and almost all of them were built on the site of springs. The Asclepieion of Epidaurus, the center of the cult, boasted an extensive collection of buildings and facilities, including temples to Asclepius, Artemis, Apollo, and Aphrodite; as well as a gym- nasium, library, guesthouse, stadium, baths, and a theater. An enigmatic circular building known as the Thalos contained an underground labyrinth and snake pit (an animal consid- ered to be sacred to Asclepius) [17, 18].

The core principle of treatment in the Asclepieion was the practice of dream incubation. Fragments from various literary sources allow us to work out what the process of dream incubation entailed. Prior to undergoing dream incu- bation, various animal sacrifices were made, the cock being a customary sacrificial animal for Asclepius, with further food offerings of honey cakes, cheese cakes, bakemeats, and figs placed upon a “holy table.” Preparatory rituals included prayers in the temple, washings in the sacred well, and the adornment of white robes. Supplicants were then led to the abaton where they lay on pallets placed on the floor through- out the sacred room. With the extinguishing of the light, they attempted to fall asleep with the hope of receiving a dream visitation from the god Asclepius [17, 18, 19].

Asclepius, in such dreams, would appear in forms similar to that presented in statues of his likeness, either as a beauti- ful young man or as an older, bearded man of experience, with a gentle and calm demeanor. He could be accompanied by a retinue of assistants, including his daughters, such as Iaso and Panacea, as well as serpents and dogs. Inscriptions in the Asclepieion of Epidaurus, which date from the fourth

1 Not to be confused with the Caduceus, which consists of twin ser- pents encircling a winged staff, the symbol of Hermes and often errone- ously used a symbol of medicine.

century BCE, detail some of the cures carried out by Ascle- pius:

Ambrosia of Athens, blind of one eye. She came as a supplicant to the god. As she walked about in the Temple she laughed at some of the cures as incredible and impossible, that the lame and the blind should be healed by merely seeing a dream. In her sleep she had a vision. It seemed to her that the god stood by her and said that he would cure her, but that in payment he would ask her to dedicate to the Temple a silver pig as a memorial of her ignorance. After saying this, he cut the diseased eyeball and poured in some drug. When day came, she walked out sound. ( InscriptionesGraecae, IV, 1 nos. 121–22, in [17] T. 423)

As alluded to in this passage and others, the early belief was that the dream figure of Asclepius carried out his treatments directly in a miraculous fashion, using both medicinal and surgical means (thus giving the term “sleep medicine” a much more different connotation in the ancient world than we know it today). As suggested by Aristophanes (456–386 BCE) in his play Platus [20], the process of dream incuba- tion in the abaton may have involved a certain amount of deceptive theatrics, with temple staff dressing up in the roles of Asclepius and his minions, and appearing at the expected time. Supplicants may even have been given soporific or narcotic substances which may have impaired their judg- ment and even allowed surgical procedures to be conducted on them [21].

Such miraculous cures, however, are not evident in later accounts of Asclepieion dream incubation. The Greek orator Aelius Aristides (118–180 AD) in his Sacred Orations [19] documented the course of an unspecified illness he was suf- fering from for nearly 17 years, and which brought him into contact with several Asclepieia-seeking treatment. Many of the 130 dreams he described in the work exhibit the discon- tinuity and bizarreness of content that are reflective of ac- tual dreams. When Asclepius does appear to Aristides in a dream, he acts as more of a consultant, not performing cures directly, but recommending to Aristides various treatments or courses of action. More symbolic dreams seem to have been interpreted by Aristides himself, after discussion with priests, doctors, and friends. Moreover, the medical treat- ments recommended to Aristides were not out of keeping with rational- or secular-based medicine of the time (Galen noted that such conservative treatments were more likely to be followed by patients when they were recommended by the god Asclepius) [17], T 401). There is evidence to suggest that physicians were at least tangentially associated with the cult of Asclepius [17, 19, 22].

The cult of Asclepius lasted over a millennium, declining only with the decline of paganism itself. Dream incubation would come to be practiced in some early Christian church- es, a practice which continued into the Middle Ages. Accord- ing to Hamilton (1906) [15], remnants of dream-incubation practice could be found in the early twentieth century.

J. Barbera

Sleep and Dreaming in Greek and Roman Philosophy

While the ancient Greeks and Romans took their belief in the divine nature of dreams to new heights, it is also in this time period that this prevailing view was challenged by phi- losophers and natural scientists. It is in this time period that we begin to see the first rationalistic accounts of sleep and dreaming in history [23].

Alcmaeon of Croton (early fifth century BCE) provides us with perhaps the first theory of sleep, stating that sleep results from the withdrawal of blood to the “blood-carrying veins,” while awakening results from the reverse process [24]. Empedocles (c. 490–430 BCE) described sleep as oc- curring from a moderate cooling of the blood, with death being the result of total cooling [25]. A similar “cooling” hypothesis was ascribed to Parmenides (early fifth century BCE) [26]. Leucippus (early fifth century BCE) described sleep as something that happened to the body, not the soul, and occurred when “the excretion of fine-textured atoms ex- ceeds the accretion of psychic warmth” (Plutarch Epitome V.25.3) [27]. Diogenes of Apollonia (fifth century BCE) be- lieved that sleep resulted from blood filling all the veins and forcing air into the back and belly which warms the breast [28] (Pseudo Plutarch, PlacitaPhilosophorum, 5.23).

With respect to dreaming, both Heraclitus (c. 535–475 BCE) and Empedocles alluded to the subjective nature of dreams. Heraclitus further described dreams as the kindling of an “inner light” that occurs when vision is extinguished [29, 30] (Fragment 26 and Fragment 89). However it is Dem- ocritus of Abdera (460–370 BCE) who provides us with the first systemic theory of dreams. Democritus, in keeping with the theory of “atomism” he promulgated, described dreams as the result of fast-moving films of atoms or “effluences” ( eidōla), which are emitted by all objects (including people), penetrating the body during sleep, and impacting directly on the soul [27] (pp. 132–134). This theory, which still sees dreams as a largely externally generated phenomena, would continue to have a long-standing influence [23].

Plato professes several views of dreams throughout his works. In earlier works, he maintains the divine origin of dreams, such as in the Crito [31], where he has Socrates di- vining the timing of his own death based on a dream (44). In a famous passage of the Republic, he ascribes to dreams a pseudo-Freudian psychological function, stating that in dreams we express a “lawless wild beast nature” (571c– 572b) that we normally repress in wakefulness [10]. Finally, in the Timaeus [32], Plato offers a naturalistic account of sleep and dreaming. At night, the “external and kindred fire,” responsible for vision, departs with a resultant induction of sleep. With the eyelids closed, the “internal fire” is directed inward. Where such fire equalizes “internal motions,” quiet sleep results; where it does not, dreaming occurs (45–46).

Plato is thus perhaps the first individual to distinguish be- tween non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Despite this naturalistic account, Plato still allows for the possibility of dream divination, even locating the site of dream prophecy to the liver (71).

It is Aristotle (Fig. 8.3) who provides us with the most comprehensive naturalistic account of both sleep and dream- ing in the ancient world, writing three full essays on the sub- ject including On Sleep and Waking ( De Somno et Vigilia), On Dreams ( De Insomniis), and On Divination Through Sleep ( De Divination per Somnum) [33]. In On Sleep and Waking, Aristotle describes sleep as resulting from the in- activation of the body’s primary sense organ, which Aris- totle believed to be the heart. Physiologically, he believed, the process of sleep began with the ingestion of food which thickened and heated the blood. This “solid matter” rises to the head where it is cooled by the brain and the subsequent reverse flow back downward causes a “seizure” in the heart which induces sleep. Similar effects were also attributed to soporific agents, states of fatigue, and certain illnesses. Wakefulness followed when digestion was completed with

Fig. 8.3 Aristotle. A prolific philosopher and natural scientist, he developed the most comprehensive naturalistic account of sleep and dreaming in the Greco-Roman world. (Image courtesy of Marie-Lan Nguyen/Wikimedia Commons)

8 The Greco-Roman Period

a separation between more solid and more pure blood. Ar- istotle believed that sleep served in the preservation of the organism, in particular, in its exercising of perception and thought.

In On Dreams, Aristotle describes dreams in terms of “movements” within the body (presumably the bloodstream) which are created during sensory stimulation in wakefulness. At night, these residual movements impact on the soul/heart to activate perception, but only in its imagining ( phantas- tikon) capacity. These residual perceptions produce the ap- pearances ( phantasamata) of dreams. The turbulence of blood accounts for the variable coherence of such appearanc- es, but, nonetheless, they are taken as real owing to the sus- pension of judgment during sleep. In On Divination through Sleep, Aristotle soundly dismisses the divinatory power of dreams. The foretelling of future events by way of dreams, he contends, is largely a matter of coincidence.

In Hellenistic philosophy, the Stoics, including Chriysi- piuus (c. 280–207 BCE) and Posidonius (c. 153–51 BCE) still supported divination in all its forms, including dreaming (Cicero, On Divination) [34]. In contrast, Epicurus (341–270 BCE) put forth a theory similar to that of Democritus pos- tulating the existence of effluences or films exuding from the surfaces of bodies and penetrating the sensory organs or going directly into the mind in waking thought and in sleep ( Epicurus to Herodotus) [35]. This theory was expanded upon by Lucretius (94–49 BCE) in his worth On the Nature of the Universe s [36]. Lucretius explained the bizarre nature of dreams as arising from the intermingling of surface films in the air prior to their entering the mind (an image of a cen- taur, for example, resulting from an amalgamation of surface films from a man and a horse). Lucretius also allowed for the successive images received by the mind to be influenced by what it is “prepared” to see, i.e., by waking preoccupations. Lucretius also conceptualized sleep as the impact of external air and internal respirations on the “vital spirit” or soul atoms diffused throughout the body.

Cicero (106–43 BCE) questioned the divinatory power of dreams in his treatise On Divination ( De Divinatione) [34]. As with Aristotle, he attributed the veridical power of dreams largely to coincidence. He also adds to previous naturalistic accounts of dreaming by suggesting that they re- sult from “an intrinsic internal energy” and even suggests an active cognitive component in the production of dreams as various “reminiscences” and daytime preoccupations come to bear on the mind in a “weak and relaxed state.”

Macrobius (c. late third century AD), in his Commen- tary on the Dream of Scipio [37], classifies dreams into five categories: the enigmatic dream, the prophetic vision, the oracular dream, the nightmare, and the apparition. The lat- ter two, he notes, have “no prophetic significance.” Night- mares, rather, are caused by “mental and physical distress, or anxiety about the future” with daytime concerns reflecting

themselves in nocturnal dreams. His description of “appari- tions” amounts to hypnagogic hallucinations, occurring as they do, in “the moment between wakefulness and slumber.” It is to this phenomenon that Macrobius ascribes the popular belief of the incubus, a demon said to lie upon sleepers dur- ing the night.

Sleep and Dreaming in Secular Greek and Roman Medicine

Traditionally considered to have originated with Hip- pocrates (c. 460–370 BCE), secular-based medicine in an- cient Greece and Rome was characterized by the eschew- ing of divine causes for disease and the conceptualization of illnesses in terms of environmental influences and humoral imbalances. Dreams continued to find a place in this ratio- nalistic-based medicine. Within the Hippocratic Corpus, the treatise Dreams [38] maintains that there are dreams that are internally driven and reflective of “bodily states.” Dream- ing of celestial bodies affected by moisture, for example, indicated an excess of moisture or phlegm within the pa- tient’s body. By analyzing the content of a patient’s dream, a physician was thus able to diagnose bodily disturbances and direct treatment accordingly [38]. This view was also held by Rufus of Ephesus (c. 100 AD) and Galen (129–216 AD) who authored a treatise on the subject—Diagnosis in Dreams [11, 39, 40]. Even Aristotle allowed for the diagnos- tic use of dreams in medical illness [33], as did Cicero in his own arguments against the divinatory power of dreams ( On Divination) [34]. On the other hand, there seem to be physi- cians in ancient Greece and Rome who did not ascribe to the diagnostic value of dreams, including Soranus ( Gynecology) [41] and those of the Methodist and Asclepiade schools [39].

Disturbances in sleep are frequently noted in the Hip- pocratic corpus as a symptom to be noted and utilized in prognostication, most notably in the Epidemics Book I and III and Prognosis[42, 43, 44]. The author of Aphorisms [45] provides the practical maxim that “both sleep and wakeful- ness are bad if they exceed their due proportion.” In Progno- sis [44], it is further added that any patient should follow the natural tendency of sleeping at night and being awake during the day and that any alteration from this was problematic. The Hippocratic author of The Sacred Disease [46], identi- fies the brain as the seat of both insomnia and sleepwalk- ing; and notes that excessive blood flow to the brain which heats it is responsible for nightmares. This is in contrast to the traditional view that parasomnic activity was due to “at- tacks of Hectate and the assaults of the Heroes.” In Regi- men II (Chapter LX) [47] and Regimen III (Chapter LXXI) [48], sleep is related to the warming and moistening effects in the body, interacting with the effects of diet and exercise.

J. Barbera

Consequently, prescriptions for sleep in relation to diet and exercise occur throughout these texts.

Galen attributed sleep to a cooling of the brain and an increase in its moisture. Insomnia, accordingly, was caused by a brain that was excessively warm and dry. Galen distin- guished natural sleep from that of comas and other forms of unconsciousness, as well as from sleep induced from hyp- notics which only increases moisture in the body [49, 50]. Galen listed sleep as one of a group of “nonnaturals” that affected the pulse, and, in the ensuing centuries, Galenism would evolve to include sleep as one of the six nonnaturals that on a larger scale affected health and disease [51].

How and to what degree disturbances in sleep were treat- ed by ancient Greek and Roman physicians is unclear. Cer- tainly, the hypnotic properties of various agents were known in antiquity. Aristotle supported his theory of sleep by citing the soporific properties of poppy, mandragora (mandrake), wine, and darnel [33]. Dioscorides (40–90 AD), in his wide- ly influential and long-standing work De material medica [52], lists a number of soporific agents including saffron, aloe, rush, opium poppy, henbane, sleepy nightshade, and mandragora. In terms of non-pharmacologic treatments, the Hippocratic treatise, Regimen in Acute Diseases [53], offers the advice that “if sleep should not come, a slow prolonged stroll, with no stops, should be taken.”

Finally, antiquity provides us with perhaps the first de- scription of sleep apnea, as related by Kryger (1983) [54]. Several sources discuss the case of Dionyisius of Heracleia (360 BCE) who was a man of such morbid obesity that he had difficulties breathing. In addition, he seems to have had significant daytime sleepiness such that his physicians are said to have prescribed him the insertion of long, fine nee- dles into his flesh, in order to awaken him whenever he fell into a deep sleep.

Conclusion

It cannot be said that, in the ancient world, there was any- thing akin to the field of “sleep medicine” as we know it today. We can, however, see in the Greco-Roman world, a marked preoccupation with sleep and, in particular, dreams. In the Greco-Roman world, the ancient belief in the super- natural origin of dreams was not only held in theory but also in practice, with the proliferation of dream interpreters and dream incubation cults such as that of Asclepius. At the same time, Greek and Roman philosophers began to question the supernatural viewpoint of dreams, and, for the first time in history, offer their own naturalistic accounts of both sleep and dreams. Finally, one can see traces of the importance of sleep and dreams for the earliest practitioners of secular medicine and attempts to translate naturalistic accounts of these phenomena into sound medical practice.

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The Aztec, Maya, and Inca Civilizations 9

Edgar S. Osuna

The discovery of America placed the European nations in contact with three major civilizations—the Aztecs in the Mexican plateau, the Mayas in the Yucatan peninsula, and the Incas in the Peruvian Andes. The Mayas had been settled for centuries in the same area and developed a civilization with high cultural manifestations, whereas the Aztecs and the Incas, in spite of their political power and strong resis- tance to the Spanish conquest, were actually cultural parv- enues among pre-Columbian people [1].

The Aztecs

The earliest Mexican civilization to leave traces in the cen- tral plateau, around 955 BC, was the Olmecs. However, most of the Aztec cultural achievements were inherited from the Toltecs. They were remarkable for city planning, a solid ar- chitecture with use of caryatids, and built observatories to plot the movement of the stars and planets.

At the time of the Spanish arrival, the Aztecs capital, Tenochtitlan, was the largest and most beautiful in America, with pyramidal temples, water supply, streets, and gardens [2].

The very name “Aztec” is debated by scholars today. It was first proposed by the explorer naturalist Alexander von Humboldt (AD 1769–1859), and later popularized by Wil- liam H. Prescott in his remarkable AD 1843 publication: The History of the Conquest of Mexico [3].

Aztec is an eponym of Aztlan, or “Place of the White Heron,” a legendary homeland of seven desert tribes called Chichimecs who miraculously emerged from caves located

E. S. Osuna ()
Department of Morphology, School of Medicine, National University of Colombia, Bogotá, Colombia
e-mail: edosunas@unal.edu.co

Department of Neurology, University Hospital Fundacion Santa Fe de Bogota, Bogotá, Colombia

at the heart of a sacred mountain far to the north of the Valley of Mexico, and left the region one by one. The seventh and last tribe, known as the Mexica, decided to move south to Lake Texcoco [3, 4]. They were forced to retreat to an island where they witnessed a miraculous vision of prophecy: An eagle perched on a cactus holding a snake at its mercy. At that moment, the sun rose, and its light caught the eagle’s feath- ers as the bird extended its wings. It was the sign of their sun god, Huitzilopochtli, for Tenochtitlan, their final destination, and, in AD 1325, Tenochtitlan was officially founded [1–3].

By the time of the Spanish arrival in AD 1519, the Mexica had formed a strong alliance with their neighbors—the Ac- olhuacans of Texcoco and the Tepanecas of Tlacopan—and forged a vast empire, the Aztec empire [5]. Eventually, they were to give their name to the nation of Mexico, while their city of Tenochtitlan became what we know as Mexico City.

The diet was based on maize, beans, chili, amaranth, squashes, maguey, and several sources of animal protein were present—turkey, hairless dog, fish, and game. From the ma- guey plant were produced extensive quantities of an alcoholic drink ( octil or pulque). Pulque provided relief from gout and was used blended with other substances to heal open wounds.

The Aztecs had an astronomical calendar extending over the solar year of 365 days, divided into 18 months of 20 days each, plus 5 complementary unlucky days nemontemi. In addition, there was the astrological or religious calendar Tonalamatl of 260 days, divided into 13 months, each under a god. The fate of an individual—health, disease, its progno- sis, length of life, besides profession, trade or plain luck— was determined by the Tonalamatl calendar [1, 4].

The day started early for Mesoamerican: The people of Tenochtitlan rose before dawn. When the morning star, Venus, appeared in the sky, drums and conch trumpets sounded from the Templo Mayor and the temples that were the focus of religious life in each locality. Many took a steam bath to refresh themselves at the beginning of the day [6].

Explicit cultural codes governed the interpersonal re- lations and the content of these daily activities. The codes were, in many ways, common to all members of the society,

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_9, 55 © Springer Science+Business Media, LLC 2015

E. S. Osuna

but varied substantially according to class, gender, age, and special positions. For example, a nobleman advised his son to live in accordance with eight rules:

First: Thou art not to give thyself excessively to sleep… lest thou will be named a heavy sleeper…a dreamer…[5]

The eight rules speak of the ideal attributes of moderation and discretion, only the first was related to sleep.

Other rules were observed during pregnancy. The expect- ant mother was to eat well and not to be denied anything she desired; she was not to sleep in the daytime, not to look at anything frightening, offending, or red. The Mexica felt that failure to observe these rules could result in a difficult birth, birth defects, stillbirth, or the death of the mother [5].

The home of a common family was a single-room struc- ture arranged in groups of several houses around a common patio. Single-room huts provided little more than a space for sleeping, with the family hearth often situated outside, beneath a canopy. All houses had a shrine to the ancestors. Aztec houses had little or no furniture: People worked, sat, and ate on the floor. They usually slept on woven mats [6, 7].

A most impressive list of works dealing with healing methods and the ideas behind them can be produced, and, practically, all of them are based on the Sahagun Codices— a group of manuscripts, on the Mexicans, written by the Franciscan friar, Bernardino de Sahagun, O.F.M. (AD 1499– 1590). Another document, written by Martin de la Cruz, that provides medical information is the Badianus Codex, also known as The Codex de la Cruz Badiano, or by its Latin title, Libellus de Medicinalibus Indorum Herbis. Visually, the Codex is strikingly similar to a sixteenth-century Euro- pean herbal [8].

The medical doctrines and practices of the Aztecs were permeated by profound religious elements. The Aztecs be- lieved in the hereafter, with a heaven, Tonatiuh, in the sun re- served for the heroes, another heaven, Tlalocan, on the earth, and the abode of rest, the underworld Mictlan.

The night was a time to be feared. The Aztecs believed that Tezcatlipoca was at large in the hours of darkness, some- times taking the form of the deadliest demon called Night Axe, or sometimes of a wandering demon who approached travelers at the crossroads. It was also the time and realm of the demons called tzitimime, malevolent female spirits. Whereas Tezcatlipoca was associated with darkness, his eternal rival and counterpart Quetzalcóatl was linked to dawn. His rising symbolized resurrection, while the darkness of Tezcatlipoca stood for death(Fig. 9.1).

The Aztecs associated owls with Tezcatlipoca, with night and sorcery [4, 9].

In the Aztec world, three souls, or animistic entities, in- habited the human body. The tonalli (hotness) inhabited the upper part of the head and was responsible for the heat or life force or destiny of an individual. It was associated with the

Fig. 9.1

sun, the supreme source of this life force. Tonalli could leave the body transiently during sleep [10]. Tonalli increased with age, and old people were respected for having strong ton- alli. When a body lost tonalli, death followed, and so corpse was cold. The second entity, the teyolia, which resided in the human heart, was the source of thoughts, creative impulses, and human personality [6]. The ihiyotl, had its seat in the liver, and was the counterpart of the underworld. Energy, life’s breath, passion, and desire were the products of ihiyotl. The health of an individual depended on the balance of these three entities, and they were affected by outside forces as well. (Fig. 9.1)

Aztecs knew how to use medicinal plants and roots. A woman or a man could be a ticitl (healer), considered to orig- inate from the first wise people. They knew specific methods for how to suture, how to splint, to immobilize a fractured or dislocated bone, and how to bleed a patient [1, 11].

The Aztecs ascribed illnesses of all kinds to three primary causes: supernatural, magical, and natural. They considered sickness the punishment inflicted by their gods for their sins. The power attributed to each deity was in relation with the sickness—the water god sent colds and rheumatism, the love goddess sent venereal diseases etc. [12].

Medical art, ticiotl, was believed by the Aztecs to have been developed among the Toltecs by four wise men; Oxo- moc, Cipactonal, Tlatetecui, and Xochicaoaca. These schol- ars knew the nature and qualities of herbs, and they devel- oped the astronomical calendar Tonalamatl. They were also familiar with the influence of the stars upon the body and were able to interpret dreams [13].

These two elements—one attached to medical botany and the other supernatural—shaped Aztec medicine. Most histo- rians have mentioned that a degree of specialization existed in the Aztec medical profession—the surgeon, phlebotomist, midwife, and the apothecary.

Quetzalcóatl’s name has two meanings. Quetzal can mean “green feather” or “precious,” and coatl can mean “serpent” or “twin.” The elements of the name taken together can mean “Plumed Serpent” or “Precious Twin.” Such dual meaning also demonstrates the concept of duality so characteristic of Mesoamerican deities and religion in general. (Taken from ref. [4])

9 The Aztec, Maya, and Inca Civilizations

On the eve of the American conquest, Aztec medicine en- joyed considerable prestige among pre-Columbian cultures, and in the eyes of the European arrivals. Many remedies quickly diffused to Europe and became common in the Eu- ropean pharmacopeia of the late sixteenth and subsequent centuries [11].

The Mayas

The ancient Maya created one of the world’s most brilliant and successful civilizations. Classic Maya civilization was truly lost until the beginning of the nineteenth century, when brief notices of crumbling jungle cities began to appear in different publications [9].

Maya territory covers roughly the eastern half of Meso- america, Yucatan Peninsula, and its broad base. Maya territo- ry covered the western part of Honduras and El Salvador, ex- tended through the lowlands of Petén in Guatemala, Belize, and most of Mexico east of the Isthmus of Tehuantepec—the states of Yucatan, Campeche, and Quintana Roo—and most of Chiapas and part of Tabasco and Veracruz [9, 14].

Maya civilization is divided into three periods: the Pre- classic, the Classic, and the Postclassic. The Preclassic in- cludes the origins and apogee of the first Maya kingdoms from about 1000 BC to AD 250. The Classic Maya period started in AD 300, a date which was found carved, as part of the Maya calendar, on a jade plate. The Classic period defines the highest point of Maya civilization in architecture, art, writing, and population size [15].

The highest cultural sophistication of the Maya was hi- eroglyphic writing going beyond pictographic representa- tion. The finest Mayan hieroglyphs are found in the Maya Codices still extant—one in Dresden, one in Paris, and an- other in Madrid. As all codices had some religious content, they were destroyed by the Catholic missionaries after the arrival of the Spaniards [9, 14].

The Maya and their ancestors have lived for some 4500 years. The Spanish conquest ended Maya civilization, but the Maya people survived this trauma and 500 years of sub- sequent oppression. Today, several million Maya people continue to live in their ancient homeland and have retained their culture and languages [15]. Rigoberta Menchu is an indigenous Guatemalan of the Quiche branch of Mayan culture. She received the 1992 Nobel Peace Prize. Over the years, Rigoberta Menchu has become widely known as an advocate of the Indian rights [16].

The Maya believed their world was created by Hunab, and his son Itzammá, who was the Lord of Heavens, also Lord of Day and of Night. Ixchel, his wife, was the goddess of floods, pregnancy, and medical matters [14].

The Maya universe was defined by cosmic trees set at its four cardinal points, together with a fifth, axis mundi, placed

Fig. 9.2

at the center, the ceiba [8]. The ceiba was a sacred tree for the Mayas, and it dominated the center of the cosmos (Fig. 9.2). There is no other nation in history, where the concept of time produced a stronger impact, nor a people who measured

passing time, so accurately, as did the Mayas.
The daily journey formed the basis of the calendar which

includes the Sacred Round that was 260 days long, and a sec- ond cycle of 365 days long, divided into 18 months (uinal) of 20 days with a final period of only 5 days. Each day could be named in terms of both the 260- and 365-day cycles. There was worldwide interest in what might happen on December 21, 2012, as shown by films, books, television specials, and magazines that speak of some kind of universal or cosmic shift in our lives. In fact, the date does mark the completion of a 5125-year Great Cycle. But anyone who understands the Maya timekeeping knows that this date will be followed by a new cosmic cycle that repeats the patterns of the past and reveals new mysteries [13, 17].

In a Maya village, the majority rose before dawn, took a steam bath, ate a maize breakfast, and made their ways to the fields.

Their houses were rectangular, with rounded corners, white walls of stone, mud blocks or adobe, and a special thatch roof. The house contained one or two rooms at most. They slept on mats using cloaks as coverings [6].

They grew corn, beans, squash, groves of fruit, and bread- nut trees—a source of food if the corn crops failed. Maize represented more than mere food to the Maya; it was a god— depicted as a young man holding the plant—and the basis

The Maya believed that the center of the world was defined by a cosmic tree. Its upper branches were the heavenly home of the Principal Bird Deity, while its roots sank into the Underworld. This il- lustration by Heather Hurts (2007) depicts a detail from the West Wall of the murals at San Bartolo

E. S. Osuna

of their lives. They believed that man was created by their gods from maize. Protein supplements were obtained from domestic fowls, turkeys, deers, and fishes. Low iodine intake has been mentioned as the cause of pre-Columbian goiter [14].

The physician ah-men, was a member of the priestly hi- erarchy and a product of inherited position and training. The sciences which they taught were the reckoning of the year, the omens of the days, prophecies or events, remedies for sickness, and the art of reading and writing. Physicians im- posed the confession upon the patient prior to any treatment as it was customary in the Aztec civilization.

Sweathouses where dry heat with steam was given, per- fumed with aromatic plants, were used for the treatment of diseases.

Maya induced cranial deformities during childhood by progressively flattening the frontal and occipital bones be- tween two flat pieces of wood. In this way, Maya obtained the retracted profile which is so characteristic of archeologi- cal paintings and bas-reliefs.

The idea of disease of the Mayas was always related to religious and ethical concepts. In the PopulVuh, it is asserted that disease is caused by external actions, enemies, or the evil eye.

They identified more clinical syndromes for mental dis- eases than probably any other culture, for instance, madness, melancholia, delirium, and hallucinations.

A greater part of the treatment was based on the adminis- tration of prescriptions made up, in most cases, from medici- nal plants. The number of days of treatment was usually 13 for men and 9 for women.

In referring to therapy, it is important to mention that the Mayas used phlebotomy with special lancets, ta, as a method of treatment, not only for its physical merit but also as a reli- gious act of penitence.

Tobacco mixed with cal, and chewed, was used by them to obtain energy and to quench thirst while at home or trav- eling or before starting work. Contrary to current sleep hy- giene recommendations, the Mayas used tobacco to ease sleep and calm the effects of the daily activities. Tobacco was used also for different diseases such as asthma, fever and convulsions [18].

The Incas

By the early sixteenth century, the Incas built up an empire extending along the Andes, from north Chile and Argentina to south Colombia. The Inca culture was the longest in ex- tension in ancient America.

The Inca empire, called Tawantinsuyu (Four Quarters), was divided into four regions, each supervised by an impe- rial governor. At the head of the empire was the Inca (lord),

who was held to be divine. The Inca ruled from the capital city of Cuzco (currently in Peru), founded by MancoCápac.

The principal crops were corn and potatoes. These were extensively cultivated through a well-planned system of ter- races and irrigation canals. A portion of the harvest was kept each year, in storehouses, in case of necessity.

The dwellings of the common people were very primi- tive. The walls were of beaten earth, and the roof was of thatch. There were no windows. In this dark and smelly hovel, children and guinea pigs were crowded around a little clay hearth. Llama skins, thrown on the ground and folded, served as beds [19].

The Sun was a very useful patron god for the Incas, as he could be perceived, and, therefore, worshipped from any- where in the empire. It is significant that it is the light not the heat that is emphasized in Inca cosmology.

In the Inca cosmology, the categories of male and female were not ultimately based on biological sex, but rather on cultural ideas. Males were deemed to be dominant, and fe- males subordinate. The fundamental structure of Inca cos- mology, the dualities of right (associated with day) and left (associated with night), high and low, male and female, front and back, were in fact, derived from the human body. Al- though male is usually considered as being superior to fe- male, right superior to left, and so on, in Andean thought, each is essential to the existence of the other. There can be no body without both right and left sides, and no normal adult body is complete without a partner of the opposite sex [20]. The human body, thus, in itself or paired in complementary opposites, is a basic symbol of wholeness and integrity in the Andes.

The duality of sleep and wake could be taken as opposing, and, at the same time, complementary forces, that maintain a constant equilibrium. This has not been described, at least to my knowledge, but it is in accordance with the fundamental structure of Inca cosmology. Sleep is essential to wakeful- ness, and vice versa, which is similar to the current concept of sleep–wake homeostasis.

The branch of surgery, which seems to have been most practiced in Peru, was trephining (Fig. 9.3).

Medicine consisted of empirical processes and magic practices [21]. The Inca curers, called, in general, hampiyok, used various methods for removing a disease from a pa- tient’s body; one of the most effective was herbal infusions, of which the hampiyok had an extensive knowledge. Other methods included sucking the disease out of a patient, blood- letting, and leaving the patient’s clothes by the roadside so that the illness would be carried away by whomever came by and picked the clothes up. According to the Incas, illness was often caused by hucha or sin, an element that disrupted the unity of the whole.

According to Garcilaso de la Vega, babies were washed in cold water, exposed to night air, and kept swaddled in cradles

9 The Aztec, Maya, and Inca Civilizations 59

Fig. 9.3

Acknowledgment I thank Jenny Milena Macheta and Diego Prieto for their assistance at the Universidad de los Andes, School of Medicine Library.

References

1. Guerra F. Aztec medicine. Med Hist. 1966;10(4):315–38.
2. Gimeno D. Grandes Civilizaciones de la Historia. Imperio Az-

teca: Editorial Sol 90; 2008.
3. Pohl J. Aztecs: a new perspective. History Today. 10–17 Dec.

2002.
4. Phillips Ch, Jones D. The mythology of the Aztec and Maya.

Southwater: Anness; 2006.
5. Berdan FF. The Aztecs of Central Mexico: an imperial society.

2nd ed. Belmont: Thomson & Wadsworth; 2005.
6. Phillips Ch, Jones D. The Aztec and Maya World. Lorenz Books;

2006.
7. Solis F. The Aztec Empire. Solom R. Guggenheim Museum. In-

stituto Nacional de Antropologia e Historia/CONACULTA, New

York, Oct. 15, 2004.
8. Gimmel M. Reading medicine in the Codex de la Cruz Badiano. J

Hist Ideas. 2008 Apr; 69(2):168–92.
9. Stuart G, Stuart G, The mysterious Maya, The National Geo-

graphic Society, 1977.
10. Gutierrez MJ, Guierrez CM. Historia de la Medicina: Orga-

nización Médica Mexica (Azteca) y sus Tratamientos con Enfasis en la Epilepsia. Revista Mexicana de Neurociencias. Julio-Agos- to. 2009;10(4):294–300.

11. Harvey H. Public health in Aztec society. Bull N Y Acad Med. 1981 Mar;57(2):157–65.

12. Aguilar-Moreno Manuel. Handbook to life in the Aztec world. Oxford: Oxford University Press; 2006.

13. Carrasco D. Sessions Scott. Daily life of the Aztecs. 2nd ed. Greenwood; 2011.

14. Guerra F. Maya medicine, lecture Osler Club, at the Wellcome Historical Medical Library, N.W. Feb. 13, 1963.

15. Sharer R. Who Were The Maya? Expedition Spring 2012;54(1):12 -16. http://www.penn.museum.

16. Gimeno D. Cassan F, Contreras J. Grandes Civilizaciones de la Historia. Mayas: Editorial Sol 90; 2008:8.

17. Martin S. Time, Kingship, and the Maya Universe Maya Calen- dars. Expedition. Spring 2012;54(1):18–24. http://www.penn.museum.

18. Thompson JE. Historia y religión de los. Mayas: Sigloveintiuno ed.; 2004.

19. Gimeno D. Cassan F, Contreras J. Grandes Civilizaciones de la Historia. Incas y Culturas Andinas. Editorial Sol 90; 2008:2.
20. Classen C. Inca cosmology and the human body. Salt Lake City:

The University of Utah Press, 1993.
21. Baudin L, Bradford W. Daily Life in Peru. Allen Unwin; 1St Edn.,

1961.
22. Aminoff M, Boller F, Swaab D. Handbook of clinical neurology.

2010;95:3-13.
23. Victor W von Hagen. The ancient Sun Kingdoms of the Americas.

Cleveland: The World Publishing; 1961.
24. Golden W. Peru, History of Coca: The Divine plant of the Incas.

New York: J.H. Vail & Company. 1901.
25. Fairley HB. La anestesia en el imperioincaico. Rev Esp Anestesiol

Reanim. 2007;54:556–62.

An Inca skull with five healed trepanations (four are visible in this photograph) of similar size and shape. (From the site of Patl-

lacta, near Cuzco, Peru) [21]

until they were three months old. Mothers never held their children in their arms or laps, or even while breast-feeding. The mother placed small planks on the forehead and the back of the head of the baby. To avoid immediate difficulties, the mother tightened these barbarous instruments, a little more each day, until she had obtained the desired shape [23].

The Incas located reason and emotions in the sonco, or heart and stomach, and memory in the head or uma. Physical sensation was believed to reside in the bones, or tullu, and to remain there after death.

Treatment by herbal medicines was, by far, the most important. Available plants that had central effects include maize (which they used to prepare an alcoholic beverage called chica). Of course, coca came to head the list [24]. To make it edible, some alkaline material must be added, usu- ally ashes of quinua. Coca taken in moderation enables an Indian to show a surprising resistance to fatigue; but taken in excess, it leads to stupidity and laziness [21, 24]. According to the Indians, coca cures sickness and hemorrhages; when infused, it puts a stop to diarrhea and colic, and its juice dries up ulcers. An infusion of Datura calmed the nerves and in- duced sleep, although taken in large doses it could be a poi- son [25].

Belladona ( Datura ferox) is well known: It yields at- ropine and was once widely used as a “twilight sleep” for childbirth [23].

Part II

Sleep Medicine from the Medieval Period to the 19th Century

Sleep Medicine in the Middle Ages and the Renaissance

A. Roger Ekirch

Early in the Middle Ages,
social upheaval, and feudal
the “ancients” found refuge among other prized manuscripts in the cloistered recesses of monasteries. Drawn from Hip- pocrates, other early Greek writers, and from Galen, the emi- nent medical theorist of second-century Rome, knowledge of the human body and its care evidenced little advance- ment until the early twelfth century and the founding of the Salerno medical school in southern Italy. There, ancient texts, formerly preserved in Arabic, became more accessi- ble in Latin. This era witnessed the emergence of a steady succession of universities, commencing with Paris (1110), Bologna (1158), and Oxford (1167), that pursued the study of medicine with newfound enthusiasm. In medieval cities, hospitals and medical guilds also ourished in increasing numbers [1].

For most writers, the ancient Greeks continued to exert immense influence, as did Galen and his emphasis upon a proper regimen in everyday health based upon the manage- ment and quality of six “nonnatural things” pertaining to the body (air, exercise and rest, food and drink, sleep and wakefulness, mental activity and emotions, and the retention and discharge of waste). The attraction of classical writings only intensified during the Renaissance with a heightened reliance upon early medical texts in Greek, unadulterated, according to scholarly opinion, by flawed translations into Arabic and Latin. As in poetry and philosophy, so too in medicine, “admiration for all things Greek was in the air,” asthehistorianRoyPorterhaswritten—not,however,tothe complete exclusion of other texts, including the influential writings of the eleventh-century Persian scientist Avicenna, whose Canon of Medicine became available in Latin in the 1400s. Meanwhile, the advent of printing aided in the rapid dissemination of texts, creating, in turn, new lines of inquiry inspired by Renaissance humanism. Most dramatic, perhaps,

A. R. Ekirch ()
Department of History, Virginia Tech, Blacksburg, VA 24061, USA e-mail: arekirch@vt.edu

was the advent of diverse drugs and herbs, aided by advances in chemistry, and the discovery of plants and other foreign vegetation in the New World—all of which, by the sixteenth century, popular medical texts, brimming with household ad- vice and no shortage of remedies, made more available to the European public [1].

It is upon these texts that our understanding of early Eu- ropean sleep medicine largely rests, coupled with passing references gleaned from diaries and literary works. Informa- tion, as such, is more far plentiful for the Renaissance than for the Middle Ages. Written for the most part by physicians, medical texts typically went through multiple printings. The Castel of Helthe (1539), by Thomas Elyot, for example, spawned more than a dozen editions in the 1500s. A number of titles were also translated into English from other tongues, including The Touchstone of Complexions by the Dutch doc- tor Levinus Lemnius and Guglielmo Grataroli’s A Direction for the Health of Magistrates and Students (1574), originally published in Latin in 1555. Translations, aiding in the cross- pollination of treatments and techniques, only facilitated the congruity of medical opinion during the Renaissance, including discourses about sleep, a topic that most medical texts addressed, however, briefly. With few exceptions, there arose, as a consequence, a broad consensus relating to the physiology of sleep and its role in everyday life [1–3].

As in other medical realms, most physicians depended heavily on the ancients for their understanding of sleep, es- pecially Aristotle and Hippocrates. On the subject of sleep’s origins, Aristotle’s De Somnoet Vigilia was a common source, as it was for Avicenna’s “On Sleep and the Waking State” (Hippocrates, by contrast, was notably silent on the subject on what caused sleep). Standard was the Aristotelian notion of “concoction,” whereby food, digesting in the stom- ach, generated warm fumes that ascended to the brain ( som- nuscausatur ex vaporecibi, qui vadit ad cerebrum). There, upon cooling and descending to the chest, they enveloped the heart and precipitated sleep. Later, Galen located the cen- ter of sensory perception in the brain rather than the heart, a

a time of foreign invasions, warlords, medical texts from

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_10, 63 © Springer Science+Business Media, LLC 2015

A. R. Ekirch

view that physicians began to adopt by the late Renaissance. Thus, for the English writer Thomas Cogan in The Haven of Health (1588), vapors, on reaching the head, became con- gealed “through coldnesse of the brain” and “do stop the conduits and ways of the senses, and so procure sleep.” [2, 4]

Significantly, sleep in the preindustrial age was seg- mented, consisting of a “first sleep” and a “second sleep” that were bridged by an interval of up to an hour or more of wakefulness during which persons prayed, performed domestic tasks, or, even on occasion, pilfered a neighbor’s firewood. “When you do wake of your fyrsteslepe,” advised the Tudor physician Andrew Boorde, make water if you feel your bladder charged.” [5–7] Other physicians, like Laurent Joubert in France, thought it a prime time for rested couples to conceive children—“after the first sleep” when “they have more enjoyment” and “do it better.” Boorde objected to “venerous actes before the fyrsteslepe” lest they “ingendre the crampe, the goute, and other displeasures.” [5, 21]

Not all sleepers, of course, followed an identical time- table, though most appear to have awakened not long after midnight [6]. According to Ramón Lull, a medieval Cata- lan philosopher, primo somno extended from midevening to early morning. The English historian William Harrison al- luded in his Description of England (1557) to “the dull or dead of the night, which is midnight, when men be in their first or dead sleep,” whereas Noel Taillepied’s A Treatise of Ghosts (1588) referred to “about midnight when a man wakes from his first sleep” [9–11].

In the tradition of Aristotle, physicians urged that persons take their first sleep on the right side in order to assist di- gestion by allowing food to descend “from the mouthe of stomake,” near the liver, which operated “as fyre under the pot.” Turning, then, to one’s left side during second sleep, claimed Cogan, “doth greatly ease the body and helpeth con- coction.” Doctors also recommended this period of wakeful- ness for taking medicine, including pills for sores and small- pox [4, 7].

Notwithstanding an early medieval belief that sleep was God’s punishment for the fall of man, Renaissance writers celebrated its virtues, all the more, for the importance ac- corded to sleep in both the holy scriptures and the writings of Aristotle and Hippocrates [2, 7, 12]. Rather than an obliga- tory hiatus or, worse, a necessary evil, slumber was thought essential to the health of all living creatures. For humans, ob- served the French doctor André Du Laurens, it was “one of the chief poynts of well ordering and governing one’s self.” By bringing “all things to rest,” it comforted the senses and strengthened the body. Boorde noted approvingly that it not only aided digestion but also made “the body fatter.” More than that, it restored spirits and lessened cares, if only by allowing weary souls to forget daily travails. Sleep “taketh away sorrow and asswagethfurie of the minde,” wrote Wil- liam Vaughan [5, 13, 14].

Popular lore echoed medical writings—hence the French proverb, “Quand on estrompu, il fait bon passer le lit.” [15] Specially telling was the primacy given to beds and bedding. To judge from surviving wills and estate inventories, beds were the most prized—and the most expensive—articles of household furniture for men and women of property, howev- er modest their means. In the Middle Ages, beds in affluent households consisted of wooden frames generally made of oak or pine. The frame supported a layer of straw topped by a mattress filled with material ranging from straw or woolen wadding to feathers and down. Blankets were commonly lined with fur. For newlyweds a fourteenth-century French writer advised, “For your household you need…mattress, cushions, bed, and straw.” [7, 16] And by the mid-1500s, beds had improved in less sumptuous households. Of his youth, Harrison observed, “Our fathers, yea, and we our- selves also, have lien full oft upon straw pallets, on rough mats covered only with a sheet, under coverlets made of dagswain or hapharlots…and a good round log under their heads, instead of a bolster,” which was reserved only for women in childbirth. Bedding, praised Harrison, was one of the “things” most “marvelously altered in England,” particu- larly with the growing prevalence of linen sheets and woolen blankets. “Because nothing,” wrote Lemnius, “is holesomer than sounde and quiet sleepe,” one should “take his full ease and sleepe in a soft bedde.” [9, 17] Equally important, the frame needed to be elevated to avoid the cold ground, ac- companied, if necessary, by a wooden footstep. In wealthy homes, canopies and curtains enclosed beds in order to block drafts. The poor, however, were fortunate to claim so much as a filthy mattress and tattered bedding, with many indi- gent families forced to sleep together atop clumps of straw on earthen floors. “Outcasts” slept outdoors “under butchers’ stalls,” according to the fifteenth-century French poet Fran- çois Villon [6, 7].

Overwhelmingly, night was the favored time for slumber, according to both God and nature. The shrouded tranquility of evening made it uniquely well suited, as did, in Cogan’s view, the value of “its moisture, silence, and darkness” to the progress of concoction [4, 7]. Opinions differed, however, over the proper length of sleep, complicated by allowances for age, health, the seasons (long winter nights required the most), personal temperaments, and diverse tasks and trades. Vaughan, for example, advised extra 2 h for melancholic persons, whereas Lemnius, from his standard prescription of 8 h, excluded porters and sailors among other laborers. In general, a period of 7 or 8 h was advised, except for young children who required more rest [6, 12, 16]. In pointed con- trast to Hippocrates, who in “ancient time” had urged a more generous interval, Gratarolo favored 8 h of sleep according to “common custom.” Of particular importance, instructed the French surgeon Ambroise Paré, was that food be com- pletely digested in the course of sleep [16, 20].

10 Sleep Medicine in the Middle Ages and the Renaissance

In spite of its manifold benefits, immoderate rest was deeply discouraged. Not for another century would a height- ened sense of time consciousness, fueled, in part, by the growth of puritanism, sharply stigmatize “unnecessary slug- gishness.” Even so, excessive sleep increasingly became a popular source of ridicule and scorn for its association with indolence, all the more when taken during the day [6, 21]. “A little sleep, a little slumber, a little folding of the hands to rest—and poverty will come on you like a bandit,” warned a passage in Proverbs (24:33–34).

More alarming, however, were the medical perils that immoderate sleep posed, from indigestion and infertility to palsy and apoplexy. “Much slepingendereth diseases and payne, / It dulles the wyt and hurteth the brayne,” declared The Schoole of Vertue in 1557 [22]. Then, too, naps allegedly gave rise to fevers and headaches. If unavoidable, they were best kept short and taken in the morning. Vaughan urged the removal of shoes, less thick leather soles prevent danger- ous vapors from evaporating. Moreover, napping upright in a chair was thought preferable to lying prone in case the warmth of the bedding proves excessive—“for as too much colde, so too much heate, doth astonish the minde and spir- its.” [4, 5, 13, 14, 17, 28]

Preparations at bedtime were painstaking. It was not just the quality but also the safety of sleep that stirred concern. Rarely, in Western life, had nighttime appeared so forbid- ding as during the era from the late Middle Ages to the eigh- teenth century. Fears, both real and imaginary, fueled anxiety as households readied for bed, and at no point other than sleep were persons more vulnerable, incapable of rational thought, and insensible of their surroundings. Even worse, souls, if death struck during sleep, might not be prepared for salvation. “O Lord,” beseeched an Englishman, “now that the darke night is come, which is a signe of horror, death, and woe; and that I am to lie and sleepe on my bedde, which is an image of the grave, protect, direct, and comfort me.” [6, 23]

Fire, crime, natural calamities, not to mention satan- ic spirits, all grew more perilous after dark. “The night is no man’s friend,” declared a French adage. With dogs and weapons kept close, doors were bolted, shutters closed, and fires banked. The English antiquary John Aubrey recorded that families drew a cross in the ashes of a hearth before assembling to recite evening prayers—or to invoke ancient spells. Affirmed an early Welsh verse, “No ill dreams shall vex his bed, Hell’s dark land he ne’er shall tread.” [6, 24, 25] Bodies needed to be carefully inspected for lice and fleas. Smoke from burning hay afforded a medieval deterrent to mosquitoes. On cold nights, beds required warming by hot stones wrapped in rags or, in well-to-do homes, by cop- per pans with coals. Finally, whether one was yet awake or asleep, moral dangers lurked in the dead of night. A twelfth- century theologian warned families “to restrain stirrings of

the flesh and the attacks of the devil which are the most to be feared and avoided in the darkness of this world” [6, 26]. Physicians, for their part, dispensed advice to render sleep both healthy and sound. Common wisdom prescribed that persons not retire immediately after supper. Grataroli and Lemnius advised a minimal period of one and one-half hours, while Du Laurens suggested 3 or 4 h in the event of a heavy meal [13, 17, 19]. “Take heed,” warned Cogan, “that wee goe not to bed straightway after supper, but to tarry the time untill the meate be well mingled and gone downe to the bot- tome of the stomache, which may the better come to passe, [if] we walke softly an houre or two after supper.” Boorde also recommended a maximum of two or three dishes [4, 5]. Apart from being encouraged to lie first on their right side, individuals were strongly cautioned against sleeping on their back. “Many thereby, are made starkeded in their sleepe,” warned William Bullein [3, 5, 20, 27]. Keeping the head slightly raised was important to keep food in the stom- ach from reentering the esophagus, and never was the one to sleep with an open mouth [4, 13, 17]. Regardless of social class, sleeping in the nude was customary, with the exception of a nightcap to warm the head. Night garments, consisting chiefly of chemises and smocks, were still a relative novelty by the sixteenth century, even for the propertied classes [2,

6, 16].
Medical knowledge of sleep disorders was at best el-

ementary, confined chiefly to the mysteries of insomnia. An exception was the nightmare, alternately known as the incu- bus or night hag, which aroused the early interest of classical writers. Symptoms included, in the midst of sleep, a sensa- tion of pressure upon the chest, resulting in breathlessness and an inability to speak. Whereas the Greeks had attrib- uted these frightening sensations to the organic causes, the Church in the Middle Ages blamed the violent attacks of sa- tanic demons seeking sexual intercourse. Renaissance phy- sicians, however, hewed to a wide variety of physiological explanations, from overeating and drinking to fevers [2, 13, 16]. More seriously, Wirsung thought the symptoms might represent an early stage of epilepsy. All the more reason, be- lieved Bullein, not to sleep on one’s back. He also ridiculed the writings of “superstitious hypocrites, [and] Infidelles” who touted “charmes, coniurynges, and relickeshangying about the necke, to fraie the Mare.” [25, 28]

Occurrences of somnambulism, an affliction that, in time, would figure famously in Macbeth, are recorded for the twelfth and thirteenth centuries. In the early 1200s, a work titled Questions de Maître Laurent observed, “It happens that many men get up at night while asleep, take up weapons or staffs, or get on horseback.” [16] Sensational episodes of sleep violence also drew attention. In the fourteenth century, instances of murder figured in a report by the Council of Vienne in southern France. Even so, physicians appear to have evidenced little interest in such isolated episodes—un-

A. R. Ekirch

like legal authorities forced to weigh personal culpability. Prevailing opinion exonerated acts, however aggravated, committed during an unconscious state. As early as 1312, the canon Si Furiosus observed, “If a madman, a child, or a sleeper mutilates or kills a man, he incurs no penalty for this,” a view echoed by the sixteenth-century Spanish schol- ar Diego de Covarrubias who noted that “such a one lacks understanding and reason and is like a madman.” [29, 30]

Far more common was the malady of insomnia, some- times referred to as “watching” to signify either an inability or a disinclination to sleep. Poor slumber, for many, was commonplace—one of the greatest “miseries in the life of man,” thought the Elizabethan poet Nicholas Breton. Ill- ness posed the greatest threat. As in modern life, symptoms associated with cluster headaches, ulcers, gout, and tooth- aches, among other maladies, all likely intensified at night, as did asthma whose victims were forced to sleep upright. Anxiety contributed to broken sleep, magnified, all the more, by night’s perils. “Our thoughts troubled and vexed when they are retired from labour to ease,” observed the writer Thomas Nashe [6, 13, 32]. Nor, from a modern per- spective, it is easy to appreciate the environmental annoy- ances of preindustrial life, from timbered homes afflicted by drafty windows, ill-fitted doors, and leaky roofs to in- festations of bedbugs, present in England by the 1500s, or the putrid stench of chamber pots. “Some make the chim- nie chamber pot to smellyke filthy sinke,” complained a sixteenth-century Englishman [6, 33]. Then, as now, some bouts of wakefulness defied explanation during instances of sleep-onset insomnia. In sharp contrast, sleep manage- ment insomnia—waking in the middle of the night—was thought utterly normal in the absence of a specific cause such as illness. Rather than a reason for concern or analysis, the interval of “watching” between the first and the second sleep only figured in medical literature as an occasion for engaging in sexual intercourse, ingesting medicine, or for turning from one’s right side to assist digestion [6].

In the sentimental view of poets and playwrights, sleep afforded a refuge from the cares and tensions of daily life, particularly for members of the lower ranks, untroubled by the responsibilities of rich and powerful men. In Henry V (ca. 1599), Shakespeare, for example, wrote that none “can sleep so soundly as the wretched slave, / Who with a body fill’d and vacant mind / Gets him to rest.” More on the mark was the Bolognese curate who in reference to the poor asked, “Whether due to sleeping on a bed fouler than a rubbish heap, or not being able to cover onseself, who can explain how much harm is done?” [6, 34]

In the absence of safe and effective soporifics, there was no shortage of lotions, potions, and pills purportedly de- signed to induce sleep—by “inward” as well as “outward means,” as Du Laurens wrote [13]. Some remedies, if only by lessening anxiety, may even have afforded a measure of

reassurance. Meant to be applied externally were powders, nosegays, ointments, and plasters, with the temples of the forehead and the nostrils often preferred for the most suc- cessful application. Du Laurens himself endorsed 11 rem- edies. Of one, he reported, “There are some which with good successed oeappliehorseleaches behind the eares, and having taken away the horseleaches, they put by little and little a graine of opium upon the hole.” [2, 6, 13, 35] Opium fig- ured prominently in medications. In feudal times, “poppy juice” was applied externally. Advised a Neapolitan physi- cian in the late 1200s, “Opium alone, diluted with woman’s milk, under the nostrils provokes unlimited sleep.” Later, laudanum, a mixture containing alcohol, was employed by the upper ranks despite the danger of being “cast” into “an endlessesleepe.” [6, 16] The continental traveler FynesMo- ryson insisted that Germans, by contrast, refused “to suffer any man to goe to bed” sober [36].

And yet, a significant, if indeterminable, segment of the preindustrial population likely suffered some degree of sleep deprivation. Rather than consisting of two segments of tran- quil slumber, their sleep was vulnerable to intermittent dis- ruption—a sequence of “brief arousals” that made daily life all the more arduous in a harsh and punishing age. Medical care remained primitive at best. Despite the earnest advice of physicians, many people may have felt more rested when retiring to bed than rising at dawn [6].

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25. Jones G, compiler. The Oxford book of Welsh verse in English.
Oxford: Oxford University Press; 1977.

26. Alanus de Insulis. The art of preaching. (Evans GR, translator)
Kalamazoo: Cistercian; 1981.

27. Bullein W. A new ebook eentituled the gouernement of healthe. London: John Day; 1558.

28. Bullein W. Bullein’s bulwarke of defence againste all sicknes, sornes, and woundes. London: John Kyngston; 1562.

29. Ekirch AR, Shneerson JM. Nineteenth-Century sleep cases: a his- torical view. Sleep Med Clin. 2011 Dec; 6(4):483–91.

30. Walker N. Crime and insanity in England: the historical perspec- tive. Edinburgh: Edinburgh University Press; 1968.

31. Grosart AB, editor. The works in verse and prose of Nicholas Breton II, New York: AMS; 1966.

32. McKerrow RB, editor. The works of Thomas Nashe. I. Oxford: Oxford University Press; 1958.

33. Henke JT. Gutter life and language in the early “street” literature of

England: a glossary of terms and topics chie y of the sixteenth and

seventeenth centuries. West Cornwall: Locust Hill; 1988.
34. Camporesi P. Bread of dreams: food and fantasy in early Modern Europe. (Gentilcore D, translator) Chicago: University of Chicago

Press; 1989.
35. Wirsung C. :Praxis medicinae universalis or a general practise of

physicke. (Mosan J, translator) London: George Bishop; 1598.
36. Moryson F. An itinerary containing his ten yeeres travell IV.

Glasgow: Macmillan; 1907.

Sleep in the Seventeenth and Eighteenth Centuries

Michael Thorpy

During the seventeenth century, medicine underwent a major

change from the doctrines that had in uenced it up to that

time, such as Aristotelianism, Galenism, and Paracelsianism,

to more scienti cally directed theories with the underlying

teleological desire to accumulate knowledge on the way

things work [1]. This time was known as the Age of Scienti c Revolution and included the major medical developments of Francis Bacon (1561–1626), William Harvey (1578–1657), and Marcello Malpighi (1628–1694).

Medicine, in general, was then being viewed as advance- ment in mankind’s control over nature and was more soundly based on scientific principles. However, it was still a time to be speculative and philosophical about medicine:

He sleeps well who knows not that he sleeps ill.
(Francis Bacon, Ornamentata Rationalia, IV; quote from Pub- lilius Syrus, Sententiae: Wight Duff and Duff Arnold, 1994) [2]

The scientific revolution began with the theories of Rene Descartes (1596–1650) who rejected Aristotle’s doctrines and developed theories based on mechanisms [3]. In this re- gard, Descartes was similar to Francis Bacon who espoused experimentation and utilitarianism. Descartes developed a hydraulic model of sleep, which considered that the pineal gland maintained fullness of the cerebral ventricles for the maintenance of alertness. The loss of “animal spirits” from the pineal causes the ventricles to collapse, thereby inducing sleep. Descartes also believed that the brain existed in two states; waking, in which its fibers are tense, its spirits strong but rapidly exhausted, and sleep in which its fibers are lax, its spirits gradually replenished (Figs. 11.1 and 11.2).

The beginning of the seventeenth century was the time of William Shakespeare (1564–1616) who made many ref- erences to sleep in his writings. Insomnia was a particular topic, as was sleepwalking [4].

M. Thorpy ()
The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Yeshiva University, 111 East 210th Street, 10461 Bronx, NY, USA
e-mail: thorpy@aecom.yu.edu

…the innocent sleep,
Sleep that knits up the ravell’d sleave of care, …Chief nourisher of life’s feast. Shakespeare: Macbeth, Act II [4].

The chemical principles of Paracelsus were advanced in the seventeenth century, and medicines, including the use of mercurials, began to take over from treatments such as purg- ing and bloodletting. Illness was then considered to be some- thing that attacked the body in a distinct manner, and the galenic and earlier concepts that disease was a derangement of humors, the essential elements of the body, were starting to fade. The concept of disease was “exogenous” compared to “endogenous” of previous times, so that therapy was aimed at an external cause.

Atomism involved the theory that the natural world con- sists of two fundamental parts: indivisible atoms and empty void. Atomism, which had been proposed by Democritus, Leucippus, and Epicurus, several centuries before the time of Christ, underwent a revival in the seventeenth century, and was supported by the findings of Jan Baptista van Helmont (1577–1644), who coined the term “gas” and recognized that air was composed of a variety of gases [5]. Van Helmont regarded disease as an internal reaction to some provocation or stimulus from the environment.

Robert Boyle (1627–1691) demonstrated the importance of air for life, and the effect of gases under pressure, which led to the discovery that the reddening of venous blood oc- curred because of exposure of blood to gases in the air. How- ever, the major discovery of the seventeenth century was that of William Harvey, who was the first to demonstrate that blood was pumped around the body by the heart. It was against this background that the great neurologists, Thomas Willis (1621–1675) and Thomas Sydenham (1624–1689), developed the principles and practice of clinical neurology.

Willis contributed to the knowledge of various disorders in sleep, including restless legs syndrome, nightmares, and insomnia. He recognized that a component contained in coffee could prevent sleep and that sleep was not a disease but primarily a symptom of underlying causes. His book The Practice of Physick devoted four chapters to disorders

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_11, 69 © Springer Science+Business Media, LLC 2015

M. Thorpy

Fig. 11.1 Descartes’ (1632) model of the brain awake showing tense fibers and strong spirits. Diagram M. The spirits leave gland h ( pineal), having dilated a ( ventricles) and having partly opened all pores (a), and flow to b ( fibrous mesh of the brain substance) and then to c ( mem- brane enveloping this mesh) and finally into d ( origins of the cranial nerves) [3]

Fig. 11.2

producing sleepiness and insomnia [6]. As with Descartes, he considered that the animal spirits contained within the body undergo rest during sleep. However, he believed that the animal spirits residing in the cerebellum became active during sleep to maintain a control over physiology. He be- lieved that some of the “animal spirits” became intermittent- ly unrestrained, leading to the development of dreams. He also described restless legs syndrome, which he considered an escape of the animal humors into the nerves supplying the limbs:

when being abed, they betake themselves to sleep, presently in the arms and legs, leapings and contractions of the tendons, and so great a restlessness and tossings of their members ensue, that

the diseased are no more able to sleep, than if they were in a place of the greatest torture.
(Willis, 1684) [6]

Willis discovered that laudanum, a solution of powdered opium, was effective in treating the restless legs syndrome. Willis also wrote extensively about sleepiness and lethargy. One form of sleepiness that was often reported in the seven- teenth and eighteenth centuries and discussed by Willis was “continual sleepiness”:

…the affected as to other things are well enough, they eat and drink well, they walk about,…they now and then nod, and unless they are stirred by others, they are presently overwhelmed with sleep: and after this manner they sleep almost continual sleep, not only for some days or months, but for many years… Thomas Willis 1684 [6]

In 1705, William Oliver described a patient in detail in an article entitled “An account of an extraordinary sleepy per- son,” who was 25 years of age when he developed sleepiness which initially lasted a month, where he could only arouse to eat and drink [7]. Two years later, he had further episodes that lasted 6 weeks and 10 weeks. One year later, after a brief acute illness, he again fell into a deep sleep that lasted 3 months. The nature of these prolonged sleep episodes has never been explained; however, a number of additional re- ports around the sixteenth, seventeenth, and eighteenth cen- turies suggest that an infective cause, such as influenza, may have been responsible.

Willis also described, in 1672, a case of “Pickwickian syndrome” [6]:

…growing aged, being given to idleness and drunkenness, became dull and stupid, and also dropsical, with a great paunch, and his thighs and legs swelled. Yet from these diseases (which he frequently fell into) when he abstained at any time from drinking, and took physick, he oftentimes quickly grew well. But at length, though he was freed from the dropsie, he was oppressed with so heavy a sleepiness, and that he almost per- petually, that in whatever place soever he was, or what ever he was doing he would sleep; then being awakened by his servants or friends, his mind appeared well enough, and for a few minutes he would discourse of any thing well enough, then immediately fall again into sleep. [6]

A few years earlier, in 1614, Felix Platter (1536–1614) had described a man “who tended to fall asleep all the time; in the course of talking, even while eating…. Now this man’s body was so enormously fat that he could hardly advance his feet to stride ahead…” [8]. His description predates that of John Fothergill who, in 1781, had described a similar case that suggested the symptoms of Pickwickian syndrome or obstructive sleep apnea [9].

One of the first chronobiological experiments had been that of Sanctorious (1561–1636) who measured the cyclical pattern of change in a number of his own physiological vari- ables [10]. His experimental apparatus has been regarded as the first “laboratory for chronobiology.” Subsequently, the

Descartes’ (1632) model of the brain asleep, showing lax fi- bers, and spirits reduced and gradually become replenished. Diagram n. The spirits have left gland h ( pineal), the ventricles are mainly reduced and the pores (a) become shut down, and flow to b ( fibrous mesh of the brain substance) and c ( membrane enveloping this mesh) is reduced and the nerves d ( origins of the cranial nerves) become relaxed. Parts of the ventricles are still dilated ( dotted lines) that allows for dreaming during sleep [3]

11 Sleep in the Seventeenth and Eighteenth Centuries

intrinsic pattern of circadian activity was demonstrated in the experiment performed by Jacques de Mairan, in 1729, which was reported by M. Marchant [11]. De Mairan placed a he- liotrope plant in a dark closet and observed that the leaves continued to open in darkness, at the same time of the day as they had in sunlight. This experiment illustrated the presence of an intrinsic circadian rhythm in the absence of environ- mental lighting conditions. De Mairan also recognized the importance of this observation for understanding the behav- ior of patients:

this seems to be related to the sensitivity of a great number of

bed-ridden sick people, who, in their con nement, are aware of the differences of day and night. M. Marchant [11]

Despite some setbacks, a scientific approach to medicine continued with the works of Linnaeus and von Haller. Karl von Linne (1707–1778), called Linnaeus, made important contributions to the classifications of botany, zoology, and medicine [12]. He emphasized the importance of cyclical changes in botany, which was nowhere more clearly present- ed than in his flower clock. The flower clock was developed upon the principle that different species of flowers open their leaves at various times of the day. Therefore, a garden of flowers, arranged in a circular pattern, could give an estimate of the time of day, by the pattern of flower and leaf openings and closings.

As far back as ancient Greece, there had been some recog- nition of variation in the behavior of plants and animals, not only on a seasonal basis but also on a daily basis. Linnaeus’ finding was an important early milestone in the development of the science of biological rhythms in plants and animals.

During the seventeenth and eighteenth centuries, medical schools had rapidly expanded throughout Europe, with those north of the French–Italian Alps beginning to gain in promi- nence. The Swiss-born scientist Albrecht von Haller (1708– 1777), a pupil of Boerhaave of the University of Leiden, an important medical center in Europe, made major contribu- tions to many scientific topics including medicine. Von Haller performed numerous experiments on the nervous system and demonstrated the sensitivity of nerve and the irritability of muscle; in doing so, he dispelled much of the mysticism of previous eras. Von Haller produced a major work entitled Elementa Physiologiae in which he devoted 36 pages to the physiology of sleep and proposed a theory for its cause [13].

The many theories of the cause of sleep can be placed into four main groups: vascular (mechanical, anemic, conges- tive), chemical (humoral), neural (histological) and a fourth group, which explains the reason for sleep rather than the physiological cause of sleep, the behavioral (psychological, biological) theories [14].

The vascular theories were paramount in the seventeenth and eighteenth centuries. In a vascular concept, similar to that of Alcmaeon in the fifth century BC, von Haller believed

that sleep was caused by the flow of blood to the head, which induced pressure on the brain, thereby inducing sleep by cut- ting off the “animal spirits.” Von Haller derived his beliefs from the views of his mentor Hermann Boerhaave (1667– 1738). Von Haller’s theory was expanded in the nineteenth century into the congestion theory of the cause of sleep, a theory that was still believed into the early part of the twenti- eth century. Von Haller also considered dreams to be a symp- tom of disease, “a stimulating cause, by which the perfect tranquility of the sensorium is interrupted.”

The vascular theories described the cause of sleep to be related to the blood vessels, either congestion (pressure of blood) or anemia (lack of blood) in the brain. Johann Fred- reich Blumenbach (1752–1840), professor at Göttingen, who is regarded as the founder of modern anthropology, was the first to observe the brain of a sleeping subject in 1795 [15]. He noted that the surface of the brain was pale during sleep compared with wakefulness; contrary to earlier theories, he proposed that sleep was caused by the lack of blood in the brain.

The late eighteenth century was also the time of the dis- covery of oxygen by Karl Scheele (1742–1786) and Joseph Priestley (1733–1804). But it was Antoine-Laurent Lavoisier (1743–1794), who coined the name “oxygen” and recognized its importance in the maintenance of living tissue. Despite the important advances in clinical medicine that occurred in the eighteenth century, there were very few therapeutic advances. Medications still consisted of potions developed from plant and animal tissues, and opium was still the main form of sedation in a common formulation called “Hoff- mann’s anodyne of opium.” The ancient practices of bleed- ing and purging continued to be widely prescribed through- out the eighteenth century. Infection was a major source of sleep disorders in the seventeenth and eighteenth centuries, both insomnia and excessive sleepiness. An early report of African sleeping sickness was made in 1735 by John Atkins (1685–1757), a naval surgeon, after travels to Guinea and Somalia. [16].

It was not until the late 1700s that the greatest advance of that time was made in the development of sleep medicine. It occurred in Bologna in 1771 with Luigi Galvani’s (1737– 1798) demonstration of electrical activity of the nervous system in the frog (Fig. 11.3) [17]. Galvani, a professor of anatomy and gynecology, was particularly interested in elec- tricity, and his findings led to the subsequent development of the field of electrophysiology, and the gradual destruction of the humoralist theory of nervous activity.

With the development of the scientific approach to medi- cine, the discovery of atomism, animal electrophysiology, the advances in respiratory and cardiovascular physiology, as well as treatment advances, such as quinine for malaria and digitalis for heart disease, medicine was about to enter its modern era, the nineteenth century.

72 M. Thorpy

Fig. 11.3 Galvani’s experiment of the frog with the first demon- stration of electrical activity of the nervous tissue [17]

References

1. Thorpy M. History of sleep medicine. Handb Clin Neurol. 2011;98:3–25.

2. Wight DJ, Duff AM. Minor Latin poets. Vol I. Publilius Syrus. Harvard: Harvard University Press; 1994.

3. Descartes R. Treatise of man. Reprinted in 1972. In: Hall TS, edi- tor. Cambridge: Harvard University Press; 1632.

4. Shakespeare W. Macbeth. (Thomas Marc Parrott, editor). New York: American Book; 1904.

5. Van Helmont JB. Ortus medicinæ: id est initia physicæ inaudita. Amsterdam: Apud Ludovicum Elzevirium; 1648.

6. Willis T. Practice of physick. London: Dring T, Harper C, Leigh J; 1684.

7. Oliver O. An account of an extraordinary sleepy person. Philos Trans. 1705;304:2177–82.

8. Platter Felix. Observationum, in hominis affectibus plerisque, cor- pori et animo, functionum laesione, dolore, aliave molestia et vitio incommodantibus, libri tres, Basel Koenig, 5–6, 1614.

9. Simpson HN. Obesity, heart failure due to (a further note on). New Engl J Med. 1958;259:34.

10. Santorio Santorio. De Statica medicina aphorismorum sectiones septem, accendunt in hoc opus commentarii martini lister, et geor- gii baglivii. Venice: Novelli; 1759.

11. de Mairan J. Observation Botanique. Paris: Histoire de 1’Acadé- mie Royale des Sciences; 1729.

12. Linnaeus C. Philosophia Botanica. Stockholm: God of Kiesewet- ter; 1751.

13. Von Haller A. Elementa Physiologiae Corporis Humani. 8 Vols. Lausannae: Sumptibus; 1766.

14. Wittern R. Sleep theories in the antiquity and in the Renaissance. In: Horne JA, editor. Sleep 88. Stuttgart: Fischer Verlag; 1989. pp. 11–22.

15. Blumenbach J. Anfangs Grande de Physiologie. Göttingen: J.C. Dieterich; 1795.

16. Atkins J. A voyage to Guinea, Brazil, and the West Indies. London: Ward C., Chandler R. 1735. pp. 72–3.

17. Galvani L. De viribus electricitatis in motu musculari commen- tarius. Bologna: Ex typographia Instituti Scientiarum; 1791.

Part III The Early Evolution of Modern Sleep Medicine

The Evolution of Sleep Medicine in the Nineteenth and the Early Twentieth Century

Hartmut Schulz and Piero Salzarulo

Introduction

Until the middle of the nineteenth century, knowledge on sleep and its disorders was based exclusively on the infor- mation given to the physician by the sleeper himself and the inspection of the sleeper’s behavior by an outside observer, interpreted in the frame of the general medical context and philosophical reasoning. This procedure allowed recognition of a wide spectrum of sleep disturbances, characterized by insufficient sleep (insomnia), insufficient wakefulness (som- nolence), or strange behaviors during sleep, such as sleep- walking, and some other sleep disturbances.

It was only in the second half of the nineteenth century that sleep was subject to experimental manipulation and measurement. Four main events heralded the transforma- tion of the study of sleep into an experimental science, al- lowing far reaching consequences for sleep medicine: (1) Kohlschütter’s pioneering studies on the depth or “firm- ness” of sleep by measuring reactions of sleeping subjects to acoustic stimuli [1]; (2) studies on the effect of prolonged sleep deprivation in animals [2] and human subjects [3]; (3) physiological measurements of organic functions, such as body temperature, circulation, respiration, excretion, and others, during sleep or across the sleep–waking cycle; and (4) epidemiological studies using questionnaires and scales to gather information on sleep habits and dreaming [4, 5].

The systematic study of “the sleep of others” [6, 7] be- came the basis of sleep research as a scientific discipline (Table 12.1). There were two major developments in in- strumentation in the early twentieth century, which finally made it feasible to focus on sleep as an object of scientific measurement. One was actimetry which allowed to record

H. Schulz ()
Rankestr. 32, 99096 Erfurt, Germany e-mail: Hartmut.schulz@gmx.de

P. Salzarulo

Trento, Italy
e-mail: piersal@yahoo.com

rest and activity continuously, and thus sleep–wake cycles in different species, including human beings [8]; and the other was electroencephalography, recording electrical activity of the brain during wakefulness and sleep [9, 10]. Sleep medi- cine gained from the combination of traditional techniques of medical diagnosis (skilful observation and patient’s re- port) and the availability of technical methods to measure bodily functions in sleep.

Historical Classifications of Sleep Disorders

Early in the nineteenth century, Frank [11, 12] presented a comprehensive classification of sleep disorders, as part of a classification of diseases of the nervous system, updat- ing previous nosological systems [13–15]. Frank described seven classes of sleep disturbances: (1) cataphoria, a more intense and prolonged sleep than normal, which occurs in a symptomatic and an idiopathic form. Cataphoria best cor- responds to hypersomnia in actual nosological systems; (2) agrypnia or insomnia, subdivided again into a symptomatic and an idiopathic form. Idiopathic insomnia (“l’agrypnie primitive”) occurs in children and adults. In adults, the dis- order was classified according to its etiology into (a) inflam- matory, (b) gastric, (c) arthritic, and (d) nervous types; (3) a group of disorders characterized by alterations of the appear- ance of sleep (“par sa manière d’être”), i.e., disorders which are grouped in actual nosological terms as parasomnias. The group includes (a) snoring, (b) jactations, cramps, and epi- sodes of nocturnal heat (“chaleurs nocturnes”), and (c) sleep terrors (“frayeurs nocturnes”); (4) anxiety dreams (“songes effrayants”); (5) nightmare (incubus); (6) somnambulism; and finally (7) somniation, a form of sudden, sometimes peri- odic episodes of dream-or sleep-like behavior (gesticulation, writhing, speaking, walking, etc.)-during waking, followed by amnesia for the event. For all these disorders, Frank gave a definition, a description of symptoms, causes, diagnosis, and treatment, supplemented by an extensive bibliography, citing all available references from earlier authors.

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_12, 75 © Springer Science+Business Media, LLC 2015

H. Schulz and P. Salzarulo

Table 12.1

Year 1862

1865

1867

1877

1880

1890

1894

1896

1900

1909

1913

1916

1917

1923

1929

1935

1939

1949

1953

Milestones in sleep research and medicine between 1800 and 1953 Event

Ernst Kohlschütter performs laboratory-based measurements of reactivity to stimuli during sleep (depth of sleep curve) Alfred Maury. Le sommeil et les rèves
Hervey de Saint-Denis. Les rêves et comment les diriger
Carl Westphal presents a patient with the clinical picture of narcolepsy

Jean Baptiste Gélineau publishes his patient with narcolepsy and coins the term narcolepsy Ludwig Mauthner. First attempt to localize a “sleep center”
Maria Manaseïna. First study on sleep deprivation in puppies [2]
G. T. W. Patrick and J. A. Gilbert. First study on sleep deprivation in humans

Sigmund Freud. Die Traumdeutung
Kuniomi Ishimori. Sleep-inducing substances from sleep-deprived animals
Henri Piéron. Le problème physiologique du sommeil
J. S. Szymanski. 24-h rest–activity distribution in different animals, measured by actigraphy
Constantin von Economo. First publications on encephalitis lethargica [16]
I. P. Pavlov. Theory of sleep as “generalized inhibition” [17]
W. R. Hess. Electrical brain stimulation and sleep [18]
Hans Berger. First publications on the electroencephalogram (EEG)
Frédéric Bremer. Cerveau “isolé” and physiology of sleep [19]
A. L. Loomis, E. N. Harvey and G. Hobart. First EEG sleep studies in man
Nathaniel Kleitman. Sleep and Wakefulness as Alternating Phases in the Cycle of Existence [20]
G. Moruzzi and H. W. Magoun. Brain stem reticular formation and activation of the EEG [21]
E. Aserinsky and N. Kleitman describe regularly occurring periods of eye motility, and concomitant phenomena, during sleep

About the same time, Hosack [22] published a syllabus containing a synopsis of the main 13 nosological systems of illnesses, published in the second half of the eighteenth and the early nineteenth century. All different sorts of sleep disorders can be found there, with varying terminology and scattered over different diagnostic classes. Table 12.2 sum- marizes all sleep-related disorders contained in these noso- logical systems, rearranged according to the categories of the actual International Classification of Sleep Disorders [23]. To get a more complete picture of the historical develop- ment, 12 more classifications of sleep disorders were added, which cover the time span from 1838 to 1970. While the selection of these 12 references is fortuitous, the aim was to include diagnostic systems from different countries. These latter entries were not drawn from comprehensive nosologi- cal systems of illnesses but from sleep-specific publications. The entries in Table 12.2 show a dominance of three diagnos- tic categories (insomnias, hypersomnias, and parasomnias) in the considered period; while entries in other American Academy of Sleep Medicine (AASM), diagnostic categories were rare. Abnormal movements in sleep were listed, for the first time, as a separate class of disturbances by Romagna Manoia in 1923 [24]. Most astonishing is the near absence of entries to the category of sleep-related breathing disorders (SRBD), while the lack of circadian sleep rhythm disorders is less surprising for a time when shift work was rare [25], and living conditions of the majority of people were more regular than nowadays.

Publications on Sleep Disorders

Between 1800 and 1880, about 50 publications per decade on sleep disturbances appeared in the medical literature (Fig. 12.1). Publications on sleep and sleep disturbances made up a very small segment of the medical literature. There were very few scientific journals available, mainly in London and Paris. The situation changed clearly in the last third of the nineteenth century with the number of publica- tions on sleep disturbances doubling or tripling at the end of the century. The next steep increase came in the third and fourth decade of the twentieth century, emphasizing the elec- trophysiological area of sleep research. Figure 12.2 displays publications schematically showing publications in four categories of sleep disorders (insomnia, hypersomnias, pa- rasomnias, and narcolepsy) per decade. Parasomnias domi- nated the publications in the first six decades; whereas in the seventh decade, insomnia, hypersomnias, and parasomnias had about an equal number of publications. In the eighth de- cade, narcolepsy appeared as a new diagnosis category. In the past four decades, ending with the year 1950, insomnia was the leading diagnosis, followed by narcolepsy, parasom- nias, and hypersomnias.

Insomnia

The definition of insomnia by Macfarlane [35] as “loss of sleep” and “the want of sleep” addresses two different per- spectives (one empirical, the other subjective). An important

12 The Evolution of Sleep Medicine in the Nineteenth and the Early Twentieth Century 77

Table 12.2

Selected nosological systems

between 1762 and 1970

Insomnia

Sleep-related breathing disorders

Hypersomnia

Circadian sleep rhythm disorders

Parasomnias

Sleep-related movement disorders

Isolated symptoms

Other sleep disorders

Year of publication

Agrypnia

–

Lethargus,b cataphora,
carus
Somnolentia, lethar- gus, cataphora, carus Lethargus, tor-

–

Ephialte,
hallucinations, somnambulism Somnambulism, ephialtes

–

Stertor

–

1762 (1)a

Agrypnia

– Apnea

– –

Stertor Stertor

–

1763 (2) 1772 (3)

Agrypnia

–

por, carus, coma, somnolentia Lethargus, cata- phora, carus

–

Ephialtes, somnambulismus

–

Stertor

–

1776 (4)

–
–
Somnus inter- ruptus, vigilia invita (involuntary watchfulness)

– – –

–
–
Lassitudio (fatigue)

– – –

– –

– – –

– Oneirodynia

1772 (5) 1785 (6) 1796 (7)

– –

Lethargus,catalepsis –

– –

Somnambulans, incubus Somnambulism, nocturna oppressio
–

– –

1804 (8) 1809 (9)

– Agrypnia – Agrypnia

– – – –

– –

– – – –

–
–
–
Rhonchus (snor- ing, wheezing), paroniria (sleep- talking, night pollution) Snoring

Oneirodynia –
–
–

1809 (10) 1812 (11) 1813 (12) 1817 (13)

Agrypnia

–

Cataphoria

–

Sleep terrors, nightmare, somnambulism

Jactations, cramps

Nocturnal heat, anxiety dreams, somniation
–

1838 (14)

Agrypnia Insomnia

–

Cataphora Narcolepsy (all forms of hypersomnia) Narcolepsy,

–

Pavor nocturnus, Incubus Somnambulism

–

1863 (15) 1896 (16)

Insomnia

–

Sleeping sickness (Trypanosomiasis), hysterical sleep (lethargy)

1914 (17)

Incubus

Somnium, hypnobatasis

Somnambulism, incubus (nightmare)

Somnium (dreams), somnus periodicus (periods of sleep), Studii inanis periodus (periods of reverie)

Ephialtes (nightmare), paroniria (sleepwalking)

78 H. Schulz and P. Salzarulo

Table 12.2 (continued)

Insomnia

Sleep-related breathing disorders

Hypersomnia

Circadian sleep rhythm disorders

Parasomnias

Sleep-related movement disorders

Isolated symptoms

Other sleep disorders

Year of publication

Insomnia Insomnia

–

Hypersomnia, narcolepsy Somnolence, narcolepsy

–

Parasomnia (incubus, sleep terrors, somnambulism) Night terrors, nightmares, Somnambulism, sleep drunkenness, nocturnal enuresis, sleep paralysis

Abnormal move- ments in sleep
–

Confusional awakening
Sensory and motor shocks (at sleep onset), states of fear (at awakening), sleep numbness

Dreamy states

1923 (18) 1929 (19)

Insomnia Insomnia

–

Narcolepsy Hypersomnias

–

Somnambulism, confu- sional states
Parasomnias (nightmares, night terrors, somniloquy, somnambulism, teeth grind- ing, jactations, enuresis, numbness, hypnalgia, personality dissociations) Nightmare, night terrors, sleepwalking

–

1931 (20) 1932 (21)

Insufficient and restless sleep

Excessive sleepi- ness, drowsiness, narcolepsy

Inversion of the natural order
of sleeping and waking

1935 (22)

Insomnia

–

Hypersomnias (encephalitis lethar- gica), narcolepsy Narcolepsy, enceph- alitis lethargica, hypersomnias, and comas Hypersomnias, Narcolepsy, Kleine– Levin syndrome, encephalitis lethargica

–

Somnambulism

–

Sleep epilepsy, Addi- son disease

1940 (23)

Insomnia or hyposomnia

Sleep paralysis

Catalepsy, epilepsy

1963 (24)

Insomnia

Pickwick syndrome

Somnambulism, enuresis

Bruxism

Cranial pain, sleep epilepsy

1970 (25)

Respiratory failure in sleep (remark: not by nasopharyn- geal obstruction)

Reversal of sleep-rhythm

Nocturnal epilepsy, sleeppains

a Sources: 1. Sauvages, 2. Linnaeus, 3. Vogel, 4. Sagar, 5. Macbride, 6. Cullen, 7. Darwin, 8. Crichton, 9. Pinel, 10. Parr, 11. Swediauer, 12. Young, 13. Good, 14. Frank [12], 15. Dobbert [26], 16. Manacéine [27], 17. Dejerine [28], 18. Romagna Manoia [24], 19. Gillespie [29], 20. Lhermitte [30], 21. Roger [31], 22. Kanner [32], 23. Müller [33], 24. Kleitman [20], 25. Finke and Schulte [34], For Sources 1 to 13, see Hosack 1821 [22]; sources 14 to 25 see References.
b Terminology. Agrypnia insomnia, Lethargus lethargy, Carus deep sleep, Catalepsis suspension of sensation and rigid posture, Cataphora somnolence, Ephialte/Incubus sleep paralysis, Stertor heavy snoring, Paroniria morbid dreaming, Somnium dreaming, Hypnobatasis sleepwalking, Oneirodynia distressing dreams, Somniation dreamlike state during wakefulness

12 The Evolution of Sleep Medicine in the Nineteenth and the Early Twentieth Century 79

Fig. 12.1 The figure shows the total number of publications on sleep disturbances from 1800 to 1950 in 10-year segments. Data were drawn from the literature data bank of one of us (H.S.) using words from titles, excerpts, summaries, and added key words. If more than one sleep dis- order was treated in the same publication, this resulted in double or multiple counting of the same publication. While the rate of publica- tions on sleep disorders was quite stable before 1880, there was a steep

point, still discussed today, concerns the status of insomnia: Is it a symptom or a disease? The majority of authors at the end of the nineteenth and in the first half of the twentieth century considered insomnia as a symptom, similar to Mac- farlane’s concept who stated: “It is not a disease, but a symp- tom of many diseases, differing widely in their nature and complexity, as well as gravity.” [35, p. 28]

Kroker, in his book on the history of sleep research, claimed that from 1960 onward “The diagnosis and treat- ment of insomnia came to rely on laboratory-based studies of sleep.” and “sleep…emerged to become a public concern by the end of the twentieth century.” [6, p. 349] Kroker fur- ther stated that insomnia was a “crucial component of the medical knowledge of sleep” (p. 349) but “if insomnia was a routine concern for clinicians, its status in terms of medi-

rise in the number of publications thereafter. This trend was inverted twice, presumably as a consequence of the First and Second World War. The total number of references was n = 1616 which corresponds to 22.3 % of all stored sleep-related references for that period. While the ab- solute number of publications on sleep disorders increased, the relative proportion of publications on sleep disorders decreased from 31.1 % (1800–1849) to 26.7 % (1850–1899) and finally to 19.5 % (1900–1950)

cal research was virtually non-existent.” “Its experience was personal, as was knowledge and diagnosis of its condition. The physician’s role was simply to facilitate the treatment of what the patient already knew to be the problem.” (p. 350) Early writers were concerned with the search for an etiol- ogy and also for pharmacological treatment (hypnotics) of insomnia.

Classifications of Insomnia

Macfarlane [35, pp. 61–63] gave an overview of the causes of insomnia, based on his own record of patient data and those from two other general practitioners. The combined statistics of 273 cases showed that eight causes accounted for

H. Schulz and P. Salzarulo

Fig. 12.2 The figure displays the same data as Fig. 12.1, however, referenced to the total number of publications on the four diagnostic groups of sleep disorders. While publications on parasomnias domi- nated the field before 1870, insomnia became the leading topic of later publications. Reasons for an enhanced interest in insomnia may have

67.4 % of all insomnia cases (Table 12.3). Leading causes were neurasthenia (13.6 %) and worry (13.2 %).

A further analysis of the same 273 cases by age and sex showed a wide age distribution of insomnia onset with an earlier onset in females. Apparently, in both genders, it started rarely before the age of 10 or after 70 years, and the distribution reached its maximum at the age 40–50 years (Table 12.4).

Different aspects of these historical data reflect charac- teristics of insomnia which are also valid today such as the prevalence of psychological factors and higher prevalence and earlier onset of insomnia in females.

Sée [36], cited by Hurd [37, p. 29] and Clarke [38, p. 853], listed nine etiological categories as causes of insomnia: (1) dolorous, (2) digestive, (3) cardiac and dispnoeal, (4) cere- brospinal and neurotic (general paralysis, acute and chronic mania–hysteria–hypochondriasis), (5) psychic insomnia, (6)

been the rising physiological research on the central nervous system and its pathologies, changes in work, social and environmental con- ditions [27] and, finally, the development of new hypnotics, which quickly replaced opium as the earlier treatment of choice. Especially psychiatrists, who had to care for sleepless insanes, became interested in new treatment options

insomnia of physical fatigue, (7) genito-urinary, (8) febrile and autotoxic, and (9) toxic. Sée’s classification was later mentioned also by the pharmacologist Rudolf who, however, criticized the nine classes as “pigeon-holes in which we may put most cases of insomnia, but beyond that they were not

Table 12.3 Main causes of insomnia for 273 insomnia cases. (Adapted from [35, p. 64])

Cause Cases Percent

Neurasthenia 37 13.6

Worry 35 13.2

Gout 26 9.5

Overwork 23 8

Menopause 18 6.6

Dyspepsia 17 6.2

Alcoholism 16 5.9

Senility 12 4.4

12 The Evolution of Sleep Medicine in the Nineteenth and the Early Twentieth Century 81

Table 12.4 Ages of onset of insomnia. (Adapted from [35, p. 65])

Age 1–10 10–20 20–30 30–40 40–50 50–60 60–70 70–80 80–90 Total

Males 5 7 7 18 31 18 8 7 4 105

Females5 11 17 40 51 16 16 7 5 168

Total 10 18 24 58 82 34 24 14 9 273

of much value, as these did not follow any rational basis of classification” [39, p. 378]. He classified causes of insomnia into two categories:

I. Nervous system hypersensitivity owing to:

a. Inheritance, bad habit, alteration in habits

b. Fatigue or neurasthenia

c. Circulatory disturbances, especially arteriosclerosis and
aortic regurgitation

d. Excitatory toxins produced in the alimentary tract or other
body tissues, or introduced from outside.

II. Increase in afferent impulses (e.g., from noise, light, heat, cold, mental and physical discomfort, or pain).

This classification, of causes of insomnia anticipated the present-day concept of “hyperarousal” [40], as a major cause of insomnia.

A further etiological classification proposed in the same period by the neurologist Symonds [41], included three cat- egories: (1) disease of the central nervous system (CNS; e.g., certain cases of encephalitis lethargica), (2) hyperexcitabil- ity of the cortical cells due to intoxication, and (3) insomnia caused by unwanted stimuli (e.g., muscular, pain, emotional factor).

Treatment

At the end of the nineteenth and beginning of the twentieth century, several substances to induce sleep were used—in particular, chloral hydrate and bromides. Clarke [38] men- tions some “new” hypnotics like paraldehyde and sulphonal. Clarke pointed out that “it is difficult to find any particular drug likely to meet all physiological requirements” (p. 854). Oswald reiterated the same theme much later in 1968 [42]. The pharmacologist Cushny [43, p. 1005] wrote: “the ideal hypnotic should depress CNS (cerebrum) and be devoid of effects on other organs.”

Several clinicians drew attention to the danger of routine use of hypnotics [38, 44, p. 854, 45]. Similar warning was given later by Rudolf [39].

It is interesting to compare the role of pharmacological and non-pharmacological treatment options for sleepless- ness in the medical literature from 1850 to 1950. Non-phar- macological treatment options included sleep hygiene [46], psychotherapy [47], behavioral procedures [48], relaxation therapy [49], hydrotherapy [50, 51], and electrotherapy [52]. The data in Table 12.5 show a comparable increase of publi- cations for both treatment strategies between 1850 and 1910. In the following years, however, the situation changed dra- matically. While the number of papers on treatment of in- somnia with hypnotics increased further, those on non-phar- macological treatments fell back to a very low level. It was only much later in the twentieth century that behavior thera- py was developed by psychologists, and, even later, specific behavioral and cognitive techniques were introduced into the field of sleep medicine and became a valuable alternative to pharmacotherapy of insomnia.

Sleep-Related Breathing Disorders

It is an enigma that physicians in the nineteenth and early twentieth century rarely reported on SRBD [53–56]. Was the disease infrequent at that time? There were good reasons for such an assumption because the general population was much younger [57, 58], and the distribution of body mass measures was shifted to lower values compared to present-day values [59, 60], probably associated with changes in food supply, meal habits, and physical activity. According to Helmchen and Henderson [59], the percentage of overweight persons among white American men aged 50–59 years increased from 3.4 to 35.0 % between 1890 and 2000. Respiratory dif- ficulties, associated with vascular signs, and somnolence or daytime sleepiness were known mainly in very obese per- sons, later referred to as Pickwickian syndrome [61], or mis- taken for narcolepsy [62, 63]. Recurrent respiratory pauses in sleep were also observed occasionally in stroke patients as described by Broadbent [64] in a stroke patient:

Table 12.5 Comparison of the number of publicationsa on treatment of sleeplessness either with hypnotics or with non-pharmacological treat- ment options from 1850 to 1950

Treatment

Pharmacological Non-pharmacological

1850–1869 1870–1889 1890–1909

. 4 9 25

. 5 10 26

1910–1929 1930–1949

28 44

21 13

a Data were drawn from our data bank of historical sleep references

H. Schulz and P. Salzarulo

Fig. 12.3 Three continuous tracings which show periodic breathing of a 70-year-old healthy male subject during sleep (pneumographic re- cording from the thorax). Apneic pauses are most marked in the second

The breathing then began in shallow and gentle inspirations and expirations, and gradually rose to a sort of climax, when the movements of the chest were free and forcible and the entry and exit of air at the nostrils or mouth noisy. There was then a grad- ual subsidence, and a complete arrest in from thirty to thirty- ve seconds. This cycle of breathing and pause was maintained with great regularity, the breathing going on for thirty or thirty- ve seconds, the cessation lasting fteen or twenty seconds. It was scarcely disturbed by conversation, but was at times interrupted by yawns. (p. 308)

This case reminded Broadbent what he had observed many years before “something like Cheyne–Stokes’ respiration during sleep in a gentleman now more than 80 years of age.” He continued:

When a person, especially advanced in years, is lying on his back in heavy sleep and snoring loudly, it very commonly hap- pens that every now and then the inspiration fails to overcome the resistance in the pharynx of which stertor or snoring is the audible sign, and there will be perfect silence through two, three, or four respiratory periods, in which there are ineffectual chest movements; nally air enters with a loud snort, after which there are several compensatory deep inspirations before the breathing settles down to its usual rhythms. In the case to which I allude there was something more than this. The snoring ceased at regu- lar intervals, and the pause was so long as to excite attention, and indeed alarm; I found, on investigation, that there was not simply obstruction by the falling back of the tongue, but actual cessation of all respiratory movements; these then began gradu- ally, but did not at rst attain suf cient force to overcome the pharyngeal resistance.

Here, we have, in 1877, the perfect clinical description of what is called today obstructive (case 1) and central (case 2) sleep apnea, both included under the term Cheyne–Stokes respiration almost a century before cardiorespiratory poly- somnography came into use as a diagnostic procedure.

Angelo Mosso, an early expert in respiratory physiology, described periodic breathing and luxury respiration [65] as follows: “In sleep a momentary interruption of the respira- tory movements is a fairly common phenomenon, and I have to regard it as absolutely physiological, if in sleep, beside the aforementioned fluctuations even complete interruptions occur, just as if a respiratory movement would be absent” (p. 60, our transl). Mosso documented intermittent respira- tory pauses with a duration of up to 30 s in a 70-year-old spritely subject who showed no pathological changes in the

tracing. In the third tracing, A indicates the restart of respiratory move- ments and B a head movement, followed by normal respiration for the next quarter of an hour. (From [65], plate IV)

heart, lungs, or any other organ (Fig. 12.3). The occurrence of respiratory pauses during sleep, in normal subjects, was later confirmed by Pembrey [66].

It is interesting that George Johnson, a physician at King’s College Hospital, London, England, presented the case of a 45-year-old lady who experienced nightly attacks of suffoca- tion. An examination of her throat showed a “very long and slender uvula, which was always in contact with the back of her tongue.” Johnson “cut off about two-thirds of the uvula, and from that time she had no more attacks of suffocation.” [67, p. 654] This is obviously an early case of surgical treat- ment for probable obstructive sleep apnea by resection of the soft tissue which blocked the airway passage during sleep. Another English surgeon, Thorne in 1902 [68] removed parts of the soft palate to treat obstructive breathing in sleep. The effect of the operation was to increase the width of margin of the soft palate and to shorten its length from below upward, thus affording a freer passage for nasal respiration, and mak- ing it much less likely that the postnasal space will be glued up with tenacious mucus and so obstruct respiration through the nose.

Hypersomnias

In the nineteenth and early twentieth century, three major events strongly influenced the concept of excessive sleepi- ness, and these included African sleeping sickness (de- scribed in Chap. 21), narcolepsy (see also Chap. 26), and encephalitis lethargica (see Chap. 20).

Excessive Sleepiness and Narcolepsy

Impressive case reports on severe sleepiness appeared from time to time in the Western medical literature. Many of them were collected by Heinrich Bruno Schindler and integrated, together with his own extensive case reports, into his book Idiopathische, chronische Schlafsucht (idiopathic chronic sleepiness), the first book completely devoted to hypersom- nia [69]. He described varieties of sleep attacks, short sleep episodes, periodic sleep episodes, and continuous sleepi-

12 The Evolution of Sleep Medicine in the Nineteenth and the Early Twentieth Century 83

ness lasting for days, months, even years, combined with a characteristic inability to awaken the person while in a state of pathological sleepiness. In most of the 20 case reports, which he assembled, the etiology was obscure. Physiologi- cal knowledge and clinical experience were insufficient, at that time, to explain the observed phenomena of hypersom- nia and sort out potential neurological, psychiatric, and other aspects that induced the prolonged and recurrent states of sleepiness. For historical evaluation and general description of idiopathic and recurrent hypersomnia, see Chaps. 27 and 28 in this volume.

A very different type of sleepiness was reported later in the nineteenth century by Westphal ([70] see also [71] and [72]) who had made both careful observations of patients with irresistible sleep attacks and sudden loss of muscle tone, typically evoked by surprise or emotional excitement. Based on these two core symptoms of the disease, Gélineau coined the term narcolepsy from the greek ναρκωσις (som- nolent) and λαμβανειν (seize). Earlier case reports with nar- colepsy-like symptoms were described by Bright [73, case no. 5], Graves [74], Caffe [75], and Jones [76, case no. 82]; however, in all these cases SRBD could not be ruled out. Narcolepsy quickly gained a special significance for further development of sleep medicine since narcoleptic sleep at- tacks associated with cataplexy were very different from other forms of protracted sleep or hypersomnia. In the fol- lowing years, however, confusion arose when some sleep experts included any form of excessive sleepiness under the new diagnostic category [see 27, pp. 106–119]. Brailovsky [77] distinguished the following five etiological groups for individuals complaining of sleepiness: (1) functional narco- lepsy, triggered by a special event, (2) narcolepsy associated with morbid physical conditions, (3) narcolepsy in organic disease of the central nervous system (CNS), (4) narcolepsy in toxic–infectious conditions of the CNS, and (5) genu- ine narcolepsy. This latter group was the most difficult one from an etiological point of view, and Brailovsky wrote: “Finally one can identify a group in which the underlying disease is hard to determine; this problematic group we must treat separately as genuine narcolepsy” (p. 267, our transl.). Brailovsky accepted Pavlov’s concept of spread of inhibition as a common mechanism for different forms of sleepiness; however, he emphasized the role of subcortical centers (not considered by Pavlov) in the causation of narcolepsy to ex- plain the rapid onset of sleep and cataplectic attacks. In sharp contrast to the broad concept of narcolepsy, Redlich [78] and others favored a much more strict use of the term narcolepsy to include sleep attacks and cataplexy as the core symptoms. Much later, Yoss and Daly [79], based on the analysis of 241 of their own cases, suggested the narcoleptic tetrad, a symp- tom complex of daytime sleepiness, cataplexy, sleep paraly- sis, and hypnagogic hallucinations.

Parasomnias and Sleep-Related Movement Disorders

Parasomnias and sleep-related movement disorders, in- cluding restless legs syndrome and rhythmic movement disorder, were known and described in the nineteenth- and twentieth-century sleep medicine. The readers are referred to Chaps. 29, 44, and 45, for evolution and description of some of these entities. Here, we briefly mention about nightmare disorders (REM parasomnias) as well as sleepwalking, sleep terrors, and confusional arousal (all grouped under non- REM parasomnias). The term parasomnia was probably first used by the Swiss psychologist Claparède [80, p. 333] when he spoke about three forms of pathological sleep (insomnia, hypersomnia, and parasomnia). A few years later, Salmon [81] included nightmares, sleep talking, and sleepwalking into the category of parasomnias.

In contrast to motor parasomnias, sleep-related move- ment disorders “are conditions that are primarily character- ized by relatively simple, usually stereotyped, movements that disturb sleep or by other sleep-related monophasic movement disorders such as sleep-related leg cramps” [23, p. 177]. Romagna Manoia [24] was presumably the first who made a distinction between sleep-related movement disor- ders and parasomnias when he classified sleep disorders (see Table 12.2). Incubus or nightmare, a typical rapid eye move- ment (REM) sleep parasomnia disorder, which attracted observer’s attention all along, is reviewed in the following section.

Nightmare Disorders

The most impressive treatise on nightmare stems from John Waller, a ship doctor of the Royal Navy who himself was severely afflicted by the disorder [82]: “As I have so long been an unfortunate victim to this enemy of repose, and have suffered more from its repeated attacks than any other person I have ever met with, I hope to be able to throw some light on the nature of this affection, and to point out some mode of relief to the unfortunate victims of it.” (p. 11) Waller’s trea- tise is a suspense-filled piece of literature, though a few of the dramatic case reports, which he presents, would be rather categorized today as REM sleep behavior disorder (e.g., p. 16 f.). When the nightmare attack occurs, the afflicted per- son is either just fallen asleep or in deep sleep:

If the patient be in a profound sleep, he is generally alarmed with some disagreeable dream; he imagines that he is exposed to some danger, or pursued by some enemy which he cannot avoid; frequently he feels as though his legs were tied, or deprived of the power of motion; sometimes he faces himself con ned in some very close place, where he is in danger of suffocation, or at the bottom of a cavern or vault from which his return is inter-

H. Schulz and P. Salzarulo

cepted. It will not infrequently happen, that this is the whole of the sensation which the disease, for the time, produces, when it goes off without creating any further annoyance: the patient either falls into an oblivious slumber, or the alarming dream is succeeded by one more pleasant. In this case the disease is not fully formed, but only threatens an invasion; it proves however that the pre-disposition to it exists, and that the person is in danger of it. But when the paroxysm does actually take place, the uneasiness of the patient in his dream rapidly increases, till it ends in a kind of consciousness that he is in bed, and asleep; but he feels to be oppressed with some weight which con nes him upon his back and prevents his breathing, which is now become extremely laborious, so that the lungs cannot be fully in ated by any effort he can make. The sensation is now the most painful that can be conceived; the person becomes every instant more awake and conscious of his situation: he makes violent efforts to move his limbs, especially his arms, with a view of throwing off the incumbent weight, but not a muscle will obey the impulse of the will: he groans aloud, if he has strength to do it, while every effort he makes seems to exhaust the little remaining vigour. The dif culty of breathing goes on increasing, so that every breath he draws, seems to be almost the last that he is likely to draw; the heart generally moves with increased velocity, sometimes is affected with palpitation; the countenance appears ghastly, and the eyes are half open. The patient, if left to himself, lies in this state generally about a minute or two, when he recovers all at once the power of volition: upon which he either jumps up in bed, or instantly changes his position, so as to wake himself thoroughly. If this be not done, the paroxysm is very apt to recur again immediately, as the propensity to sleep is almost irresist- ible, and, if yielded to, another paroxysm of Night-Mare is for the most part inevitable. (p. 21)

Finally, it is mentioned that nightmares are frequently ac- companied by penile erections, thus completing a set of events (sleeping, dreaming, muscle atonia, and erections) which is typical for a state of sleep which is known as REM sleep today [83]. Waller discusses many occasions of night- mare-associated hallucinations and “visions’’, produced by a state of consciousness between sleep and wakefulness. More recently hypnagogic mental states were analyzed in detail by Mavromatis [84]. From his own experiences, Waller concluded that neither lying on the back, what most authors gave as primary reason for a nightmare attack, nor late meals and a full stomach, are responsible for nightmares. Waller, who admits his ignorance on the true causes of the disease, recommends to avoid dyspepsia and over-acidification by a careful diet and the use of carbonate of soda in a palatable form.

Nightmare, as described in the nineteenth century medi- cal literature and earlier, differs from the actual classification [23], in that it combined what is now separated into two dis- tinct sleep disorders, (i) recurrent isolated sleep paralysis and (ii) nightmare disorder. In the historical literature, the feeling of oppression in combination with an inability to move and bad dreams was seen as a disease unit. Familial occurrence of the disease has been exemplified with two pedigrees by Ebstein [85].

Somnambulism or Sleepwalking

The nineteenth century became the peak time of publications on somnambulism or sleepwalking (a non-REM parasom- nia) with more than 200 publications, well above the number of publications before (eighteenth century: just over 60) or after (1900–1950: about 50). Manacéïne [27] confirmed that somnambulism occurred primarily in adolescents and young persons, i.e., those who required high amounts of muscular activity during daytime, and she raised the question whether somnambulism could result from a lack of physical activity during the day which, in turn, may provoke motor events at night. She referred to cases where somnambulism disap- peared after extensive physical work. Somnambulism gained renewed interest for army psychiatrists who had to diagnose soldiers who were sleepwalking. Sandler [86] noted in af- flicted subjects “a great number of concomitant neurotic symptoms of other kinds” besides somnambulism, and the treatment of choice was psychotherapy in combination with sodium amytal.

Pavor Nocturnus: Sleep Terrors

“Sleep terrors consist of arousals from slow-wave sleep ac- companied by a cry or piercing scream and autonomic ner- vous system and behavioral manifestations of intensive fear” [23]. Pavor nocturnus was known to the nineteenth-century Saxonian physician, Carl Gustav Hesse, who had written a remarkable monograph of this sleep disorder, which typical- ly affects children [87]. One of the aims of Hesse’s treatise was to differentiate pavor nocturnus from nightmare disor- ders and sleepwalking. The attacks start most frequently 1 or 2 h after sleep onset, the child startles up “as hit by an electrical shock” in full panic, mostly with a shrieking-shrill cry, sometimes jumping out of bed, obviously in avoidance of the horrible scene. Consciousness of the concerned child (or adult) seems to be altered; he or she does not recognize persons and does not understand when someone speaks to them, much in contrast to nightmare sufferers. After the inci- dence, many children are unable to report what was horrify- ing them; others are remembering frightening persons, ani- mals, fire, or other phantasms. The event lasts in most cases from 15 to 30 min and it comes only slowly to its end. The frequency of occurrence and the intervals between recurring events vary widely. Hesse, as others, differentiated between symptomatic and idiopathic forms.

The classification into idiopathic and symptomatic forms of pavor nocturnus was later rejected by Braun [88] who re- garded the disease as a form of neurasthenia, defined as an increased irritability of the nervous system. He emphasized

12 The Evolution of Sleep Medicine in the Nineteenth and the Early Twentieth Century 85

educational measures for prevention, medication (bromides, chloral, chinin) in severe cases only, and warm or tepid baths.

Confusional Arousal and Its Forensic Aspects

An early and detailed account of a case of violent confusion- al arousal was presented by the Berlin physician Heim [89, 90]. The person concerned was a longtime friend of Heim who described him as an honest businessman, with lively and jovial temperament, and a powerful body. One night, about an hour after going to bed, his wife became alarmed when she heard him groan, and she tried to awaken him by shaking. The man sat up and opened his eyes without recog- nizing his wife, and, after a short while, the man jumped out of bed, grabbed her by the hair, and tried to throw her out of the window. About half an hour later, the doctor arrived and saw the wife, covered with blood. The man recognized the doctor, called him by name, and asked him why he and the other persons were there. Heim’s report rekindled inter- est in questions of consciousness in the borderland between sleep and wakefulness, and captured the lawyers’ attention regarding questions of responsibility for acts committed dur- ing such states of reduced or unclear consciousness. Nearly a century later, the psychiatrist Gudden reviewed 18 pub- lished cases of confusional arousal, raising medico-legal questions [91]. He understood confusional arousal, calling it Schlaftrunkenheit or sleep drunkenness at that time, as a disorder of consciousness out of sleep, associated with hy- peresthesia, psychomotor agitation, and a lack of prudence. Schmidt [92] had reviewed the medico-legal literature over a time span of 150 years and was able to locate 15 case reports of homicide and 20 cases of other crimes. Wharton and Stillé [93] emphasized that it is important to distinguish “Som- nolentia or Sleep-drunkenness, which is a state which to a greater or less extent is incidental to every individual, from Somnambulism, which is an abnormal condition incident to a very few” (p. 122).

Circadian Rhythm Sleep Disorders

In the period from 1800 to mid-twentieth century, a basis was provided for the later intensive research on circadian rhythms. The Belgian astronomer and social statistician Adolphe Quetelet was one of the first who collected statis- tical data on the influence of annual and daily rhythms on human life and functioning. He showed that the number of births is higher in the night compared to the daytime hours at a ratio of 5:4. [94]. The influence of the night on diseases was also discussed at that time [95, 96]. Later, in the nine- teenth century, an increasing amount of physiological stud- ies was devoted to 24-h alterations of body temperature

[97], metabolism [98], urine secretion and its constituents [99], and the activity of different organs [100]. It was recog- nized that most of these diurnal changes were independent of sleep and continued even when sleep was prevented or shifted [101]. In the early twentieth century, it was shown in rodents, kept under constant conditions (total darkness), that the daily cycle of activity and rest was self-sustained and not driven by external cues [102]. This finding became the starting point for a search for pacemakers or biological clocks that regulate the timing of behavior, performance, and mood. Curt Richter was one of the early researchers contrib- uting to an understanding of biological clocks in medicine and psychiatry [103]. Early examples of circadian rhythm sleep disturbance were provided by Von Economo’s [104] description of encephalitis lethargic and Roasenda’s [105] description of inversion of sleep in encephalitis. Another field which gained growing importance in the twentieth cen- tury was shift work causing disruption of the alignment of sleep and circadian clock, giving rise to a shift work disorder [106]. However, a more deep understanding of the interac- tion between sleep and circadian rhythms began only in the second half of the twentieth century, when results from circa- dian and sleep research were combined [107–109].

Sleep Disturbances and Childhood Development

Most of the papers published in the beginning of the eigh- teenth century concerned episodic phenomena occurring during sleep, such as sleep terrors and enuresis in children, while much less interest was devoted to insomnia. In ad- dition to some interest in sleep disorders, the relevance of sleep for the development was also pointed out including in- formation for mothers [110, 111]. Capuron [112] dedicated six pages of his handbook “Traité des maladies des enfants” to sleep disturbances and Fonssagrives [113] devoted a sec- tion of his book “Leçons d’hygiène infantile” to sleep and insomnia. He underscored the danger of sleep disturbances to general health due to physical causes and use of opioids. However, most books on sleep disturbances did not include diseases of the children and the elderly (Hammond 1869).

It is worth mentioning a publication (probably the first description of obstructive sleep apnea in infants and conse- quences) by the otolaryngologist Bosworth in 1896 [114] describing upper airway obstructions by enlargement of adenoids causing frequent occurrence of nightmares in chil- dren: “While the interference with respiration may not cause any conscious symptoms of dyspnœa, yet it does cause the nightmare so frequently observed in children. It arises from the fact that, the entrance of air to the lungs being slightly impeded during sleep, there follows a slowly but surely in- creasing lack of proper oxygenation of the blood, resulting

H. Schulz and P. Salzarulo

in an increase of the besoin de respirer, until it culminates in a sense of oppression or suffocation, under the influence of which the child awakens alarmed and terrified” (p. 433).

The term “sleep disorders” became more frequent after 1920 since Goldschmidt’s [115] publication of a case of nar- colepsy and Pototzky’s [116] work on infantile sleep, insom- nia, and disturbances of sleep. Pototzky assumed that sleep disturbances were related to four constitutional types, and- therapy was different for each type.

The growth of child neuropsychiatry began in the 1920s and 1930s [32, 117–120]. Kanner, a well-known child psy- chiatrist, emphasized the necessity to consider global aspects of behavior to understand sleep problems in older children. He pointed out the importance of the behavior before sleep proposing a continuity between waking and sleeping behav- ior. Many of the points raised by Kanner were developed further in the second half of the twentieth century; whereas in the first half of the twentieth century, experimental psy- chophysiology [121] made important contributions to chil- dren’s sleep problems.

Before 1950, statistics about frequencies of sleep dis- turbances in children were extremely rare. There was one remarkable study by Benjamin [122] on the frequency of sleep disturbances in relation to other neurotic symptoms (Table 12.6) presenting data from 205 children (63 % males, 37 % females): “In the course of childhood a symptom

change of the neurosis occurs, in such a way that eating dis- orders decrease from 44 to 11 %, habits from 40 to 8 %, fear from 40 to 19 %, sleep disturbances from 42 to 14 %, vomit- ing from 28 to 2 %, enuresis from 20 to 8 %, and language impairment decrease from 16 to 4 %. Noteworthy is the tem- porary increase of enuresis from the 8th to the 11th year of life” (p. 88, our transl.).

Conclusions

In the beginning of the period under consideration, physi- cians had to rely on reports of patients and occasional obser- vations of the sleeper’s behavior as sole sources of informa- tion for diagnosis and treatment. Knowledge on the physiol- ogy of sleep was extremely limited at that time. The situation changed with the rapid development of physiology and other branches of medicine, organic chemistry, psychology, and availability of instruments for measurement and recording devices [123, pp. 9–26]. In addition, the pharmaceutical in- dustry started to produce new hypnotic agents.

Among the different sleep disorders, insomnia gained its leading position in the second half of the nineteenth century (Figs. 12.1 and 12.2). Since insomnia was seen by the ma- jority of authors as a symptomatic disorder, treatment was primarily aimed at removing or alleviating the assumed

Table 12.6 Frequency of sleep disturbances in relation to demographic data and neurotic symptoms

12 The Evolution of Sleep Medicine in the Nineteenth and the Early Twentieth Century 87

causal factor [35]. While opium was traditionally used for sleeplessness, the situation changed later in the nineteenth century, when a whole series of newly developed hypnot- ics like bromide salts, chloral hydrate, paraldehyde, and others were marketed, and finally in the twentieth century when barbiturates were introduced. Any new drug met with caution and an ambivalent reaction was seen throughout the history of hypnotic drug use [124]. The most popular non- pharmacological treatment option was sleep hygiene. Only in the first half of the twentieth century, psychotherapy [125] and behavioral therapy (e.g., muscle relaxation therapy) [49] became treatment options for insomnia.

Hypersomnias due to brain diseases, such as tumors or encephalitis, were separated from genuine narcolepsy and recurrent hypersomnia. Narcolepsy was quickly recognized as a potential key for understanding of sleep–wake regula- tion as confirmed in later studies [126].

The term RLS was introduced by Ekbom [127] giving a full clinical description based on a series of his own cases. Even more surprising is the near-total absence of description of SRBD throughout the nineteenth and the first half of the twentieth century.

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The History of Polysomnography: Tool of Scienti c Discovery

Max Hirshkowitz

EEG and Sleep: The Beginnings

Berger and the String Galvanometer

Hans Berger, considered the father of electroencephalogra- phy (EEG), made his first recordings using a device called the string galvanometer in 1924 [1]. It involved suspending a reed between electromagnets using a string so that the oscil- lations could expose a light-sensitive material (see Fig. 13.1). With this device, he was able to record EEG activity (fluc- tuating potential differences) and found an 8–13-cycle-per- second waveform when an individual remained relaxed but wakeful. He named this rhythm “alpha” but many referred to it as the “Berger’s wave.” Another finding, for which he is much less known, was that when a person fell asleep, the alpha rhythm disappeared. As unlikely as it seems, almost a century later we still essentially define sleep onset by de- termining the point at which alpha EEG activity diminishes. This simple finding conceptually marked the beginning of what decades later would evolve into polysomnography (PSG). Nonetheless, at the time Berger was not highly re- garded and considered by many a “crank” until Lord Adrian confirmed his findings [2]. By 1938, EEG gained general recognition. Accounts vary concerning Berger’s life after

M. Hirshkowitz ()
Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Blvd-Stop Code 111i, Sleep Center, 3426 LinkwoodTX, USA
e-mail: max.hirshkowitz@gmail.com

Department of Medicine and Menninger, Baylor College of Medicine, Houston, USA

Department of Psychiatry, Baylor College of Medicine, Houston, USA

Sleep Disorders & Research Center, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX 77030, USA

1938. Whether the Nazi regime forced his retirement or he joined the Schutzstaffel (SS) is unclear; however, he com- mitted suicide in 1941.

Oscillographs, Drum Kymographs, and Strip Chart Recorder

The string galvanometer was not suitable for making record- ings over extended time periods. Oscillographs could also be used with bromide paper but long-duration recordings pre- sented a technical problem. However, another device invent- ed decades earlier could be adapted. A German physiologist named Carl Ludwig invented a “wave writer” or kymograph [3] that utilized a cylinder or drum around which a piece of paper could be attached (see Fig. 13.2). A stylus marked the paper as the drum rotated. Early versions used the sty- lus to scrape off soot from pre-smoked sheet but eventually ink became the preferred writing medium. In this manner, scientists could make recordings over longer time periods, especially when the stylus traversed a worm screw prevent- ing overwriting after the drum completed a full rotation. An alternative approach involved moving a continuous strip of paper (from a roll or fanfolded) under ink pens at a constant speed. The drive mechanism typically incorporated several gear ratios that could move the paper ribbon or strip with rotating sprockets, pinch rollers, or some other mechanism.

Gibbs and Garceau were able to construct a one-channel EEG machine by adapting the Weston Union Morse Code inkwriting undulator while Albert Grass who was working on earthquake seismographs created a three-channel EEG machine. After 1938, EEG rapidly gained popularity as both a research and clinical tool. Polygraphic recording devices (e.g., the grass model 1) became commercially available (see Fig. 13.3). Groups in both Europe and America applied this new approach to psychiatric and neurologic disorders, describing, documenting, and naming various waveforms. Some recordings were made during sleep by sampling EEG and researchers described periods of low-amplitude mixed-

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_13, 91 © Springer Science+Business Media, LLC 2015

M. Hirshkowitz

Fig. 13.1

Illustration of a drum kymograph

Fig. 13.3 Grass model I polygraph

passion for science. He spent the fortune he made through in- vestments to fund scientific research by the greatest minds in his time (including Heisenberg, Bohr, Fermi, and Einstein). In 1937, Loomis, along with Harvey and Hobart, published the first report from continuous, all-night studies of human sleep [6]. They had constructed an 8-ft.-long, 44-in.-circum- ference drum recorder (see Fig. 13.4) and monitored up to three channels at a time of signals switched through some sort of selector panel. Recording sites included (midline vertex, midline occiput, behind left and right ears, and just above and to the left of the left eye). They described a fourth channel that could be used to record signal markers, heart- beats, or respiration. They could manage 3.5 h of recording before paper needed changing. They wrote the following “… we have been able to establish very definite states of sleep which change suddenly from time to time, and to correlate

Fig. 13.4

Fig. 13.2

Hans Berger’s string galvanometer

frequency activity alternating with high-amplitude slow waves. Gibbs and Gibbs also remarked that EEG was mostly symmetrical during sleep, except during the low-voltage, mixed-frequency episodes [4].

Tuxedo Park

Alfred Loomis was an eccentric, and very wealthy, lawyer- turned Wall Street tycoon who established a research center in Tuxedo Park in the 1930s sometimes called the Loomis Laboratories [5]. Loomis excelled at mathematics and had a

Loomis’s drum recorder designed to conduct sleep studies

13 The History of Polysomnography: Tool of Scientific Discovery

Fig. 13.5 Hypnogram as depicted by Loomis and colleaguesFig.

these with movements, with dreams, and with external stim- uli applied to the sleeping subject.” They described alpha, low voltage, spindles, “random,” and spindles plus random sleep state sequences. Interestingly, they recorded and de- scribed eye movement activity but did not establish an eye movement dreaming state of sleep. Their graphical depic- tion of sleep’s progression across the night looks remarkably similar to our contemporary hypnograms (see Fig. 13.5). Loomis invited Harvard professor Hallowell Davis and his wife Pauline to TuxedoPark and offered to fund his clini- cal EEG research. Davis accepted the offer. Loomis had a hopeful but ultimately misguided belief that EEG could be applied to psychological and psychoanalysis and he invited many distinguished psychiatrists to his laboratory. When World War II broke out, the Loomis Laboratories changed direction to help in the war effort. He helped by bankrolling the development of high-powered radio detection and rang- ing (RADAR) and Loomis radio navigation (LRN), later re- named long range navigation (LORAN); technologies that ultimately helped win the war (Fig. 13.6).

Discover of REM Sleep

In 1953, Aserinsky and Kleitman published data showing dreaming occurred during the sleep stage associated with low-voltage, mixed-frequency activity [7]. Furthermore, rapid eye movement (REM) accompanied these events. In his book Sleep and Wakefulness, Kleitman describes the dis- covery in the following manner: “…we literally stumbled on an objective method of studying dreaming while explor- ing eye motility in adults…” [8]. He further noted that Ladd (in1892), based only on introspection, posited eye move- ments during dreaming and Jacobson (in 1937) had written “When a person dreams…most often his eyes are active.” Nonetheless, the electrophysiological evidence in their land- mark paper officially ushered in a key step toward more fully describing sleep. Meanwhile, Jouvet found his cats lost muscle tone during “paradoxical sleep” episodes which completed our picture of stage REM sleep [9]. These discov- eries also marshaled the beginning of multichannel electro-

Fig. 13.6

Present author with sleep analyzing hybrid computer

physiological recording of EEG, electrooculogram (EOG), and sometimes electromyogram (EMG) for studying sleep.

Exploring REM sleep and comparing its mental and phys- iological correlates to other stages of sleep became a stan- dard paradigm. Dream content, both spontaneous and pro- voked, during REM represented a very hot topic. After all, Freud had called dreaming the royal road to the unconscious mind [10]. Sleep studies targeting stage REM now provided a laboratory tool to explore the unconscious processes. Con- comitant recordings of respiration, heart rhythm, electroder- mal activity, paved the way toward what we now call PSG.

The Standardized Manual

As more investigators began researching sleep phenomena, scientists realized that a standardization of techniques could immensely facilitate communication and possibly progress. After REM sleep’s discovery, summarizing sleep integrity, continuity, and architecture required more sophistication that the Loomis system offered. Thus, research groups created their own terminology and scoring rules. Dement and Kleit- man evolved a system to classify sleep according to EEG criteria [11]. Essentially, a time domain of the set duration was established and the dominant activity within that time- frame-dictated classification. This time domain, called an epoch, could be classified as sleep stage 1, 2, 3, or 4 or awake according to EEG characteristics. When REMs occurred dur- ing stage 1 sleep, the stage was designated REM sleep. How- ever, recording technique and terminology differed between sleep laboratories. REM sleep was also called paradoxical sleep, desynchronized sleep, active sleep, D sleep, and even unorthodox sleep.

Ultimately, an ad hoc committee was formed to develop “A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects.” [12]

M. Hirshkowitz

Chaired jointly by Drs. Allan Rechtschaffen and Anthony Kales the committee was a who’s who of sleep experts, in- cluding William C. Dement, Michel Jouvet, Bedrich Roth, Laverne C. Johnson, Howard P. Roffwarg, Ralph J. Berger, Allan Jacobson, Lawrence J. Monroe, Ian Oswald, and Rich- ard D. Walter. The group standardized procedures, scoring rules, and terminology. More important, they reached con- sensus and thereafter used the procedures (for the most part) to conduct human sleep research. In essence, this was the real key to R&K (as it was called after the chairmen’s ini- tials) successes. My understanding from stories I have been told by various participants indicated there were very strong (verging on violent) disagreements, shouting arguments, and name calling. In the heat of one less than civil debate, report- edly one of the chairmen barred the doors, decreeing that no one could leave until consensus was reached. Ultimately, consensus was reached and this is why R&K succeeded.

PSG, at least for sleep staging was established!

Psychophysiological Study of Normal Sleep

This new field, PSG, was ripe for discovery. In 1961, a re- search society emerged called the Association for the Psy- chophysiological Study of Sleep (APSS) and annual meet- ings were held to discuss research findings. The meeting proceedings were originally published in the Psychophysi- ology (the journal for the Society for Psychophysiological Research) which sported the image of a PSG tracing on its cover. Research laboratories at major universities, at US Naval and Army research centers, in European research in- stitutes, and large medical centers began recording human sleep to describe its biology and to try to understand its un- derlying process. Whether a particular line of inquiry aimed to elucidate the function of sleep or to derive the intricacies of its process, progress, and some breakthroughs were being made. Sleep deprivation was a popular paradigm in the at- tempt to infer function. The examination of sleep stage re- bound in response to selective stage deprivation provided a model to explore sleep’s homeostatic regulation. The mili- tary was interested in the adverse effects sleep deprivation had on behavior, attention, cognition, and physical ability.

Many studies focused on REM sleep phenomena. Obvi- ously, dreaming represented a very seductive and intriguing topic; however, no unified theory of dreaming grew out of PSG research. Nonetheless, scientists found the eye move- ments generally corresponded to direction of gaze in the dream sensorium, middle ear muscle activity concorded with dreamt sounds, and nocturnal erections accompanied REM sleep but did not correspond to sexual dream content. Physiologic events associated with PSG stages other than REM sleep included timing and release of growth hormone during slow-wave sleep, slow-wave activity as a marker for

homeostatic drive, other endocrine secretions in sleep, and physiological stability of cardiopulmonary functions during non-REM (NREM) sleep. Note the intuitive appeal of refer- ring to sleep as REM and NREM. However, this terminol- ogy highlights how enamored polysomnographers were with REM sleep. REM sleep is the minor partner in sleep, yet we label the majority of sleep as not REM. Perhaps we should refer to wakefulness as non-sleep.

Sleep Latency Tests

Multiple Sleep Latency Test

The sleep studies performed in the Stanford summer sleep camp on children and teenage as well as other studies per- formed on college students and patients with sleep disorders led to conceptualization of daytime sleep latency as a bio- marker for sleepiness. The studies in children were part of Mary A. Carskadon’s doctoral dissertation “Determinants of Daytime Sleepiness: Adolescent Development, Extended and Restricted Nocturnal Sleep (1979).” Carskadon and De- ment [13] described multiple sleep latency changes across the day during an experimental 90-min sleep–wake sched- ule in Sleep Research. Sleep Research, at the time, was a major vehicle for sharing information in the sleep commu- nity. Their subjects had 16 opportunities to fall asleep (and were instructed to “close your eyes, lie quietly, and try to fall asleep”) over each 24-h period as they underwent base- line, sleep deprivation, and recovery periods. PSG record- ings from these studies helped form procedures later used in multiple sleep latency test (MSLT). The following year, Richardson et al. [14] published daytime sleep latency find- ings for patients with narcolepsy and controls. Sleep latency as a biomarker for sleepiness validation came soon after with experimental studies of acute sleep deprivation, chronic sleep restriction, and concordance with other performance measures [15, 16].

The PSG and operational procedures for conducting and analyzing the MSLT were extremely well thought out and effective right from the start. Methods quickly became stan- dardized and a coherent body of literature emerged. A re- search version (minimizing accumulated sleep) and a clini- cal version (providing 15 min of sleep to permit REM oc- currence) evolved. MSLT’s utility for objectively measuring sleepiness and confirming narcolepsy (by REM occurrence) made MSLT an essential part of sleep research and sleep medicine. Guidelines for MSLT were formally adopted in 1986 in the journal Sleep [17]. Current clinical guidelines continue to endorse MSLT for diagnosing narcolepsy [18] and research projects still turn to the MSLT when they need an objective measure for sleepiness.

13 The History of Polysomnography: Tool of Scientific Discovery

Maintenance of Wakefulness Test

While the ability to fall asleep depends on underlying sleep drive, the ability to remain awake in the face of sleepiness involves additional factors. The inability to volitionally maintain wakefulness in soporific circumstances became the focus of many sleep researchers, clinicians, and regulators. The role of sleepiness in fatigue-related accidents needed definition. The failure of the brain’s alertness system in sleep restricted, deprived, or impaired individuals contributes to fa- tigueinamannerthatcannotbeengineeredawaybyhuman factors or ergonomic improvements. Mitler et al. developed maintenance of wakefulness test (MWT) using procedures similar to MSLT but changed the instructions from “try to fall asleep” to “try to remain awake.” Criterion group valida- tion in patients suffering from sleepiness succeeded [19, 20]. MWT is a powerful tool (the US Federal Aviation Adminis- tration endorsed its use) but methodology varied from study to study, sometimes making it difficult to compare results. A critical variation is test session length which ranges from 20 to 60 min. After a normative data trial [21], test session length settled on 40 min. Current clinical guidelines published in 2005 endorse 40-min sessions, provide standard procedures, and stipulate clinical indications for use [18].

Clinical PSG

Exploration, Biomarkers, and Diagnostics

Just as EEG proved useful in clinical applications, PSG held similar promise. Robert L. Williams was a pioneer and unsung leader in sleep medicine. He explained to me that understanding sleep disorders first required characterizing normal human sleep. Beginning in 1959, his sleep laboratory at the University of Florida, College of Medicine in Gaines- ville began making continuous all-night sleep recordings in normal, healthy male and female children, adolescents, teen- agers, young adults, adults, and seniors. A decade and a half later these “norms” were published in The EEG of Human Sleep [22].

It was well known that in adults, REM sleep did not occur until after approximately 70–100 min of NREM sleep. Fur- thermore, REM sleep seldom, if ever, occurred during day- time naps. PSG evidence verified REM sleep occurring on or near sleep onset both during nocturnal sleep studies and dur- ing daytime naps in patients with narcolepsy [23]. This find- ing established a PSG diagnostic marker. The hunt was on! It was noted that patients with major depressive disorders had shorter than normal REM sleep latencies [24]. Sleep- related erection monitoring helped differentiate men suffer- ing from organic versus psychological erectile dysfunction

to aid clinicians in selecting appropriate therapeutic inter- ventions [25].

PSG illuminated sleep pathophysiologies. Obvious ones like cessation of breathing with arousals, oxyhemoglobin desaturations, or both were soon discovered. Driven by tech- nological advances in oximetry, thermistors, thermocouples, and devices/techniques to detect respiratory effort, sleep apnea syndromes were indisputably verified [26]. Commer- cially available fast-response oximetry systems included the Waters, Hewlett-Packard, and eventually the Biox devices. Airflow detection devices were still largely homemade but ready-to-use commercially available recording sensors quickly followed. Periodic leg movement activity became apparent and its potential for disturbing sleep understood. Abnormal EEG activity or lack thereof, during some sleep- related odd or abnormal behaviors provided differentiation between nocturnal seizure and parasomnias. Also, clinical PSG led to discovery of new sleep disorders; for example, REM sleep behavior disorder [27].

PSG also provided an objective technique to assess insom- nia. While this approach ultimately was deemed impractical except under specific circumstances [28], PSG application for investigating drug effects on sleep was a more productive enterprise, especially if waveform changes were analyzed [29]. PSG testing of new drugs for treating insomnia became de rigueur. Multi-night, multicenter, randomized controlled trials with PSG primary and/or secondary outcome measures provided the objective evidence to determine whether an in- vestigational new drug will be approved by federal oversight agencies, such as the US Food and Drug Administration. This represents applied clinical science in its ultimate form.

Clinical Guidelines and Professional Society Rec- ommendations

The sudden and rapid expansion of clinical PSG application quickly outdistanced any standardized recommendations. To a large degree, methods for various PSG procedures were scattered in dozens of papers and textbooks, and they all dif- fered. The pivotal publication with respect to PSG methods was Guilleminault’s 1982 book Sleeping and Waking Dis- orders: Indications and Techniques [30]. This text imme- diately became a de facto standard. The methods described by Bornstein’s (a.k.a. Sharon Keenan) to record and assess sleep-disordered breathing served as the basic roadmap in many laboratories [31]. It was not until many years after the book was out of print that the Chicago Group’s sleep apnea recommendations were published [32] (and these were en- dorsed for research rather than for standard clinical rou- tine). Richard Coleman’s chapter [33] served as a primer for PSG evaluation of periodic leg movements. Other chapters detailed MSLT, gastroesophageal (GE) reflux monitoring,

M. Hirshkowitz

and sleep-related erection testing. The book also contained a comprehensive sleep questionnaire.

The original sleep society, APSS, was now trying to serve both scientists and clinicians. Similarly, the annual meetings had basic research, clinical research, and clinical develop- ments on its agenda. Eventually, the Association of Sleep Disorders Centers (ASDC) was formed in 1975 and it ulti- mately grew an individual member wing called the Clinical Sleep Society (CSS) in 1984. In the meanwhile, the Asso- ciation of Polysomnographic Technologists (APT) formed in 1978 and a board of polysomnographic technologist registry (BRPT) administered its first examination in 1979. These groups ultimately formed a confederation in 1986 called the Association of Professional Sleep Societies (reusing the initials APSS) and ASDC was renamed the American Sleep Disorders Association (ASDA) the following year (eventu- ally becoming the American Academy of Sleep Medicine (AASM) in 1999). All the while, some progress was being made to have societally endorsed PSG standards. There were task forces to establish procedures for conducting the MSLT [34], recording, and scoring central nervous system (CNS) arousals from sleep [35] and periodic leg movements [36]. The AASM finally formed a standards of practice commit- tee to make recommendations concerning clinical PSG and diagnostics using evidence-based medicine and Rand appro- priateness approaches [37, 38]. Additionally, international groups formed to develop standards for recording and scor- ing clinical PSG information. Notable among these are the group that published an atlas for cyclic alternating pattern scoring [39] and the World Association of Sleep Medicine (WASM) in collaboration with the International Restless Legs Syndrome Study Group (IRLSSG) who updated the guidelines for periodic leg movement assessment (which ul- timately was adopted virtually unchanged by AASM) [40].

Finally, in 2007, the AASM published a manual that cov- ered recording and scoring all of the routinely used clinical PSG data [41]. The manual includes terminology, technique, and scoring criteria for sleep staging, CNS arousals, respi- ratory events, periodic leg movements, other movements, and electrocardiographic abnormalities. The AASM seems committed to updating the manual regularly and providing web-based availability through subscription. The other area of standardization addressed in the manual relates to digital PSG. Sorely needed minimum specifications for comput- erized PSG systems were developed by a task force I co- chaired with Thomas Penzel. These guidelines were long overdue and hopefully will set a standard to assure that our clinical tools remain reliable and valid.

Growth of Sleep Disorders Laboratories and PSG’s “Killer App”

As clinical PSG gained ground, sleep disorders center began to open. Some notable early program included the ones in Baptist Memorial (Memphis), Baylor College of Medicine (Houston), Western Psychiatric (Pittsburgh), Presbyterian (Oklahoma City), Ohio State (Columbus), Montefiore (New York), Henry Ford (Detroit), Mount Sinai (Miami), Stanford University (Palo Alto, CA), University of California (Irvine, CA), and Holy Cross (Mission Hills). This core group col- laborated on a variety of projects and their leaders were in- strumental in developing PSG applications for sleep medi- cine [42]. These sleep disorders centers created a nucleus from which the ASDC grew. The main focus of these sleep centers was the laboratory designed to conduct clinical PSG procedures. As of 2011, there were nearly 2000 AASM-ac- credited sleep disorders centers [43].

Sleep apnea was the engine driving this huge expansion of sleep laboratories conducting clinical PSGs. Currently, 80–90 % of all clinical PSG conducted attempt to rule-in or rule-out sleep-disordered breathing. In the parlance of Silicon Valley, this makes sleep apnea PSG’s “killer app” (application). Although sleep-disordered breathing was first identified in 1965 by Gastaut et al. [44], it took a decade before clinical and research machinery were adequately mo- bilized. In 1975, sleep apnea papers still only registered trace amounts in the overall sleep literature. If we inspect journal publication trends, however, by 1995, sleep apnea papers reached approximately 50 % of the overall sleep literature.

Computerization

Signal Processing

One thing about PSG was painfully clear from the begin- ning to researchers and clinicians. It is an intensively time- consuming process. Even after 6–8 h of recording, analysis could require another 2+ h. From a data processing perspec- tive, each night created a near-Herculean task. As laboratory minicomputers evolved in the 1970s, signal processing tech- niques held the promise of reducing workload and providing new perspectives to expand scientific horizons by automat- ing sleep analysis.

EEG characterization had already matured and automated spike detection, power analysis, and compressed spectral arrays dazzled onlookers. Signal analysis could character- ize ongoing EEG according to frequency, duration, and/or power. These indices could be grouped according to band- widths relevant to human physiology. The Dement–Kleit- man scoring system was particularly amenable to this ap- proach. Fourier transforms, period amplitude analysis,

13 The History of Polysomnography: Tool of Scientific Discovery

complex demodulation, and coherence analysis were some of the techniques applied. The text Principles of Neurobio- logical Signal Analysis by Glasser and Ruchkin [45] became a standard reference for some developers. Concerns about the details of aliasing, leakage, analog-to-digital conversion, multiplexing, cross talk, digital, and recursive filtering occu- pied the minds of programmers and engineers involved with PSG applications. Three issues reared up to impede progress of the completely digital analytic approach: artifacts, event detection, and technological limitations.

PSG Artifacts

The first, most important, and even now not fully resolved issue involves artifact recognition. An artifact is an electri- cal signal arising from activity other than that under study and may masquerade as potentially valid data. PSGs always contain artifact (at least I have never seen an overnight sleep study that was completely artifact free). Artifacts contami- nate data and can compromise analysis. Perhaps the earli- est adage popularized in computer sciences was “garbage- in, garbage-out” (GIGO). Undetected electrophysiological artifact represents garbage. Artifact can be biological or environmental; it can take many shapes and forms. While humans can (usually) easily detect artifacts, programmers must invent strategies and write code to recognize hundreds of possible scenarios.

Biological artifacts include blinking and eye movements masquerading as EEG waveforms, movement, and EMG ac- tivity contaminating EEG signals with high-frequency com- ponents, and heartbeat intruding into other bioelectric trac- ings. Other biological sources of EEG artifact include sweat- ing, twitching, coughing, teeth clinching or grinding, and shivering, to name a few. Environmental artifacts include electrode popping, alternating current (50 or 60 cycles per second) interference, and any other electrical signal in con- tact with the sleeping subject (for example, a pacemaker). Furthermore, each of these potential artifacts can manifest in dozens of ways, making automated recognition difficult and programming complicated.

Event Detection

Signal processing techniques mostly served to decompose electrophysiological data into its frequency components that could be expressed as duration or power. By contrast, specific event detection requires feature or envelop analy- sis. Spike detection came early on in clinical EEG but K- complex, sleep spindle, REMs, and slow eye movements lagged far behind. More importantly, some of these wave- forms defined sleep stages and have overlapping frequency signatures. Available laboratory computers had far less ca- pacity than today’s powerful microprocessors. Thus, some automation attempts approached signal detection using hy- brid analog–digital techniques. One of the great pioneers in

PSG computerization, Jack Smith, an engineering professor at the University of Florida developed the sleep-analyzing hybrid computer (SAHC). The SAHC contained specific analog waveform detectors whose output was compiled with a laboratory minicomputer. In later reincarnations, the detec- tors were interfaced with microcomputer systems.

Technological Limitations

Looking back on laboratory minicomputers, it seems amaz- ing that we were able to accomplish anything. What seemed like the frontiers of high technology now looks like stone knives and axes, in retrospect. Using assembly language (or sometimes compilable languages like FORTRAN II), limit- ed addressable memory space (sometimes only 64 KB), very expensive but quite limited overhead storage devices (Digi- tal Equipment Corporation (DEC) tapes, Diablo or Pertec 15-in. removable disk drives offering maybe 5 MB storage) PSG analysis systems were constructed, programmed, and used in large laboratories. These systems mainly analyzed research data; a particularly popular application involved de- scribing drug effects on sleep in great detail. The promise of automatic sleep stage, sleep apnea, and periodic movement scoring took much longer to reach fruition. Processing speed represented another major hurdle (which is why assembly language was used). Squeezing enough cycle time to process incoming signals was a challenge using OS8 and RT11 op- erating systems. More complex processing often proceeded offline by playing instrument-analog-recorded PSG data into computers (using Hewlett-Packard, Ampex, Sangamo, Hon- eywell, and other very expensive tape machines). Eight-bit laboratory minicomputers like the DEC PDP12, 8, Link 8, 8e progressed to 16-bit systems like the Texas Instrument 980, DEC PDP 11/03,/23,/38, and eventually VAX. Each inno- vation added power, speed, and storage capacity. However, upward migration was sometimes painful because assembly languages were not necessarily compatible which sometimes meant having to jettison software libraries and data as a sac- rifice to implementing more capable hardware.

Commercialization

By the mid-1970s, microcomputer began to appear in labo- ratories. Microcomputers could fit on a desktop (rather than take up the entire end of a room) and cost a fraction of the price. Microcomputers rapidly gained popularity both in the PSG analysis world as well as in all other work environments, becoming smaller and smaller and more and more powerful. By the time I retired my homebrewed original Imsai 8080 and Altair-MITS disk subsystem, IBM had entered the mar- ket with their “personal computer,” and commercial integra- tions for PSG applications had appeared. There was a tipping point sometime in the early 1990s where microcomputer

M. Hirshkowitz

systems reach adequate power at a low enough cost to be- come marketable. Improving software, programming video graphics, and integrating large and larger capability storage devices became imperative.

Oddly enough, the original systems mainly provided a technique for replacing paper. A single PSG was recorded, stored, and could be retrieved, viewed, and annotated on a video display. Automatic scoring was unreliable. The sav- ings in paper cost and paper record storage expense drove the market. Most paper PSGs recorded 30 s of data on one sheet of fanfolded paper. Thus, an 8-h recording required 960 PSG pages. Not accidentally, a box of paper had 1000 fanfolded sheets and usually measured 12.5 × 12.5 × 3.0 in. Thus, each night, our four-bed laboratory produced more than a cubic foot of paper to store. Ten nights would fill a file cabinet. Today, an equivalent number of PSGs would fit in my shirt pocket. The promise of automated scoring and expanding horizons of sleep science were temporarily forgotten.

Scaling data represented the other major advantage when reviewing digital PSGs. With paper, once recorded, the PSG’s temporal resolution is set and immutable. Digital PSGs can be viewed as a slow trace (2–5 min per page), at traditional resolution (30 s per page), or expanded (10 s per page). Some systems evolved to allow split screen display with differ- ent resolution for selected channels. Initially signal quality eroded but, in time, digital amplifier quality improved. Soon, trade journals, society newsletters, and exposition areas at annual meetings became crowded with digital PSG advertis- ing. Systems like CNS, Telefactor Sassy, Oxford Medilog SAC, Telediagnostic Vista, Melville Diagnostics Sandman, Biologic, Healthdyne NightWatch competed for space with positive airway pressure machines. Traditional pen-and- paper PSG systems were on their way out; eventually even Grass, Nihon Kohden, Nicolet, and TECA developed digital PSG systems.

The Rise of Home Sleep Testing

The most significant change for clinical sleep evaluation is happening right now. For 40 years, attended PSG dominated as the preferred technique for evaluating sleep apnea and/ or titrating positive airway pressure therapy. As previously explained, diagnosing sleep apnea is PSG’s “killer app.” The widespread recognition of sleep apnea as a significant medi- cal condition, paired with PSG’s billable current procedural terminology (CPT) code produced the meteoric rise of sleep medicine. However, economics are now driving the market toward finding a less expensive alternative; thus, the new “killer app” for diagnosing sleep apnea is becoming car- diopulmonary recording, also known as home sleep testing (HST) [46]. HST involves making overnight recordings of

airflow, respiratory effort, oxyhemoglobin saturation level, heart rate, and sometimes snoring sounds and EEG. Its only validated use is to verify the presence of sleep apnea.

HST technology is not new. It being recommended for first-line routine clinical use is! As with many new applica- tions, its proper use and limitations are poorly understood. As a tool, it has specific utility but improper use can be dangerous. Our group has used HST for many years and the three most important things we have learned are: (1) HST re- quires a full-scale clinical sleep program to be effective, (2) HST can rule-in but not rule-out sleep apnea, and (3) careful review to determine technical recording quality is absolutely essential. As HST can rule-in but not rule-out sleep apnea, only those patients with a high pretest probability based on signs, symptoms, and comorbidities should be tested. If in- dividuals for whom there is not a high clinical suspicion are tested, HST becomes an additional, ineffectual test. Follow- up laboratory PSG is needed in two circumstances. (1) Pa- tients with high pretest probability and negative HST require attended laboratory PSG. (2) Patients in whom HST con- firms sleep apnea but who continue to have sleep problems after the apnea is treated also require PSG to assess for other sleep pathophysiologies. Thus, PSG still represents the “gold standard” for evaluating sleep disorders.

Conclusion

A significant part of the sleep science and sleep medicine history coincides with the history of PSG. The polysomno- gram, born out of EEG, raised by psychophysiology, matured with clinical science, and ultimately became employed by sleep medicine. Amazingly, PSG continues to be our major tool for evaluating sleep and sleep disorders. Originally our analog amplifiers displayed bioelectrical activity by inking tracings on paper. Now, digital amplifiers record similar information on magnetic, silicon, and/or optical media that can be retrieved for display on flat panel screens. Although the recording devices and the display medium have changed dramatically in the past 40 years, how we apply this tool has not. Indeed, the scoring system has evolved somewhat with successive refinements but except for data-tracing scalability (which was not possible with paper recordings), the basic polysomnographer’s review process is remarkably similar to what it was 25–35 years ago. Does this mean the field’s pioneers had tremendous acumen and incredible insight con- cerning the immediate and future needs? Does it mean that PSG sufficiently met our needs? Or, does it mean that PSG has reached asymptote and is no longer progressing? This empirical question will be answered as history continues to unfold.

13 The History of Polysomnography: Tool of Scientific Discovery 99

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Coleman Coleman RM, Roffwarg HP, Kennedy SJ, Guil- leminault C, Cinque J, Cohn MA, Karacan I, Kupfer DJ, Lemmi H, Miles LE, Orr WC, Phillips ER, Roth T, Sassin JF, Schmidt HS, Weitzman ED, Dement WC. Sleep-wake disorders based on a polysomnographic diagnosis. A national cooperative study. JAMA. 1982;247:997–1003.

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46. Hirshkowitz M, Sharafkhaneh A. Comparison of portable moni- toring with laboratory polysomnography for diagnosing sleep- related breathing disorders: scoring and interpretation. Sleep Med Clin 2011; 6: 283–292.

Part IV

Sleep Medicine Societies, Professional Societies, and Journals

A History Behind the Development
of Sleep Medicine and Sleep Societies

Brendon Richard Peters and Christian Guilleminault

In considering the founding and development of the major sleep societies, it is useful to recall that the entire process is ultimately about people and the exchange of ideas. This “his- tory” is a personal (CG) one and its narrative is inspired by individuals who shared a passion and interest in advancing sleep medicine.

The first sleep society created was the “Association for the Psycho-physiological Study of Sleep” or APSS. It was created by William C. Dement as an informal society where individuals interested in the investigation of sleep could in- teract. At that time, there were no clear standards to score sleep and wakefulness in laboratory animals or in humans and there was the need to have a forum where ideas could be exchanged between researchers. Its initial members were few but it had an international representation. Individuals integrating sleep and circadian rhythms as well as those in- terested in sleep and dreams were involved. The early mem- bers included many enthusiastic individuals attracted by this new field of research, e.g., Michel Jouvet, Danielle Mounier, Allan Rechtschaffen, Eliot Weitzman, Howard Roffwarg, Michael Chase, Gerald Voegel, Laverne C. Johnson, Ro- salind D. Cartwright, Wilse Webb, Truett Allison, Ralph Berger, Frank Snyder, Ismet Karacan, Charles Fisher, Mil- ton Kramer, David Foulkes, Thomas Anders, Allan Hobson, M. Barry Sterman, Peter Hauri, Antony Kales, Walter Baust, Werner Koella, Pier Parmegggiani, Peter Morgane, Olga Petre-Quadens, and Ian Oswald. These participants helped develop structure and purpose for the group.

C. Guilleminault ()
Sleep Medicine Division, Stanford University Outpatient Medical Center, 450 Broadway, Redwood City, CA 94063, USA
e-mail: cguil@stanford.edu

B. R. Peters
Stanford Sleep Medicine Center, Stanford School of Medicine, Redwood City, CA, USA

In addition, there were specific places that quickly became important to the study of sleep and generated increasing in- terest and membership. In the USA, Chicago, New York, and Stanford became especially influential. Dement, work- ing at Stanford, the University of California, Los Angeles (UCLA) group, and the navy hospital in San Diego brought many individuals into the society. These members included the following: Vincent Zarcone, Georges Gulevitch, Jon Sas- sin, Ardie Lubin, Denis McGinty, Anna Taylor, and Ronald Harper. In Lyon, France, Marc Jeannerod, and Odile Benoit were brought into the fold. Not everyone was convinced, however, of the utility of binding common interests.

In particular, two individuals were missing from this ef- fort: Nathaniel Kleitman and Eugene Aserinsky. Much later, Nathaniel Kleitman explained his lack of involvement in this way when speaking with one of the authors (CG) of this chapter about rapid eye movement (REM) sleep, “this is the stuff of Dement.” The implication was that this was not his primary interest. Greater importance was placed on the un- derstanding of the sleep rhythms in general, with REM sleep being only one of them.

There were clear divisions of interest within sleep. There were a large number of individuals interested in the elec- trophysiology, pharmacology, and cellular mechanisms of sleep. Still others were more focused on “sleep and dreams.” Some people pursued the interactions between seizures and sleep or on other brain disorders and sleep. Finally, there was a small group who was interested in the development of sleep from infancy to childhood. Many times it proved difficult to unite these divergent interests into a common set of purpose and agenda. It became clear early on that it was necessary to develop a common language when considering sleep in humans. Moreover, it was critical to “codify” the electroencephalography (EEG) changes seen when monitor- ing the brain, in either animals or humans. One of the major early accomplishments of this heterogeneous group, brought together in part by Dement, was the creation of two sleep atlases that are still used today. This was no small feat.

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_14, 103 © Springer Science+Business Media, LLC 2015

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In order to develop these standards, numerous initial ob- stacles had to be overcome, including differing techniques and equipment. In North America, the standard equipment used to investigate sleep was the “Grass recorder.” In Europe, where sleep was part of the tools used by clinical neurophys- iologists in their search for seizure disorders, the most com- mon recorder was the AlvarTM equipment. Even the speed at which the paper moved through the equipment varied. In general, a large amount of recording paper was needed to study sleep, but the goals were often different. EEG special- ists wanted to see many EEG leads at a fast speed. However, individuals investigating “sleep and dreams,” or the body phenomena associated with sleep onset, were more parsimo- nious with paper. They wanted to recognize non-REM and REM sleep as well as other phenomena. The basic record- ing speed was 20 s per epoch in western Europe and 30 s per epoch in the USA. Compromise was eventually reached, but only after individuals committed to their interests were involved (sometimes following heated battles).

One hard-working individual was Dr. Dreyfuss-Brissac in the Port Royal Maternity Hospital in Paris. She was involved in continuous monitoring of premature and newborn infants. She also had an integral role in educating a large number of infant sleep researchers in western Europe. She faced off with Dement who was looking to understand REM sleep in humans and the possible use of sleep recording to investigate psycho-physiology and the role of sleep, and particularly REM sleep deprivation, a research topic far separated from an understanding of the development of sleep in premature infants. These had been quite divergent goals for many years. In Europe, many more EEG leads than in USA were used in monitoring, reflecting very different agendas of the sleep re- searchers. To their credit, these individuals ultimately knew how to compromise and were able to join efforts to set mini- mum standards and create a work that is still today the basis of human sleep recording.

The informal gathering of the early APSS became more structured with advancing years. Dement was always a driv- ing force behind this group, pushing the development of the field. He understood that there was the need for a uni- fied front if basic sleep research were to gain a foothold in the National Institute of Health grant funding. Cohesion and growth were central in his view to advance the field of sleep research. The presentation of scientific results in front of peers, as is the standard in many other fundamental re- search fields, was the only way to have recognition of sleep as a valid, independent, scientific field. Dement had many friends who joined him in these efforts, but two were impor- tant at this stage: Allan Rechtschaffen and Michel Jouvet.

Both Dement and Jouvet were fascinated by REM sleep and were dedicated to understanding its mechanisms as well as the development and maintenance of the state of alertness.

Both gave the impression of being “REM or paradoxical sleep scientists.” They both had great mutual respect for each other’s work. Jouvet would come and visit Dement regularly in the basement of the Stanford anatomy building where cats and mice were continuously monitored. They exchanged data and discussed hypotheses. As funding was still difficult for sleep research in France (even though Jouvet had a much more luxurious university setting compared to Dement), De- ment played a critical role in supporting Jouvet on a project submitted to the US Air Force. They also jointly supported the advances presented at the now yearly meetings of the APSS more than any other scientists in the field.

The APSS was still a young society with little formal activity between annual meetings. The organization of the meetings that did occur was thus vitally important. It was coordinated by senior investigators and always located in the USA. The cost of travel was still high for the Europeans and Japanese, who were the two major groups joining the research efforts on sleep. In 1970, the USA was in the mid- dle of an important crisis related to the war in Vietnam. The APSS annual meeting was scheduled to be in Santa Fe, New Mexico in the mid-spring. Snow was still on the surrounding mountains, but the sun was everywhere in the small town. The meeting occurred in a room that could contain about 150 people. Many were young college students taking a year off to do research as pre- and postdoctoral fellows. The APSS had succeeded in attracting young individuals securing its chance to survive over time. The Dement group was the larg- est with Stephen Henricksen, James Ferguson, Eric Hoddes, as well as young associates from Jack Barchas’s biochem- istry laboratory and the neurophysiology laboratory of Dr. Chow. There were foreign scientists, not only Jouvet and Olga Petre-Quadens but also Swedish scientists, particularly K. Fuxe and Anita Dahlstrom indicating the extension of their interest in the field of sleep research. It was decided that the next meetings would be held internationally every 5 years opening opportunities for foreign young scientists to come and listen to the senior researchers from other parts of the world.

The first meeting abroad was in 1971, organized by Dr. Olga Petre-Quadens. Though held in Belgium, it was not in Brussels, but in the city of Bruges, a somewhat smaller place and a tourist attraction. For the first time, there was a book published out of the meeting, The Sleeping Brain. The orga- nizing committee included Walter Baust, Carmine Clemente, William C. Dement, Laverne Johnson, Michel Jouvet, An- thony Kales, Werner Koella, Toshioko Tokirane, and Jolyon West. Olga Petre-Quadens was the local host and new figures were involved in the program, including Ronald Harper and Barry Jacobs. Frederic Bremer and Nathaniel Kleitman were named the two “honorary presidents.” Bremer wrote that this first international meeting of the APSS “marks the date when

14 A History Behind the Development of Sleep Medicine and Sleep Societies 105

sleep research became a discipline into itself.” Nathaniel Kleitman was less enthusiastic about the accomplishments, writing, “The topic of the ten symposia…are representative of the current concerns of investigators that are interested in the understanding of the processes underlying sleep and wakefulness.” He added, “Future sleep research may lead to the elucidation of the mechanism of wakefulness, as well as that of sleep.” His remarks reflected his belief that the field was missing the real goals. It was also at this meeting that for the first time the role of computers in sleep research was approached with timidity. These efforts were led by Antoine Remond of France and Jack R. Smith of Florida. In addition, Mary Brazier championed the potentially incredible role that computers could play in EEG analysis, but she was not in- vited.

It was also at this meeting that two very different groups met for the first time: the European neurologists who had studied disorders of sleep within the context of neurologi- cal disorders and the US-based “sleep researchers” who had created the APSS. The scientific symposium was organized under the guidance of Roger Broughton who had been a stu- dent of Henri Gastaut (the individual who could have created the field of sleep medicine, but did not believe in it). Elio Lugaresi, Alberto Tassinari, Pierre Passouant, and Bederich Roth represented European neurology. They did not see a new field, but rather a subdiscipline of neurology, an error that pulmonary specialists repeated later on after investiga- tion of the sleep apnea syndrome. Despite their support for the investigation of the brain during sleep, it was clear that it was viewed as only a small part of neurology, the “noble sci- ence,” and not a new field. Ten years later, Elio Lugaresi was invited to another international sleep meeting where he in- dicated his strong views on the subject in a conversation in- volving Dement and Guilleminault, stating, “Do you realize that you are making me a simple sleep researcher, when I am a Neurologist?” Clearly, following Gastaut, most of the fa- mous neurologists did not want the label of “sleep research- ers.” What was sleep when you were the head of the Neuro- logical Institute? Sleep was viewed as a minor segment of neurology. Two years later, Pierre Passouant expressed the same views when he decided to send Michel Billiard for one year to Stanford; sleep was to be part of a great neurology department. Such philosophy persisted in Montpellier until the second millennium. The term sleep department never emerged, but the sleep laboratory (probably one of the larg- est in Europe for a long time) was part of the department of neurology of the Montpellier Medical School in France. In some respects, the first international APSS congress dem- onstrated the isolation of the few individuals who wanted to create a new research discipline, a primary goal of the APSS. In addition, the European neurologists realized that there was a complete absence of the concept of a clinical discipline, and that the APSS was essentially an American-based sleep

research society including PhDs with little clinical interest or expertise. And, at that time, none of the senior members of the APSS were interested in clinical sleep medicine.

One individual (CG) had a very different view. He attend- ed the 1970 APSS meeting and had decided that there was a new discipline that he called sleep medicine. CG opened a sleep medicine laboratory in La Salepetriere Hospital, against the desire of his chair and dean. Through contact with his contemporary colleagues who also had just finished or were finishing their residencies, CG monitored adults and children from different departments, including internal med- icine, metabolism and endocrinology, and pediatrics. He was effectively alone, having only the help of young individu- als he taught such as interns and medical students. The only professional support was from his direct colleagues that he had spent the past 4 years with in that very large hospital in Paris. He was financially supported by a one-year grant from the “Societe Medicale des Hopitaux de Paris.” In June 1971, he attended the first international meeting in Bruges and the future did not look promising; the same head of La Salpetri- ere neurology department was not supportive of his venture, despite the fact that the laboratory had been a success with more than 400 sleep medicine patients monitored in a two- bedroom EEG laboratory. During a lunch break with Vincent Zarcone, who was doing alcohol and sleep research at the Palo Alto VA Hospital and who also worked at the animal sleep laboratory of Dement, CG expressed his views and his belief in a new specialty called sleep medicine. Return- ing to California, Zarcone learned that Dement wanted to secure a large grant to investigate narcolepsy as a disorder of REM sleep incorporating both animal and human research for a better understanding of REM sleep. Neurologists were not interested as it was mostly a low-paid research position based on a grant. Zarcone suggested that Dement should contact Guilleminault, which he did in August 1971. Guil- leminault was initially not very interested, considering the conditions and the focus on only narcolepsy and not on sleep medicine, including adults and children. As his situation de- teriorated in France within the following four months, Guil- leminault agreed to go to Stanford and arrived on January 4, 1972, to take the position and participate in the write-up of a very large grant on narcolepsy. He succeeded in includ- ing 10 pages (out of the 300 of the total grant) on breathing and heart monitoring in adults and children. The grant was funded and most of the next three years were used to perform the work outlined in those 10 pages.

Meanwhile, Anthony Kales at UCLA had opened a human sleep and pharmacology unit and was performing research for the pharmaceutical industry, testing the effects of hypnotics on sleep of normal volunteers and insomniacs. Dement saw a way to support basic research through simi- lar funds from pharmaceutical research. The Dement labo- ratory had most of its research focused on animal models

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and on narcolepsy as a disorder of REM sleep. There was a postdoctoral fellow, Terry Pivick, who was doing a research project on sleep in pregnant women, monitoring them in the medical center in a two-bedroom laboratory. Recruitment for pharmacological studies on insomnia was also happening there. It was decided that studies on narcoleptics would also be performed in the same place. The recruitment of patients complaining of insomnia quickly expanded to include vari- ous sleep disorders. A young neurologist, Dr. Robert Wil- son, doing a year of fellowship was there to help, and CG pushed forward with his idea to develop a sleep disorders clinic. Pursuing his own interest, CG went to the Veterans Administration Hospital to work in collaboration with pul- monary medicine (Dr. Fred Eldridge, the senior researcher) and cardiology (Dr. Ara Tilkian, a fellow in cardiology). He attracted the interest of the head of the pediatric intensive care unit (ICU; Dr Philip Sunshine) whose office was just opposite the two-bedroom sleep laboratory, in referring in- fants and children for monitoring and evaluation of sleep complaints. Adding the information collected in Paris to that gathered at Stanford, new findings became apparent and CG was able to present these at an international meeting orga- nized by Elio Lugaresi on Pickwickian syndrome and hy- persomnia. Guilleminault and Dement had many discussions on the possibility of creating a clinical service where money would be obtained for services and tests. But at the 1972 APSS meeting, the presentation of clinical results fell mostly on deaf ears. The society was much more focused on funda- mental research and not interested in any clinical endeavor. William Dement was himself somewhat ambivalent: phar- maceutical research was very different from the creation of a clinical field. For many years, the goal of advancing sleep research would be the primary concern for Dement, and the goal of creating a clinical field of sleep medicine remained primarily with Guilleminault. Nevertheless, these two goals were complementary to ultimately create a specialty of sleep medicine, establish a sleep center at the National Institutes of Health (NIH), and have a medical board recognized by Edu- cational Council for General Medical Education (ECGME). Before any of these achievements, it became quickly appar- ent that the APSS was not the avenue to create such a clinical field. In fact, many participants were outright opposed to it. The senior members of the APSS were already appointed to faculty positions within well-established departments, and there was no reason to disrupt this well-organized order with a well-established line of advancement and research support. The only individuals who could be interested were young individuals who were not established and thus had nothing to lose, or good friends who wanted to change careers and aim for something different.

In order to secure fee for service, the field needed a well- defined test. Guilleminault proposed to perform nocturnal sleep recording and 24-h sleep recording for individuals

with excessive daytime sleepiness. There was the need for a name and Jerome Holland, a retired psychiatrist tapped by Dement to help with administrative issues (particularly with California insurance companies), came up with one. He coined the name “polysomnogram” in 1974. Shortly there- after at a meeting, Jouvet jokingly indicated that this new field of sleep medicine started with the demonstration of il- literacy, as it should have been either “polyhypnogram” or “multisomnogram.” Nevertheless, the name stuck, and it was subsequently recognized and placed in insurance books and thus was not changed in the future.

The resistance to establishing sleep medicine as a field within the APSS body extended to rebutting the suggestion of creating a journal supporting the field. Michael Chase, representing the majority opinion, responded that there was no need for a new journal, as all the good articles were published in neuroscience or physiological journals. Such a move would be detrimental to the recognition of the field of sleep research in neuroscience and in funding research grants. There were many further discussions between De- ment and Guilleminault, the latter indicating that there would be no long-term future for sleep research in the medical field if there was not a strong medical service and patient care unit behind it. Things seemed to be at an impasse. Regardless, the Stanford sleep clinic was slowly growing. There was also a unit led by Antony Kales at UCLA. In addition, Ismet Kara- can was doing a patient-related service using nocturnal sleep recording to differentiate organic from psychogenic impo- tence, and this was paid by insurance companies in Texas.

Around this time, Eliott Weitzman, a good friend of De- ment, was found to have a hematological cancer and the number one treatment place in the USA for this malady was Stanford. He came on sabbatical to the hospital and became interested in the sleep service. Weitzman also worked with a Stanford medical student Charles Czeisler, who was very much interested in the integration of sleep and circadian rhythms. Further, Weitzman decided to leave Montefiore Hospital and join Cornell University where very large, new sleep research facilities were built. Volunteers could live in isolation from day–night cues and the interaction between circadian rhythms and sleep–wake cycles in normal and pathological conditions could be investigated. Concurrent- ly, there was the beginning of a feud between Dement and Kales about short- and long-acting benzodiazepine hypnot- ics and support from the pharmaceutical industry. This feud was never resolved and lasted a long time. Ultimately, Kales moved from UCLA to Hershey, Pennsylvania and with his students created a separate society related to sleep and its disorders that ended with his retirement.

The only way to advance the medical arm of sleep re- search was to create an association of individuals interested in the clinical aspect of sleep. There were many people who would clearly participate, including Howard Roffward and

14 A History Behind the Development of Sleep Medicine and Sleep Societies 107

Eliott Weitzman, Ismet Karacan, Peter Hauri (at Dartmouth who was interested in insomnia), Milton Kramer and a young PhD, Thomas Roth, working in his department. All told, there were about five or six centers that would join, enough to create an official association. There was also a need to cultivate support outside of research, including political in- fluence in the evolving health care system. The efforts at Stanford could raise the standards of clinical service and de- velop research clinical protocols, but there was also the need to face insurance companies and to gain support from many quarters, including the Congress people in Washington, DC. This latter role was nearly exclusively fulfilled by William Dement. Young medical graduates and specialists were the most enthusiastic about the potential opening of a new clini- cal field. One of these recruits was Helmut Schmidt, who was trying to set up a sleep disorders unit in the department of psychiatry at Ohio State University. As most sleep disor- ders at this time included insomnia which was addressed by psychiatrists, David Kupfer was also a choice recruit for the field. As these clinicians sought inclusion in the APSS, there was resistance by members within the USA who were basic science researchers.

In 1975, there were frequent meetings at Stanford and De- ment was going regularly to the East Coast. Overall, numbers were still low, but there were more and more places where clinical sleep disorder patients were being seen. It became evident that it would be possible to join these efforts to raise funds and advance the clinical field. There were also discus- sions on the recruitment of more members. One individual, Roger Broughton, who had trained with Henri Gastaut, be- came involved. Coming from the Canadian health system, he did not see the problems in the same way. In fact, the only questions and opposition to diverse proposals seem- ingly came from him. But he also supported the creation of a broader society. Finally, in the winter of 1975 in Chicago, the decision to create a new society called the Association of Sleep Disorder Centers (ASDC) was voted upon. Once passed, there was the need to write bylaws and formalize the society. Initially, there were only five centers that could pay dues, but this was the beginning of clinical sleep medicine.

Early in 1976, the society began to function with William Dement as president, Eliott Weitzman as vice president, Mer- rill Mitler as secretary (a crucial role as raising funds was a key issue), and two members at large, Peter Hauri and David Kupfer. One of the urgent goals of this society was to gain recognition of sleep specialists who could be reimbursed by insurance companies under a fee-for-service arrangement. Discussions indicated that there was great concern within the business community that anybody could bill for a “sleep work-up.” One of the first decisions of this new society was to form an education committee in charge of developing a recognized body of knowledge. This would be outlined in a formal textbook and would include the procedures to be per-

formed by the specialist. In addition, a method was created for practitioners to demonstrate competency. Guilleminault was selected as head of this committee and within a year there was a subcommittee in charge of examination headed by Helmut Schmidt.

There was a need to employ an examination for certifi- cation quickly. Materials were gathered, including tests and recordings previously prepared by Mary Carskadon to test graduate students who had training with her to help in a very large project at Stanford, called sleep camp. In addi- tion, recordings performed at Stanford and Cincinnati, Ohio, were used by Thomas Roth to prepare the first examination. This was administered at Stanford by Thomas Roth, Helmut Schmidt, and Christian Guilleminault. Ultimately, the task of developing a professional examination was given to Helmut Schmidt. He engaged the help of developers involved in the board examination for neurology and psychiatry located at Ohio State University. As a result, for the next 12 years the examination would be administered in Columbus, Ohio.

With a long-standing history, sleep medicine also contin- ued its development in Japan. Early contributors included Dr. Kazoo Azumi, who had spent months at Stanford University in late 1960. Dr. Y. Hishikawa was a neurologist from Osaka University and in the late 1960s he traveled via the trans-Si- berian train for days to go to Europe and visit Henri Gastaut and Elio Lugaresi who represented clinical neurology and sleep research, particularly related to sleep and epilepsy. In the early 1970s, he studied overweight, Pickwickian-type patients, and reported on the abnormal breathing observed during sleep. He was one of the participants at the Bologna Symposium organized by Elio Lugaresi on hypersomnia in Pickwickian syndrome. Basic researchers in Japan were very much influenced by Michel Jouvet, and many of them went to spend time in his research laboratory. There was not a formal society dedicated to sleep, however, with most indi- viduals belonging to neurophysiological and neurologic so- cieties that had sleep sections. Nevertheless, sleep research was much developed in Japan, and Japanese researchers had gone to the APSS meetings from the very beginning. Armed with a strong interest in fundamental and clinical sleep re- search combined with contacts in major research centers in Europe and USA, Japan became the place where major advancements occurred. The association between human leukocyte antigen (HLA)-DR2 and narcolepsy–cataplexy was first described by Juji and Honda. What later became known as REM behavior disorder (RBD), was first described by Tachibana et al. and Hishikawa et al. as “stage 1 REM” and “dissociation of REM sleep.” In the context of this rich environment, a formal Japanese sleep society was created.

With a typical Japanese twist, the officers of the society were very senior individuals, reflecting the respect of elders integral to the more formal Japanese society. William De- ment sought assistance, including financial support, from the

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Japanese laboratories and clinical sleep researchers for the new clinical sleep society. He contacted Dr. Azumi to see what the potential involvement of the Japanese specialists could be. The Japanese were surprised by the inquiry, but the individuals involved in the new ASDC were very well known by their Japanese counterparts, and nobody wanted to abruptly reject the offer. The Japanese scientists responded by asking for a visit to Japan by a member of the group. Dement, who traveled extensively within the USA, was un- comfortable traveling abroad and ruled out going to Japan. He suggested that Guilleminault go in his place as an envoy. Considering the age differences and the structure of the Japa- nese society at that time, this was probably a poor choice. Nevertheless, the Japanese scientists accepted the envoy.

Guilleminault planned to go before the Christmas season in 1975. He intended to meet with the scientists and spend the official Christmas vacation visiting Japan in winter. However, the Japanese scientists were faced with a difficult decision. They wanted to have the presence and involve- ment of all the senior members working in sleep, indepen- dent of their primary specialty. Upon arriving, the envoy was informed that a response to the proposal would not be given as planned. Instead, it would have to wait until after the ceremonies associated with the first of the year in Japan. A formal meeting was organized on January 5. There were about 50 individuals invited to a formal dinner. The response was that the Japanese sleep researchers would not support the new society, but that they would like to organize the 3rd International APSS Meeting or an equivalent international meeting to present Japanese sleep research to the world. This congress would prove to be the last international meeting of the APSS. It was held in Tokyo in July 1979. Yashuo Shima- zono was president, Teruo Okuma served as secretary, and Kazoo Azumi was in charge of local accommodations. The Japanese Sleep Society further grew and led to the creation of the regional sleep society called the Asian Sleep Society, keeping for years the presidency of the regional sleep society and supporting it financially.

Although the APSS had been very indifferent to the ef- forts toward a clinical field, having voted down the idea of having a journal representing the field with clinical articles in 1974, things began to change. Between this vote and the second international meeting of the APSS held in Edinburgh, Scotland, in 1976 with Ian Oswald as the local host, new developments happened in Europe.

A group led by German-Swiss researchers organized a mostly European congress on the “Nature of Sleep” in Wurzburg, Germany in September 1971. Dr. Uros J. Jova- novic was the local host and Professor Werner Koella, who had left his US university position to go back to Switzerland and work in part for Ciba-Geigy and the University of Basel (Switzerland), was the central figure. The majority of the participants were German, but clinical groups not belonging to the APSS, for example, the Italian and French constituen-

cies of the European clinical neurophysiology society were also present, and they were very much involved in the clini- cal syndromes associated with sleep. Science was presented, but there were also political decisions made, including a large push to organize a European society. This initiative was particularly emphasized by the German group led by Koella and Jovanovic. The society was not created at the meeting, but seeds were planted, including establishing a more clini- cally oriented focus compared to the APSS. And, within a brief period, a European Sleep Research Society (ESRS) was eventually formed from this initial effort.

These movements in Europe had some consequences, in- cluding the creation of a new sleep journal. The Germano- Swiss group that had grants from the pharmaceutical com- panies decided to create a journal representing the field of sleep called Sleep and Wakefulness with Dr. Uros J. Jova- novic from Wurzburg, Germany as editor-in-chief. The first issue was published in 1976 before the international meeting in Scotland. There was a strong opposition to this journal as it was created without any input from the APSS and it had received clear support from the pharmaceutical industry. At the next meeting, this new development was hotly discussed, and the APSS voted to reverse its prior position to support a journal. The membership was not really convinced, refusing to support the journal by having their dues in any way used for it or to publish an abstract of the yearly meeting as there was a prior agreement with Michael Chase and Brain Infor- mation Service to do so. Moreover, nobody wanted to be in charge of this new journal.

In this context, there was a reunion of the APSS board members and the executive committee at the international meeting. Some expressed the view that the Europeans were responsible for the existence of the other journal and they should take charge now. Ian Oswald was selected by consen- sus as the best candidate for the position of editor-in-chief and he absolutely refused. Dement asked Guilleminault, “Would you take the job?” Guilleminault believed that a clinical field needed a journal where advances could be presented. He also believed that it could be used to show outside individuals and organizations that there was a body of knowledge that directly supported the field. He agreed to take the job.

There was then a closed-door meeting of the senior mem- bers of the APSS. About one hour later, while Guilleminault was drinking beer in the hotel bar, a small delegation of the APSS council, including Laverne Johnson and Dement, ar- rived. They conveyed his selection as editor-in-chief of the new journal. The financial issues related to the journal would be handled by Dement. Unfortunately, there was no budget to support the journal and no financial commitment from the society, just the right to indicate “sponsored by the APSS.” Soon thereafter there was also an agreement to have the sponsorship of the ASDC, with the same conditions as the APSS. Any formal plan had to be approved by the executive committees of the two societies before going ahead.

14 A History Behind the Development of Sleep Medicine and Sleep Societies 109

Between this nomination and the publication of the first issue, there was a full year of setbacks and continuous ef- forts. No publishing company wanted to publish a journal that they did not own or where the associated societies did not give some financial support from annual dues or re- quest member subscription, even with reduced fees. Nego- tiation with all major publishers ended negatively. Elliott Weitzman knew a recently created and aggressive publish- ing company named Raven Press. The publisher was willing to take the risk and leave ownership to the society, but had a specific request: The journal would be quarterly initially and the first issue would be published only when the content of the first four issues had been received by the publisher. The articles must have been reviewed not only for content but also for grammar by the editorial office, and galley proofing would be done by the editor’s office only after receiving back galley proofs from the authors. This required an edito- rial assistant in the editorial office, with no funding from anywhere. Dement, who remained in charge of finance for the journal, and Guilleminault met several times with the publisher. These meetings were always very difficult with great disagreement between the publisher and Dement. The publisher finally agreed to support a portion of the salary of the assistant, but refused to go any further. After a par- ticularly difficult meeting, with refusal by the publisher to pay for an electric typewriter for the editorial assistant, there was a complete severance of communication between the two individuals, and the two persons never met face to face again leaving Guilleminault as the “go-between” on all fi- nancial issues.

In spite of this turmoil, the journal came to life with four issues in the hands of the publisher by the fall of 1977. This was due in large part to the help of the managing editor at Raven Press, Ms. Charlotte Fan. She was the wife of a well- known professor of neurology in New York and she under- stood the potential of the field and the research behind it. She gave a very helpful and diplomatic hand to the journal with the additional editorial assistance of Ms. Mary Smith who spent many unpaid hours to “translate” into English many valid submissions from foreign researchers. The creation of the journal and the adherence to scientific excellence helped to reinforce the goals of the ASDC. Progressively, members of the APSS gave more attention to this instrument of the field, despite the fact that for many years there remained no official support. In fact, for two years the legal ownership was in the hands of Guilleminault and Dement as “sponsor- ship” was not even legally approved. With the election of Pierre Passouant as the second president of the European society and Michel Billiard as secretary of the ESRS, the ESRS became one of the three societies sponsoring the jour- nal Sleep. This persisted until the creation of the Journal of Sleep Research, the official journal of the ESRS, with the first publication in March 1992 with Dr. J. A. Horne as first editor.

The development of the APSS and ASDC and the contin- ued expansion of the field led to the founding of the Southern Sleep Society in 1978. Ed Lucas and Helio Lemmi served as the first officials. Ed Lucas had spent a sabbatical time at Stanford and Helio Lemmi was one of the early members of the ASDC with a sleep disorders center in Memphis, TN. Many of these individuals, while originally from abroad and working in the USA, served as beacons for the development of sleep medicine throughout the world. Dr. Lemmi remem- bering his origins, often received fellows from Brazil who would spend a year in his center learning about sleep medi- cine. Similarly, Dr. Ismet Karacan always had numerous Turkish physicians involved in sleep research. His legacy included the founding and development of the first Turkish sleep society, originating from the sleep laboratory created by his students in the Neurological University Department in Istanbul and Dr. Sergio Tufik after his time in Memphis with Dr. Lemmi was quite prolific and he went on to create the de- partment of psychobiology of the Federal University of Sao Paulo, the Sleep Institute (Instituto de Sono) in Sao Paulo, the regional Latin America Sleep Society, and the Brazilian Sleep Society, where he was reelected president for many years.

After his own reelection several times over as president of the ASDC, William Dement saw materialization of his ef- forts to create a sleep center at the NIH signed into law by President Bill Clinton in 1993. By this time, the two major branches of sleep medicine had moved much closer together and there was a need to unify the efforts. The Association for the Psychophysiology Study of Sleep, representing a large number of fundamental researchers, became the Sleep Re- search Society. The ASDC became first the American Asso- ciation of Sleep Medicine and, a short time later, the Ameri- can Academy of Sleep Medicine.

During this time, national sleep societies burgeoned all over the world. An important one was the Australian sleep society, championed by a charismatic individual who died too soon to see the success of his efforts, Dr. David J. C. Read. He made Australians realize that there was a field in which they could play a major role. His interest was not met without its own resistance.

In 1977, Guilleminault and Dement wanted to organize a meeting on the sleep apnea syndromes. Guilleminault want- ed to differentiate these from the Pickwickian syndrome and the obstructive sleep apnea (OSA) associated with this obe- sity-related syndrome, well reported previously at the 1972 congress in Rimini, Italy. The Krock Foundation, after hesi- tation and one rejection, agreed to sponsor a “small meeting” with a limited number of participants at its facilities in the Santa Ynez Mountains of California in July 1977. Dr. David Henderson-Smart, involved in pediatric research, was the individual selected to attend from the department of physiol- ogy in Sydney. From the same department, and with a great interest in the subject, Dr. Read asked if he could come at

110

B. R. Peters and C. Guilleminault

his own expense to participate in the meeting. The admin- istrative arm of the foundation initially refused, but under pressure from the organizers finally accepted. Unfriendly provisions were made; however, including the request that Dr. Read come only at the time of the presentations and then promptly leave the premises to go to a motel, miles away and not involving the foundation in any way. Dr. Read agreed to these negative conditions and came on the morning of the first day. However, after the head of the foundation Dr. Rob- ert L. Krock and his head administrator Dr. Peter Amacher met him, they were immediately impressed by his brightness and social skills. By the end of the first day, he had received a personal invitation from Dr. Krock to stay and had the most luxurious room of all the participants. By the end of the con- ference, when the official photo was taken, in the front row sat Amacher, Krock, and Read indicating the social skills of Dr. Read.

Dr. Read strongly believed that the field was ripe for im- portant advances and he wanted Australia to be very much involved. He had many substantive conversations during the 1977 conference and asked to host the next meeting in Syd- ney. This assured that Australian sleep researchers would be centrally involved in the organization of the conference. He had sent young researchers, including Drs. Colin Sullivan and Berthon-Jones, to work in Toronto with Professor Eliot A. Phillipson in sleep. He assured leaders in the field that there were many other individuals interested in the field. As a result, in 1980, Dr. Read welcomed researchers from all over the world to Sydney in a brilliant reunion that strongly estab- lished the interests of Australia in sleep research. Unfortu- nately, he died of a rare, untreatable cancer shortly thereafter, but he had started a movement that led to the establishment of a strong society. His superlative social skills were greatly missed in time to come as dissention grew between more senior and very productive researchers.

Another individual responsible for the creation of a strong presence of sleep medicine was Professor Xi Zhen Huang from the department of pulmonary medicine in Peking Union Hospital at Beijing University in China. Dr. Huang came to Stanford’s sleep center in 1986 to study sleep medi- cine and spent both days and nights doing the tasks of physi- cians and technologists alike. She enchanted the entire clinic with her Chinese cooking and her continual search for novel ideas to bring back to China. In the medical field, exchanges with China were still rare at that time, but Dr. Huang was determined to create a new field. Upon her return to China, she immediately opened a service at her hospital and began training many individuals coming from all over China. She came from a very different province than the capital, and kept her accent when speaking her language, but her enthu- siasm was tremendous. Even into her early 80s she was still recently presiding at international meetings bringing sleep researchers to China.

The first society created was the Chinese Sleep Research Society that was established in 1994. But this society’s members were doing more fundamental research and the sleep-medicine field was attracting attention from different specialists. Each specialty began pushing the development of the field and created more focused educational programs. One of these very successful and important programs was led by otolaryngologists, most particularly by Professor Denim Han. He was also president of the otolaryngological institute within Tongren Hospital at Capital University in Beijing. These influential individuals were involved in congresses on specialties within sleep medicine, bringing foreign spe- cialists to China and educating young individuals. There was also the creation of clinical sleep societies, including the Sleep Assembly of the Chinese Thoracic Society in 2000 and the Sleep Assembly of the Chinese Neurologic Society in 2010. But realizing the danger of segmenting the field, under the leadership of Dr. Fang Han from Beijing Univer- sity, the Chinese Sleep Research Society decided to unify all parties. Fundamental and clinical researchers as well as sleep medicine practitioners were brought together under one large roof, with the first newly styled meeting in 2012.

In Europe, several national societies were created early on, largely due to the efforts of one individual in each coun- try. Dr. J. Herman Peters in Germany was one of these indi- viduals. He had done physiological work and public health studies looking at train drivers and their risk of falling asleep during nocturnal duties. He worked in internal medicine and within the subsection of pulmonary medicine. The head of the department of medicine at the University of Marburg was Professor P. von Wichert. He let Dr. Peters develop a research and clinical service oriented toward sleep and pul- monary medicine, with great attention paid to OSA and the associated cardiovascular complications. Given that OSA had first been described in Germany in Pickwickian patients by Jung and Kuhlo, it should not have been unexpected that it attracted the attention of German specialists. Germany also had clinical electrophysiologists that had done sleep re- search, particularly on narcolepsy. Germany had also had a strong involvement in the creation of the ESRS. Dr. Peters attracted a faithful following of young specialists with in- terests not only in pulmonology but also in cardiology and surgery. Marburg became the first place where maxillo-man- dibular advancement for OSA was performed in Europe as an example. It was also the first place where electrical stimu- lation of the hypoglossal nerve was done. Individuals includ- ing Thomas Podszus, Thomas Penzel, Riccardo Stoohs, and Hartmut Schneider were active in research while completing their specialization in internal medicine by working in the sleep center, headquartered in an old military—style house called “The Barrack.” Professor von Wichert was not com- pletely sold on the integration of sleep into his internal medi- cine department. He came to visit the Stanford Sleep Center

14 A History Behind the Development of Sleep Medicine and Sleep Societies 111

and, after his visit, Guilleminault received a Humboldt grant to spend 12 months in Marburg in 1989. Unfortunately, Dr. Peters broke several vertebrae while skiing during the win- ter, limiting the interaction between these two individuals. However, Dr. Peters always envisioned a strong sleep medi- cine service and desired to unite the specialists involved into one society. This included not only colleagues in pulmo- nary medicine but also neuropsychiatry, such as Professor Meier-Ewert, and physiology, such as Professor Marianne E. Schlake. In many ways, Dr. Peters had the same politi- cal acumen as William Dement; he understood that support was needed from everywhere, including the state insurance and the federal government. He fought hard to obtain such support. His efforts resulted in a very strong German sleep society. This was the first national society to have a well- read journal, Somnology, that became the official journal not only of the German sleep society but also of the Austrian and Swiss sleep societies. Unfortunately, cancer forced Dr. Peters to depart the scene early to fight another battle. Nev- ertheless, he had created a strong field in his country with a wide-reaching influence. His students including Drs. Ricca- rdo Stoohs, Hartmut Schneider, and Thomas Penzel became internationally well-known sleep medicine specialists work- ing beyond Germany.

Another individual in Europe who was behind the build- up of a national sleep society was Dr. Markku Partinen in Finland. He had trained in part at the Montpellier Medical School in France and had been in the neurology department headed by a well-known French sleep researcher, Professor Pierre Passouant. He also spent over a year at the Stanford Sleep Clinic. After returning to Helsinki, he decided to put sleep medicine on the map of his country. He had Christian Guilleminault visit for some months to provide guidance. He also had the help of Dr. Olli Pollo in Turku, Christian Hub- lin, and Tina Telakivi in Helsinki. They also had a dedicated group of young specialists interested in the field. One of the first efforts of the Finnish Sleep Society, supported by the Sillampaa foundation, was the organization of a large inter- national symposium on Sleep Disordered Breathing in 1989, showcasing the strength of the Nordic research.

Early in the history of sleep medicine, many societies were created throughout the world under the efforts of only a handful of individuals, some working in isolation and under duress. These efforts persist to this day as sleep medicine gains footing throughout the world. Rene Druker Colin in Mexico had the support of his old colleagues at UCLA in California as well as years of experience organizing national and international meetings and congresses, including the 1975 international congress on the “Neurobiology of Sleep

and Memory” in Mexico. This no doubt helped him to create the Mexican Sleep Society. This was not the case for Edgar Osuna, a young neurologist in Bogota, Colombia in the mid- 1980s who struggled to convince foreign researchers attend- ing official meetings in Argentina or Chile to take a detour to Bogota to present their latest research results to the few interested members of the sleep section of the Colombian Neurology Association. The same was true, much later in the second millennium, when Dr. Darwin Vizcarra in Lima, Peru had to push hard to bring sleep medicine to his corner of the world.

Far-East Asia was sometimes even more complicated. South Korea at one time had three different sleep societies due to dissention between different types of specialists. As had been seen earlier in history, the more democratic and open society has been the one to grow and survive. Dr. Ning- Hung Chen in Taiwan and Dr. K. Puvanendram in Singapore worked for many years in the field. They were successful in attracting the attention of their colleagues to the world of sleep, leading to the creation of national sleep societies. The work of Dr. J. C. Suri in New Delhi furthered India’s sleep society and journal, uniting the efforts with Indian research- ers around the world.

The grand history of sleep medicine and its societies un- folded with layered efforts occurring throughout the world. This short history cannot hope to summarize all of these di- verse efforts, championed by countless individuals. Hopeful- ly, these gaps will be filled by more in-depth histories written by each individual society as recognition of its founders and contributors.

References

1. Dement, WC, Vaughan C. The promise of sleep Delaporte Press- Random House, New York, NY 1999. pp. 1–521.

2. Chase M, editor. The sleeping brain. BIS/BRI. Los Angeles: Uni- versity of California; 1972, pp. 1–537.

3. Jovanovic UJ, editor. The nature of sleep. Stuttgart: G. Fisher Verlag; pp. 1–308.

4. Guilleminault C, Dement WC, Passouant P, editors. Narcolepsy, vol. 3, advances in sleep research. New York: Spectrum Publica- tions; 1976. pp. 1–684.

5. Guilleminault C, Dement WC, editors. Sleep apnea syndromes. New York: Alan R. Liss, Inc.; 1978. pp. 1–372.

6. Guilleminault C and Partinen M. Obstructive sleep apnea syndrome: clinical research and treatment. New York: Raven Press; 1990.

7. Sullivan CE, Henderson-Smart DJ, Reid J, editors. The control of breathing during sleep. Sleep 1980;3:221–467.

8. Peters JH, Podszus T, von Wichert P. Sleep related disorders and internal diseases. Berlin: Spinger-Verlag; 1987. pp. 1–393.

9. Drucker-Colin RR, McGaugh JL. Neurobiology of sleep and memory. New York: Academic; 1977. pp. 1–456.

Development of Sleep Medicine in Europe

Michel Billiard

To present a history of sleep medicine in Europe is certainly a great challenge given the number of countries, cultures and political regimes in Europe at the dawn of this new medical era. Moreover there is a great risk in citing the names of his- torical figures and centres because of inadvertent omission of the names of others for which the author apologizes in advance for any frustration that may be caused. In order to cover the field, this chapter will first consider the European neurophysiological background, and then review the main precursors of sleep medicine and the founding congresses, and finally the first and second periods of sleep medicine centres will be mentioned. In addition a list of the first sleep medicine centres in each single European country is at- tached. (Table 15.1)

The Neurophysiological Background

Europe is certainly the place where first fundamental neuro- physiological studies on sleep were undertaken.

Maria de Manacéine (1843–1903), a physiologist in Saint-Petersburg, carried out in France, in 1894, the first well-documented experiments of prolonged sleep depriva- tion in puppies, using forced walking and handling. Doing so, she inspired the first sleep deprivation study in human subjects, conducted by Patrick and Gilbert at the Iowa Uni- versity Psychological Laboratory in USA [1] and the sleep deprivation experiments in dogs by Legendre and Pieron in Paris [2].

Ivan Pavlov (1849–1936), also from Saint-Petersburg, a medical doctor and a physiologist, was not only the inventor of the classical conditioning, a form of learning in which the first conditioned stimulus signals the occurrence of a second

M. Billiard ()
Department of Neurology, Gui de Chauliac Hospital
80 Avenue Augustin Fliche, 34295 Montpellier, Cedex 5, France e-mail :mbilliard@orange.fr

stimulus, the unconditioned stimulus but also was interested in sleep that he defined as “spreading cortical inhibition”.

Sigmund Freud (1856–1939) from Vienna, a neurologist and a psychiatrist, developed his psycho-analytic theory of dreaming and attributed three functions to dreams. First, they allow the expression of unconscious wishes. Second, by disguising the wishes and allowing them to be expressed, they provide a safety valve, a means of “discharging” the unconscious and releasing the psychic tension and excitation that result from the unconscious wishes. Third, they serve as a “guardian” for sleep and allow it to continue, the dream- work transforming the wish so thoroughly, that full arousal and awakening do not occur despite the release of the uncon- scious excitation [3].

Hans Berger (1873–1941), a neurologist from Jena (Ger- many), recorded the electrical activity of the brain through the scalp with an original method which he called electroen- cephalogram [4].

Constantin von Economo (1876–1931) worked in Vienna (Austria). His broad education in physiology, neurology, psychiatry and comparative neuro-anatomy set the ground for outstanding contributions. He was the first to describe encephalitis lethargica in 1917 [5], and then went on to pro- pose his concept of a sleep-regulation centre distinguishing two distinct areas: one rostral, in the diencephalic-mesen- cephalic region, responsible for sleep and one posterior, in the mesencephalic tegmentum and posterior hypothalamus, responsible for waking [6].

Henri Pieron (1881–1964), a psychologist in Paris (France), studied the effects of sleep deprivation. Together with René Legendre, in the years 1907–1910, they subjected dogs to complete sleep deprivation for several days and then had their serum or cerebrospinal fluid injected to nonsleep- deprived dogs. They observed extremely accentuated sleep phenomena in these dogs, suggesting the existence of a sleep factor that they called “hypnotoxine” [2].

Walter R. Hess (1881–1973), a physiologist in Zurich (Switzerland), received the Nobel Prize for his stimulation

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_15, 113 © Springer Science+Business Media, LLC 2015

114 M. Billiard

Table 15.1

List of the rst sleep medicine centres in European countries (up to ve per country)

Country

Town

Institution

Chairman or Director

Initial main interest

Approximate date of first clinical polysomnography

Austria

Vienna Vienna Innsbruck

Dept. of Psychiatry, Vienna General Hospital Dept. of Neurology, Vienna General Hospital Dept. of Neurology, Innsbruck University

Bernd Saletu Josef Zeitlhofer Gerhard Bauer

Pharmacopsychiatry
Sleep and neurological disorders Sleep and neurological disorders Sleep related breathing disorders

1975

1985

1988

Belgium

Brussels

Dept. Development and Sleep
Saint Pierre Hospital
Dept. Clin Neurophysiol, Cliniques Univ. Saint-Luc Dept. of Neurology, University Hospital
Dept. of Psychiatry, University Hospital
Dept. of Psychiatry, Erasme Hospital
for the Study of Sleep (BASS), 1983

André Kahn

Sudden infant death syndrome Nutrition and sleep
Sleep related breathing disorders Sleep and epilepsy

1978

Bulgaria

Alexander Alexiev

Narcolepsy
Sleep related breathing disorders Full spectrum of sleep disorders

1975
1984
early 1970s 2001

Croatia

Vera Dürrigl

Sleep and schizophrenia
Sleep and epilepsy
Sleep related breathing disorders

Czech

Prague

Dept. of Neurology 1st, Faculty of Medicine, Charles University

Bedrich Roth Miroslav Moran Milos Matousek
Jana Vyskocilova Gordon Wildschiödtz

Hypersomnias of central origin

1965a 1995 1998 2000 1981

Denmark

Plzen
Czech Sleep Research and Sleep Medicine Society, 2001 Copenhagen Danish Centre of Sleep Medicine

Sleep and mood disorders

Estonia

Tartu Sleep Disorders Centre, Psychiatry Clinic, Tartu Univer- sity Hospital

Veiko Vasar
Tuuliki Hion Enn-Jaagup Püttsepp Erve Sooru

Full spectrum of sleep disorders Sleep related breathing disorders

1996 1997

Austrian Society for Sleep Medicine and Sleep Research (ASRA), 1992 Journal: “Somnologie” (Journal of the German Sleep Medicine Society), 2007

Brussels
Liege
Antwerp
Brussels
Belgian Association
Book: 25 years of Belgian Sleep (2008)
Sofia Dept. of Neurology, Alexandrovska Hospital

Geneviève Aubert Georges Frank Roger Matthys Julien Mendelwicz

Insomnia
Sleep and psychiatric disorders

1979

1980

Plovdiv Dept. of Neurology, Sveti Georgi Hospital
Bulgarian Society of Sleep Medicine, 2008
Zagreb EEG and Clin Psychophysiol, Psychiatric Hospital Vrapce

Zacharie Zachariev

Split Sleep laboratory, University Hospital Split Society for Sleep Medicine of the Croatian Medical Association, 1994

Zoran Dogas Goran Racic

Brno

Dept. of Neurology, University Hospital Prague Psychiatric Centre
Dept. of Pulmonology, University Hospital

Sleep and epilepsy
Sleep related breathing disorders Insomnia
Sleep and psychiatric disorders Sleep related breathing disorders

Prague

Dept. of Clin Neurophysiol, Glostrup Hospital Danish Society for Sleep Medicine, 1996

Tartu Lung Clinic, Tartu University Hospital Estonian Sleep Medicine Association (2005)

15 Development of Sleep Medicine in Europe 115

Table 15.1

(continued) Town

Country

Institution

Chairman or Director

Initial main interest

Approximate date of first clinical polysomnography

Finland

Helsinki Turku

Dept. of Neurology, Meilahti Hospital Dept. of Physiology, University of Turku

Markku Partinen

Hypersomnias
Snoring
Sleep related breathing disorders Autonomous nervous activity

1978 1978

France

Montpellier

Dept. Clin Neurophysiol, St Charles Hospital

Pierre Passouant
Jean Cadilhac
Michel Baldy-Moulinier Marion Delange
Michel Jouvet

Epilepsy Narcolepsy

1960

Germany

Würzburg

Dept. of Neurology, University Hospital

Uros J. Jovanovic

Sleep and neurologic disorders Sleep and psychiatric disorders Sleep and sexual disturbances Sleep structure

1964

Helsinki Tempere

Ullanlinna Sleep Disorders Clinic

Markku Partinen

during sleep
Narcolepsy
Seasonal affective disorders Computer aided analysis of sleep Sleep related breathing disorders

1986 1993

Strasbourg Paris

Dept. Clin Neurophysiol, Hôpitaux Universitaires Dept. Clin Neurophysiol, Pitié-Salpêtrière Hospital

Daniel Kurtz
Jean Scherrer
Lucile Garma Françoise Goldenberg

Sleep related breathing disorders Parasomnias
Insomnia

1970 1971

Munich

Max Plank Institute für Psychiatry

Hartmut Schulz

1972 1976

Treysa

Neurological Clinic, Hephata
Dept. of Psychiatry, University Hospital
Dept. of Internal Medicine, Philipps University Hospital

Karl-Heinz Meier-Ewert Eckart Rüther

Sleep and depression Narcolepsy Narcolepsy

1978

1979

1981

Munich

Sleep and psychiatric disorders Insomnia
Sleep related breathing disorders

Marburg

Jörg-Hermann Peter

German Sleep Society,1992
Journal: Somnologie/Somnology, 1997

Dept. of Pulmonary Medicine, Tampere University Hospital

Joel Hasan Jaakko Herrala

Finnish Sleep Research Society (SUS), 1988 Journal: Sleep News (Uniuutiset), 1999

Lyon Paris

Sleep Laboratory, Neurology Hospital

Sleep and neurological disorders Narcolepsy and hypersomnia Neonatal medicine (epilepsy,

1962b 1962

Centre for Neonatal Biological Research, Port-Royal Hospital

Colette Dreyfus-Brisac Nicole Monod

sleep related breathing dis- orders, sudden infant death syndrome)

French Sleep Research and Medicine Society, 1986 Journal: Sleep Medicine, 2004

Jukka Alihanka Joel Hasan

116 M. Billiard

Table 15.1

(continued) Town

Country

Institution

Chairman or Director

Initial main interest

Approximate date of first clinical polysomnography

Greece

Athens

Dept. of Psychiatry, Eginition Hospital

Constantin Soldatos

Insomnia
Sleep and psychiatric disorders Sleep related breathing disorders Sleep related breathing disorders

1979

Hungary

Budapest Budapest

National Institute of Neurology and Psychiatry National Institute of Neurology and Psychiatry Army Hospital
Koranyi National Institute for Tuberculosis and

Péter Halasz Péter Köves

Sleep and epilepsy
Sleep related breathing disorders Movement disorders in sleep Sleep related breathing disorders

1991 1995

Iceland

Reykjavik Dept. of Respiratory Medicine and Sleep, Landspital Univ. Hospital

Thorarrin Gislasson Helgi Kristbjarnarson

Sleep related breathing disorders

1987

Ireland

The Icelandic Sleep Research Society (1991)
Dublin Sleep Laboratory, St Vincent’s Hospital Irish Sleep Society, 2004

Walter McNicholas

Sleep related breathing disorders

1984

Italy

Bologna

Institute of Neurology, University of Bologna

Elio Lugaresi

Sleep related movement disorders Sleep related breathing disorders Parasomnias
Insomnia

1965

Lithuania

Kaunas Kaunas Kaunas

Dept. of Cardiology, University Hospital
Dept. of Neurology, University Hospital
Dept. of Pulmonology and Immunology, University

Giedrius Varoneckas Vanda Liesiene Skaidrius Miliauskas

Sleep and cardiovascular diseases Epilepsy
Sleep related breathing disorders

1984

2001

2003

Luxembourg

Esch-sur-Alzette Luxembourg Heeze

Emile Mayrisch Hospital
Dept. of Neurosciences, Luxembourg Hospital Centre for Sleep-Wake Disorders Kempenhaeghe

Michel Kruger Nico Diederich Guus Declerck

Full spectrum of sleep disorders Sleep and neurological disorders

1996

1994

Netherlands

Insomnia & Narcolepsy
Sleep related breathing disorders Full spectrum of sleep disorders

Thessaloniki Athens

Dept. of Pulmonology, Papanikolaou Hospital Dept. of Critical Care and Pulmonary Medicine,

Dimitris Patakas Charalampos Roussos

1983 1990

Evangelismos Hospital Hellenic Sleep Research Society, 1995

Budapest

Nagy György Boszormenyi

1996

Pulmonology Hungarian Sleep Society, 1997

Milan

Dept. of Neurology, Institute San Raffaele

Salvatore Smirne

1969

Pisa

Institute of Neurology, University of Pisa

Alberto Muratorio

Parasomnias
Sleep related breathing disorders Sleep and depression, and neuro-

1969

Parma Udine

Dept. of Neurology, University of Parma

Mario G. Terzano Gian L. Gigli

logical diseases Sleep and epilepsy Sleep and neurological

1979 1981

Vilnius
Lithuanian Sleep Medicine Society, 2000

The Hague

Dept. of Neurology and Clin Neurophysiol, Westeinde Hospital

Hilbert Kamphuisen

1995

Dept. of Neurology, University of Udine

Italian Sleep Medicine Society, 1991
Journal: AIMS Bulletin, 1995-2007, Somnomed, 2008

Hospital
Centre of Neurology, Vilnius Univ. Hospital

Raminta Masaitiene

Sleep and neurological disorders

2005

15 Development of Sleep Medicine in Europe 117

Table 15.1

(continued)
Town Institution

Country

Chairman or Director

Initial main interest

Approximate date of first clinical polysomnography

Norway

Dutch Society for Sleep-Wake Research (NSWO), 1990
Journal: Sleep-Wake Research in the Netherlands, 1990 (one issue per year) Bergen Bergen Sleep Disorders Centre (private)

Several doctors Bjorn Bjorvatn

Full spectrum of sleep disorders Full spectrum of sleep disorders

1998 2004

Poland

Warsaw

Dept. of Psychiatry, Medical University

Andrzej. Jus Karolina Jus Juliusz Narebski

Sleep and mental disorders Evaluation of psychotropic drugs Sleep in children

1966

Portugal

Journal: Sen, 2001 Lisbon

EEG and Sleep Dept., Centro Estudos Egas Moniz, Hos- pital Santa Maria

Teresa Paiva

Sleep and psychiatry Biomedical methodologies for

1983

Romania

Tirgu-Mures Bucharest Timisoara

Department of Neurology, Tirgu-Mures Hospital Romanian Institute of Pneumology
Victor Babes University of Medicine and Pharmacy, Vic-

Liviu Popoviciu Florin Mihaltan Stefan Mihaicuta

Hypersomnias of central origin Sleep related breathing disorders Sleep and cardiovascular

1971

1994

2005

Russian Federationc

Moscow

Sechenov 1st Moscow Medical Institute, Dept. of Neurol- ogy, Faculty of Advanced Postgraduate training

Alexander M. Vein Valeriy L. Golubev Gennadiy V. Kovrov

Sleep and neurological disorders Hypersomnias

1992d 1994

Serbia

Belgrade Dept. of Epilepsy and Clin Neurophysiol, Institute of Mental Health

Zarko Martinovic

Dreams in chronic alcoholism Epilepsy

1978

Slovakia

Serbian Sleep Society, 2011
Kosice Dept. of Pathophysiology, University of Kosice

Zoltan Tomori

Sleep related breathing disorders

1996

Leiden Dept. of Neurology and Clin Neurophysiol, Leiden Univ. Medical Center

Gert Jan Lammers Gert Jan Dijk

Narcolepsy and related disorders

1995

Oporto
Coimbra
Portuguese Sleep Association, 1991

Moscow Moscow

Centre of Sleep Medicine
Clin Sanatorium “Barvikha” Sleep Medicine Division Federal Medical-Biological Centre of Sleep Medicine

Mikhail G Poluektov Roman V. Buzunov Alexander L. Kalinkin

1994

1995

1998

Norwegian Competence Centre for Sleep Disorders, University of Bergen

Norwegian Society for Sleep Research and Sleep Medicine (2007) Journal: SOVN, 2009 (two issues per year)

Torun and Bydgoszcz

Dept. of Pediatric Neurology

1972

Warsaw Gdansk

Institute of Psychiatry and Neurology

Halina Ekiert Zbigniew Nowicki

Sleep and mood disorders Sleep and mood disorders

1978 1983

Dept. of Psychiatry and Neurology Polish Society of Sleep Research, 1991

Dept. Clin Neurophysiol, Hospital Santo Antonio Sleep laboratory, Centro Hospit de Coimbra

Antonio Martins da Silva José Moutinho dos Santos

sleep
Sleep and epilepsy
Sleep related breathing disorders

1983 1991

tor Babes Hospital Romanian Sleep Society, 2006

disorders

Dept. of the Pathology of Autonomic Nervous System

Sleep and stress
Insomnia
Full spectrum of sleep disorders Sleep related breathing disorders Sleep related breathing disorders

Russian Somnological Society (section of the Pavlovian Physiological Society of the Russian Academy of Sciences), 2007 National Society for Somnology and Sleep Medicine, 2010

118 M. Billiard

Table 15.1

(continued) Town

Country

Institution

Chairman or Director

Initial main interest

Approximate date of first clinical polysomnography

Slovenia

Institute Clin Neurophysiol, University Medical Centre University Clinic of Respiratory and Allergic Diseases

Leja Dolenc-Groselj Matjaz Flezar

Full spectrum of sleep disorders Sleep related breathing disorders

1994 1994

Spain

Madrid

Dept. Clin Neurophysiol, University Hospital San Carlos

Rosa Peraita-Adrados Antonio Vela-Bueno

Sleep and epilepsy
Full spectrum of sleep disorders Pharmacology
Sleep related breathing disorders Sleep and neurological disorders Sleep and neurological disorders Pediatric sleep disorders

1971

Sweden

Uppsala

Dept. of Psychiatry, Uppsala University Hospital

Björn-Erik Roos Jerker Hetta Gaby Bader

Sleep and psychiatry Pharmacotherapy

1985

Switzerland

Rudolph Max Hess Jean-Michel Gaillard

Sleep and neurological Insomnia

Turkey

Istanbul

Dept. of Neurology, Cerrahpasa Faculty of Medicine

Erbil Gözükirmizi Hakan Kaynak Hamdullah Aydin Sadik Ardic

Full spectrum of sleep disorders

1985

Ljubljana
Golnik
Slovene Sleep Society, 2005

Barcelona

Dept. Clin Neurophysiol, Hospital Vall d’Hebron

Teresa Sagales Dolores de la Calzada Antonio Beneto
José M. Vergara

1972

Valencia Zaragoza

Dept. Clin Neurophysiol, University Hospital La Fe Dept. Clin Neurophysiol, University Hospital Miguel Servet
Dept. Clin Neurophysiol, University Hospital Marqués de Valdecilla

1972 1980

Santander

Rosario Carpizo

Sleep and neurological

disorders

1980

Iberian Association of Sleep Pathology (AIPS) now Spanish Sleep Society, 1991 Journal : Vigilia-Sueno, 1992

Gothenburg Gothenburg

Dept. Clin Neurophysiol, Sahlgren’s Univ. Hospital

Hypersomnias Insomnia
Sleep related breathing

early 1980s 1990s 1990s 1960

Lund
Swedish Society for Zurich
Geneva

Dept. Clinical Neurophysiol, Lund University Hospital Sleep Research and Sleep Medicine, 1989
EEG Laboratory, Neurological Univ. Dept.
EEG laboratory, University Hospital, Chêne-Bourg

Sleep related breathing

Centre for Sleep and Wake Disorders, Remströmska Hospital

Jan Hedner Sören Berg

disorders disorders disorders

Berne
Swiss Society for Sleep Research, Sleep Medicine and Chronobiology, 1991

Christian W. Hess

Pharmacology of sleep Quantitative analysis of sleep Narcolepsy
Sleep related breathing disorders

1982

Ankara Ankara

Dept. of Psychiatry, Gulhane Military Med Acad

Full spectrum of sleep disorders Sleep related breathing disorders

1987 1994

EEG Laboratory, Neurogical Univ. Dept., Inselspital

Yildrim Beyazit Training and Research Hospital

Turkish Sleep Medicine Society, 1992
Journal: Journal of Turkish Sleep Medicine, 2009

1969

15 Development of Sleep Medicine in Europe 119

Table 15.1 (continued) Country Town

Institution

Chairman or Director

Initial main interest

Approximate date of first clinical polysomnography

United Kingdom Edinburgh London

Dept. Psychol Medicine, Royal Edinburgh Hospital Academic Department of Psychiatry, Middlesex Hospital

Ian Oswald

Insomnia
Pharmacology of sleep Sleep and mental disorders

1959e 1972

Edinburgh
Oxford
Leicester
British Sleep Society, 1989

Department of Medicine, Royal infirmary
Chest Clinic, Churchill Hospital
Sleep Disorders Service, Leicester General Hospital

Arthur Crisp
Georg Fenton
Peter Fenwick
Neil Douglas
John Stradling Christopher Hanning

Sleep related breathing disorders Sleep related breathing disorders Sleep related breathing disorders

1979

1979*

1986

This list has been established thanks to the help of senior sleep disorder specialists in each European country. The names of institutions and chairmen or directors are those of the centres at the origin. The date of first polysomnography is approximate and it does not necessarily match with the date of opening of the sleep medicine centre
a Bedrich Roth was interested in patients with hypersomnias of central origin as soon as 1949, performed his first all night EEG recordings in 1951, but due to political situation could not perform polysomnography before 1965

b Michel Jouvet’s main activity was animal research but he run in parallel a human sleep medicine centre
c Russian Federation is a very large country. Only the first sleep medicine centers located in Moscow are presented here d Alexander Vein performed his first polysomnography in 1968, but the sleep medicine centre was opened later in 1992 e The main activity of the centre was research, but Ian Oswald would see now and again patients with sleep disorders

120

M. Billiard

studies in freely moving cats with electrodes located at pre- cisely defined anatomical sites in the brain. By stimulating a relatively widespread region extending from the medial thalamus towards the caudate nucleus, at a low frequency of 4–12 c/sec and with stimuli of long duration, typically 12.5– 25 ms, with ramp-like, attenuated upward and downward slopes and trains of stimulation lasting from 30 s to 1 min, he obtained what appeared to be physiological sleep [7]. The cat first looked for a suitable sleeping place, then curled up comfortably before falling asleep. Moreover, the cat, like in physiological sleep, could be re-awakened at any time. All these findings were in favour of sleep as an active process.

Frederic Bremer (1897–1982), a brilliant neurologist in Brussels (Belgium), performed his famous “cerveau isolé” and “encéphale isolé” preparations in the cat. In the first ex- periment the cat was in a state of deep sleep with a regular rhythm of highly synchronous 6–10 Hz waves. Bremer at- tributed this finding to the deafferentation of the telencepha- lon, which deprived the brain from the flow of sensory im- pulses [8]. In the second experiment, the transection of the brainstem above its junction with the spinal cord left intact a majority of sensory pathways, and a normal alternation be- tween sleep and wakefulness was maintained. Bremer inter- preted these results, as an evidence that sleep in mammals results from a decrease in cortical tone which is maintained by the flux of sensory information to the brain, a view in favour of sleep as a passive phenomenon [9].

Thereafter, Giuseppe Moruzzi (1910–1986), a neuro- physiologist in Pisa (Italy), worked with Horace Magoun (1907–1991) in Chicago. Together they discovered “the presence in the brainstem of a system of ascending reticular relay, whose direct stimulation activates or desynchronizes the EEG”, which they called the activating reticular system [10]. This discovery paved the way for a greater understand- ing of sleep-wakefulness mechanisms.

Michel Jouvet (1925-), the last but not the least on the list, a neurophysiologist in Lyon (France), is famous for having implanted electrodes in or very near the oculomotor nuclei (VI) in the pons, and in the neck of pontine cats, and having observed every 30–40 min a periodic appearance of “spin- dle-like” activity in the pons, coincident with the total disap- pearance of the EMG of the neck. These curious episodes lasted about 6 min and occurred periodically every 50 min [11]. Then, performing similar polygraphic recordings in in- tact cats, he observed a cortical activity similar to that seen during waking, associated with a much increased threshold for arousal. This was a paradoxical finding. Thus, he could state that Dement’s rapid eye movement (REM) sleep was a sleep state different from wakefulness and non-REM (NREM) sleep, a kind of rhombencephalic state opposite to the NREM telencephalic type of sleep.

The European Precursors of Sleep Medicine

Rudolph Max Hess (1913–2007), the son of Nobel Laureate Walter R. Hess, studied medicine in Lausanne and Zurich (Switzerland) and in Kiel (Germany), before specializing at the Kantonsspital in Zurich (Switzerland). He then visited the National Hospital for Nervous Diseases, Queen Square in London. In 1948 he was back in Zurich, successively in the EEG, Neurosurgery and Neurology departments. He spent half-a-year in the USA and Canada in 1953–1954. Rudolf Max Hess then came back to Zurich and started to perform clinical polysomnography in 1960.

Pierre Passouant (1913−1983) got his MD in Montpellier

(France) in 1943 and created one of the first EEG laborato- ries in France, at the Saint Charles Hospital in 1947. Begin- ning in 1953, he assembled a highly talented research group in neurophysiology who worked on the rhinencephalon and the hippocampus, and later on the cerebrum and the bulbar olive. In parallel he was interested in epilepsy. In 1960 he performed polysomnographic studies in epileptic and later in narcoleptic patients. In 1971 he moved to the Gui de Chauli- ac Hospital and established a fully equipped sleep laboratory starting with two bedrooms. Among his main interests were the effects of sleep on epilepsy and the effects of epilepsy on sleep, the ultradian rhythm of sleep attacks in narcoleptics and the suppression of REM sleep by clomipramine.

Andrzej (1914–1992) and Karolina (1914–2002) Jus are the two researchers who first performed polysomnography in Poland. Andrzej received his MD at the University of Jan Kazimierz in Lwow (Ukraine) in 1939 and Karolina her MD at the University of Wroclaw (Poland) in 1946. They had a very tragic story during Second World War: all the members of Karolina’s family were killed in the Holocaust. Andrzej and Karolina married in 1941. In 1947 they participated in a post-doc fellowship at the University Paris Sorbonne. Andrzej worked successively in Wroclaw, Pruszkow and eventually in the Department of Psychiatry at the Medical University of Warsaw in 1950. There, together with his wife, he organized a clinical and scientific laboratory of EEG and sleep research. The first polysomnography was performed in 1966, and the next year they began publishing papers on polysomnography in the international literature [12, 13]. Their main interest was sleep in mental disorders and the influence of psychotropic medications on sleep. In 1970, An- drzej and his wife moved to Canada.

Henri Gastaut (1915–1995) graduated at Marseille Uni- versity (France) in 1945. He was the scientific director and chief doctor of the Centre Saint-Paul for epileptic children from 1957 to 1968. He devoted his brilliant career in ep- ilepsy with a number of studies on sleep and epilepsy. In 1965, after Richard Jung and Wolfgang Kuhlo in Freiburg (Germany) had published a case report of sleep disordered breathing in a patient with the Pickwickian syndrome [14],

15 Development of Sleep Medicine in Europe

121

technical improvements allowed Gastaut et al. to refine the evaluation performed by the German authors and to clearly identify three different abnormal breathing patterns during sleep in Pickwickian patients, obstructive, mixed and central apneas [15].

Colette Dreyfus-Brisac (1916–2006) graduated in Paris (France) in 1946, after being in the Resistance during the Second World War. She first worked in Fishgolds’s EEG laboratory at the Pitié Hospital and in parallel at the Ma- ternity of the Baudeloque Hospital. In 1953, she was joined by Nicole Monod, her closest collaborator during her whole carrier. She headed a team of neurophysiologists working in close contact with neonatologists and paediatric neurolo- gists. She attracted EEG specialists from all over the world. The new Port Royal Hospital was built in the early 1960 and a first paper entitled “Disorders of the organization of sleep in the pathological newborn child” was published by Nicole Monod et al. in 1966 [16].

The very first person interested in sleep medicine in Europe is certainly Bedrich Roth (1919–1989). After a ter- rible time in Slovakia during Second World War, he fled to Switzerland, studied medicine in Berne from 1943 to 1944, then in Paris from 1945 to 1946, and eventually returned to Prague (Czechoslovakia) where he got his MD in 1947. He specialized in neurology in Hradec Kralové, East of Prague, and came back to the Prague’s Neurological Clinic headed by the famous neurologist Kamil Henner in 1949. Not long after his return to Prague he started seeing patients with nar- colepsy and hypersomnia. In 1951, he managed to perform his first all night sleep EEG on a Grass machine which was replaced later by a Kaiser EEG machine. Patients were fre- quently referred to him from Prague and from all over the country. From May 1,1949 to May 1,1955, he saw, in his outpatient clinic, 251 subjects with excessive daytime sleepi- ness, including 155 with narcolepsy and 96 with hypersom- nia [17]. The sleep disorder centre was born. However due to the political situation, the classical polysomnographic re- cordings did not start before 1965 on a Bioscript apparatus from East Germany.

Uros Jovan Jovanovic was a member of the University De- partment of Neurology in Würzburg (Germany). He worked in the fields of epilepsy and sleep, psychiatric diseases and sleep and penile erections during sleep. He was famous for organizing an international sleep symposium “the Nature of Sleep”, during which a “founding committee” including Drs Baust, Gottesmann, Jovanovic, Koella (Chairman), Oswald and Popoviciu was established, as a preparation for the fu- ture first European Congress of Sleep Research which took place one year later in Basel. In addition, he launched the first international journal on sleep, “Waking and Sleeping”, in 1976. Unfortunately the journal went out of business in 1980 and a few years later Uros J. Jovanovic quitted the field of sleep.

Elio Lugaresi (1926–) is in every respect a giant in the field of sleep. He graduated from the Bologna University School of Medicine in 1952 and became a post-graduate fellow in the same university. In 1956–1957, he spent one year in the EEG laboratory chaired by Henri Gastaut at the Hospital la Timone in Marseille. Then he returned to Bolo- gna where he set up a research team at the Neurology clinic with the help of Giorgio Coccagna. Elio Lugaresi must be acknowledged for being the first to document the major fluc- tuations in pulmonary and systemic arterial pressure during obstructive apneas [18], describe restless legs syndrome and periodic leg movements in sleep [19], identify nocturnal par- oxysmal dystonia [20] and last but not the least, discover a new prion disease, the “Fatal Familial Insomnia” [21].

Alexander Vein (1928–2003) was the disciple of the dis- tinguished neurologist Nicolay Grashchenkov who died in 1966. He was the founder of sleep medicine and human sleep physiology in Russia. He was interested in insomnia, sleep apneas, movement disorders in sleep, sleep and epilepsy, sleep and stress. His first polysomnographic recordings were performed at the Grashchenkov laboratory in 1968 and he set up the first Russian sleep medicine centre at the Sechenov first Moscow medical Institute in 1992.

Ian Oswald (1929–2012) graduated in both experimental psychology and medicine at Cambridge University and was awarded an MD for research. His first use of EEG was when he did his national service in the Royal Air Force and was involved in checking airmen for possible epileptic propensi- ty. He then, had a fellowship at Oxford University where he did many research studies using EEG equipment. He moved to Edinburgh in 1959 to become a lecturer in Psychologi- cal Medicine at Edinburgh University, with clinical duties in the Royal Edinburgh Hospital. He continued his research on sleep using polysomnography and would now and then see patients with sleep disorders.

Key Meetings

A few meetings can be considered as cornerstones in the de- velopment of sleep medicine in Europe.

The first one is probably the 1963 meeting of the French Speaking Society of Electroencephalography and Clinical Neurophysiology devoted to night sleep. This meeting was held in Paris under the chairmanship of Henri Fischgold. It gathered speakers from Belgium, France, Germany, Italy and the UK. The primary clinical emphasis in this meeting was the documentation of sleep-related epileptic seizures and a number of related studies on sleep and tumours, sleep-relat- ed movement disorders, African sleeping sickness and sleep in patients with mental disorders. This program certainly did not cover all range of sleep disorders, but it served as an incentive to direct the attention to sleep and sleep disorders.

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M. Billiard

Proceedings of this congress were gathered in a book entitled “Le sommeil de nuit normal et pathologique, Etudes électro- encéphalographiques” [22].

The second important meeting is the XVth European meeting on electroencephalography, which was organized in Bologna in 1967 under the chairmanship of Henri Gastaut and Elio Lugaresi. This meeting gathered a large number of speakers and participants. The program covered a more rep- resentative range of sleep disorders with sessions on neuro- physiological and neurochemical basis of sleep, insomnia, narcolepsy, Pickwickian syndrome and episodic phenomena of sleep. Proceedings of this congress can be found in a book entitled “The abnormalities of sleep in man” [23].

Then came four International congresses within a 16- month period. Ten years after the first meeting of the Asso- ciation for the Psychophysiological Study of Sleep (APSS), the APSS organized an international congress in Bruges, Belgium (June 19–24, 1971). About three months later an- other International Symposium, “the Nature of Sleep”, was organized by Uros J. Jovanovic in Würzburg (Germany) (September 23–26, 1971) and at the end of this symposium, a preliminary committee headed by Werner P. Koella was formed to organize a European Society of Sleep Research. About eight months later (May 25–27,1972) a symposium entitled “Hypersomnia with periodic breathing”, was orga- nized in Rimini, a small resort on the Adriatic coast”. This symposium was organized by Elio Lugaresi and Paul Sadoul, a pulmonologist from Nancy (France). It was mostly devoted to defining the Pickwickian syndrome into different sleep- related breathing disorders. Proceedings were published in 1972, in a special issue of the Bulletin de Physiopathologie Respiratoire (Nancy) under the auspices of the French Na- tional Institute of Health and Medical Research [24]. Finally, the first European Congress of Sleep Research was orga- nized by Werner P. Koella in Basel (October 3–6, 1972). It was there that the European Sleep Research Society (ESRS) was founded and it was agreed that the ESRS would organize a scientific Congress every other year. The 40th anniversary of the Society was celebrated during the 21st congress held in Paris in September 2012 and the 22nd Congress of the ESRS was held in Tallin (Estonia) (September 16–20, 2014).

Sleep Medicine Centres

The Beginning of All Night Sleep Recordings (1950–1975)

The use of all night sleep recordings started in the 1960s, mostly in departments of clinical neurophysiology interested in epilepsy and in departments of psychiatry interested in in- somnia and the effects of psychotropic drugs on sleep. Apart from insomnia, sleep disorders were neither identified nor

recognized by the medical community and recording sleep throughout the night was viewed with scepticism. Medicine occupied itself wholly with diseases and disorders that could be seen and diagnosed in waking patients. Formal outpatient clinics devoted to sleep disorders and sleep medicine cen- tres did not exist, with the notable exception of the Prague sleep medicine centre organized by Bedrich Roth in the early 1950s, which included clinical evaluation and nocturnal EEG recording. At best, patients with sleep disorders could be di- agnosed and treated if they were lucky enough to be referred to one of the rare physicians interested in these disorders. Patients benefitted from all night sleep recording on the basis of manifestations occurring during the night, such as epilep- tic seizures or movement disorders rather than because of insomnia or hypersomnia. There were no established sleep facilities. Patients had their sleep recorded wherever it was possible, often in a nurse’s or a physician’s office or even in a corridor. There was no technician and patients were hooked up and observed by the doctors themselves at night. To be a sleep doctor was a real challenge as it did not exempt from daily duties and did not match well with family life. In an article entitled “A personal history of sleep disorders medicine”, William Dement writes that, during his residency at the Mount Sinai Hospital in New York in 1958–1959, “I worked nearly every night at the Hospital. This finally be- came intolerable to my wife. However, because federal funds were so loosely administered at that time, I was able to obtain a grant that paid the rent on a large apartment, half of which I converted into my family’s living quarters and half into a comfortable two-bedroom sleep laboratory” [25]. At the be- ginning, only sleep EEG was recorded, and only later EOG and EMG were added. EEG machines consisted of Artex and Alvar in France, Marconi and Ediswan in England, Toenniies and Schwarzer in Germany, and van Gogh in the Netherlands [26]. There were technical problems with fixation of elec- trodes on the patients’ scalp, with electric wires, ink pens, ink pots and blocks of papers. The quality of the tracings often failed to meet expectations. Analysis of tracings still rested on EEG criteria suggested by Loomis et al. [27]. It took time for the definition of sleep stages as proposed by Dement and Kleitman in 1957 [28] and later elaborated by Rechtschaffen and Kales in the “Manual of standardized terminology, tech- niques and scoring system for sleep stages of human sub- jects” in 1968 [29], to be introduced in Europe and accepted by EEG specialists. All these limitations explain the time it took to implement real sleep medicine centres.

The Development of Sleep Medicine Centres (1975–2000)

Several factors played in favour of establishing sleep medi- cine centres.

15 Development of Sleep Medicine in Europe 123

First of all, the identification of the sleep apnoea syndrome by Christian Guilleminault in 1976 [30], the progressive perception of its high prevalence in the general population and of its health consequences on the short and long terms, and the introduction of continuous positive airway pressure (CPAP) as an effective treatment of this syndrome in 1981 [31]. Second, the publication of the “Diagnostic Classifica- tion of Sleep and Arousal Disorders” in 1979, after 3 years of extraordinary efforts by a small group of dedicated in- dividuals who composed the “nosology” committee chaired by Howard Roffwarg [32]. This classification contained four major groupings of sleep disorders, disorders of initiating and maintaining sleep, disorders of excessive somnolence, disorders of the sleep-wake schedule and dysfunctions as- sociated with sleep, sleep stages, or partial arousals. It raised sleep medicine to the rank of other medicine specialties. Third, the publication of epidemiologic surveys showing the high prevalence of different sleep disorders and their cost for the entire society. Fourth, the progressive interest of pulmo- nologists, neurologists, cardiologists, psychiatrists, paedia- tricians, ENT surgeons, etc., for the manifestations of their respective diseases during sleep. Fifth, the introduction of new techniques including computerized polysomnography and automatic analysis of sleep.

This is reflected in the rapid development of sleep medi- cine centres with a primary interest in sleep-related breath- ing disorders and then of sleep disorders centres interested in the full range of sleep disorders. A good thing or a bad thing? On one hand, sleep disorders medicine was born and accepted, and a crowd of unrecognized patients could now benefit from diagnoses and treatments. On the other hand, untrained and incompetent doctors used automatic analysis of sleep and ended up with incorrect diagnoses and treat- ments, hence the action plan was initiated by the European Sleep Research Society including the process of accredita- tion of sleep medicine centers and certification of sleep med- icine experts [33–34].

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Evolution of Sleep Medicine in Japan

Masako Okawa

Ishimori [1] from Japan in 1909 and Pieron and Legendre in 1913 from France [2] independently performed sleep- deprivation experiments in dogs and then injected the cere- brospinal uid from the dogs into the cerebral ventricles of nonsleep-deprived dogs. The recipient animals quickly fell asleep, suggesting the accumulation of sleep-inducing fac- tors (called “hypnotoxin” by Pieron) in the brain during wak- ing state. The discovery of sleep substance by Ishimori was considered to be the rst milestone of sleep research in Japan. The Japanese researchers continued investigative work on sleep factors and discovered in the 1990s sleep-inducing fac- tors from the brainstems of sleep-deprived rats [3].

Japanese Society of Sleep Research

In 1973, the Japanese Research Committee of Sleep (JRCS) was formed, and in 1977, JRCS was renamed as Japanese Society of Sleep Research (JSSR). Since then, the society had regular annual meetings, and in 1979, it successfully or- ganized the third International Conference of Sleep Research jointly with the 19th APSS meeting in Tokyo. Japanese sleep researchers have made significant contributions in sleep re- search (e.g., early description of rapid eye movement (REM) sleep behavior disorder in patients with delirium tremens and multiple system atrophy by Hishikawa [4], the discovery of the association of specific human leukocyte antigen (HLA) antigen with narcolepsy–cataplexy by Honda [5], and the discovery of sleep factors, such as uridine, by Inoue [6], oxi- dized glutathione by Komoda [3], and prostagrandin D2 by Hayaishi [7]). The research field of sleep later expanded to include biological rhythms. The membership grew rapidly in the past 10 years, and the numbers reached more than 3000 in 2012 (Fig. 16.1).

M. Okawa ()
Department of Sleep Medicine, Shiga University of Medical Science, Otsu, Japan
e-mail: Okawa10022@gmail.com

The history of growth of sleep medicine in Japan is rather recent. It was only in 1994 when all night polysomnography (PSG) was covered by the public health insurance. Prior to that, PSG was performed only for research purposes in a few university hospitals or research institutes, mostly by psychi- atrists or basic researchers. No clinical polysomnographer existed at that time. The number of sleep disorder clinics in- creased rapidly, since PSG was covered by the public health insurance. Pulmonologists and otolaryngologists, who were not sleep specialists, ran most of the newly developed sleep disorder clinics, only caring for patients with sleep-disor- dered breathing (SDB). The growth of sleep medicine clinics and laboratories accelerated rapidly following the news in 2003 that the bullet train driver dozed off while driving, and he was reported to be suffering from sleep apnea (Fig. 16.2).

Fig. 16.1

The research field of sleep later expanded to include biologi- cal rhythms. The membership grew rapidly in the past 10 years, and the numbers reached more than 3000 in 2012

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M. Okawa

Fig. 16.2 The growth of sleep medicine clinics and laboratories accelerated rapidly following the news in 2003 that the bullet train driver dozed off while driving, and he was reported to be suffer- ing from sleep apnea

Fig. 16.3 An important contribu- tion to sleep research in Japan was the establishment of “som- nology” proposed by the Japanese Society of Sleep Research (JSSR) Commission in 2002

The Journal of Sleep and Biological Rhythm (SBR), launched in 2001, became the official journal of JSSR and the Asian Sleep Research Society (ASRS) in 2002.

Establishment of Somnology

An important contribution to sleep research in Japan was the establishment of “somnology” (Fig. 16.3) proposed by the JSSR Commission in 2002.

Somnology consisted of three divisions: (1) sleep sci- ence, concerned with basic science aspects of sleep; (2) sleep medicine, dealing with clinical disorders of sleep; (3) sleep sociology, dealing with sleep issues in industry, schools, the community, as well as those related to environmental, public health, and economic situations.

It is our hope that the establishment of this new specialty of somnology will lead to further progress in sleep and bio- logical rhythm research not only in Japan but also through- out the world.

16 Evolution of Sleep Medicine in Japan 127

References

1. Ishimori K. Sleep-inducing substance(s) demonstrated in the brain parenchyma of sleep-deprived animals – a true cause of sleep. Tokyo Igakkai Zasshi 1909; 23: 429–57. (Japanese).

2. Legendre R, Pieron H. Recherches sur le besoin de sommeil con- sécutif à une veille prolongée. A Allgem Physiol. 1913;14:235–62.

3. Komoda Y, Honda K, Inoue S. SPS-B, a physiological sleep regula- tor, from the brainstems of sleep-deprived rats, identified as oxi- dized glutathione. Chem Pharm Bull (Tokyo). 1990;38:2057–9.

4. Tachibana M, Tanaka K, Hishikawa Y, et al. A sleep study of acute psychotic states due to alcohol and meprobamate addiction. Advances Sleep Res. 1975; 2:177–205.

5. Honda Y, Juji T, Matsuki K, et al. HLA-DR2 and Dw2 in narcolepsy and in other disorders of excessive somnolence without cataplexy. Sleep. 1986; 9(1 Pt 2):133–42.

6. Inoue S, Schneider-Helmert D, editors. Sleep peptides: basic and clinical approaches. Tokyo: Japan Scientific Societies Press/ Springer; 1988.

7. Hayaishi O. Humoral mechanisms of sleep-wake regulation: histor- ical review of prostaglandin D2 and related substances. Sleep Biol Rhythms. 2011;9(Suppl. 1):3–9.

Introduction

The Fragmentary Clinical Sleep Practice

in the 1990s

History of Japanese Clinical Sleep Medicine

Naoko Tachibana

Clinical sleep medicine in Japan is still in developing stage. There is no established consensus about what sleep medicine is, what kind of disorders sleep medicine should deal with, who should be involved in practicing sleep medicine, and how sleep disorders should be investigated and treated. In order to make progress to step into the next stage, establish- ing an identity of clinical sleep medicine is an urgent matter. People in different countries who are tackling with the prac- tice of sleep medicine should find some information in here.

The Earliest Days

The beginning of Japanese clinical sleep medicine can be dated back to 1990 when polysomnography (PSG) was first covered by the national health insurance. It was achieved by the petitionary activity by Japanese Society of Electroenceph- alography and Electromyography (currently, Japanese Soci- ety of Clinical Neurophysiology), Japanese Society of Sleep Research (JSSR), and The Japan Epilepsy Society. Until that year sleep had been considered one of the subjects of research in psychology, physiology, and psychiatry, and PSG had not been performed routinely for the purpose of clinical diagnosis and treatment. As the Japanese medical care system is virtu- ally controlled by the government, anything without official reimbursement cannot be recognized as clinically necessary; therefore, this was the first step into clinical sleep medicine [1]. However, PSG reimbursement at that time was only 15000 JPY (33000 JPY in 2015), and the manpower resource for PSG remained in the side of physicians who worked with- out salary in university hospitals as postgraduate students doing clinical sleep research at the same time [2].

N. Tachibana ()
Center for Sleep-related Disorders, Kansai Electric Power Hospital, 2–1-7 Fukushima, Fukushima, Osaka 553–0003, Japan
e-mail: NanaOsaka@aol.com

JSSR in the 1990s was composed of mainly psychiatrists, neurophysiologists, and psychologists. Among this group of people, only psychiatrists were allowed to directly deal with patients under the Japanese Medical Service Act. Since these psychiatrists did not compose the major portions of psychia- try community, therefore, sleep was not within psychiatrists’ interest except that insomnia widely received psychiatric attention. Although JSSR organized a special symposium about sleep apnea syndrome (SAS) at the 9th Annual Meet- ing held as early as 1984, they failed to transmit the new knowledge to wider medical community.

On the other hand, some pulmonologists who had been involved in physiological research of sleep apnea started to hold regular meetings organizing Sleep-disordered Breath- ing Research Group in 1988, which was differently com- posed from JSSR in that their members are mostly respira- tory physicians and otorhinolaryngologists who are more in- terested in treatment of SAS. In addition, their approach was based on traditional medical methods and they focused on definition of SAS and its epidemiology at the kickoff point. However, the other important aspects of sleep medicine such as sleep health, circadian rhythm, or sleep disorders other than SAS were beyond their scope.

Another important aspect that should be mentioned was that under the Japanese Medical Service Act, the practice of sleep medicine or practice of seeing patients with sleep disorder was not allowed to advertise. This rule applied to the naming of departments of clinics and hospitals, for ex- ample, you were allowed to show the name of Sleep Dis- orders Center inside the clinic or hospital buildings, but not outside. This situation precluded patients seeking for help to their sleep problems from finding proper places to go for a long time until the Internet information had got the status of exception.

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N. Tachibana

In summary, in 1990s, although sleep medicine practice partially started, its existence was hard to be recognized and different places offered different medical services that were fragmentary to the patients [3].

Complicated Reimbursement on Continuous Positive Airway Pressure (CPAP)

The second important milestone in the development of clinical sleep medicine was when continuous positive air- way pressure (CPAP) treatment was covered by the national health insurance in 1998. For this coverage, some pulmon- ologists, acting as a pressure group, had a lot of difficulty to prescribe CPAP. Although CPAP machines themselves had been already available in Japan in the early 1990s, the only way to let obstructive sleep apnea syndrome (OSAS) patients use CPAP machines was first to purchase them by research money at some universities, then prescribe them in the affili- ated university hospitals. Direct purchase from CPAP dealers by patients was strictly forbidden by the regulation.

Reimbursement for CPAP treatment in Japan was some- what unique and complicated, as the insurance covers all the CPAP machines and expendable supplies at the same price on a monthly basis (12100 JPY per month) regardless of the type of machines, attached humidifiers, and how often the patient needs to replace masks. This insurance coverage is only available with the mandatory monthly consultation, which means that the CPAP users should come up to the clin- ics once per month despite their medically good conditions, until they become free from the CPAP machines or opt out for other treatment.

This reimbursement was a great progress in respect of treatment option, but the definition of OSAS for patients under this CPAP treatment insurance coverage included an apnea–hypopnea index (AHI) of ≥ 20 proven by PSG or AHI ≥ 40 by portable respiratory monitoring with other complications such as hypersomnolence. This definition was not evidence-based or the result of expert opinions, rather influenced by lobbying activity by the industry. It should be especially noted that home monitoring was already included as the method to make a diagnosis in 1998 with the national insurance coverage, which was later regarded as one of the reasons why in-lab full PSG was not widely available in Japan [4].

Accreditation System by JSSR

In 1998, Dr. Meir Kryger, who came to Japan as an invited speaker at various meetings related to OSAS, visited some sleep labs and exchanged information with Japanese sleep researchers and clinicians about the current status of practice

of sleep medicine. Summing up his experience, he expressed his view and recommended necessary measures to promote clinical sleep medicine in newsletter of JSSR. He pointed out the importance of organizing a taskforce for standardizing sleep lab and the finalized standard should be approved by not only JSSR but also by other related societies of neurol- ogy, psychiatry, and pulmonology [5].

In response to this proposal and in line with the growing interest in OSAS among physicians who do not belong to JSSR, this society started to build an accreditation system that is for sleep physicians, sleep dentists, sleep technolo- gists, and sleep labs. This business was in action in 2001. However, now that there are so many societies and certifica- tions about various subspecialties in Japan where no addi- tional doctors’ fee is accepted under the national insurance, the significance of this kind of certification at least for physi- cians is getting questionable.

Sudden Public Recognition of OSAS

How people began to recognize sleep-related problems in Japan was strongly influenced by a single incident on 26th February, 2003. On this day, a bullet train driver was found to have been sleeping for 8 min while operating a train at 270 km/h and the train was eventually stopped by an emer- gency device. Several days after this incident, this driver was found to have suffered from unrecognized OSAS, which helped OSAS to be widely recognized under the mass-me- dia coverage. As the public was made to believe that OSAS was the only reason for sleepiness and dozing off, sleepy people were screened by Epworth Sleepiness Scale at the an- nual checkup organized by their companies, and there was a strong demand for sleep labs and sleep specialists for making a diagnosis of OSAS.

As a result, a lot of possible OSAS patients (or they may suffer from lack of sleep because of poor working condi- tion) have been seen by non-sleep specialists or the value of AHI alone was used for diagnosis and treatment decision without questioning about his/her sleep health. Since there has been no umbrella clinical sleep organization including all the clinicians who actually see patients on the ground, this situation has not been controlled by JSSR or other societies related to OSAS.

Foundation of Clinical Sleep Society

Looking back on this Japanese situation, the dichotomy of academic somnology with little emphasis on sleep apnea and SAS medicine under the compelling circumstance have not yet merged. What is more remarkable is that recently CPAP dealers started marketing CPAP and assisted servo-ventila-

17 History of Japanese Clinical Sleep Medicine

131

tion to cardiologists for the treatment of patients with heart failure. Because of an unsatisfactory and confusing situation, a group of people established a completely new society, Inte- grated Sleep Medicine Society Japan (ISMSJ) in 2008. The urgent need is to develop infrastructure of sleep medicine (i.e., modified sleep labs suitable for Japanese medical care system) and to offer basic, but comprehensive, education about sleep and sleep disorders for the younger generation to have practical medical training, because specialists cannot function properly without good collaboration with primary care physicians or other specialists in different fields. People with other careers such as medical technicians who perform PSG, nurses, psychologists, and school teachers should be encouraged to join the field of sleep medicine to set up a team for good medical care. There is further work to be done until clinical sleep medicine is established in Japan.

References

1. Campbell JC, Ikegami N. The art of balance in health policy: main- taining Japan’s low-cost, egalitarian system. Cambridge: Cambridge University Press; 2008.

2. Coleman S. Japanese science: from the inside. Abington: Routledge; 1999.

3. Tachibana N. Imbalance between the reality of sleep specialists and the demands of society in Japan. Ind Health. 2005;43:49–52.

4. Tachibana N, Ayas NT, White DP. Japanese versus USA clinical ser- vices for sleep medicine. Sleep Biol Rhythm. 2003;1:215–20.

5. Hishikawa Y. The message for Japanese sleep medicine researchers from Dr. M. Kryger. JSSR Newsl. 1999;19:1–3. (In Japanese).

Sleep Medicine Around the World (Beyond North American and European Continents, and Japan)

Sudhansu Chokroverty

Introduction

zil, Argentina, Chile, Uruguay, Colombia, and Peru and later Venezuela, Panama, Ecuador, and Paraguay [1,2].

The major milestone in the development of clinical sleep medicine in Latin America was the foundation of the Federation of Latin American Sleep Societies (FLASS) in 1985. Many exchanges developed between those countries and North America and Europe (mainly Spain) with sleep specialists being invited to participate in FLASS meetings, national sleep societies meetings and sleep training courses, and Latin American sleep specialists presenting their work in the meetings of the Associated Professional Sleep Societ- ies (APSS), the European Sleep Research Society (ESRS), the World Federation of Sleep Research Societies (WFSRS), and the World Association of Sleep Medicine (WASM). From the very beginning, the WASM has been promoting clinical sleep medicine in South America as part of its mis- sion of spreading sleep health worldwide.

In fact, some key members of the FLASS served or are presently serving on the governing councils of the WASM (Sergio Tufik and Dalva Poyares from Brazil) and the World Sleep Day committee (Julia Santin from Chile).

Since the foundation of FLASS and the WFSRS (Ennio VivaldifromChile),severalLatinAmericancountriesestab- lished sleep societies (See Table 18.2) to promote research, patient care, and education in sleep medicine.

Except for Brazil, the rest of the Latin American countries do not have facilities for normal training, certification, or guideline assessing minimal competences to practice sleep medicine at present. The field is still young but there is in- tense interest in advancing the field in Latin America which bodes well for future development of sleep medicine.

Sleep Medicine in India

Great strides have been made in promoting sleep medicine in India in the last two decades [3]. As in the USA and other parts of the world, sleep medicine is a multidisciplinary specialty, but the pulmonary physicians took the lead in

This chapter will briefly summarize the development of sleep medicine beyond North American (See Chap. 14) and Euro- pean (See Chap. 15) continents and Japan (See Chap. 16 and 17). The major focus will be the current state-of-the-art in- volving growth and development of sleep medicine in Latin America and Asia (briefly alluded to in Chap. 14) as well as some comments about contemporary sleep medicine in Africa and Australasia. Finally, developmental milestones of international sleep organizations will be briefly mentioned. Tables 18.1, 18.2, 18.3 and 18.4 list the National and Conti- nental, the Latin American, the Asian, and the International Sleep Societies, respectively.

Sleep Medicine in Latin America

As it has been the case in North America and even more in Europe, basic animal and human research has preceded the development of sleep medicine in Latin America. In the 1960s, pioneering research in those fields was conducted by Raul Hernandez Peon (Neurophysiology) in Mexico and Jaime Monti (Pharmacology) in Uruguay. In the 1970s, Rene Drucker Colin (Neurophysiology) in Mexico, Daniel Cardinali (Neuroendocrinology) in Argentina, Sergio Tufik (Psychobiology) in Brazil, and Ricardo Velluti (Neurophysi- ology) in Uruguay conducted similar research. It was only in the 1980s that many individuals became interested in clinical sleep medicine, and after having training in sleep medicine either in North America or Europe, established sleep disor- ders centers initially in Brazil, Argentina, Uruguay, Chile, and Colombia, later in Peru, with representatives from Bra-

S. Chokroverty ()
JFK New Jersey Neuroscience Institute, 65 James Street, Edison, NJ 08818, USA
e-mail: schok@att.net

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Table 18.1 Historical milestones for the national and continental sleep societies
Name of society
The Association for the Psychophysiological Study of Sleep (APSS) 1964 The European Sleep Research Society (ESRS) 1971 The Japanese Research Committee of Sleep (JRCS) 1973 The Association of Sleep Disorders Centers (ASDC) 1975 The Japanese Society of Sleep Research (JSSR) 1977 The Association of Polysomnographic Technologists (APT) 1978 The APSS is renamed the Sleep Research Society (SRS) 1983 The Clinical Sleep Society (CSS) is founded as a branch of ASDC 1984 The Latin American Sleep Society (LASS) 1985

The Federated Association of Professional Sleep Societies (APSS) composed of ASDC, CSS, APT, and SRS. A few years later 1986 the APT withdrew from the Federation following which the name was changed to Associated Professional Sleep Society (The acronym APSS was retained)
The Sleep Society of Canada (SSC)

Year founded

The ASDC and CSS were reorganized changing the name to The American Sleep Disorders Association (ASDA) The National Sleep Foundation (NSF) was created
The Academy of Dental Sleep Medicine (ADSM)
The Sleep Society of South Africa (SSSA)

The United States Congress passed a legislation to create The National Centers for Sleep Disorders Research (NCSDR) The Asian Sleep Research Society (ASRS)
The ASDA was renamed The American Academy of Sleep Medicine (AASM)
The Australasian Sleep Association (ASA)

The Society of Behavioral Sleep Medicine (SBSM) The Society of Anesthesia and Sleep Medicine (SASM)

Table 18.2 Current Latin American sleep societies
Name
The Brazilian Sleep Society (The Associacao Brasileira do Sono (ABS)
The Argentinian Sleep Association (Asociacion Argentina de Medicina del Sueno [AAMS])
The Chilean Sleep Society (Sociedad Chilena de Medicina del Sueno) [SOCHIMES])
The Mexican Sleep Society (Sociedad Mexicana para la Investigacion y Medicina del Sueno [SMIMS]) The Colombian Sleep Society (Asociacion Colombiana de Medicina del Sueno [ACMES])
The Uruguayan Sleep Society (La Sociedad Uruguaya de Investigaciones del Sueno [SUIDES])
The Peruvian Sleep Society (Asociacion Peruana de Medicina del Sueno [APEMES])

The Ecuadorian Sleep Society (La Sociedad Equadoriana de Medicina del Sueno [SEMES]) The Bolivian Sleep Society (la Asociacion Boliviana de Medicina del Sueno [ABOMES])

Year 1985

1995

2006

1997

1999

2001

2007

1986

1987

1990

1991

1992

1993

1994

1999

2010

2011

founded

developing and running sleep laboratories, however, neu- rologists, psychiatrists, otolaryngologists, and dentists had been increasingly interested in practicing sleep medicine. In absence of guidelines with strict enforcement, sleep labora- tories had been popping up in a variety of hospitals, nursing homes, and diagnostic centers to diagnose and treat sleep apnea with positive pressure therapy using continuous posi- tive airway pressure (CPAP) equipment. It is hoped that this situation will soon be rectified because the standardization and certification process in sleep medicine are underway. There are some 120 sleep laboratories across India (a trivial number in a country with more than a billion population) with over 20 in Delhi. Most of the sleep-related activities initially happened in New Delhi quickly followed by centers and laboratories in Chennai, Mumbai, Kolkata, Kerala, Ban-

galore, and Hyderabad. The initial push for sleep medicine came from basic scientists led by Dr. V Mohan Kumar at the All India Institute of Medical Sciences (AIIMS) in New Delhi with the founding of the Indian Society for Sleep Re- search (ISSR) in 1992. It is notable that as early as 1934, when sleep medicine was in its infancy, Dr. Dixshit had pro- vided experimental evidence to show the existence of sleep center in the hypothalamus [4]. The clinicians did not wait too long to spread the mission of promoting clinical sleep medicine. In these efforts Dr. JC Suri, Head of the Depart- ment of Pulmonary, Critical Care and Sleep Medicine at Safdarjung Hospital, Delhi where the first sleep laboratory of the country was established, took the lead in founding the Clinical Sleep Medicine Society, the Indian Sleep Disorders Association (ISDA) in 1995. Dr. Suri became the founding

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135

Table 18.3 Asian sleep societies

Name of the organization

The Asian Sleep Research Society (ASRS)

The Indian Society for Sleep Research (ISSR)

The Indian Sleep Disorders Association (ISDA)

The Israel Sleep Medicine Association (ISMA)

The Israel Sleep Research Society (ISRS)

The Japanese Society of Sleep Research (JSSR)

The Chinese Sleep Research Society (CSRS)

The Korean Society of Sleep Medicine (KSSM)

The Taiwan Sleep Society (TSS)

The Hong Kong Society of Sleep Medicine (HKSS)

The Thailand Sleep Medicine Society (TSMS)

The Singapore Sleep Research Society (SSRS) The Palestinian Sleep Medicine Society (PSMS)

Name of organization

World Federation of Sleep Research Society (WFSRS)
WFSRS was renamed to World Federation of Sleep Research and Sleep Medicine Societies (WFSRSMS)
WFSRSMS later adopted an abbreviated name, World Sleep Federation (WSF)

World Association of Sleep Medicine (WASM)

World Congress on Sleep Apnea (WCS) International Pediatric Sleep Association (IPSA)

Year founded

1994

1992

1995

1977

1994

2010

Year founded

1987 2006

2008

2003

1985

2005

Table 18.4

societies

International sleep

president. Since 1996, the ISDA has been organizing annual meetings and courses under the heading “Sleepcon” at vari- ous cities across the country, and inviting foreign dignitaries from USA, UK, Canada, Israel, China, Europe, Japan, and Australia, including the present writer (Sudhansu Chokro- verty), Drs. Christian Guilleminault, Robert Thomas, Clau- dia Trenkwalder, Patrick Strollo, and Neal Douglas. The other significant activities of the ISDA include introduction of fellowships and conferring diploma in sleep medicine after successfully completing a certification examination, and initiation of a sleep technologists’ certification examina- tion.

Drs. Garima Shukla and Manvir Bhatia, two neurologists from the AIIMS in New Delhi quickly joined Dr. Suri and other physicians in the late 1990s in promoting sleep medi- cine by organizing symposia and courses. Soon, Dr. Anand Kumar at Amrita Institute of Medical Sciences (AIMS) in Cochi, Kerala, Dr. Suresh Kumar, and later Dr. N. Ramak- rishnan from Chennai began organizing symposia with par- ticipation by sleep specialists from the USA (Drs. Sudhansu Chokroverty, Wayne Hening, Robert Thomas) and other foreign countries. In these endeavors, WASM actively col- laborated with the Indian sleep specialists to promote sleep health throughout India and other parts of the world. Cur- rently, most of the major cities including Kolkata (the city where I grew up) are actively practicing and promoting sleep disorders medicine. As in other parts of the world pulmon- ologists took lead in establishing sleep laboratories and clin- ics in Kolkata and unfortunately, most of the senior neurolo-

gists there showed a distinct lack of interest in sleep medi- cine but the junior neurologists are increasingly becoming interested in understanding the basic and clinical science of sleep which is very encouraging. Dr Dhrubajyoti Roy, a pul- monary-sleep specialist at PULSAR clinic in Kolkata, took the lead on behalf of ISDA and Indian Chest Society (ICS) in organizing educational activities. India is on the move and I am very optimistic that sleep medicine will be in the fore- front of medical science there in not too distant future.

Sleep Medicine in China

Sleep medicine is still in its infancy in China, but because of increasing interest and awareness amongst physicians and the public, the field has been growing rapidly in the last de- cade [5]. There are two major sleep medicine organizations in China: One based on the modern Western tradition (Al- lopathic Medicine) is the Chinese Sleep Research Society (CSRS) and the other based on Traditional Chinese Medi- cine (TCM) is the TCM Sleep Medicine Society. The CSRS was founded in 1994 and initially was fragmented but later became truly multidisciplinary encompassing members from pulmonary medicine, psychology, ENT, physiology, neuro- science, basic science, and other fields interested in sleep medicine. This society is affiliated with China Association for Science and Technology and has been expanding and pro- moting the integration and development of clinical and basic sleep science. There are more than 1500 sleep centers in

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China (small number considering a population of over a bil- lion), mostly in major cities like Beijing, Shanghai, Guang- zhou, Nanjing, Xi’an. CSRS holds its academic meeting every 2 years with participation from many foreign coun- tries including members of the WASM (e.g., Drs. Christian Guilleminault, Sudhansu Chokroverty, Kingman Strohl, and others). There are, however, no standard guidelines, training program, or certification to assess minimal competence to practice sleep medicine. The practice of modern sleep medi- cine in China actually started with the first recognition of sleep apnea in a patient in 1981 by Dr. Xi-Zhen Huang of Pe- king Union Hospital [5]. Dr. Huang has rightly been recog- nized as the founder and the mother of Chinese Sleep Medi- cine. Dr. Huang’s group designed the first polysomnographic system from the existing electroencephalography (EEG) ma- chine in 1983. Dr. Huang also set up the first sleep laboratory in China in 1986 after completing six months of training in sleep medicine at Stanford University in the USA. She is also actively involved in WASM activities being a member of the program committee of the 2nd WASM Congress in 2007. The contemporary physicians contributing significant- ly toward growth and development of clinical sleep medicine in China include Drs. Yuping Wang, Chairman of Neurology Department at Xuanwu Hospital, Peking University, Beijing; Fang Han at the Department of pulmonary medicine, The People’s Hospital, Peking University, Beijing; Han Denim, Chairman of Otolaryngology at Peking University, Beijing; Shen Xiaoming, a pediatrician at Shangai Children’s Medi- cal Center affiliated with Shangai Jiao Tong University’s School of Medicine; and Yuoming Luo at the department of pulmonary medicine, Guanzhou General Hospital in addi- tion to numerous other multidisciplinary physicians in dif- ferent universities throughout China. It is interesting to note that the first continuous positive airway pressure (CPAP) machine was used in 1987 in China and in 1995 China began to use its own homemade CPAP machines.

The man spearheading promotion of TCM sleep medi- cine in China is Professor Weidong Wang of Beijing Guang’anmen Hospital with the founding of the Internation- al Sleep Medicine Society of Traditional and Modern Medi- cine (ISMSTM). Professor Wang had been ably assisted by many doctors including Wang Fang (Jenny) and others at Guang’anmen Hospital. At the second ISMSTM meet- ing in 2008, several WASM members (e.g., Drs. Sudhansu Chokroverty, Christian Guilleminalt, Wayne Hening, and Arthur Walters) were invited. Three years later, Professor Wang founded the World Sleep Medicine Association hold- ing the first TCM Congress in Beijing. TCM sleep medicine provides a different philosophical perspective to the general population, practitioners, and researchers.

Sleep Medicine in Other Parts of Asia

Sleep medicine (both clinical and basic science) in Israel is at par with that in the USA and Western Europe. It has its own Research and Clinical Sleep Medicine Societies (See Table 18.3). Drs. Peritz Lavie and Jean Askenasy are two prominent sleep scientists and clinicians who have played a significant role in elevating the standard of sleep medicine in Israel.

Sleep medicine is well advanced in South Korea with an established society, Korean Society of Sleep Medicine (KSSM) whose members are derived from multiple disci- plines (e.g., neurology, pulmonary, psychiatry, psychology, ENT, etc). The society conducts regular meetings with par- ticipation of foreign sleep specialists. In 2010, KSSM es- tablished its own journal. KSSM collaborate with WASM in organizing the sixth WASM World Congress in Seoul on March 21 to March 25, 2015. Besides Dr. Seung Bong Hong, several other prominent sleep physicians (e.g., Drs. Seung Chul Hong, Chul Hee Lee, Chol Shin, Jung Hie Lee, and others) took the lead in promoting sleep medicine in South Korea.

Taiwan, Hong Kong, Singapore, Thailand, and Malaysia have made great strides in sleep medicine and have been trying to promote sleep medicine by conducting research, publishing in peer-reviewed journals and trying to practice high-standard patient care. Most of these places, however, lack standard guidelines and certification process in sleep medicine. Thailand is very active in sleep medicine and re- search and is being spearheaded by Dr. Nick Kotchabhakdi. Thailand Sleep Society (TSS) was the local organizer for the second WASM Congress in Bangkok in 2007. TSS also or- ganized International Sleep Brain and Behavior Symposium with participation by foreign delegates including several ac- tive WASM members.

Sleep Medicine in Africa

Sleep medicine has not been a top priority accounting for a lack of growth and development in continental Africa except in South Africa and later in Egypt. Sleep Society of South Africa (SSSA) was established early in 1992 but the speed of growth has been rather sluggish [6]. Dr. Alyson Bentley of Johannesburg (a member of the WASM governing council from 2003–2011) played an important role in pushing for sleep medicine in that region. Later Dr. Tarek Asaad, Profes- sor of Psychiatry at the Institute of Psychiatry in Ain Shams University in Cairo, Egypt, began to organize symposia and courses in sleep medicine in order to stimulate public and

18 Sleep Medicine Around the World (Beyond North American and European Continents, and Japan) 137

professionals’ interest in understanding sleep and its disor- ders which may have serious consequences for individu- als and society. Several other individuals in Cairo, Egypt (e.g., Drs. Lamia Afifi, Shahira Loza), had been devoting their time and effort to promote sleep medicine in Africa. In 2011, Dr. Afifi was elected to the WASM governing council to represent Africa which opened an opportunity for her to promote sleep medicine there through WASM activities. In 2013, at the fifth WASM congress in Valencia, Spain, Dr. Loza replaced Dr. Afifi as the WASM Governing Council member to represent Africa. When I visited Ain Shams Uni- versity in Cairo in 2010 just before the Arab Spring and rev- olution began to spread, I saw a great deal of interest and en- thusiasm for sleep medicine there. Unfortunately, spread of people’s unrest subsequently impeded the rapid and progres- sive growth of sleep medicine. It is hoped that the leaders in South Africa and Egypt realizing the importance of sleep health will be able to overcome the obstacles to stimulate public and the profession to be aware of the importance of a good night’s sleep and adverse consequences in its absence.

Sleep Medicine in Australia and New Zealand

Australia and New Zealand have strict training requirements in sleep medicine certification without an exit examination [7]. These two countries have high standard of practice of sleep medicine concentrated mostly in major cities. It is important to remember that the recommended treatment of moderate to severe obstructive sleep apnea syndrome (OSAS) is upper airway pressurization using CPAP equip- ment which was invented by Dr. Colin Sullivan, a pulmo- nologist from Sydney, Australia in 1981. Naturally, there is a major emphasis on sleep apnea treatment, research, and education in Australia. The Australasian Sleep Association (ASA) was founded in 1999.

International Sleep Societies

Currently, there are four major organizations dealing with dissemination of knowledge in sleep medicine and research worldwide (Table 18.4).

The World Federation of Sleep Research Society

The World Federation of Sleep Research Society (WFSRS) was founded in 1987 to represent international sleep research- ers. Dr. Michel Chase, a noted basic scientist from Califor- nia, USA making fundamental contributions in understand- ing rapid eye movement (REM) sleep atonia mechanism, and other basic sleep research took the lead in founding the

Federation. Since founding the organization, the Federation had been conducting quadrennial congress to promote sleep medicine to the international community. In 2006, WFSRS changed its name to World Federation of Sleep Research and Sleep Medicine Societies (WFSRSM) driven by the com- petitive incentive from other organizations and to reflect its involvement in clinical besides basic science research in sleep medicine. In 2008, however, the governing council de- cided to use the abbreviated name of World Sleep Federation (WSF) to circumvent the cumbersome and perceived media unfriendly name of WFSRSM. The WSF is composed of the continental and two regional member societies, ESRS, SRS, AASM, ASRS, ASA, LASS, JSRS, and SSC unlike other international organizations catering to individual members rather than sleep societies.

The World Association of Sleep Medicine

The idea for forming a world association for the sleep clini- cians came from Dr. Sudhansu Chokroverty (the author of this chapter) who floated the concept in Parma, Italy in No- vember 2001 during the first international EEG cyclic alter- nating pattern (CAP) meeting organized by Professor Mario Terzano assisted by Dr. Liborio Parrino [8]. The response was sufficiently encouraging to move ahead. We sent an invi- tation to many sleep clinicians in each continent of the world and organized a planning meeting to found a new WASM on June 11, 2002, in the Hilton Hotel during the APSS annual meeting in Seattle, Washington State, USA. During the plan- ning meeting, Dr. Chokroverty (the present author) gave an introductory statement explaining the rationale and mission. Most spoke in favor of the formation of a new world body, catering to the sleep clinicians. Few, however, had reserva- tion about starting another new world organization.

WASM was chosen as the best name for the new organi- zation by those present at the planning meeting. The found- ing members (39) at the planning meeting (those who agreed to be members and indicated so by signing the agreement) elected a bylaws committee chaired by Dr. Wayne Hening with members drawn from the USA, Europe, and Asia. Be- tween June 2002 and June 2003, the bylaws committee de- veloped the bylaws, which had been revised several times after receiving comments from the initial founding members.

Next, an organizational meeting was held on June 6, 2003, at the Swissotel, Chicago, Illinois, USA, to officially found the WASM during the APSS meeting. The founding members (39 from the initial planning meeting) and those present at the organizational meeting (an additional 29) for a total of 68 members voted to accept the final version of the WASM bylaws, requiring biennial meetings and incorporat- ing the organization in Kassel, Germany. By a secret ballot, the founding members voted for the officers of the WASM

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executive committee for a 2-year term as follows: President, Dr. Sudhansu Chokroverty; President Elect, Dr. Markku Partinen; Secretary, Dr. Richard Allen; and Treasurer, Dr. Claudia Trenkwalder.

On a beautiful bright Saturday morning (June 7, 2003), the officers of the executive committee and the chair of the bylaws committee went to the German consular office on Chicago’s Michigan Avenue to ratify the bylaws to officially found WASM with the office incorporated in Kassel, Ger- many.

In course of the next few years, WASM captured the enthusiasm and strong support from many sleep clinicians throughout the globe who embraced WASM as an exciting international organization. WASM had six very successful world congresses: The first one was in Berlin, Europe, in 2005; the second one was in 2007 in Bangkok, Thailand; the third congress was in 2009 in Sao Paulo, Brazil; the fourth one was in 2011 in Quebec City, Quebec, Canada; the fifth one was in 2013 in Valencia (Spain) and the sixth one in Seoul, South Korea, on March 21–25, 2015.

WASM has a noble mission of promoting sleep medicine and sleep health throughout the globe, particularly in those parts of the world where sleep medicine has not sufficiently progressed (our mission and bylaws are available on the In- ternet at the Web site address: http://www.WASMonline.org).

WASM has an affiliated journal—Sleep Medicine, an in- ternational journal—published by Elsevier Publishing Com- pany in Amsterdam, Europe. The journal was founded in 2000 and Dr. Sudhansu Chokroverty is the founding editor in chief. Initially, the journal was published 4 times a year and the frequency of publication was increased to 6, then 8, 10, and currently 12 issues a year. WASM has established two awards for young investigators: The Christian Guil- leminault WASM-Elsevier Award for Sleep Research and Elio Lugaresi WASM-Elsevier Award for Sleep Medicine. WASM had sponsored regional workshops and endorsed meetings in different parts of the world. WASM developed WASM—International Restless Legs Syndrome Study Group (IRLSSG) guidelines for periodic limb movements in sleep (PLMS) and periodic limb movements in wakefulness (PLMW) (published in Sleep Medicine in 2006).WASM has developed educational guidelines and international certifi- cation for practice of sleep medicine in every region of the world, taking into consideration regional concerns and cul- ture. WASM will continually encourage young physicians to develop skills in sleep science. These are the people who are the future of this world and who will be the driving force to fulfill the mission and vision of WASM. The WASM later formed a World Sleep Day (WSD) committee. WSD is an an- nual event to celebrate sleep around the globe, and it is orga- nized by the WSD Committee of the WASM. It is co-chaired by Dr. Antonio Culebras, Professor of Neurology, Syracuse University, Syracuse, New York, USA, and Dr. Liborio Par-

rino, Associate Professor of Neurology, Parma, Italy, and is assisted by several international committee members.

The idea of a “World Sleep Day (WSD),” to celebrate sleep on a particular day in the year (generally around mid- dle of March), came about during the WASM Governing council meeting at the second WASM Congress in Bangkok, Thailand, February 4th–8th in 2007.

The first WSD was held on March 14, 2008, under the slogan, “Sleep Well, Live Fully Awake.” The 2009 WSD was held on March 20 under the slogan, “Drive Alert, Ar- rive Safe.” In 2010, it was held on March 19 and the slogan was “Sleep Well, Stay Healthy.” The 2011 WSD was held on March 18 under the slogan, “Sleep Well, Grow Healthy.” The WSD in 2012 was celebrated on March 16 under the slogan, “Breathe Easily, Sleep Well.” The slogan for 2013 was “Good Sleep, Healthy Aging” and was held on March 15th, and that for 2014 was “Sleep, Easy Breathing, Healthy Body” which was held on March 14, 2014. The slogan for 2015 WSD (held on March 13, 2015) was “When sleep is sound, health and happiness abound.”

The WSD events take place primarily online at www. WorldSleepDay.org, featuring educational and historical videos, educational materials, and public service announce- ments. WSD has grown steadily since its inception and cur- rently has over 120 WSD delegates spreading awareness of sleep issues in over 50 countries around the globe. These delegates contact local media, organize public awareness events, host conferences, translate WSD materials in differ- ent languages, and much more.

World Congress on Sleep Apnea (WCS) This interna- tional organization was founded in 1985 by a group of sleep specialists interested in increasing awareness of the interna- tional community about a common but often undiagnosed or under-diagnosed condition of sleep apnea and its adverse (short-term and long-term) consequences. The WCS has been conducting an international meeting every 3 years in different parts of the world with participation of sleep spe- cialists catering to patients with sleep apnea to highlight important areas of research in sleep apnea. The ninth WCS Congress was held in Seoul, South Korea on March 25–28, 2009, and the tenth Congress was held in Rome on August 27–September 1, 2012. Many WASM members including the present writer and Dr. Christian Guilleminault as well as WSF members had participated in these meetings as invited delegates.

International Pediatric Sleep Association

This international association originated as an offshoot from the European Pediatric Sleep Club (EPSC) and the IPSA was founded in 2005 (See also Chap. 54) following the val-

18 Sleep Medicine Around the World (Beyond North American and European Continents, and Japan) 139

iant efforts of Professor Andre Kahn of Belgium assisted by many noted pediatric sleep clinicians from Europe includ- ing Dr. Oliviero Bruni of Rome. Sadly, Andre Kahn died prematurely in 2004 before the actual founding of the IPSA on October 13, 2005, following the first congress of the WASM in Berlin. The IPSA decided to affiliate with Sleep Medicine journal which has already been an affiliate journal of the WASM. Initially, IPSA met during WASM congress but in 2010 the second IPSA Congress was organized sepa- rately by Oliviero Bruni in Rome which was a huge success. IPSA continued its meeting every 2 years in different parts of the world. The third IPSA meeting was held in Manchester, England in 2012, and the fourth meeting was held in 2014 in Porto Alegre in Brazil.

References

1. Averbuch M, Paez S, Meza M, Pedemonte M, Velluti R, Escobar F, et al. Current status of Latin American sleep societies. Sleep Sci. 2011;4(1):34–6.

2. Osuna E. Sleep medicine in South America. In: Sleep health around

the world [Internet]. 2006;1(1):15. http//www.friglobalevents.com/

wasmonline/PDF/WASM_Newsletter_2_final.pdf 2006:1(1):15.

Accessed 12 Jan 2011.
3. Shukla G, Bhatia M. The sleep scenario in India. In: Sleep health

around the world [Internet]. 2006;1(1):15. http//www.frigloba- levents.com/wasmonline/PDF/WASM_Newsletter_2_final.pdf 2006:1(1):15. Accessed 12 Jan 2011.

4. Dikshit VV. Action of acetylcholine on the “sleep center”. J Physiol. 1934;83:42–….

5. Han F. Development of modern sleep medicine in China. In: Sleep health around the world [Internet]. 2006;1(1):15. http//www.friglo- balevents.com/wasmonline/PDF/WASM_Newsletter_2_final.pdf 2006:1(1):15. Accessed 12 Jan 2011.

6. Bentley AJ. Sleep medicine in South Africa. In: Sleep health around the world [Internet]. 2006;1(1):15. http//www.friglobalevents.com/was- monline/PDF/WASM_Newsletter_2_final.pdf 2006:1(1):15. Accessed 12 Jan 2011.

7. Cunnington D. Sleep medicine training in Australia and New Zea-

land. In: Sleep health around the world [Internet]. 2007;(1):12.

http://www.friglobalevents.com/wasmonline/PDF/WASM_News-

letter_2_final.pdf. Accessed 12 Jan 2011.
8. Chokroverty S. Historical milestones. In: Sleep health around the world

[Internet]. 2006;1(1):15. http//www.friglobalevents.com/wasmonline/

PDF/WASM_Newsletter_2_final.pdf 2006:1(1):15. Accessed 12 Jan 2011.

Part V Sleep Disorders in Historic Diseases

Cholera

Donatien Moukassa, Obengui and Jean-Rosaire Ibara

Cholera is a highly contagious acute intestinal infection that is speci c to humans. It is caused by a Gram-negative bacte- rium belonging to the 0:1 or 0:139 Vibrio cholerae serotypes. The pathogen bears an endotoxin that provokes cataclysmic diarrhea causing severe dehydration that may trigger shock. If untreated, cholera proves to be fatal in 25–30 % of cases. Treatment, especially rehydration, reduces the mortality rate to less than 1 % [1].

Early descriptions date back to the beginning of the six- teenth century, but cholera epidemics only started in the nineteenth century. The disease spread out across all con- tinents, sometimes implying devastating demographic con- sequences. Since its first occurrence in Sub-Saharan Africa in 1971, cholera has become endemic and epidemic in sub- Saharan Africa. Nowadays, cholera represents a real public health problem in large African cities where refugees con- centrate after fleeing away from wars and political unrest.

Although, the current volume is concerned with the im- pact of diseases in sleep medicine, no scientific reports have been made on cholera and sleep to our knowledge, except anecdotal observations.

Natural History of Cholera

D. Moukassa ()
Medical and Morphology Laboratory, Loandjili General Hospital, Pointe-Noire, Congo
e-mail: donatienmoukassa@gmail.com

Obengui

Department of Infectious Disease, University Hospital of Brazzaville, Congo

J.-R. Ibara

Department of Gastroenterology and Medicine, University Hospital of Brazzaville, Congo

The Growth of Epidemic Waves into Pandemics (Sixteenth Century to Twenty-first Century)

Historically, the first case of cholera was reported in 1503 in one of the Vasco de Gama officers. The outbreak of profuse cataclysmic diarrhea became rapidly fatal to some 20,000 individuals in Calicut, India [2]. For more than three centu- ries, cholera was confined to Asia (India, China, and Indone- sia). From the delta of the Ganges in the nineteenth century, cholera spread out in a pandemic manner to Europe, North Africa, and the Americas (Table 19.1), killing millions of in- dividuals.

The seventh epidemic hit sub-Saharan Africa in 1971. Since initial reports, several epidemic outbreaks were re- ported. The recent Congo–Brazzaville (2009–2013) epidem- ic is illustrated in Table 19.2. The epidemic spread widely in the Likouala region—an area where forestry alternates with marshes drained by large rivers (Likouala aux herbes, Sang- ha, Likouala Mossaka, Oubangui). It affected populations living in scattered villages and campsites. The epidemic was less active in the Cuvette and Plateaux regions. The outbreak concentrated in the large cities of Brazzaville (in 2009 and 2012) and Pointe-Noire (2012–2013). The number of casu- alties was greater in Brazzaville than in other cities, despite modern hospital facilities. This paradox may be linked to the degraded environment created by poor water supply and sanitation.

Vibrio cholerae and Pathogenicity

Vibrio cholerae was discovered by Filippo Pacini in 1854 [3, 4], but the bacterium microscopic structure was only specified by Robert Koch in 1884 [3] in Calcutta, India. Koch linked his Bacillus komma to cholera. In 1885, Ferran proposed the concept of cholera vaccine for humans [5]. In 1894, Pfeiffer initiated the concept of “endotoxin” released

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_19, 143 © Springer Science+Business Media, LLC 2015

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D. Moukassa et al.

Table 19.1

Dates

1817–1825

1826–1841

1846–1861

1863–1876

1883–1896

1899–1923

1961 on

Table 19.2

Region

The seven cholera epidemics

Geographical reaches

Asia and East Africa, spreading to Russia and Europe in 1823

Spreading from Mecca to Egypt, Europe and Algeria

Spreading from China to Maghreb, crossed the Atlantic to Latin America

Starting from India and China, invading Europe via the French troops coming back from Indochina, and reaching the United States, Latin America, Russia and Poland (1866), and North Africa

Starting from India

Spread from Asia to Russia, and Central and Eastern Europe

Starting from Indonesia, generalized to Asia (1962), India (1964), Middle East (1966) and Eastern Europe (1970), and Latin America (1991). The epidemics reached sub-Saharan Africa (1970), extended to the Great Lakes region (1973) and generalized to the whole continent (1979)

Epidemiological situation during the Congo outbreaks (2009-2013)

Public health measures and particular events

The 1851 International Health Conference edited hygiene measures that allowed to spare the United States and England

Helped by the opening of the Suez Canal (1863), by the Secession War and by population displacements in Eastern Europe

Bouchet observes the bacteria. Koch describes its characteristics. Ferran proposes the first vaccine

The new extension to Latin America came after almost a century free of the disease. It has been attributed to climatic disasters

Likouala 154,115

Cuvette 156,044

Plateaux 174,591

Brazzaville 1,373,382

Pointe-Noire 715,334

Total 2,573,466

479.5

38.5

49.8

13.1

33.6

50.7

Casualties Proportion of casualties (% of cholera cases)

22 3.0

1 1.7

4 4.6

9 5.0

8 3.3

44 3.4

of cases remained low in America (36 cases, with 5 cases in the USA, and 3 cases in Canada), and 7 European countries reported only 21 imported cases (13 in UK).

The number of reported cases increased to 230,000 in 2006 with approximately 6000 deaths [11]. However, the true incidence is probably higher.

Factors Favoring Outbreaks (OMS [24])

Cholera outbreaks are favored by degraded environments. Natural climatic disasters have been followed by epidemics, such as in Haiti after the 2010 earthquake [11], in Central America after Hurricane Mitch (1998), and in Mozambique after large floods in 2000. The El Nino phenomenon may have been at the origin of the Horn of Africa outbreaks in 1997–1998 [11].

Civil war or political unrest may also favor cholera out- breaks. A massive outbreak (58,000 cases and 4200 deaths) hit Rwandan refugee camps in Goma, Democratic Republic of Congo in 1994. Wars favored the appearance of cholera in Darfur, worsened the 1997 and 1998 outbreaks in the Horn of Africa, and caused outbreaks in Kabul (Afghanistan).

Degraded environments, favored by the anarchic devel- opment of metropolitan cities, where water supply and treat- ment are often deficient, contribute to cholera outbreaks.

Population

Cholera cases

739

180

240

1306

Incidence per 100,000

by the Vibrio cholerae membrane. The choleragen toxin was identified in the 1950s in India and was purified and crystal- lized by Finkelstein in 1969 [4, 6, 7]. The bactericidal action of the waters of the Ganges River was described in 1896, es- pecially on Vibrio cholerae [8]. The El Tor biotype was dis- covered in 1905 from pilgrim corpses in the Sinai. Between 1907 and 1920 in Indela, Sir Leonard Rogers rehydrated the patients with intravenous hypertonic saline, which signifi- cantly changed the death toll of patients from 60–70 % to 3–0 %. In 1911, a cholera epidemic was stopped in Marseille by water chlorination. In 1931, Hérelle and Eliava marketed the first anticholera Tbilisi phages [1, 8, 9].

Descriptive Epidemiology

Incidence (OMS [10])

Nearly all developing countries are dealing with a cholera outbreak or threat of an epidemic. According to the World Health Organization (WHO) [10], in 2003, 45 countries re- ported a total of 111,575 cases and 1984 deaths (CFR 1.7 %). African cases amounted to 108,067, representing 96 % of the world incidence. In 2004, 56 countries reported 101,389 cases and 2,345 deaths (CFR 2.31 %). Although the number of cases had decreased by 9 % compared to 2003, the num- ber of deaths had increased by 24 %. In contrast, the number

19 Cholera

145

Analytical Epidemiology [10, 12, 13, 14]

The pathogen is a slightly curved, mobile, 2–3-μm-long, Gram-negative bacterium. It favors a pH 8 milieu at 37 °C and dislikes heat, cold, and acidity. It is sensitive to antisep- tics and many antibiotics (including cyclins). It may survive for weeks in shaded fecal matters and 10–15 days in the host. The El Tor biotype of Vibrio cholerae, the agent of current outbreaks, has the greatest vitality compared to conventional cholerae and albensis biotypes.

Serotypes 0:1 and 0:139 of El Tor Vibrio cholerae cause outbreaks, the latter having appeared in Bangladesh in 1992. Three 0:1 serotypes combine the A, B, and C antigenic LPS: Ogawa (AB), Inaba (AC), and Hikojima (ABC). Ogawa and Inaba serotypes are mostly responsible for the seventh pan- demic, [8] Inaba being responsible for Congo outbreaks.

Factors Leading to Contamination [14, 15]

Genetic Factors

In patients well equipped with intestinal gangliosides (re- ceivers), the incubation period is shorter and the symptoms of cholera are more serious. Alkaline pH multiplies by 40 the risk of severity of cholera (alkalizing consumers, gastrecto- mized, or vagotomized patients).

Environmental Factors

Vibrio reservoirs are represented by humans and aquatic environments favorable to algal blooms (plankton), such as blackish waters and estuaries. The ongoing climatic warming might create a favorable environment for Vibrio cholerae.

Socio–Economic and Demographic Factors

The disease occurs mainly in individuals with poor living conditions, especially in highly populated human concentra- tions with inadequate water sanitation.

Pathogenic Mechanisms and Tissue Repercussions [14]

The vibrios are ingested through contaminated water and food or through direct contact with patients or carriers. The bacteria multiply in the lumen mucus layer of the small in- testine, and adhere intimately to the brush border of entero- cytes of type 4 pili. Diarrhea is due to the in situ secretion of the vibrio exotoxin.

Immunity against Vibrio cholerae is primarily humoral and short-lasting (2–3 years), being related to the reaction of colonized Peyer’s patches that secrete immunoglobulin A (IgA) and immunoglobulin G (IgG)—immunoglobulins in the intestinal lumen. Serum antibodies peak in the second week postinfection and disappear in 4 weeks.

Lungs, liver, and kidney may host Vibrio cholerae toxin, provoking specific symptoms. The brain involvement is less documented.

Clinical Symptoms and Time Course [14]

All infected patients do not necessarily develop cholera. When it occurs, the disease is mild in 90 % of cases, typical cholera occurring in less than 10 % of cases.

Silent incubation averages 3 days. Epigastric gurgling precedes a sudden and abundant emission of feces and vom- iting. Within 1–2 h, profuse watery colorless rice-water-like diarrhea and vomiting occur repeatedly. They will eventually flow continuously through the anal sphincter and mouth. The odor is bland. The cyanotic and hypothermic (36 °C) patient suffers intense asthenia and muscle cramps. Appreciating the degree of dehydration is crucial, and Table 19.3 lists the cri- teria for estimating the degree of dehydration.

Untreated, 25–30 % of cholera patients may die from car- diovascular collapse within 1–3 days. Mortality is higher in children, elderly, and malnourished individuals.

The risk of fatal outcome reduces once the patient gets rehydrated quickly (1–5 % of body weight). Healing is com- pleted in 2–3 days without complications or sequels and re- covery is rapid. Acute renal failure with anuria complicating acute tubulopathy by hypovolemic shock is rare. Metabolic acidosis due to rapid loss of bicarbonate and hypokalemia

Table 19.3

Degree of dehydra-

tion

Light

Medium

Severe

Criteria for estimating the degree of dehydration in cholera patients

Body weight

loss

Skin fold Eye retrac- sockets tion

Eye balls Breathing Voice Mental Radial Blood Urine state pulse pressure output

Normal Normal Normal Normal Normal Normal Normal

6% Rapid Normal

6–10 % Slowed Hollow

>10 % Very slow Sunken

Hollow Deep

Dug in Deep and rapid

Hoarse

Inaudible

Restless- ness

Rapid and weak

Normal or Decreased lowered

Low, Oliguria immea-

surable

146

D. Moukassa et al.

following vomiting must be corrected rapidly to avoid para- lytic ileus.

In children, impaired consciousness or seizures may be observed, along with a rapid development of oliguria or an- uria.

Benign forms may appear as acute gastroenteritis with nonfebrile banal vomiting and diarrhea. The abortive form starts as an apparently severe form, but the patient heals spontaneously. Vomiting ceases first allowing rehydration through drinking and feeding. Diarrhea persists for several days, but diuresis recovers and general condition improves. The occurrence of a 38 °C temperature with hot sweats is of good prognosis. However, secondary collapses and cerebral involvement with agitation and delusions are possible.

The dramatic dry cholera is characterized by sudden death occurring in an asymptomatic patient.

Differential Diagnosis [14]

The differential diagnosis includes all causes of bacterial, viral, and parasitic choleriform syndrome. Cholera-like symptoms may be observed in food poisoning due to infec- tion with staphylococcus, salmonella, campylobacter, and anguilules. In children, such symptoms may be observed in rotavirus and enterotoxinogenic Escherichia coli infections.

Particular Emphasis on Cholera and Sleep Disorders

The influence of infectious factors on sleep has been stressed for the last 30 years [16]. Pyrogenic bacterial factors are also somnogenic. Muramyl dipeptides and lipopolysaccharide (LPS or endotoxin) trigger the host immune system release of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferon-β (IFN-β) or interleukin-1 (IL-1), lead- ing to sleep architectural changes. However, as in most other bacterial infections [17], no objective data are available.

Dehydration may also trigger sleep changes, as in military training, impairing performance and mood, promoting fa- tigue and provoking confusion, depression, and tension [18]. Increased slow-wave sleep after exercise has been related to body temperature elevation [19]. However, such an elevation is lowered by rehydration after exercise [20], agreeing with the fact that rehydration limits exercise-induced hyperther- mia [21].

Cholera is accompanied by the release of endotoxin and by dramatic water loss. Sleep–wake disorders may therefore occur in patients with cholera. While we were preparing this chapter, a cholera outbreak struck Pointe-Noire. Sleep disorders were investigated in 36 patients using the sleep diary proposed by Bastuji and Jouvet [22]. Figure 19.1 is a

demonstrative example of the major disorganization of the sleep–wake cycle in patients with cholera. They sleep in short bouts that alternate with wakeful bouts during which they can drink and feed. Unfortunately, polysomnography cannot be undertaken in such isolated and highly infectious and toxic patients.

Biological Diagnosis [14]

After confirmation of the first cases at the beginning of the cholera epidemic, the bacteriological diagnosis requires five steps: (I) sampling, (II) transport, (III) direct examination, (IV) culture, and (V) identification.

Sampling is done in several ways, using either swabs, or blotting paper immersed in the feces (Barua’s method: The blotting paper is sealed in plastic bags with a cellophane membrane to prevent desiccation) or feces samples.

Samples must be transported directly to the closest labo- ratory. It can also be transferred at 37°C in liquid (peptone water) or solid Blair’s media (taurocholate tellurite peptone).

Direct microscopic examination of a fresh sample reveals suspect mobility. Gram stain will show curved Gram -nega- tive bacilli.

The pathogen may be cultured. After 6 h of incubation at 37 °C, bacteria are seeded in the middle of a Petri’s box containing either gelose teepol (bacteria will grow in 2 h) or TCBS buffer (thiosulfate-citrate-bile-sucrose; bacteria will grow in 12 h).

The agglutination technique using polyvalent anti 0:1 and anti 0:139 sera, followed by monovalent anti-Ogawa, anti- Inaba, and anti-Hikojima sera may be employed to identify the pathogen.

In field campaigns and refugee camps, rapid immuno- chromatography-based strip tests may replace microscopic examination. Simply dipped in a feces sample, the strip will show one or two red lines within 2–5 min (1 line = negative, 2 = positive). Specificity of strip test is 84–100 %, sensitivity 94–100 %.

Treatment [23]

Curative Treatment

Treatment aims at controlling dehydration and its conse- quences and eliminating Vibrio cholerae from the gastroin- testinal tract. Rehydration with Ringer lactate can be com- bined with isotonic saline (SSI) and serum bicarbonate 14 % (2/3 SSI + 1/3 of serum bicarbonate). As an example, in a 60-kg adult who lost 10 % of body weight, 6 l of liquid will be infused during the first 4 h: 1 l during the first 15 min, 1 l during the following 15 min, followed by 1 l in 45 min,

19 Cholera

147

Fig. 19.1 The patient was a 52-year-old guard. He entered the hospital on the 18th of January 2013, in the evening. The diagnosis of cholera was posed, due to profuse uncolored diarrhea and vomiting. Rehydra- tion and antibiotic therapy were immediately prescribed. The patient

and then 1 l hourly. Antibiotic treatment (tetraclyclines, phenicols, sulfonamides) helps breaking Vibrio cholerae portage. Antibiotics sometimes develop resistance and in that case fluoroquinolones and third-generation cephalospo- rins may be used, but their high cost is a limiting factor in countries with limited resources.

Prophylaxis

Strict prophylactic measures will be applied in the context of epidemic risk (war, population displacement, refugee camps, etc.).

When the epidemic has started and after laboratory con- firmation of the diagnosis, several steps must be taken: strict isolation of patients; disinfection of vomiting with 5 % bleach during 4 h and disinfection of feces with 4 % cre-

left the hospital. The sleep–wake cycle was disturbed during 5 days and nights, with a complete insomnia on the fourth night at the hospital. He felt good in the morning of January 23, and only slept at night. He was released the next day in the morning.

syl sodium or warm milk during 6 h; bleaching or boiling of sanitizing utensils and patient clothes; washing corpses with water and burial disinfectant and enveloping corpses in antiseptic-sprayed shrouds before burial or cremation; disinfection of floors and walls with 5 % cresyl or bleach solutions. Caregivers should be experienced to prevent the spread of germs (wearing coat with long sleeves, boots, and masks; disinfection of hands with soap, alcohol, or bleach before returning home).

Chemoprophylaxis may not be realistic as it requires treating the whole population at risk and may trigger resis- tance to antibiotics. Furthermore, antibiotic treatment effica- cy lasts 3 weeks, after which individuals become again fully susceptible to infection.

Vaccination confers unreliable and incomplete protection, which is only valid for 3–4 months in practice.

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13. Prescott LM, Bhattacharjee NK. Viability of El Tor in common foodstuffs found in an endemic cholera area. Bull World Health Organ. 1969;40(6):980–2.

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15. Constantin de Magny G, Colwell RR. Cholera and climate: a demonstrated relationship. TransAm Clin Climatol Assoc. 2009;120:119–28.

16. Krueger JM, Majde JA. Humoral links between sleep and the im- mune system. Ann NY Acad Sci. 2003;992:9–20.

17. Buguet A, Bouteille B, Cespuglio R, Chapotot F. Maladies in- fectieuses et sommeil. In: Billiard M, Dauvilliers Y, Editors. Les troubles du sommeil. Paris: Masson; 2005. pp.309–23.

18. Lieberman HR, Bathalon GP, Falco CM, Kramer FM, Morgan CA, Niro P. Severe decrements in cognition function and mood induced by sleep loss, heat, dehydration, and undernutrition dur- ing simulated combat. Biol Psychiatry. 2005;57:422–9.

19. Buguet A, Gati R, Soriba M, Melin B, Montmayeur A, Alou S, Wamba B, Bogui P, Lonsdorfer J. Exercise and sleep in a dry trop- ical climate: preliminary results in 3 subjects. Sports Med Digest. 1991;2:15–7.

20. MontmayeurA, BuguetA, Sollin H, Lacour JR. Exercise and sleep in four African sportsmen living in the Sahel. A pilot study. Int J Sports Med. 1994;15:42–5.

21. Melin B, Curé M, Jimenez C, Savourey G, Bittel J. Déshydrata- tion, réhydratation et exercice musculaire en ambiance chaude. Cah Nutr Diét. 1990;25:383–8.

22. Bastuji H, Jouvet M. Intérêt de l’agenda de sommeil pour l’étude des troubles de la vigilance. Electroencephalogr Clin Neurophysi- ol.1985;60(4):299–305.

23. Lapeyssonnie L. Chemoprophylaxis of cholera: value, ex- pectations, and limitations. Méd Trop: Rev Corps Santé Col. 1971;31(1): 127–

Encephalitis Lethargica

David Parkes

To give even an approximate complete enumeration of the publi- cations relating to encephalitis lethargica since my rst commu- nication of 17th April 1917, when I described this new disease, is impossible owing to their immense number. (Constantin von Economo) [1]

It may be stated without reservation that our knowledge of the pathogenesis of epidemic encephalitis leaves much that is obscure…there is no evidence that the disease is contagious, and no light has been thrown on the method of transmission. The therapeutic methods are symptomatic and empirical. (Frederick Tilney and Hubert Shattuck Howe) [2]

Figure 20.1 shows a picture of Constantin von Economo, (1876–1931) in 1910 [3, 4]. From 1906, he worked in the Viennese psychiatric clinic of Wagner von Jauregg, concen- trating on mental illness, neurology, neuropathology and later on the care of the war wounded. Following an elder brother’s death in the First World War, Constantin, an Aus- trian soldier and a founder of the Viennese flying club was forbidden to fly by his parents. Medicine was to gain by his monumental studies that included work on the cerebral cor- tex and on the future evolution of the brain, as well as at least 18 papers on encephalitis lethargica written between 1917 and 1920. Despite a recent review of the subject up to 2011, essential reading for all interested in one of the most unusual of all brain diseases [5, 6], von Economo’s 1929 monograph (translated into English by Newman in 1931) remains pre- eminent [7].

Constantin von Economo came to hold the title of profes- sor both of Neurology and Psychiatry in the University of Vienna. Encephalitis lethargica may have affected in total up to a million people worldwide. The disease virtually disap- peared in 1927. Vilenski suggests that perhaps only 80 cases with typical clinical features, sometimes also with chorea, dystonia, oromandibular dystonia, myoclonus or other dyski- nesia; and in some with magnetic resonance imaging (MRI)

D. Parkes ()
Clinical Neurology, The Maudsley Hospital and King’s College Hospital, London, UK
e-mail: dandsparkes@googlemail.com

scan evidence of inflammatory change in the basal ganglia and midbrain tegmentum [8] were then reported up to 2011. In 1917, the language of sleep–wake illness was still

largely derived from ancient Greek. Rapid eye movement (REM) sleep had not been discovered, and nothing was known of sleep architecture or circadian rhythms. Although the electrical activity of the brain had been studied from the late nineteenth century, electronic amplification of brain sig- nals in man had to await the 1930s development of the valve amplifier. At best, investigation of brain disease was limited to crude examination of the cerebrospinal fluid (CSF) and a test for the then ubiquitous mimic, syphilis, developed by Wassermann and Dean initially using antigen from aborted foetuses from the dustbins of Berlin.1

As a medical student in London in the 1950s, encephali- tis lethargica as an acute illness had long died out, although assumed ‘post-encephalitic’ narcolepsy and ‘post-enceph- alitic’ Parkinsonism were common topics for presenta- tion at grand rounds in the venerable surroundings of the Saturday morning demonstrations at the lecture theatre of the London Queen Square Hospital for Nervous and Men- tal diseases. Many of the demonstrators were great dem- onstrators as well as great physicians. They included the distinguished aphasiologist Macdonald Critchley, author of The Divine Banquet of the Brain [9]; a classic precursor of Oliver Sack’s Awakenings; and the neurologist MacArdle, who may himself have had a delayed sleep phase, being well known for his sometimes late arrivals as well as for his clinical acumen. Several neurologists had first made their reputation in the 1920s by their writings about epidemic encephalitis.

The demonstrations were most valuable for their teach- ing of clinical examination skills. With hindsight, wrong at- tribution of several features may not have been uncommon at the time when a formal discipline of sleep medicine did

1 As frequently recounted by Dean to medical students when professor of pathology at Cambridge in the 1950s. I can find no written evidence however.

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_20, 149 © Springer Science+Business Media, LLC 2015

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Fig. 20.1 Constantin von Economo (1876–1931)

not exist, and the popular name ‘sleeping sickness’ for en- cephalitis lethargica was perhaps not quite correct. However, encephalitis lethargica was one of the most fearful as well as most bizarre afflictions of the brain from 1916–1917 on- wards. It breached the previous divide between neurology and psychiatry, sanity and madness, brain and mind. Any po- tential future epidemic may highlight new areas of molecu- lar biology, epigenetics and protein chemistry in sleep–wake and consciousness research.

Two of these patients remain vividly in my memory. Both, long-term survivors of acute encephalitis, were left with the abnormal postures and involuntary movements of dystonia rather than a sleep–wake disorder. The first made a mea- gre living as a hymn-writer and the second as a curator in a London art museum. Both men had bizarre postures and gait with torsion, flexion and hyperextension of the trunk, inter- rupted by functional blindness due to spontaneous oculogy- ric crises with involuntary upward gaze. Now, such patients are no longer seen. One of the most remarkable memorials to encephalitis lethargica, emphasising movement rather than sleep disorder, can be seen in a Welcome Foundation three- minute film clip from 1924 on You Tube.

As late as 1929, SA Kinnier-Wilson, physician for out- patients at the National Hospital Queen Square thought that sleep disorders could not be alluded to as diseases, and re- ported that during one 20-year period, he had not seen a case of narcolepsy, ‘although it seemed likely that this had a simi- lar physiology to epilepsy’ [10]. Wilson, when it suited him, could be a stickler for language, objecting to the term hepa- tolenticular degeneration when used to describe the condi- tion he had first identified. When this term was used in one occasion in his presence, he is reported to have said, ‘Are you referring to my disease?’ He argued that ‘encephalitis lethargica’ was a misnomer since it was the patient, not the

illness that was lethargic.2 However, by the 1940s, Wilson had come to accept the reality of the narcoleptic syndrome as well as the nomenclature of von Economo.

At the start of the twentieth century, and at the first ap- pearance of epidemic encephalitis lethargica, sleep medicine that existed was largely confined to the study of insomnia rather than to the much less common and unusual cases where apparent sleep could be accompanied by ‘numbness’, ‘powerlessness’, ‘deadness’ or ‘apathy’ [11]. An odd epi- demic of drowsiness or ‘trance’ known as ‘Nona’ had been reported to Von Economo by his mother, but this depended largely on folk memory [12]. Excess sleep and lethargy were popularly believed to be the result of low moral fibre, signs of laziness and largely confined to black Africa or the peas- antry of Ireland. Thomas Winterbottom (1766–1859) had published his best-known work about sleep, An account of the Native Africans in the Neighbourhood of Sierra Leone in 1803, and Gelineau in his monograph of 1881 given his re- port of 14 patients with the sleep seizures of ‘narcolepsy’ and so-called catalepsie but daytime sleepiness was still largely a medical curiosity [13, 14]. Loose terminology and in particu- lar the term ‘narcolepsy’ often led to more confusion than clarity. Also, the literature of psychological medicine in the first half of the twentieth century was influenced by ideas of ‘mental’ and ‘moral’ illness, separation of ‘mind’ and ‘brain’ and not least by some of the imaginings of Freud, who was an assistant professor (1904) and then full professor (1920) of neurology in Vienna at the first appearance of encephali- tis lethargica. Case reports of this illness questioned many previous concepts of clear distinction between disease of the mind and disease of the brain.

Encephalitis Lethargica

With this background, Economo in 1917 described seven patients in a first paper, an additional four in a second, with common features of lethargy and restricted eye movement [15, 16]. The onset was acute, in a matter of hours or days with malaise, fever, headache and neck stiffness, ‘subalert- ness’, ‘reduced attention’, ‘mental dazing’, ‘somnolence’, persistent sleep bordering ‘stupor’ and then ‘unrousable’ coma. One subject was a somnambulist, another fell asleep ‘whenever…standing or walking’. Yet another ‘when aroused…(was)…not alert’…with ‘attention only possible for short periods’. In contrast, another subject, a boy of 12, ‘lay awake in bed day and night’. One patient was delud- ed, and another hallucinated. There was partial or complete paralysis of eye movement, reduced or absent voluntary

2 . Perhaps it should be pointed out that James Parkinson did not have paralysis agitans, and that the term Parkinson’s disease was first used by Charcot.

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up-gaze and ‘dull, half closed eyes’. The disease was severe, ending in the death of four subjects although three made an initial complete recovery over the next 3–16 weeks. Of the 11 patients, 10 were young, aged from 12 to 38 and one was aged 56.

After Economo’s descriptions, many similar cases were reported, and the disease spread worldwide over the next decade, although the presentation was very variable from case to case and from year to year. In addition to lethargy and involvement of the third, fourth, fifth and sixth nerves, Vilenski and Gilman (2011) recorded well over 50 different signs and symptoms that might be present [17]. Both sexes were equally affected. Hall (1924) considered that of each 100 cases, 25 died in the acute phase, 25 recovered prac- tically completely, and 50 went on to develop secondary symptoms after days, weeks or months of apparent recov- ery. The most serious and frequent of these included motor disorders, change of personality and mental defect, whilst ‘lethargy’ or sleep disturbances were less pronounced than at initial presentation. The pattern of late disease depended largely on the age of initial infection. Infants went on to de- velop mental defects, and children personality disorders that were sometimes accompanied by disturbed sleep—nocturnal restless behaviour continuing from the primary illness was more common or possibly more disruptive in children than in adults. The severity of secondary symptoms was largely unrelated to the severity of the initial attack, and with late so- called hypersomnia, narcolepsy and insomnia, it was often difficult or impossible to establish a causal relationship with previous encephalitis. In contrast, Parkinsonism eventually developed in most if not all adults who survived the initial illness, and had a uniformly bad prognosis.

Encephalitis Lethargica and Spanish Flu

Cruchet first reported cases of possible encephalitis lethar- gica amongst French World War troops in Verdun at the end of 1916 and 1917 [18]. Previous sporadic outbreaks of in- fluenza had occurred in these soldiers from 1915, and it was difficult at first to separate the two illnesses. A great influ- enza pandemic, later named the Spanish flu, then broke out in Europe between 1918 and 1921. Both diseases went on to spread over all continents. Many physicians, like Cruchet, first saw encephalitis lethargica during or after flu, and it was natural to assume a connection. However, von Economo held from the start that influenza did not cause or lead on to encephalitis lethargica. The name ‘Spanish’ flu derived from the facts that the Spanish press—Spain not being involved in the Great War—was amongst the first to report extensively on the severity of the pandemic. Three major waves of in- fluenza occurred over the next 10 years, and up to a billion people, quarter to half the world population of 1.86 billion

at that time, were affected. The total loss of life worldwide from Spanish flu was estimated at perhaps 50–100 million, greater than that due to the 1914–1918 war and surpassing even the Black Death of medieval Europe. This compared with the half- to one-million deaths from encephalitis lethar- gica.

The influenza virus may have predisposed to but did not cause encephalitis lethargica. Influenza, but not encepha- litis lethargica, was highly contagious with a high rate of case-to-case, school and family transmission. The peaks of the natural frequency curves of the two conditions did not match, although as with encephalitis lethargica, most cases of influenza occurred in winter. The clinical features of the two conditions were usually quite distinct, and in most cases the tracheitis, upper respiratory infection, malaise, fever, lethargy and muscle aching of influenza recovered within a week following bed rest, although a few subjects died within 24 h of infection. Influenza does sometimes lead to brain inflammation, although this is very uncommon, occurring in perhaps 1 in 100,000 cases who go on to develop headache, vomiting, delirium and coma during influenza outbreaks.

Sleep–Wake Disturbance and Encephalitis Lethargica

Encephalitis lethargica may be more relevant to the study of wakefulness than to that of sleep: in as much as these can be separated. The defining sleep disturbance of encephalitis lethargica was described by von Economo as the inability to maintain wakefulness rather than the occurrence of sleep. His name for the illness was based on the striking lethargy of the initial meningeal and brain involvement of the first phase. Subsequent popular use of the term ‘sleeping sick- ness’ in place of ‘encephalitis lethargica’ may have over- stressed the sleep component in a multifaceted disease. In practice, signs and symptoms of extrapyramidal motor disor- der and of mental disturbance were more persistent, trouble- some, prominent and frequent in the late illness than were lethargy, too much or too little sleep.

Economo suggested that lesions causing insomnia were mainly situated in the basal forebrain, those causing hyper- somnia in the midbrain tegmentum and posterior hypothala- mus: but this division may have been more apparent than real and has little value as to the exact localisation of sleep– wake systems in the brain. Encephalitis lethargica was rarely if ever a cause of persistent true hypersomnia as opposed to stupor, of the narcoleptic syndrome, of the complaint of difficulty in falling asleep or in maintaining sleep; although it seems probable that it sometimes might have led to symp- tomatic central sleep apnoea.

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Lethargy, Hypersomnolence, Stupor

What is lethargy? The Greek term ‘lethargos’ dates from the medical school of Hippocrates, and describes forgetful- ness which, when accompanied by fever, could lead to rapid death. To drink from Lethe, the river of Hades in mythology, led to forgetfulness of the past. In the middle ages, ‘lethargic’ came to indicate morbid torpor as well as prolonged unre- sponsiveness, and in this sense was used by von Economo. ‘Lethargy’ implies physical ‘tiredness’ but although we all know what ‘tiredness’ means, it varies over time and set- ting, is not quite in the same category as ‘fatigue’, ‘arousal’, ‘awareness’ or ‘vigilance’, and carries the mental burden of disinclination. Economo did not use the term ‘lethargy’ in any of his first eleven case descriptions but rather somno- lence, delirium, confusion, stupor, tendency to sleep, mental diminution, continually dazzlement, long reaction time, re- duced consciousness, falling asleep standing, walking and sitting; drowsiness, hypersomnolence.

Lethargy, merging with stupor, may be a disorder of arousal, rather than of sleep. Arousal from stupor demands a stronger stimulus than arousal from sleep. Lethargy, un- like sleep has no definite circadian rhythm, distinction or division into various behavioural stages, and can last days, months or sometimes, years. In lethargy, there is no periodic dream mentation, no regular postural shifts nor intervallic atonia. Muscle tone in patients with post-encephalitic leth- argy was sometimes described as increased rather than di- minished, with ‘catatonic’ resistance to the movement and preservation of enforced posture: this observation may, how- ever, have been biased by extrapyramidal damage in patients with encephalitis lethargica.

Hypersomnolence implies definite sleep, and may be mis- leading if applied retrospectively to encephalitic lethargy. ‘Pseudosleep’, popular terminology in the pandemic period to describe stupor, does not totally get away with the prob- lem. To further confuse the issue, Economo observed that in three subjects ‘somnolence’ was independent of the severity of all other conditions, as well as ‘not connected with dimin- ished consciousness’. The word ‘consciousness’ defined as the ‘knowledge of what goes on in one’s own mind’ might today not be used, but the meaning is clear. Subjects with hypersomnolence had an intense desire for sleep, report- ing that ‘it was impossible… or near-impossible…to stay awake’. The emphasis is on the preservation of vigilance, motor response, and with intact cortical functions of cogni- tion, memory, personality and intellect when aroused despite ‘pressure’ for sleep or the near inability to remain awake. Several observers stressed that the ‘sleep’ itself in encepha- litis lethargica could be normal, with normal eye closure, meiosis, atonia, and dream report. Any abnormality of sleep lay only in its long duration and considerable depth, a large stimulus being required for arousal. The subject might then be immediately alert.

‘Unrousable’ sleep was sometimes associated with en- cephalitis as well as head injury, brain tumours and many other metabolic and cerebral disorders. No clear nomencla- ture was possible in a pre-encephalographic era, and without careful behavioural studies. This could last days, months, or even in the fabled case of the seven sleepers of Ephesus, for many years. Often likened to hibernation, this is journalistic, not scientific.

One EEG recording in a recent post-encephalitic subject who developed Parkinsonism, during ‘stupor’ from which the patient could be aroused only by deep painful stimuli, showed diffuse high-voltage delta and theta activity [19]. Perhaps other electroencephalographic parallels to encepha- litis lethargica today come from patients with ‘idiopathic’ hypersomnolence or the Kleine–Levin syndrome, who com- plain of lethargy and tiredness and go on to develop pro- longed sleep episodes lasting up to 20 out of 24 h, usually persisting a few days to several weeks. Here, the EEG be- tween attacks is usually completely normal. During episodes of periodic lethargy or stupor, there may be decrease in stage 3–4 non-rapid eye movement (NREM) and also in REM sleep, interrupted by alpha activity; with occasional early- onset REM sleep and a very short sleep latency.

‘Narcolepsy’ and Encephalitis Lethargica

The term ‘narcolepsy’ continues to be one of the most wide- ly misused in journalism if not in medicine. A typical mis- conception is shown by reports such as that in 2011, when an English burglar was let off from his full sentence when the defence claimed he had ‘Attention Deficit Hyperactiv- ity Disorder—which can cause disruption to sleep patterns and narcolepsy, a chronic sleep disorder characterised by an excessive urge to sleep at inappropriate times’. The 20-year- old had stolen DVDs, computer games, sandpaper, toiletries and elastic bands. The court was told that he had a ‘sleeping disorder that meant he was awake for up to two weeks at a time and then could be out like a light for one or two days’. As 24-h supervision in the community might prove difficult, health and safety concerns for his attendants combined with powerful medical advocacy and a lenient judge led to a rul- ing that he could not be sentenced to unpaid work [20].

William Gowers in his Textbook of the Nervous System stated in 1904 that most attacks of ‘narcolepsy’ occurred in hysterical subjects, and that for every case of narcolepsy, 200 cases of epilepsy came under observation. The term ‘cata- plexy’ was first introduced by Henneberg in 1916 [21], the same year as Economo first observed encephalitis. A firm terminology of narcolepsy, the narcoleptic syndrome, and of cataplexy was not established until the second half of the twentieth century although Lowenfeld in 1902 had stated that the association of sleep attacks and ‘falls’ was necessary

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for the diagnosis of the syndrome [22]. It is perhaps unfortu- nate that Lowenfeld’s requirement was not always fulfilled; and the term narcoleptic syndrome was not always adopted to describe a specific illness, narcolepsy for a symptom with many different causes.

Bassetti (2007) reported that by 1924, although the nar- coleptic syndrome was known, that a total of only 34 typi- cal cases had been described; in comparison with many thousands of cases of encephalitis lethargica [23]. Although encephalitis could result in profound and continuous sleepi- ness—or at least, ‘pseudosleep’—the concept that it might also have ever been a significant cause of the true sleep and accompanying cataplexy of the narcoleptic syndrome is un- certain. I have seen perhaps a dozen subjects over 50 years with probable or definite post-encephalitic Parkinsonism, and none with a definite post-encephalitis lethargica narco- leptic syndrome as determined by previous acute meningo- encephalitis with initial lethargy and ocular palsy. However, there are a few reports of encephalitis lethargica as a prob- able trigger to the narcoleptic syndrome.

Adie described a boy aged 14 who in 1923 developed sleeplessness, fever, delirium and jerking of the limbs, fol- lowed by restlessness during the night and sleepiness during the day; with double vision. He recovered from this state in about three months, but remained apt to drop off to sleep in the daytime, particularly with any monotonous task. He then had attacks in which, if he laughed, his knees gave way and he fell to the ground. He said, ‘at the Scout camp the boys used to amuse themselves by making me laugh and then run away, leaving me helpless on the ground. I cannot go to the picture now, because if I am amused my head flops about and people look at me instead of the pictures’. By 1926, the attacks were becoming less frequent [24].

Symonds described a somewhat similar patient who com- plained of excessive sleepiness, and noticed that whenever he laughed or felt excited, he fell down. An attack was wit- nessed; ‘a little twitching of the facial muscles, short interval of silence, he talked vaguely in Icelandic, then said, “I can- not move my arms”’. As evidence of previous encephalitis, this subject had Parkinsonism [25].

Insomnia and Encephalitis Lethargica

Overall, ‘insomnia’ was reported in about 10 % of cases of acute encephalitis lethargica, almost all in children with hy- perkinesis, as opposed to the 50–60 % of subjects who devel- oped ‘pseudosomnolence’ or ‘hypersomnolence’. ‘Insomnia’ was occasionally reported to be atypical, resistant to hypnot- ics, although Tilney and Howe in 1920 included ‘medinol’ or barbituric acid dissolved in warm milk in their therapeutic regime. ‘Insomnia’, when reported in encephalitis lethargica, may not have referred to difficulty in sleeping, staying asleep

or sleep of poor quality but rather was a term used by parents of children affected with night arousal and hyperactivity, often accompanied by restlessness, involuntary movements, dystonia or chorea. The exhausted child would then fall asleep at dawn, and be difficult to arouse until noon. Some reports described this as ‘inversion’ of the sleep rhythm, and likened this more to sleep patterns in both birds and other animals than to those of normal boys and girls.

Nocturnal excitement in children occurred in both acute and secondary cases of encephalitis; often blamed for ‘ex- hausting the brain’ and subsequent lethargy. A typical report of the time, in which observation cannot always be separated from assumption, reads ‘After sleep the rested brain is re- freshed…and the child is surprisingly normal during the rest of the day. The brain is however soon tired, and with this early fatigue the excitement recurs, once more to go through a familiar train of events. This is emphasised by the fact that other excitomotor phenomena often appear simultane- ously—respiratory, spasmodic, etc. It is a matter of common experience that such phenomena are worse when the patient is tired’. Nocturnal excitement sometimes did not begin until 7 or 8 weeks of the onset of illness, often persisted, and could prove one of the most intractable of all symptoms: ‘Towards night the parents note a change in the child’s behaviour: he becomes restless, excited, and runs about the house prying into things. He will not obey. When put to bed, he does not go to sleep, but jumps up and down, shakes the bed, talks, sings, whistles etc. He spends the whole night in constant activity. Nocturnal enuresis is not uncommon’. In one case of nocturnal wakefulness, the child made continual noises in his throat the whole night through and later was constantly blowing his nose. The syndrome was thought to be so pe- culiar as to suffice to establish a retrospective diagnosis of encephalitis lethargica.

The more usual nature of insomnia as a self-complaint of difficulty in falling or staying asleep was perhaps no more frequent in encephalitis lethargica than in any other serious physical or mental illness, and related to anxiety, depression, discomfort and pain as well as in particular to the stiffness, tremor and impaired motility of Parkinsonism.

Circadian Rhythms and Encephalitis Lethargica

Although sleep–wake inversion in children such as the above was not uncommon, the effect may have been secondary to environment, motor restlessness, fear, loneliness and the dark rather than to any primary circadian disturbance. The technology to study true circadian rhythm was still half a century distant. However, ‘alterations in the sleep cycle’ were sometimes described, and Howard and Lees reported in 1987 a post-encephalitic subject with ‘sleep inversion’.

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Respiration and Encephalitis Lethargica

Respiratory abnormalities, both sleeping and waking, with changes in frequency and rhythm were common in both acute and chronic encephalitis lethargica. Polypnoea was the most usual of these but the opposite, slow breathing, as well as apnoea and periodic respiration were observed in both acute and chronic encephalitis lethargica. Tachypnoea could alternate with periods of apnoea resulting in cyanosis, and paroxysms of hyperpnoea could lead to tetany. Such reports were uncommon and not always clearly separated from the focal dystonias of extrapyramidal disease, as when Schmidt (1921) reported ‘tetany’ as persisting in the right hand for 2 months in a case ‘without respiratory troubles’ [26]. Respi- ratory tics, only briefly controlled by an effort of will, took several forms, with sniffing, blowing, spitting and coughing. A variety of tic-like or myoclonic movements were recorded including jerking of the respiratory muscles, pectorals, and sternomastoids. Cruchet and Rocher described a child with rhythmic 76/min jerking bringing the arms forwards and the shoulders together [27]. Such involuntary movements might be limited, abolished, or confined to sleep although apnoea was almost always most prominent during slumber.

Dreams and Encephalitis Lethargica

Paralysis of eye movements and also gaze palsies would be predicted to interfere with the correlates of REM sleep. That this is the case is suggested by the finding that in progressive supranuclear palsy, comparable to encephalitis lethargica in midbrain damage and with impaired saccadic eye move- ments and failure of voluntary up-gaze, that it can be dif- ficult to identify REMs during sleep recording. In some but not all subjects there is also loss of dream mentation, with the typical report, ‘I have had no dreams for several years’. For von Economo, impaired eye movement at both nuclear and supranuclear levels was a hallmark of acute encephali- tis lethargica, although visual perception was retained. This was also the case in the secondary phase Critchley in 1928 reported that 64 of 72 subjects with post-encephalitic Parkin- sonism had ‘jerky’ eye movements [28]. Despite these find- ings, there are many reports of vivid and frequent dreaming in encephalitis lethargica. Stern (1928) reported that patients might sleep for long periods, days and nights, but contin- ued to have the same ‘dreams as normal people’: suggest- ing the preservation of at least one physiologic aspect of REM sleep [29]. A continuum has been suggested between dreams, sleep fragmentation and visual hallucinosis [30] and as with dreaming, visual hallucinosis was not uncommon in encephalitis lethargica. However, the anatomical substrate of dreaming may be different from that of visual hallucinosis; as suggested by the finding that in progressive supranuclear

palsy with ophthalmoplegia, despite a shrunken midbrain with MRI scan showing an axial midbrain diameter less than 17 mm but well preserved cortex, dream mentation or at least dream recall is lost whilst visual hallucinations still occur with the dopaminergic drugs used to treat bradyphrenia and rigidity.

Mental Disorders and Encephalitis Lethargica

The most important message of encephalitis lethargica for sleep medicine may not concern brain waves, the bio- chemistry or physiology of sleep, but asks a basic question of human freedom: whilst awake, are we slaves or free? In particular, this question was raised by the compulsive be- haviour that was especially prominent: as when involuntary upward eye movements could be accompanied by thoughts such as ‘kill. kill, kill’. About one third of subjects with acute encephalitis lethargica went on to develop compulsive be- haviour, changes in personality, cognition and memory. The typical mental state was of marked slowing of both move- ment and thought. Depression was common and suicide not infrequent, although some developed hypomania. In the late stages, emotional responses were slow or poor. Many pa- tients were unemployable in the community, impossible in the home and took up numerous places in the mental hospi- tals of the 1920s and onwards until their death.

Personality changes with hyperactivity and restlessness, both by day and by night, were reported mostly in children; described as having poor control over their behaviour and their instinctual drive, unable to concentrate at school or re- main occupied on the same task at home. Both children and adults could steal, take part in inappropriate sexual activity, and previous good behaviour was disturbed by outbursts of anger. Typical reports described previous outgoing and friendly personalities who went on to disturb the peace of their families. Hall (1924) reported a big, powerful girl who had periodic outbursts of violence to her parents if crossed in the mildest of matters, made mischief with the neighbours so that one group took her side, another that of her parents. She eventually was sent to an asylum. Psychosis was frequent and took a bewildering number of forms. Hypochondriasis might be of psychotic severity, paranoid visual and auditory hallucinatory states occurred and there were descriptions of a number of ‘schizophrenic-like’ illnesses. These states were often accompanied by motor slowing, profound apathy and lethargy as well as by Parkinsonism, overeating and obesity or alternatively and less commonly, by loss of appetite and slenderness.

Criminality was not uncommon. Auden and others re- ported cases in which the children had fallen into the hands of the police, and amongst these recorded from asylums a certain number who had been unmanageable children [31].

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MacPhail recorded a case in a 10-year-old boy who ‘took a knife to his mother’, ‘threatened to cut his brother up’, and ‘took a hatchet to his sister’. Eventually, it was necessary to send him to an asylum. In the asylum, he was ‘quarrelsome and aggressive, but mentally alert and active, and very dif- ficult in consequence [32]’. Amongst other cases reported from the asylums was one of a boy aged 15 who seemed to improve after being there a year. Soon after discharge, how- ever, he was arrested by the police for assaulting a girl of 17 who had laughed at him. He had nearly strangled her. He was bound over on the promise of his brothers to look after him, and a month later committed suicide by hanging himself to the end of his bed by his necktie. Homicide by small children was sometimes reported and encephalitis pleaded in their de- fence; although any connection may have been tenuous. The medico-legal issues of such cases were difficult, as with the defence of legal ‘insanity’ raised by the complex concerns of criminality whilst sleep-walking. Fairweather (1947) in the UK described patients in the Rampton State Institution for violent and dangerous offenders admitted following enceph- alitis with self-mutilation, sexual deviation or perversion and serious aggression of many years duration [33]. One conclu- sion drawn from cases of encephalitis lethargica like these was that men and women are robotic slaves rather than free agents or that at least any apparent freedom is limited or il- lusory.

Pathology and Aetiology of Encephalitis Lethargica

In the sleeping sickness called Nona, a probable precursor of encephalitis lethargica, Gayet in 1875 had identified lesions in the midbrain and hypothalamus [34]. Although in patients dying in the acute phase of encephalitis lethargica, the acute disease caused an inflammation of the meninges, supporting tissues and the glia rather than damaging neurones, axons or myelin of the brain, as in Nona, and the changes were usual- ly most severe in brain areas today recognised as associated with cortical activation during wakefulness. These included the central tegmentum (tegmentum—from Latin for ‘cover- ing’) of the pons and midbrain, the posterior hypothalamus and basal forebrain [35]. Both the gross pathology and its distribution were similar in nature to those of many other forms of encephalitis including other causes of drowsiness such as African sleeping sickness, syphilitic general paraly- sis of the insane, and Wernicke’s encephalopathy. In chronic encephalitis lethargica, in contrast to the acute phase, a 2009 review of 35 epidemic era cases by Anderson, Vilenski and Duvoisin showed that cortical rather than brain-stem damage was the most consistent finding [36].

Physical signs and symptoms in both the acute and chronic stages of encephalitis lethargica had little or no relationship

to the exact brain areas showing greatest damage at post- mortem. The pathological features pointed to a probable infective cause, perhaps initially via the upper respiratory tract, but no definite virus, bacterium or other organism was identified in the classic era. In later recent somewhat similar examples, Coxsackie, Echo, polio and other viruses have all been isolated: and it seems probable that encephalitis lethar- gica, despite its 1917–1927 pandemic nature, was not a sin- gle disease entity. Specific brain neurotransmitter—protein system attack, metabolic factors, vascular predilection and immune involvement have all been suggested to explain the apparent selectivity of encephalitis lethargica to midbrain amongst other areas, but no theory exactly matches the facts.

In support of neurotransmitter theories, the locus coerule- us, the main brain site of noradrenaline neurones projecting to suprachiasmatic areas as well as to cortex, could be heav- ily involved—but animal lesions of this nucleus have little effect on sleep or waking, whilst many other neurotransmit- ter molecules are found in closely adjacent areas. For meta- bolic theorists, the midbrain tegmental area, one central area of damage in encephalitis lethargica, is also that most tar- geted in Wernicke’s encephalopathy. This causes lethargy, torpor and apathy; and was eventually linked to thiamine deficiency. The metabolic importance of thiamine in glucose metabolism may suggest that brain areas involved in the mechanisms of alertness, attention, vigilance, waking and sleeping are also amongst the most metabolically active re- gions of the brain: CSF glucose levels were slightly raised in encephalitis lethargica. There is little or no present evidence of an abnormal immune mechanism, despite recent findings of anti-neuronal antibodies and a similar histopathology to that of encephalitis lethargica in immune-mediated Syden- ham’s chorea.

Finally, many of the symptoms of encephalitis lethargica have a close relation to those of thalamic infarct in vascular disease. The exact presentation here depends on the nuclei involved, but includes early reduced but varying awareness, personality change, apathy and disinhibition as well as psy- chotic mood changes. Caplan in 1980 reviewed the striking picture that resulted from occlusion of the rostral branches of the basilar artery [37]. This results in infarction of the midbrain, thalamus and portions of the temporal and oc- cipital lobes, producing an array of oculomotor, visual and behavioural abnormalities often with changes in alertness and in the sleep–wake cycle. Perhaps the most remarkable syndrome to appear is that of peduncular hallucinosis, some- times combined to a half-field, and with or without visual field defects. The hallucinations are recognised as unreal despite their dramatic nature. Caplan’s patient saw a parrot in beautiful plumage to the right, and pictures of relatives flashed on the wall to the left.

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Terminology of Subalertness

Stupor Dazed state, torpidity
Tire Grow weary, exhaust patience Vigilance Watchfulness, caution, circumspection

One important lesson for sleep medicine from encephalitis
lethargica is the importance of an exact terminology of leth-
argy, tiredness, fatigue, subalertness, stupor and allied states.
However, any ‘lethargy’ definition and grading, analogous to References those of coma, may be impossible to achieve, as dependent

on temporal as well as on both ‘inside’ and ‘outside’ factors that determine the relationship of self to environment.

It is tempting to speculate that whatever the agent, en- cephalitis lethargica was localised to a region of the brain with both high blood flow and high metabolic rate, at the centre of a computer-like system that controls wake, rest and sleep switches of the brain. The following terminology of lethargy and associated states is founded not on medicine but on the Oxford Dictionary, where quotation, common usage and habit illustrate the difficult task of matching exact language to brain physiology: of matching brain and mind. Many of these definitions can be questioned, do not fit with medical terminology, involve the idea of ‘mind’ as indepen- dent of ‘brain’ or depend on philosophy more than physics. Further understanding of these states and the boundaries be- tween brain and behaviour is one important challenge raised by encephalitis lethargica for sleep medicine today.

1. von Economo C. Encephalitis lethargica its sequelae and treat- ment. Oxford: Oxford University Press; 1931 (Newman K O trans. p. 200. The monograph EpidemicEncephalitis, by the Shef- field professor of medicine, Arthur J Hall, 1924, Wright, Bristol, pp. 229, gives 2056 references: Vilensky [2011], suggests over 9000 articles on the topic).

2. Tilney F, Shattuck HL. Epidemic encephalitis. New York: Hoeber; 1920. p. 251.

3. Spillman R. His Wife and Prof J von Wagner- Jauregg. Trans. Spillman R. Baron Constantin von Economo. His life and work. Burlington: Free Press Interstate Printing Corp; 1937. p. 126

4. van Bogaert L, Théodoridès J, von Economo C. The man and sci- entist. Wien: Verlag der Österreichischen Akademie der Wissen- schaften; 1979; p. 138.

5. Vilensky JA. (Ed.) Encephalitis lethargica. Oxford: Oxford Uni- versity Press; 2011. pp. 316.

6. Vilensky JA, Gilman S. Introduction. In: Vilensky Joel, editor. Encephalitis lethargica. Oxford: Oxford University Press; 2011. p. 3–7.

7. von Economo C. Encephalitis lethargica its sequelae and treat- ment. Trans. Newman KO. Oxford: Oxford University Press; 1931. pp. 201.

8. Howard RS, Lees AJ. Encephalitis lethargica: a report of four recent cases. Brain. 1987;110:19–33.

9. Critchley M. The divine banquet of the brain. New York: Raven; 1979. pp. 267.

10. Kinnear Wilson SAK. Modern problems in neurology. New York: William Wood and Co; 1929. pp. 364.

11. Macfarlane AW. Insomnia and its therapeutics. London: HK Lewis; 1890. pp. 366.

12. Longuet R. La Nona. Sem Méd. 1892;1:275–8.
13. Winterbottom TM. An account of the native Africans in the neigh-

bourhood of Sierra Leone: to which is added, an account of the present state of medicine among them. London: Hatchard and Morman; 1803. pp. 8.

14. Gélineau JBE. De la Narcolepsie. Tessier et Tessier. Paris: Imprim- erie de Sargeres; 1881.

15. von Economo C. Encephalitis lethargica. Wien klin Woch. 1917a;30:581–5.

16. von Economo C. Neue Beitrage zur Encephalitis lethargica. Neurol Cent. 1917b;5:866–78.

17. Vilensky JA, Gilman S. Epidemic encephalitis during the epi- demic period. In: Vilenski JA, editor. Encephalitis lethargica. Oxford: Oxford University Press; 2011. p. 8–38.

18. Cruchet R. L’Encephalite épidemique. Paris: Doin and Co; 1929. pp. 135.

19. Rail D, Scholz C, Swash M. Post-encephalitic Parkinsonism: cur- rent experience. J Neurol Neurosurg Psychiat. 1981;44:670–6.

20. The Daily Telegraph. Saturday November 19. 2011. p. 17.
21. Henneberg R. Über genuine Narcolepsie. Neurol Zbl. 1916,30:282–

90.
22. Lowenfeld L. Über Narcolepsie. Munch Med Wochenschr.

1902;49:1041–5.
23. Bassetti CL. Narcolepsy. In: A Culebras, editor. Sleep disorders

and neurological diseases. New York: Informa Healthcare; 2007. pp. 83–116.

Alert Arousal

Attention Aware Cataplexy Coma

Confusion Consciousness

Delirium

Dementia Dream

Drowsy

Fatigue Hallucination

Lethargy

Narcolepsy Parkinsonism

Sleep

Watchful, vigilant, lively
Awake from sleep, stir into activity, call into existence
Turn the mind to, apply oneself, be present Conscious, not ignorant, well-informed Sudden temporary paralysis
Unnatural heavy sleep, prolonged uncon- sciousness
Mix up in the mind
Aware, knowing in the mind, totality of a person’s thoughts and feelings
State of mind with incoherent speech, hal- lucinations and frenzied excitement Insanity, loss of intellectual power
Series of pictures or events in mind of sleeping person
Sleepy, half-asleep, dozing, sluggish, slow, languid
Weariness after exertion—weakness Illusion, apparent perception of external object not actually present
Morbid drowsiness, torpor, inert, apathy, lack of interest, drowsy, trance-like
Fits of somnolence
Disease of nervous system with tremor, muscular rigidity and emaciation
Bodily condition such as that which occurs for several hours each night

20 Encephalitis Lethargica 157

24. Adie WJ. Idiopathic narcolepsy: a disease sui generis, with remarks on the mechanisms of sleep. Brain. 1926;49:257–306.

25. Symonds CP. Narcolepsy as a symptom of encephalitis lethargica. Lancet. 1926;ii:1214–5.

26. Schmidt R. Storung des myostatischen Gleichgewichtes der Zunge nach Encephalitis epidemica. Med Klin Berl Wien. 1921;17:210.

27. Cruchet RR. Séquelle du type myorhythmique chez un enfant atteint d’encéphalomyélite epidemique. J Med Bordeaux. 1921;51:230.

28. Critchley AM. Ocular manifestations following encephalitis lethargica. Bristol Med-Chir J. 1928;45:113–24.

29. Stern F. Die Epidemische Encephalitis. Berlin: Julius Springer; 1928. pp. 541.

30. Aarsland D, Larsen JP, et al. Prevalence and clinical correlates of psychotic symptoms in Parkinson disease: a community based study. Arch Neurol. 1999;56:595–601.

31. Auden GA. Behaviour changes supervening upon encephalitis in children. Lancet. 1922;ii:901.

32. Macphail HD. Mental disorder resulting from encephalitis. J Ment Sci. 1922;68:169.

33. Fairweather DS. Psychiatric aspects of the post-encephalitic syn- drome. J Ment Sci. 1947;93:201–54.

34. Gayet M. Affection encéphalique localisée aux étages supérieurs des pédoncles cérébraux et aux couches optiques. Arch Physiol. 1875;7:341–51.

35. von Economo C. Sleep as a problem of localization. J Nerv Ment Dis. 1930;71:249–59.

36. Anderson L, Vilenski J, Duvoisin R. Neuropathology of acute phase encephalitis lethargica: a review of cases from the epidemic period. Neuropathol Appl Biol. 2009;35:462–72.

37. Carrera E, Bogousslavsky J. The thalamus and behaviour: effects of anatomically distinct strokes. Neurology. 2006;66:1817–23.

38. Caplan LR. Top of the Basilar syndrome. Neurology. 1980;30: 72–9.

African Sleeping Sickness

Alain Buguet, Raymond Cespuglio and Bernard Bouteille

Human African trypanosomiasis (HAT) or sleeping sickness is nowadays considered as one of the African “neglected diseases” [1]. Sleeping sickness is a vector-borne parasitic endemic disease in 36 sub-Saharan countries. It ravaged intertropical Africa in at least two epidemic waves in the twentieth century. Sixty million out of 400 million inhabit- ants are at risk for the lethal disease [2]. Furthermore, HAT represents a tremendous economical burden giving rise to 1.5 million disability-adjusted life years (DALYs), which make it rank just behind malaria [3].This review aims at focusing on the historical development of knowledge in the parasitological, clinical, diagnostic, therapeutic, and epide- miological aspects of HAT.

General History of HAT

Since the initial report of sleeping sickness by Ibn Khaldun [4], sleeping sickness has been studied by physicians who described essentially the clinical signs of the disease, gener- ally focusing on neurological and sleep–wake disturbances. This clinical period ended at the turn of the twentieth century, because of the promotion of research provoked by the first large and devastating epidemic that then spread across colo- nial Africa. The colonial powers commissioned medical and scientific teams to Africa to develop knowledge on sleeping sickness and improve diagnosis and treatment of the deadly disease. Between 1896 and 1910, trypanosomes were identi- fied as causal agents of the disease, the mode of transmis-

A. Buguet ()
Polyclinic Marie-Louise Poto-Djembo, B.P. 49, Pointe-Noire, Congo e-mail: a.buguet@free.fr

R. Cespuglio

Centre de recherche en neuroscience de Lyon, University of Lyon, Lyon, France

B. Bouteille

Laboratory of Parasitology, Dupuytren University Hospital of Limoges, Limoges, France

sion between sick and healthy persons through the bite of a tsetse fly was discovered, the clinical aspects were specified, diagnostic techniques were elaborated, and therapeutic strat- egies were proposed. Until then, the disease had been sepa- rated into two conditions: Trypanosoma fever and sleeping sickness which were integrated into one disease in 1909 as a continuum. The concept of HAT was born. Epidemiologi- cal mass screening techniques were developed and the mo- bile team policy was elaborated, with the goal of eliminating transmission between sick and healthy villagers. At the end of the colonial era, HAT had almost disappeared. However, the integrated control of the disease by the colonial medical services vanished, and, in conjunction with political instabil- ity and military unrest, a new epidemic wave emerged in the 1990s. The estimates by the World Health Organization [2] reached up to 500,000 cases. Fortunately, the international community was mobilized and medication manufacturers gave free access to appropriate treatment, with the help of Médecins sans frontières. These actions led to resume con- trol of the disease in 2006 [5]. Nevertheless, recently estab- lished HAT risk maps demonstrated the persistence of the so-called historical foci [6]. However, as stated by Francis Louis (2012, personal communication), it is hazardous to believe that control has been attained and that HAT is not a public health problem anymore, even though the number of diagnosed new cases continues dropping. One should learn from historical facts.

Parasite and Vector

African Trypanosomes

African Trypanosomes are extracellular unicellular parasites that belong to the Kinetoplastida order, Trypanosomatidae family, Salivaria section. In 1895, Colonel Bruce identified trypanosomes in cattle and horses as the agent of nagana. The parasite was then named Trypanosoma brucei ( T. b.) [7] and Laveran and Mesnil [8] established that humans were

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resistant to T. b. Trypanosomes were found in the blood of a feverish British patient in Gambia and were called T. gam- biense [9]. The same parasite was found in the cerebrospinal fluid (CSF) of Ugandan patients [10]. A few years later, a new species of trypanosomes, T. rhodesiense was discovered in East Africa [11].

Trypomastigotes (bloodstream form) can be detected in all body and tissue fluids, particularly in the blood and CSF. They multiply by longitudinal binary fission. The 12–42 μm long and 1.5–3.5 μm wide parasite is animated by the un- dulations of its flagellum. African trypanosomes cannot be distinguished from one another by conventional microscopic techniques. However, the use of isoenzyme characterization and DNA analysis was able to separate the T. b. group into three subspecies, of which two are infective for humans: T. b. gambiense, and T. b. rhodesiense. The absence of in- fectivity of T. b. brucei to humans has been attributed to a serum haptoglobin-related protein that acts as trypanolytic factor [12]. The gambiense group is encountered in West and Central Africa, the rhodesiense group in East Africa. Each group is responsible for a different disease, conventional sleeping sickness being due to the gambiense group. Today, the genome of trypanosomes has been sequenced [13]. How- ever, the parasite remains aggressive due to its 1000 Variant surface glycoprotein (VSG) genes that allow it to express a continuous variation of glycoprotein shell. Despite the host antibody response, the VSG variation allows some parasites to escape the immune attack, promoting a new parasite pop- ulation leading to new waves of parasitemia.

The Vector

The vector of trypanosomes is the tsetse fly ( Glossina sp.). Already in 1857, Livingstone [14] had rendered the “poison- ous” tsetse fly responsible for what he called the tsetse fly disease, or nagana. Bruce [15] demonstrated that Glossina is the vector of nagana by transmitting the parasite that became T. b. brucei. Putting an end to very active scientific contro- versies, the first report of the British Sleeping sickness com- mission in Uganda [16] attributed to Glossina palpalis the role of vector of African trypanosomes in human sleeping sickness. Entomological studies proved rapidly that the para- site follows a development cycle within the fly [17]. When the tsetse fly bites a vertebrate to take a blood meal, infec- tious metacyclic trypanosomes that are present in its salivary glands are injected.

Tsetse flies are anchored in Africa and live exclusively in sub-Saharan regions between latitudes 14°N and 20°S. Glos- sina (G.) palpalis (or G. fuscipes), that transmits T. b. gam- biense, lives under hot and humid forest coverage, especially along rivers and lakeshores of West and Central Africa. Man represents the main reservoir of parasites, although both

wild and domestic animals (mainly pigs) may also host the trypanosomes. In East Africa, where antelopes are the main reservoir, the T. b. rhodesiense vector belongs to the G. mor- sitans group in the savannah or G. pallipides at forest edges or G. fuscipes in marshlands and river shores.

Clinical Aspects

Historically, clinical presentation of the disease preceded modern biologic diagnostic techniques. Before the turn of the twentieth century, sleeping sickness was a general dis- ease with progressive neuropsychiatric disability and sleep– wake alterations leading to death. The rare pathological anal- yses revealed meningitis associated with encephalitis. By the end of the first decade of the twentieth century, the clinical characteristics of HAT were well established and the clini- cal classification of HAT was little modified until today. The French Commission in Congo divided the disease in three successive stages [18]. The hemolymphatic stage 1 marks the invasion of the blood and lymphatic organs by multiply- ing trypanosomes. It lasts until the appearance of the para- site in the CSF, giving rise to meningoencephalitic stage 2. Preterminal demyelination encephalitis fatally ends the time course of the disease, along with cachexia and doldrums [19].

The Chancre

The first manifestation of the infection is the appearance of a chancre at the bite site. The tender nodule that can reach sev- eral centimeters in diameter is hot, edematous and erythema- tous. It is more frequently observed in T. b. rhodesiense HAT and disappears in 2–3 weeks [20]. Trypanosomes can be found after scarification and microscope examination.

Hemolymphatic Stage 1

At stage 1, a general malaise is the rule. Chilliness alternates with irregular feverish bouts that resist to antimalarial drugs. The general malaise is completed by headaches, asthenia, facial edema, prostration, insomnia. Pruritus is discrete, but cutaneous trypanides give rise to large papuloerythematous polycyclic and pruritic plaques over the trunk and/or infe- rior limbs. Enlarged lymph glands, especially in the lateral cervical area, and splenomegaly result from the invasion of lymphatic organs by trypanosomes. Lumbar and dorsal back pains concomitant to deep muscle and bone pains in response to pressure are common in the still active farmer or fisherman. The conventional Kérandel’s key sign was self- described [21]. When the physician tried to turn the key in

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his door lock, he suffered an acute pain elicited by palmar pressure. Sexual drive drops, and genital frigidity is accom- panied by impotence in men and dysmenorrhea in women. Behavioral distemper and mood disorders are frequent with alternation of depressive and manic states. Sleep problems are not uniform and vary in intensity and in course of time, insomnia alternates with excessive daytime sleepiness and normal sleep.

Meningoencephalitic Stage 2

At stage 2, the general symptoms observed at stage 1 are exacerbated, especially headaches and fatigue, and sleep– wake disorders become prominent. Adenopathies and sple- nomegaly recede. Peaks of fever occur, alternating with hy- pothermic events. The temperature curve shows periods of hypothermia, especially during the neurological stage in a rat model of HAT [22].

Neuropsychiatric disorders correlate with meningeal in- flammation in both forms of HAT. Mental disturbances are dominated by the astonishing disinterest and indifference of the patient towards his own condition and his environment. The apathetic patient with drooping eyelids suffers behav- ioral disturbances; episodes of agitation and antisocial or ag- gressive behavior and sudden anger alternate with episodes of confusion, dementia, or delirium. Melancholic and manic episodes may also alternate. Extreme violent behavior has been described with theft, fire lighting, suicide, or homicide.

All types of neurological signs can be observed indicating the involvement of almost all brain structures. Disorders of tone and mobility are constant features of the disease. Ex- trapyramidal disability is revealed by movement alterations, of which the most characteristic gait disorder (e.g., cerebel- lar ataxia) was emphasized by nineteenth-century authors. Myoclonic jerks occur during wake and sleep, and restless legs syndrome and periodic limb movements in sleep have been observed during polysomnographic recordings [23, 24]. Movement disorders may also be present in the form of cho- reic agitation. Tremor is frequently described, starting at the extremities and often generalizing to the whole body. Tongue tremor has been described in nineteenth-century reports. Pa- tients frequently complain of hyperpathia, with bone and mus- cle pains. Deep tendon reflexes may be hyperactive. Primitive reflexes (palmomental reflex, sucking reflex) may be pres- ent, indicating cerebral cortical dysfunction. The Babinski or Hoffman signs indicate pyramidal tract involvement.

Sleep and wake are severely disturbed. In 1890, Mack- enzie [25] had observed in a young adult from the Congo Free State “many little sleeps in the daytime, but rarely slept for long together either by night or day, so that the total amount of sleep did not exceed the amount usually taken by healthy people.” Lhermitte [26] described the “narcolepsies of sleeping sickness,” true sleep attacks starting with brisk

drops in neck muscle tone. Recently, our group confirmed these observations using 24 h polysomnographic recordings, and described the polysomnographic syndrome of HAT that occurs mainly in stage 2 patients. Briefly, the syndrome is made of two features: the loss of circadian alternation of sleep and wakefulness, sleep and wake occurring in bouts of 80–90 min throughout the nychthemeron (24 hours); and sleep structure alterations with the occurrence of sleep-onset rapid eye movement (REM) sleep periods (SOREMP) in several sleep episodes [27]. These alterations have been pro- posed to be used as a diagnostic tool [28] and have recently been confirmed in a 5-year study on HAT patients in Congo, especially for the diagnosis of relapses during post-treatment follow-up [29].

Diencephalic and hypothalamo–hypophyseal dysfunc- tions may provoke hunger and thirst contrasting with the state of malnutrition of the patients, as well as hormonal reg- ulation alterations. Multiple endocrine dysfunction including hormonal circadian dysrhythmia may cause loss of libido, impotence, dysmenorrheal, and myxedema. Cortisol and melatonin circadian rhythm is not known to be affected or little influenced by the sleep–wake cycle. The amplitude of cortisol secretion peaks losing its circadian undulation [30], although the overall 24-h mean plasma concentration is unal- tered [31]. Melatonin nocturnal peak is delayed by 2 h com- pared to healthy Africans [32]. Prolactin secretion is linked to sleep and wake alternation, being elevated during sleep. In patients with circadian alterations of the sleep–wake cycle, the prolactin secretion loses its circadian rhythm. Plasma renin activity and growth hormone are tightly linked with slow-wave sleep. Therefore, in HAT patients, the secretion peaks of renin and growth hormone follow the alteration of the circadian distribution of slow-wave sleep, sticking with the hormone–sleep relationship [30, 33].

The Terminal Encephalitis Phase

The terminal encephalitis phase is related to demyelination and atrophy. The degenerative process leads to apathy, de- mentia, epileptic fits, and incontinence, and death will occur after a chaotic course. Magnetic resonance imaging of the brain has revealed lesions that can also be encountered in other degenerative diseases.

Particular Aspects of Gambian and Rhodesian HAT

Trypanosoma b. gambiense HAT leads to death in several months or years after a complicated and complex neurologi- cal and sleep–wake disorder. This form, therefore, deserves the name of sleeping sickness. On the contrary, the acute T. b. rhodesiense HAT leads to death in weeks or months after

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a massive weight loss developing cachexia with cardiovas- cular failure. The neurological symptoms may not have time to install, although our group found typical sleep–wake al- terations in two Caucasians who had caught the disease in Rwanda [34].

Clinical Forms

Healthy carriers have rarely been reported [35]. However, a recent report describes a possible trypanotolerance in man [36].

The observation of symptoms and signs of stage 1 is often persistent during stage 2, and the reverse can be observed concerning the occurrence of neurological signs at stage 1 [29]. In our practice [37], we have encountered discrepancies between clinical symptoms and CSF biology. In Europeans, the time course of the disease has been reported to be rapid [18, 21]. In children, neurological and behavioral symptoms are frequent with an emphasis on sleep disturbances [38, 39]. Neurological and intellectual sequels are often observed [40]. Congenital transmission of the disease has been rarely reported [41].

Diagnosis and Stage Determination

The first biological test to be used in the process of diag- nosis was the microscopic search for trypanosomes in the blood, enlarged lymph gland fluid, and CSF, although sev- eral other body fluids were investigated in the first half of the twentieth century. The tests followed the already described discovery of trypanosomes in the blood [9] and CSF [10]. The latter author already used centrifugation to concentrate the parasites. Thereafter, the analysis of the CSF was com- pleted by the white blood cell (WBC) count [42]. Several tests were designed in the first half of the twentieth centu- ry. However, most developed tests are not easily usable in field conditions. Nowadays, a mixture of “old” techniques (microscopic examination, centrifugation of samples, WBC count) and newer methods (serological tests, modern con- centration techniques, CSF lymphocyte count) are in use by mobile teams in their field screening campaigns. An example of field screening for HAT patients by the Congo (Brazza- ville) National Program for Control of HAT is detailed in Buguet et al. [37] and Buguet et al. [29].

Several other diagnostic or staging tests have been pro- posed. However, most of them require a well-equipped labo- ratory facility and qualified personnel and are not feasible in field conditions. An example is given by the analysis of immunoglobulins M (IgM) that was proposed by Mattern in 1968 [43] for the diagnosis of HAT, as IgM are highly el- evated in HAT. A latex technique that can be applied in the

field was recently developed [44]. Another example is given by polymerase chain reaction (PCR) that raised hopes after its use in the diagnostic of stage 1 HAT by Truc et al. [45]. The technique is expensive and requires laboratory equip- ment with uninterrupted cold chain. Furthermore, PCR may remain positive after treatment due to parasite DNA material remaining in body fluids and cannot be used during post- treatment follow-up [46]. The loop mediated isothermal am- plification [47] and nucleic acid sequence-based amplifica- tion [48] are cheaper and may open a new way for potential field application of DNA amplification techniques.

Treatment

Treatment at Stage 1

The treatment of stage 1 HAT has not changed since the first third of the twentieth century. Since 1936, T. b. gambiense– infected patients are treated with 7–10 intramuscular injec- tions of pentamidine at the dose of 4 mg/kg/day administered daily or every two days to avoid side effects which are rare. These consist of syncope, hypotension, cutaneous eruptions, tachycardia and arrhythmia (cardiac toxicity), hypoglycemia and/or diabetes (pancreatic toxicity), hepatic dysfunction, and hematologic disturbances.

Suramin is used to treat stage 1 T. b. rhodesiense HAT since 1916. Although it is active on T. b. gambiense, it is not used as it may produce a sudden shock in case of co-infection by Onchocerca volvulus. The dosage is 1 g intravenously on days 1, 3, 5, 14, and 21. Side effects are reactive fever, cu- taneo-mucous eruptions, nausea, vomiting, polyneuropathy, hematological toxicity, and rarely kidney failure.

Treatment at Stage 2

Melarsoprol is an arsenical released in 1949 that is still used, despite growing resistances and high toxicity, with especially a deadly reactive encephalopathy. It is administered in slow intravenous injections at a maximal dose of 3.6 mg/kg/day, in three 3-day courses at 1 week intervals. A shorter alter- native regimen has been proposed, with daily injections of 2.2 mg/kg during 10 consecutive days. However, the risk of complications remains unchanged. Apart from the deadly en- cephalopathy, other undesirable effects include convulsions, peripheral neuropathies, headaches, tremor, febrile reactions, abdominal pains, chest pains, cutaneous eruptions (potential occurrence of a Lyell’s syndrome), peripheral thrombophle- bitis, cardiac toxicity, renal or hepatic toxicity, and agranu- locytosis. Following the recommendations of the WHO, the proportion of T. b. gambiense patients treated with melarsop- rol dropped from 97 % in 2001 to 12 % in 2010 [49].

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Eflornithine or difluoromethylornithine has been used to treat stage 2 T. b. gambiense HAT since 1986. It is adminis- tered during 14 days in 4 daily slow intravenous infusions for a daily dose of 400 mg/kg. The medication is not devoid of adverse effects. Complications concern anemia, leucope- nia, diarrhea, convulsions (during the first week), vomiting, thrombopenia, fever, abdominal pains, headaches, alopecia, anorexia, vertigo, sudden deafness.

Nifurtimox is the orally administered medication of Cha- gas’s disease, the American trypanosomiasis. It is active on both stages of T. b. gambiense HAT; its activity on T. b. rho- desiense remains unknown. Administration of nifurtimox is oral: 5mg/kg twice a day during 10 consecutive days. The adverse effects of nifurtimox consist of convulsions, revers- ible cerebellar syndrome (ataxia, nystagmus, tremor, and vertigo), psychotic reactions, and anorexia, nausea, vomit- ing, and weight loss.

Today, the WHO recommends to use nifurtimox in combi- nation with eflornithine for the treatment of T. b. gambiense HAT stage 2 [50, 51]. The nifurtimox–eflornithine combi- nation therapy (NECT) has been evaluated recently mainly because of the growing resistance to melarsoprol. The pro- tocol starts with intravenous eflornithine (two 1-h infusions of 200 mg/kg each during 7 consecutive days) followed by by oral nifurtimox as above. The NECT does not, however, meet the expected synergic effects of both molecules regard- ing trypanocidal activity [52]. Furthermore, resistance phe- nomena are still under evaluation [53]. Adverse effects are those of eflornithine.

Post-treatment Follow-up

Although a shortening of the follow-up period after treat- ment has been suggested by certain teams [54, 55], we be- lieve that patients should be reexamined every 6 months dur- ing at least 18 months. Considering our own practice [37], relapses at stage 2 were observed 18 months after treatment. It is difficult for the National Programs to follow up patients for such a long time, because of several reasons: the lack of financial and logistic means to launch mobile team cam- paigns, the poor compliance of the patients to come back for mobile team visits when they occur, certainly for economical reasons and fear of lumbar puncture.

Conclusions on Present Therapeutic Strategies

The available medications are ancient and their efficacy is often imperfect, not accounting for resistance phenomena. However, since the last epidemic, the pharmaceutical in- dustry and WHO have formed a partnership to obtain free

treatment for the patients. Nevertheless, research for new therapeutic molecules and strategies should be emphasized. Two molecules are under evaluation: fexinidazole [56] and molecule derived from benzoxaboroles, SCYX-7158 [57].

Conclusion

HAT hits rural populations in remote bush villages that lack adequate healthcare facilities. During the first half of the twentieth century, efforts to control HAT almost led to its elimination. Nowadays, the number of mobile teams remains limited and they still use diagnostic techniques developed 35 years ago. Progress in therapeutic strategies is limited [58]. Medications such as suramine are almost 100 years old. Molecules used at stage 2 are toxic. Nevertheless, be- cause of international and national efforts, the prevalence of HAT is decreasing. This may, however, represent a paradoxi- cal danger as public health authorities may become inatten- tive and public funds may vanish. The patients themselves often avoid mobile team meetings. They fear lumbar punc- tures and prefer not to interrupt farming or fishing. Organiz- ing post-treatment follow-up every 6 months during 18–24 months may be difficult or impossible. However, we should have learned from past experience not to alleviate surveil- lance. New diagnostic tests, especially noninvasive, and nontoxic molecules to treat stage 2 HAT are urgently needed to improve staging and treatment strategies.

Acknowledgments Part of the work received support from the Techni- cal Services Agreement # T7/83/2 of the World Health Organization (2005–2006), from the “Action de recherche en réseau: Le syndrome du cycle veille-sommeil dans la trypanosomiase humaine africaine: méthode noninvasive de diagnostic du stade de la maladie, de vali- dation de tests biologiques et de suivi de traitement” of the Agence universitaire de la Francophonie (2005–2006), and mainly from the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) No A50468 “Polysomnogra- phy, electrochemistry, immunology & neuroanatomy to the diagnosis of Human African Trypanosomiasis” (2006–2009).

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Sleep and HIV Disease

Kenneth D. Phillips and Mary E. Gunther

Sleep and HIV Disease

Although not the fatal illness it once was, HIV/AIDS re- mains a life-threatening illness. The worldwide prevalence of HIV/AIDS at the end of 2010 was estimated to be 34 mil- lion, which includes 3.4 million children who are less than 15 years of age. The incidence of HIV infection decreased from 3.1 million in 2001 to 2.7 million in 2010. The annual number of deaths worldwide is steadily declining since peak- ing in 2005 at 2.2 million [1].

With earlier diagnosis, more highly sophisticated moni- toring of immune parameters, better antiretroviral therapy, improved recognition of viral mutations and drug resistance, and effective prophylaxis and treatments for opportunis- tic infections and malignancies, persons with HIV/AIDS (PWHA) are living longer and healthier lives, often many decades beyond their initial infection [2].While immune sta- tus and longevity have improved, PWHA experience many persistent and burdensome symptoms. Insomnia and fatigue are often reported as the most frequent and distressful symp- toms associated with HIV/AIDS [3−5]. Even so, insomnia is often underreported, underdiagnosed, and undertreated [6].

Normal Sleep Architecture

Sleep occurs in two distinct stages, rapid eye movement (REM) and non-rapid eye movement (NREM) sleep that are revealed by polysomnography recurrent. Recurrent cycles of REM and NREM sleep occur throughout a 24-h circadian day. In adults, approximately 25 % (90–120 min) of the sleep period is spent in REM sleep, which occurs in early morning.

K. D. Phillips () · M. E. Gunther
The University of Tennessee, College of Nursing, 1200 Volunteer Boulevard, 37996-4180 Knoxville, TN, USA
e-mail: kphill22@utk.edu

M. E. Gunther
e-mail: mgunther@utk.edu

The remaining 75% of the sleep period is spent in NREM sleep. Adults have four to five bouts of REM sleep per night; the first cycle of REM sleep is shorter in duration with cycles later during the night becoming longer. During REM sleep, rapid movements of the eyes are observed. REM sleep is ac- companied by decreased muscle tone and vivid dreams [7].

During wakefulness, the electroencephalogram (EEG) shows two types of brain waves. Beta waves are typical of wakefulness. Beta waves have the highest frequency, the lowest amplitude, and the most desynchronous. As the body becomes more relaxed, just prior to sleep, the brain waves change from beta waves to alpha waves and appear on the EEG as slower frequency, higher amplitude, and more syn- chronous waveforms. As a person transitions from wakeful- ness to stage 1 of sleep, the EEG changes from alpha waves to theta waves. Theta waves are even slower in frequency and greater in amplitude. As sleep deepens to stage 2, sleep spindles (sudden increase in frequency) and K complexes (sudden increase in amplitude) appear on the EEG. Stage 3 (delta sleep, slow wave sleep) is the deeper stage charac- terized by delta waves, which are the slowest waves with the greatest amplitude. Counterintuitively, sleepwalking and sleep talking do not occur during REM, but rather in the deeper stage of sleep (stage 3) [7].

Insomnia in HIV/AIDS

Insomnia is a common complaint in the general population and even higher in PWHA [6, 8−16]. It has been estimated that the prevalence of insomnia in HIV/AIDS ranges from 30 to 100 % [3, 6, 17−21] as compared to 10–35 % in the popu- lation at large [22, 23]. The wide variance in the estimated prevalence of insomnia in PWHA may be due to the use of validated and nonvalidated tools for assessing sleep quality, inconsistent inclusion and exclusion criteria, and that objec- tive measures of sleep (e.g., actigraphy and polysomnog- raphy) are not often used; therefore, the true rate of sleep

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_22, 167 © Springer Science+Business Media, LLC 2015

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disorders is not known. Many studies of the prevalence of insomnia in HIV/AIDS were conducted prior to the advent of combination antiretroviral therapy. These studies need to be repeated giving attention to stage of illness and other po- tential covariates.

Two 2012 studies looked at the prevalence of sleep quality in cross-sectional samples. Lee and colleagues characterized specific types of sleep difficulty in a sample of 290 adults (men: n = 194.67 %; women: n = 74.25 %; and transgendered persons: n=22.8%). Nearly half of the sample (45%) slept less than 6 h per night, 87% slept less than 8 h per night, and 13% sleep 8 h or more per night. Of the 290 partici- pants, 88 (30.4 %) reported good sleep; 41 (14 %) reported difficulty falling asleep only, 102 (35.2 %) reported difficulty staying asleep only, and 59 (20.3%) reported difficulty in falling asleep and staying asleep [24]. Crum-Cianflone and colleagues reported that 46% of 193 HIV-infected military beneficiaries between the ages of 18 and 50 met the criteria for insomnia and 30 % reported daytime drowsiness [12].

Insomnia and Stage of HIV Disease

HIV disease has a well-described progression. Stage 1: Acute infection occurs 2–4 weeks after infection with HIV. During the acute infection, the virus is rapidly replicating in the body, the CD4 + cell count drops rapidly, and flu-like symptoms appear. Stage 2: Clinical latency begins at the end of the acute infection when the viral load has dropped to what is termed a “viral set point.” During the early pe- riod of this stage, the virus replicates slowly and the HIV- infected person is most likely asymptomatic. Toward the end of this period, the rate of viral replication rises and the

CD4+ count declines. Constitutional symptoms such as fever, night sweats, and decreased appetite may appear. This period can last 8 years or longer. Stage 3: AIDS is diagnosed when the CD4 + cell count drops below 200 /mm3. At this point, opportunistic infections and malignancies can occur. Left untreated, life expectancy from the time of the appear- ance of an opportunistic infection is about 1–3 years. Stage unknown: A person is known to be HIV-infected, but there is no information about the CD4 cell count or AIDS-defining conditions. The Centers for Disease Control and Prevention describes these stages more quantitatively for surveillance. See Table 22.1.

Insomnia has been reported in all stages of HIV/AIDS [25] and has been consistently significantly associated with depression and fatigue [26]. Phillips and colleagues exam- ined the relationships among sleep quality: Pittsburgh Sleep Quality Index (PSQI) and the dimensions of health-related quality of life (SF-36) in a sample of HIV-infected women ( n=144). Controlling for stage of illness and whether a woman had a paying job or not, global sleep quality ex- plained significant levels of variance in bodily pain, mental health, physical functioning, role physical, social function- ing, and vitality. Sleep quality accounted for 20% of the variance in the mental component score, but for none of the variance in the physical component score [27].

Sleep and Immunity

Besedovsky, Lange, and Born provide a thorough synthe- sis of the evidence supporting the relationships between sleep, circadian rhythm, and immunity [28]. The following section summarizes key conclusion drawn in their article

Table 22.1 Stage of disease. (Source: Centers for Disease Control (2012))

In December 2008, CDC published Revised Surveillance Case Definitions for HIV Infection Among Adults, Adolescents, and Children
Aged < 18 Months and for HIV Infection and AIDS Among Children Aged 18 Months to < 13 Years—United States, 2008 (www.cdc.gov/ mmwr/preview/mmwrhtml/rr5710a1.htm). For adults and adolescents (i.e., persons aged ≥ 13 years), the surveillance case definitions for HIV infection and AIDS were revised into a single case definition for HIV infection that includes AIDS and incorporates the HIV infection staging classification system. In addition, the HIV infection case definition for children aged < 13 years and the AIDS case definition for children aged 18 months to < 13 years were revised. No changes were made to the HIV infection classification system, the 24 AIDS-defining conditions for children aged < 13 years, or the AIDS case definition for children aged < 18 months. These case definitions are intended for public health sur- veillance only and not as a guide for clinical diagnosis
A confirmed case meets the laboratory criteria for diagnosis of HIV infection and one of the four HIV infection stages (stage 1, stage 2, stage 3, or stage unknown)
HIV infection, stage 1: No AIDS-defining condition and either CD4 + T-lymphocyte count of ≥ 500 cells/μL or CD4 + T-lymphocyte percentage of total lymphocytes of ≥ 29
HIV infection, stage 2: No AIDS-defining condition and either CD4 + T-lymphocyte count of 200–499 cells/μL or CD4 + T-lymphocyte percent- age of total lymphocytes of 14–28
HIV infection, stage 3 (AIDS): CD4 + T-lymphocyte count of < 200 cells/μL or CD4 + T-lymphocyte percentage of total lymphocytes of < 14,
or documentation of an AIDS-defining condition. Documentation of an AIDS-defining condition supersedes a CD4 + T-lymphocyte count of
≥ 200 cells/μL and a CD4 + T-lymphocyte percentage of total lymphocytes of ≥ 14
HIV infection, stage unknown: No information available on CD4 + T-lymphocyte count or percentage and no information available on AIDS- defining conditions

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that support the relationships between sleep and immunity. The onset of sleep is associated with downregulation of the hypothalamic-pituitary-adrenal axis (HPAA) and the sym- pathetic nervous system (SNS). During that same period, growth hormone, prolactin, melatonin, and leptin steeply rise. These hormones participate in the regulation of the immune response, by stimulating activation, proliferation, and differentiation of immune cells, which then produce proinflammatory cytokines. Proinflammatory cytokines include interleukin-1 (IL-1), tumor necrosis factor (TNF- alpha) and interferon (IFN-gamma). When the HPPA (in- creasing production of cortisol) and the SNS (increasing the production of catecholamines) are upregulated, proin- flammatory immune functions are suppressed. Therefore, during sleep, particularly during slow-wave sleep (SWS), proinflammatory functions peak and during wakefulness anti-inflammatory activity becomes apparent. It has also been demonstrated that immune cell numbers in early dif- ferentiation peak during the early sleep period. Production of IL-12, a proinflammatory cytokine, increases and there is a shift of the Th1/Th2 balance toward the production of proinflammatory cytokines. Downregulation of the stress hormones during early sleep may lead to increased prolif- eration of T helper cell proliferation and migration of naïve T cells to the lymph nodes. Wakefulness is associated with an increase in cytotoxic T lymphocytes and natural killer cells.

Sleep and Immunity in HIV Disease

An inverse relationship was found between frequency of sleep complaint and CD4+ cells which suggests that sleep disturbances may increase as the disease progresses. Rela- tionships between SWS and certain immune variables (i.e., NKCA, antibody production, T cell proliferation and dif- ferentiation, and cytotoxic T cell proliferation and differen- tiation) have been observed. These findings suggest that in- somnia adversely affects immunity. Darko et al. hypothesize that IL-1-β and TNF-α may be responsible for the changes in SWS in PWHA [29].

Cruess and colleagues examined the relationship between psychological distress (Impact of Event Scale), subjective sleep disturbance (PSQI) and immune status (CD3+CD4+ [T helper/inducer cells] and CD3 + CD8 + [T suppressor cells]) in 57 PWHA. The sample consisted of both men ( n = 41) and women ( n = 16) with a mean age 38.8 ± 8.5. Nei- ther psychological distress nor sleep quality was significantly related to T helper/inducer cells, but both were significantly associated with T suppressor cell even after controlling for age, T helper/inducer cells, and viral load. They concluded that sleep quality mediated the relationship between psycho- logical distress and T suppressor cells [30].

Insomnia and Quality of Life in HIV Infection

HIV/AIDS-related insomnia is associated with a significant burden for PWHA in that it further adds to functional impair- ment and reduces quality of life (QOL) [19, 27]. Insomnia contributes to fatigue, disability, eventual unemployment, and decreased QOL in PWHIV [8]. Insomnia occurs fre- quently in PWHIV prior to diagnosis and continues through- out the course of the disease. In fact, excessive daytime sleepiness may be one of the presenting symptoms of HIV disease, [31] and insomnia may even serve as an early mark- er of HIV disease [13].

Sleep Architecture and HIV/AIDS

Changes in sleep architecture in HIV/AIDS have been stud- ied in small samples. Most of these studies did not include seronegative case controls. Little attention was given to the HIV stage of illness in these small studies. Therefore, the changes in sleep architecture have not been clearly charac- terized.

Early studies demonstrated an increase in SWS, particu- larly during the latter half of the sleep period. Norman and colleagues [32] examined sleep architecture in a sample of eight asymptomatic HIV-positive men and compared their sleep to three HIV-negative men. They reported an increase in total percentage of SWS, with most of the SWS occurring in the latter half of the sleep period. This finding has not been replicated in any other study.

A subsequent study by Norman and colleagues compared the sleep architecture of ten HIV-positive men to that of five HIV-negative men. They reported a significant difference (8% more) in the amount of delta (slow wave) sleep in the HIV-positive men [31]. In another study of six asymptomat- ic HIV-positive men, they reported that alpha-delta patterns were consistently observed throughout the sleep period [33].

Kubicki and colleagues examined sleep architecture in five men with AIDS. They reported a greater number of awakenings and arousals, reduced REM sleep, and a de- crease in sleep efficiency in persons who have progressed to AIDS [34].

Wiegand and colleagues [14, 35] on the other hand, found no SWS disruptions in PWHA. Using nocturnal sleep en- cephalography, they found more frequent shifts to stage 1 sleep equated to a reduction in stage 2 sleep. Sleep-onset latency increased, but total sleep time and sleep efficiency decreased. The number of REM periods increased, but the average duration of a REM episode decreased.

Ferini-Strambi et al. examined sleep architecture in nine HIV-positive men and eight age matched controls. Their study showed a significant reduction in SWS and higher cyclic alternating patterns (CAP), representing the stability

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of sleep in PWHA compared to controls [36]. A significant relationship was found between a higher CAP rate and poor subjective sleep quality. Unlike Norman and colleagues, this group of researchers did not find a higher percentage of SWS in the second half of the night [36].

Wheatley and Smith found that HIV+ patients reported greater delay in sleep onset, earlier morning awakening, more frequent nocturnal awakenings, and poorer well-being on waking. A higher degree of insomnia was observed in in- dividuals who were not taking antiretroviral therapy. They suggested that the observed sleep architecture changes might be related to depression.

Pharmacological Factors Related to Insomnia in HIV/AIDS

Many medications used to treat HIV/AIDS and its complica- tions have insomnia as a side effect.

Adherence to Medications

A high degree of adherence to antiretroviral therapy in HIV/ AIDS is necessary to decrease viral replication and to achieve viral suppression (HIV-1 RNA < 50 copies per milliliter) [37, 38]. With monitoring and adjustment of combinations of an- tiretroviral agents, it is possible to decrease the rate of viral mutation and the evolution of drug resistance [39]. Further benefits of viral suppression include: slowing disease pro- gression [40], prolonging life [41], and possibly decreasing the risk of transmitting HIV to others [42]. Viral suppression is also important in reducing overall health care costs.

Many improvements to drug regimens have been made. The number of medications and frequency of medications through the day have decreased by several agents into fewer pills. There are not as many food restrictions as before and it is easier to store medications. However, many barriers to adherence persist. These barriers include stigma, limited ac- cess to qualified providers, travel distances to receive care, and limited access to mental health and substance-abuse care. Symptom burden, which is the sum of the severity and impact of symptoms, predict nonadherence to antiretroviral drugs. Depression has been identified in various studies as barriers that decrease adherence to antiretroviral therapy [10, 43−45]. A cross-sectional analysis conducted by Phil- lips and colleagues demonstrated that HIV-infected women who reported more depressive symptoms and poorer sleep quality also reported lower adherence to medications [44]. Associations between sleep quality and adherence have been demonstrated by others since that study [43, 46].

People who have difficulty sleeping report impaired day- time functioning, which includes decreased attention and concentration, greater fatigue, impaired memory, and de- creased ability to carry out daily tasks [10, 47, 48].

In a cross-sectional study of HIV-infected women living in the southeastern USA, Phillips and colleagues [44] found that two thirds of the participants endured severe sleep dis- turbance and that sleep disturbance was significantly related to adherence to antiretroviral therapy due to daytime dys- function.

Gay and colleagues, in a study of 350 women and men with HIV infection, found that overall symptom burden was related to medication adherence. Troubling sleep was strongly associated with nonadherence to medications in that study. “Forgetting” and “sleeping through the dose time” were the most frequent reasons identified for failing to take a prescribed dose [49].

Saberi and colleagues [10] conducted a large cross-sec- tional study ( n=2.846) of HIV-infected men and women to determine the prevalence of sleep disturbance and to identify the relationship between sleep quality and medication non- adherence. Together, these findings support that sleep distur- bances are associated with nonadherence, and future studies of interventions for improving sleep quality should include medication adherence outcome measures.

Correlates of Sleep in HIV/AIDS

In studies involving the general population, researchers rec- ognize the major correlates of diminished quality of sleep as (a) fatigue, (b) excessive daytime sleepiness, (c) perceived stress, and (d) depression. All of these exist in PWHA in ad- dition to anxiety and pain [3, 6, 17]. In an integrated litera- ture review examining insomnia in PWHA, Reid and Dwyer noted that all of the associated correlates are entangled due to “overlap at both measurement and conceptual levels” (p. 267) [9]. Similarly, Nokes and Kendrew [17] reported that the intercorrelations between symptom severity, exces- sive sleepiness, depression, state anxiety, and functional sta- tus precluded attempts to statistically “untangle the effects of the variables” (p. 21). The fact that PWHA usually pres- ent with multiple symptoms [50] compounds the difficulty. While both physiologic and psychological variables affect quality of sleep in PWHA, the latter (depression, stress, and anxiety) display strongest statistical correlation. For the PWHA, this manifests as marked delays in sleep onset, more awakenings during the night, and less transition into non- REM sleep [3]. In turn, the resultant insomnia exacerbates the psychological distress of the chronically ill [51].

While existing data sources do not allow calculation of incidence [52], fatigue leads as the most prevalent complaint of PWHA with estimates ranging from less than 50% to more than 80%. Whereas Lerdal et al. [53] simply define fatigue as a “sense of exhaustion, lack of energy, tiredness unrelieved by a night of good quality sleep” (p. 2204), other authors capture a more graphic characterization. In what is considered a classic analysis of the phenomenon, Ream and

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Richardson, as cited in Barroso and Voss [52], described fa- tigue as a “subjective, unpleasant symptom that incorporates total feelings ranging from tiredness to exhaustion, creating an unrelenting overall condition that interferes with individ- uals’ ability to function to their normal capacities” (p. S5). Asked to explain it, PWHA attribute their fatigue to either the disease itself or existing physical attributes (e.g., being overweight), overexertion, or medication side effects [54]. Despite instrument scores indicating significant pathology, respondents have been known to rate the quality of their sleep as “fairly good” [3].

Diminished quality of life arises from the awareness of the imbalance of resources, capacity, and performance [52, 55]. Significantly correlated with quality of sleep, fatigue is a constant across all stages of the disease [56] resulting in per- sistent impaired daytime functioning [10, 47, 48] and, some- what paradoxically, increased sleep-onset difficulties [20]. In turn, daytime dysfunction has been significantly related to adherence to antiretroviral therapy regimens [27, 55]. Study- ing fatigue and insomnia in homosexual men (62 HIV+ and 50 HIV−), Darko et al. [8] found that HIV+ subjects were more likely to: be unemployed, feel fatigued throughout the day, sleep more, nap more, and have diminished alertness. Both fatigue and insomnia significantly contributed to mor- bidity and mortality in the HIV+ subjects. They concluded that the cognitive dysfunction seen in early HIV infection (asymptomatic) is related more to loss of sleep than to actual neurological impairment.

Twenty years later, Harmon et al. documented that the fatigue PWHA experience differs in both quality and sever- ity than that experienced before becoming infected [57]. HIV-Related Fatigue Scale (HRFS) scores from their study sample ( N=128) indicated that fatigue interfered with cog- nition (mental clarity and facility), task performance (activi- ties of daily living), and socialization (work and leisure). The researchers determined that those who have lived the longest with the diagnosis have lower self-reported rates of fatigue attributed to learned coping mechanisms. From this study’s findings, increased rates of fatigue can be predicted both in the presence of lower monthly income and pharma- cologic treatment of depression. In 2009, Lee et al. [5] re- ported on clinical characteristics of symptom experiences among PWHA ( N=350 adults) noting that most prevalent were “lack of energy” and “feeling drowsy” due to “trouble sleeping.” These states resulted in difficulty concentrating as well as mild symptoms of depression and anxiety.

A more recent study by Lerdal et al. [53] began exploring patterns of fatigue among PWHA. A sample of 318 PWHA completed self-report questionnaires related to symptoms Memorial Symptom Assessment Scale (MSAS), fatigue (Lee Fatigue Scale; Fatigue Severity Scale 7), sleep qual- ity (PSQI), depression (CES-D), anxiety (POMS), and qual- ity of life (Medical Outcome Study Health Related QOL). Participants were asked to complete the assessments 30 min

after awakening and again 30 min before going to sleep for three consecutive days. Overall, evening fatigue level scores were significantly higher than morning fatigue level scores. While 30% reported fatigue either in the morning or in the evening only, it was noted that those who reported high fa- tigue in the morning were likely also to report high fatigue in the evening. Using those who reported low levels of fatigue both in the morning and evening (35 % of respondents) as a reference group, three patterns were identified: (a) high-fa- tigue levels only in the morning; (b) high-fatigue levels only in the evening; and (c) high-fatigue levels both morning and evening. High-fatigue levels only reported in the morning were associated with higher anxiety and depression scores; while high-fatigue levels reported only in the evening were associated with high-anxiety scores. Labeled the most debili- tating and distressing, high-fatigue levels in both the morn- ing and evening were associated with high-anxiety scores, high-depression scores, and significant sleep disturbances. It is important to note that anxiety is an important antecedent of fatigue regardless of diurnal patterns. Acknowledging the cyclical interaction of psychological variables and quality of sleep suggests once again that mental health states are more predictive of fatigue than the HIV/AIDS disease state. And in turn, while psychological correlates affect sleep, only fa- tigue maintains statistical significance when exploring the association with sleep quality [3].

EDS is an inability to stay awake in quiet, sedentary situ- ations (such as when reading, watching television, or even driving). While drowsiness (a milder form of daytime sleepi- ness) may be a by-product of lack of sleep or medication, EDS is usually associated with pathological sleep disorders such as obstructive sleep apnea (OSA) [5, 51]. Prevalence of OSA in PWHA has not been explored or documented despite the presence of several risk factors such as ART-associated lipodystrophy and opioid dependence [51]. In the majority of the studies examining sleep correlates, EDS is determined using the Epworth Sleepiness Scale (ESS), an 8-item self- administered questionnaire validated in obstructive sleep apnea, narcolepsy, and idiopathic hypersomnia. Using this instrument, EDS is defined using a standard cut-point of ESS ≥ 10.

Crum-Cianflone and colleagues examined sleep quality (PSQI) and daytime sleepiness (Epworth Daytime Sleepi- ness Scale) in 193 HIV-infected participants and compared them with 50 HIV-negative participants. The HIV-infected group did not differ from the HIV-negative group by mean age, gender, race, rank, or duty status, but they did differ in that the HIV-infected group was slightly better educated, more depressed (Beck Depression Inventory), and were more likely to be hypertensive than the HIV-negative group. No differences were found between the HIV-infected group and the HIV-negative group on the total sleep quality score, any of the seven sleep quality component scores, or on daytime sleepiness. The authors concluded that HIV-infected patients

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who are diagnosed and treated early may have similar rates of sleep disturbances as the general population [12].

In a similar study examining correlates of sleep in 58 PWHA, Nokes and Kendrew noted that the majority of the participants were unemployed and 79 % reported taking day- time naps at varying frequency [17]. Wanting to determine if sleep quality mediated the stress–fatigue relationship, Sala- huddin et al. examined levels of fatigue, sleep quality, and daytime sleepiness in 128 PWHA (majority African-Amer- ican males; median age 44 years) most of whom had lived with the infection for 10 or more years [58]. Using scores from the HIV-Related Fatigue Scale (HRFS), PSQI, ESS, and a checklist of possibly stressful life events, they found weak correlations between EDS and both fatigue and sleep qual- ity despite the fact that PSQI scores indicated pathological problems. While there was a significant relationship between and among sleep quality, fatigue, and daytime functioning, excessive sleepiness did not add to symptom. Furthermore, Salahuddin et al. found that the association between stress and fatigue-related daytime dysfunction was only marginally explained by EDS and sleep quality yet remains significant when examining daytime dysfunction [58].

The relationship between fatigue and depression is well documented in both the general population and PWHA. In- deed, Lerdal et al. [53] observes that “tiredness” is the sec- ond most prevalent symptom among depressed adults while Harmon et al. [57] cites depression as the most influential concomitant accompanying fatigue. Reid and Dwyer noted that the most notable finding of their integrated review of research literature is that the prevalence of depression in PWHA is markedly and significantly related to quality of sleep rather than CD4 count or disease stage [9]. Moneyham et al. observe that it is possible that many of the symptoms manifested in PWHA are manifestations of depression [59].

Working with a sample ( N = 278) of predominantly Af- rican-American women, Moneyham and colleagues found that depressive symptoms vary significantly with education, income levels, and living arrangements [59]. These findings are similar to those from studies examining the role of fa- tigue in the lives of PWHA and support the observed interre- lationship between and among the correlates of sleep quality. In this case, analysis of data from a longitudinal study sup- ported their hypothesis that social support and coping strate- gies can intervene in the relationship between stress (symp- tom burden and daily functioning) and depression. Indeed, the intensity of symptom burden plus its impact on ability to function in performance of daily activities becomes a signifi- cant predictor of depression. These findings are supported by Low et al. who reported that, if present, depression is the central companion of fatigue [60].

Noting that depression levels may decrease as years liv- ing with the diagnosis increase [57, 58], contemporary re- searchers advocate studies that include lifestyle, environ- mental, cultural, and health belief factors in order to identify and implement interventions leading to effective symptom management [9, 55, 59]. Such interventions might serve to break the patterns of anxiety that have been shown to be as- sociated with therapeutic regimen adherence and quality of life [5, 61].

As life expectancy of PWHA increases, more attention is being given to quality of life. In 2009, Lee et al. reported that reported prevalence of pain in PWHA ranged from 30 to 90%. The wide range was attributed to varying stages of disease among research participants and the use of dif- ferent measurement instruments by the researchers. In one of the few studies examining the relationship of pain and sleep quality, Aouizerat and colleagues compared differ- ences in fatigue, sleep disturbances, anxiety, and depression in PWHA with and without pain [50]. They reported sig- nificantly greater problems across all variables in the group experiencing pain than in participants reporting no pain. The concern is that providers have been underestimating the relationship between pain and sleep, and therefore, not effectively intervening. From findings of their study of the experience of pain in PWHA, Kowal et al. concluded that interventions strengthening effective coping strategies and improving daily functioning will result in decreased vulner- ability to depressive symptoms [62].

Nonpharmacological Treatments for Insomnia

Psychological interventions for PWHA with chronic insom- nia offer many benefits when compared to sedative hypnot- ics [63, 64]. Therefore, it is reasonable and prudent that the first line of treatment should be a psychological intervention.

Cognitive Behavioral Therapy (CBT)

CBT is the current standard of care for first-line treatment of insomnia in the general population. The National Institutes of Health State-of-the-Science Conference on insomnia has listed CBT as a safe and effective means of managing chron- ic insomnia [65]. Cognitive behavioral therapy and cognitive behavioral therapy with relaxation for insomnia are support- ed by research. Cognitive behavioral therapy may produce moderate to large effect sizes for sleep-onset latency and sleep quality, and it produces small to moderate effects sizes for number of awakenings, duration of awakenings, and total sleep time [66−74].

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Cognitive therapy is based on these premises (1) that cog- nitive activity (e.g., thoughts, attitudes, and beliefs) affects behavior; (2) cognitive activity can be changed; and (3) be- havior and emotions can be monitored and changed [75, 76]. Cognitive activity is part of the adaptive process; however, sometimes cognitions become distorted and lead to malad- aptation. Examples of cognitive distortions about sleep in- clude: (1) a person’s belief that he or she will not be able to sleep without a medication, (2) a person’s belief that if he or she is unable to sleep, it is better to just stay in bed and rest, (3) a person’s belief that there is nothing he or she can do to improve sleep, and (4) they will have to deal with insomnia forever. Maladaptative cognitions such as these can lead to chronic insomnia. When cognitive distortions are identified, the goal of therapy is to help the person replace cognitive distortions with adaptive cognitions.

Cognitive behavioral therapy combines cognitive ther- apy and specific behavioral treatments [77]. Research find- ings support the efficacy of CBT for primary and comorbid insomnia (associated with a physiological or psychological condition) [78−83]. A randomized, placebo-controlled trial was conducted among 63 young and middle-aged adults with chronic insomnia. Participants were randomly assigned to one of three of three groups: CBT alone, pharmacotherapy alone (zolpidem), or combined CBT and pharmacotherapy. Cognitive behavioral therapy produced greater improve- ments in sleep-onset latency and sleep efficiency, resulted in the greatest number of normal sleepers following treatment, and maintained these beneficial changes longer [84]. In an earlier clinical trial, 78 adults with chronic and primary in- somnia completed an intervention of CBT, pharmacotherapy (temazepam), combined CBT and pharmacotherapy, or a pla- cebo. Treatment outcomes were time awake after sleep onset as measured by sleep diaries and polysomnography and clini- cal ratings from subjects, significant others, and clinicians. All three active intervention arms resulted in improvements in sleep. The researchers concluded that both CBT and pharma- cological interventions were effective for the short time, but the beneficial gains were maintained longer following CBT alone or in or in combination with behavioral treatment [81].

A small pilot study of eight female survivors of breast cancer demonstrated efficacy of CBT by a reduction in total wake time and increased sleep efficiency as measured by a sleep diary and by polysomnography [85]. In a subsequent more adequately powered study, this group of researchers provided 8 weekly sessions of CBT to small groups of par- ticipants and compared them to participants in a waitlist con- trol group. They found that CBT effectively increased sleep efficiency, decreased total wake time, decreased sleep onset latency, and decreased wake after sleep onset as measured by polysomnography. Significant reductions in the number of hypnotic medicated nights, insomnia severity, anxiety, and depression were also observed [86].

Many questions about CBT for the treatment of insomnia remain unexplored. These include the number and length of sessions needed to obtain beneficial results.

Sleep Hygiene

Sleep hygiene is a self-managed behavioral intervention that is the most commonly recommended intervention to pro- mote good sleep [87]. Sleep hygiene education can be done easily in a clinician’s office.

Sleep hygiene refers to sleep-related behaviors and en- vironmental factors that can be altered to improve sleep quality [88, 89]. The principles of sleep hygiene include eat- ing a healthy diet, limiting the amount of caffeine intake, and going to bed and getting out of bed at consistent times, sleeping in a quiet, dark, temperature-controlled room on a comfortable mattress and pillow. Daytime naps and exercise within 4 h of bedtime are avoided. Eating, drinking (both alcoholic and nonalcoholic beverages), and smoking before going to bed should be avoided. The bed should be used only for sleep and sexual intercourse. The use of electronic de- vices near bedtime should be avoided [90, 91].

Only two studies have examined the effectiveness of sleep hygiene education for improving the sleep of PWHA [92, 93]. Webel and colleagues tested a sleep hygiene inter- vention in 40 PWHA. Participants were randomly assigned to one of two groups, with the intervention group receiving a sleep hygiene intervention known as System CHANGE- HIV. Participants in the intervention group had increased sleep efficiency and decreased sleep fragmentation when compared to the control group [93]. Dreher examined the effects of caffeine reduction in an international sample of 88 HIV-positive men and women who experienced insomnia or any other sleeping problem on an occasional or frequent basis. All participants had a total score greater than five on the PSQI at baseline [92]. Participants were randomized to one of two groups. The experimental group was instructed to withdraw from caffeine gradually and then to avoid all caffeine sources for 30 days. In that study, participants in the experimental group reduced their caffeine intake by 90 % compared to a 6 % reduction of caffeine intake in the control group. No difference in the change in sleep quality from pre- test to posttest between the groups was observed. However, a 35% improvement in sleep quality was observed in the experimental group when sleep quality was controlled for health status [92].

Even though sleep hygiene is commonly recommended in clinical practice, randomized studies that are sufficiently powered to demonstrate the efficacy of this intervention do not exist. There is little consensus about which sleep hygiene principles should be included in a treatment plan, and no two studies have used the same set of sleep hygiene principles. Small sample sizes, the inclusion of other interventions, and

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examining only one aspect of sleep hygiene fail to provide sufficient evidence for the efficacy of sleep hygiene in im- proving sleep quality [74, 94]. However, sleep hygiene is a common sense approach and the principles of sleep hygiene can be easily taught; therefore, it is one of the most frequent- ly used clinical interventions for disrupted sleep quality.

Relaxation Training

Relaxation training exercises have been used successfully to promote sleep. Relaxation techniques include progressive muscle relaxation and autogenic training (used to reduce so- matic tension), and guided imagery and meditation (used to reduce intrusive thoughts at bedtime).

Progressive Muscle Relaxation

Progressive muscle relaxation involves alternately tensing (5 s) and relaxing successive muscle groups (25 s). The per- son is guided to discriminate between how the muscle feels when contracted and when tensed. As the person becomes more experienced with progressive muscle relaxation over time, the difference between tenseness and relaxation can be discerned without actually having to contract the mus- cles [95]. Progressive muscle relaxation is a recommended intervention for the treatment of chronic insomnia [74, 78, 96]. Autogenic training uses autosuggestions, very similar to self-hypnosis. Autogenic training helps a person to experi- ence relaxation, heaviness, and warmth in the limbs, while at the same time recognizing a calm heart beat and slower respirations [97, 98]. Autogenic training is recommended by the American Association of Sleep Medicine [74, 81, 99]. Guided imagery refers to a mind–body technique in which a person is guided to imagine a place that is safe and com- fortable to them. During that time the person is imaging this safe and comfortable place, they are instructed to visualize muscle relaxation, to breathe in and out of the nose, and to feel how relaxed they are. Guided imagery is recommended by the Association of Sleep Medicine [74, 81, 99]. Medita- tion, as taught by Benson, [100] uses a word, a prayer, or movement to induce the relaxation response. These induc- tions are repeated continuously over 10–20 min and are often linked mentally with one’s breathing pattern. During this re- laxation response, other thoughts may occur, but the person is instructed to not judge the thoughts or respond to them. While learning to meditate, a person is instructed to select the induction behavior, to sit still in comfortable place, to close their eyes, to feel their muscles relax, to focus on their breathing patterns, and to meditate for 10–20 min. When the mind wanders during meditation, the person is taught to re- turn to a focus on the induction behavior [74, 81, 99].

Stimulus Control Therapy

Stimulus control therapy is based on the principles of classi- cal conditioning. For some people, going to bed has become associated with difficulty sleeping. For them, going to bed triggers negative emotions, such as fear, anxiety, frustration, and worry about not being able to sleep. The goals of stimu- lus control therapy are to help insomnia patients associate the bed and the bedroom only with sleep and to establish regular sleep–wake times. Stimulus control therapy incorporates the following: Use the bedroom only for sleep or sexual activity. Establish consistent times for going to bed, waking up, and getting out of bed and adhere to those times. Get into sun- light or another bright light as soon as possible after awak- ening. Go to bed only when you become sleepy; sleepiness should be distinguished from fatigue and exhaustion. After going to bed, if you do not fall to sleep within 15–20 min, get out of bed and go to another room to do something relaxing, and when you feel sleepy, return to bed and try to fall asleep again. Do not take daytime naps. It may take several weeks of stimulus control to reestablish normal sleeping patterns. Stimulus control therapy is a recommended psychological intervention for chronic insomnia [74, 101−105].

Sleep Restriction

Sleep restriction is based on the homeostatic sleep drive— the longer a person stays awake, the greater the drive to sleep and the deeper the sleep in the next sleep period [106]. At the beginning of therapy, the person restricts time in bed to the amount of time of actual sleep that is recorded in a sleep diary. This continues for 1 week. At the end of the week if the person has slept at least 90 % of the time actually in bed, then another 15 min is added to the sleep period. If wake time increases resulting in sleep time that is less than 80% of the time in bed, the sleep period is decreased by 15 min. This process continues until the person achieves the desired amount of sleep. For many people, their sleep becomes more robust as the sleep becomes deeper. They experience fewer awakenings, and maintain sleep for longer periods [106−108].

Pharmacological Treatments for Insomnia in HIV/AIDS

The most common treatments for chronic insomnia are over the counter antihistamines, alcohol, and prescription medica- tions [65]. Other treatments include melatonin and valerian. Prescription medications are frequently prescribed as well. The following is a discussion of the use of medications that promote sleep in HIV/AIDS.

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Nonprescription Sleep Aids

Diphenhydramine hydrochloride and doxylamine succinate are over-the-counter H1 receptor antagonists which have his- torical Food and Drug Administration (FDA) approval for the treatment of insomnia. The American Academy of Sleep Medicine, however, does not recommend either diphenhydr- amine hydrochloride or doxylamine succinate for the treat- ment of chronic insomnia, because safety and efficacy data are insufficient [99, 109]. Benadryl may aggravate cognitive impairment in HIV disease and should not be used for the treatment of chronic insomnia [110].

Melatonine is a naturally occurring hormone produced by the pineal gland which helps regulate circadian rhythm [111]. People over 55 years of age often experience a reduc- tion in endogenous melatonin, which may lead to insomnia. The greatest benefits of melatonin use for restoring normal sleep has been for people 55 years of age or older [112]. In HIV/AIDS, mean serum melatonin levels are lower in HIV- infected patients and decline with HIV disease progression [113]. The efficacy and the safety of melatonin for treating chronic insomnia in HIV/AIDS have not been studied.

Table 22.2 Use of sedative/hypnotics in HIV/AIDS

Sedative Hypnotics

Sedative hypnotics fall into two broad categories: benzodi- azepines and nonbenzodiazepine receptor agonists. Benefits of these medications for long-term use have not been studied sufficiently in the general population, and there is a notable absence of comparative effective studies of the safety and efficacy of sleep medications in HIV/AIDS. The lack of re- search in this area is problematic in that these medications may produce additional daytime sleepiness, daytime dys- function, cognitive impairment, and motor incoordination [65], in PWHA who may already experience these symptoms.

Metabolism of Sedative Hypnotics

Sedative hypnotics may increase or decrease blood levels of antiretroviral medications. Sedative hypnotics that are CYP3A inhibitors are generally expected to increase plasma concentrations of antiretroviral medications that are metabo- lized by the CYP3A hepatic enzyme system. CYP3A induc- ers are expected to decrease plasma concentrations of anti- retroviral medications. See Table 22.2.

Brand names

Benzodiazepines

ProSom®

Dalmane®

Doral®

Restoril®

Halcion®

Nonbenzodiazepines

Sonata

Lunesta®

Ambien®

Generic names

Estrazolam

Flurazepam

Quazepam

Temazepam

Triazolam

Zaleplon

Eszopiclone

Zolpidem

Mechanism

Stimulates the GABA-BZ1 receptors Stimulates the GABA-BZ1 receptors

Stimulates the GABA-BZ1 receptors Stimulates the BZ1 receptors

Stimulates the GABA-BZ1 receptors

Stimulates GABA-BZ1 receptors

Unknown, but is thought to stimulate the GABA-BZ1 receptors
Interacts with the GABA-BZ1 receptors

Stimulates melatonin receptors

Antagonizes alpha-1,
5-HT2A, and H-1 receptors at low doses Serotonin-norepinephrine reuptake inhibitor
Sedative effect is likely due to hista- mine-1 receptor antagonism

Sedative effect is likely due to hista- mine-1 receptor antagonism

Metabolism

CYP3A

Specific CYP450 enzyme has not been identified

CYP3A4

CYP isoforms convert temaze- pam to oxazepam

CYP3A

CYP3A4

Converted to hydroxylated metabolites by CYP3A4 isoenzymes

CYP1A2 (primarily), CYP2C, and CYP3A4

CYP450 2D6

CYP450 2C19 CYP450 2D6

Half-life

10–24 h

2–3 h;
47–100 h active metabolites

39–41 h

3.5–24 h

1.5–5.5 h

5–6 h

1.4–3.8 h

2–5 h

4–9 h

31–46 h

Melatonin Receptor Agonist

Rozerim®

Histamine-1 Antagonists

Desyrel®

Elavil®

Sinequan®

Ramelteon

Trazodone

Amitriptyline

Doxepin

Remeron®

Mirtazapine

Antagonizes 5-HT2A, 5-HT2C, and H-1

CYP450 2D6

20–40 h

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Cytochrome P450 (CYP450) is a class of enzymes usu- ally expressed in liver cells but can also be found in the small intestines, lungs, placenta, and kidneys. These enzymes are located in the smooth endoplasmic reticulum, contain a heme molecule, and absorb light at the wavelength of 450 nm. This class of enzymes is essential for cholesterol, steroid, prosta- cyclin, and thromboxane A2 production, in addition to medi- cation metabolism and chemical detoxification. There are over 50 enzymes but six of them constitute approximately 90 % of drug metabolism with CYP3A4 and CYP2D6 being the most significant players [114].

CYP450 enzymes can be inhibited or induced by drugs. Inhibitors are known to block metabolic activity of CYP enzymes while inducers increase the enzyme activity and synthesis, both of which can alter medication blood levels. Some drugs have the ability to be metabolized and then in- hibit/induce the same or different enzymes. Medications can be intentionally combined by health care professionals to take advantage of CYP450 enzymes. In HIV patients, lipo- novir serum levels increased when combined with ritonavir, a protease inhibitor and CYP3A4 inhibitor. However, most combinations of these agents lead to significant adverse drug interactions involving increased side effects or decreased drug effectiveness. This is important since many antiretro- viral agents used for HIV contain similar metabolic path- ways as most commonly used drugs. Information regarding CYP450 metabolism can be found on drug labels or at the FDA website [114].

Histamine-1 Receptor Antagonists

Histamine helps regulate the sleep–wake cycle [109]. An- tidepressant medications (trazodone, doxepin, amitriptyline, and mirtazapine) that are H1 receptor antagonists are used off label for the treatment of insomnia. An exception to this is doxepin, which has received FDA approval for use in sleep maintenance disorders [109].

Trazodone is widely prescribed for its sedating effects and is one of the most commonly prescribed medications for treating insomnia in the USA [65]. Trazodone most likely results from binding of H1 receptors, alpha-1 receptors, and 5-HT2A receptors. Empirical evidence for using trazodone to treat insomnia is limited. Short-term efficacy of trazodone as a hypnotic has been demonstrated for up to 2 weeks, but its long-term effectiveness is unknown [65].

Doxepin has the most empirical support for the treatment of insomnia, especially for sleep maintenance insomnia. The efficacy of doxepin has been studied in healthy adults, adults with primary insomnia, and elderly adults. These tri- als have demonstrated consistent improvement in subjective sleep quality and objective sleep measures including wake after sleep onset (a reduction of 5–20 min), total sleep time

(an increase of 25–51 min), and sleep efficiency (an increase of 6–10 %) [115−121]. Doxepin improves appetite, promotes weight gain, helps control diarrhea, and reduces the chronic pain of peripheral neuropathy [122].

Amitriptyline is a tricyclic antidepressant that has sedat- ing effects. Amitriptyline is highly effective in treating major depression. However, the small difference between the ther- apeutic dose and a toxic dose. Amitriptyline overdose can lead to fatal cardiac arrhythmias. Tricyclic antidepressants are antihistamine (sedation), anticholinergic (constipation), and block alpha adrenergic receptors (erectile dysfunction, orthostatic, and hypotension). Amitriptyline may add to dry- ing of the mouth and other secretions, which is one of the most frequent complaints of PWHA. Amitriptyline may in- crease appetite and thus be beneficial to persons who need to gain weight. Amitriptyline can be beneficial in the treatment of peripheral neuropathy [109, 122]. There are two studies that suggest that tricyclic antidepressants are not effective in HIV-related peripheral neuropathies [123]. Amitriptyline does not appear to affect immune status in HIV/AIDS [124].

Mirtazapine is an FDA-approved tetracyclic antidepres- sant. The sedative property of mirtazapine is most likely due to the fact that it blocks the H1 receptors. It also blocks 5HT2A and 5HT2C receptors which may promote sedation. Lower doses of mirtazapine may produce more sedation than higher doses, because at higher doses it may stimulate nor- adrenergic responses [125]. Clinical evidence for the use of mirtazapine for the treatment of chronic insomnia in HIV/ AIDS is inadequate to recommend it for use solely for its sedative properties for PWHA [109].

The American Academy of Sleep Medicine recommends the use of sedating antidepressants when short-acting or intermediate-acting benzodiazepine receptor agonists have failed. They are particularly beneficial for persons with co- morbid depression or anxiety [99].

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Part VI

Historical Milestones of Individual Sleep Disorders

Evolution of the Classi cation of Sleep Disorders

Michael Thorpy

The classi cation of sleep disorders continues to evolve as

we gain more information about different types of sleep dis- orders and their pathophysiology. The branch of medicine that deals with the classi cation of diseases is called nosol- ogy, and classi cation systems have varied uses. The Inter- national Classi cation of Disease (ICD) is the main interna- tional health classi cation system used to code illness and to track disease for medical, public health, reimbursement, statistical analysis, and medical informatics reasons. Other classi cation systems not only have a numerical coding system but are also used to classify diseases and disorders, symptoms, and medical signs for clinical decision making. The American Psychiatric Association’s Diagnostic and Sta- tistical Manual (DSM) and the International Classi cation of Sleep Disorders (ICSD) fall into this latter category.

For most of recorded history, there was a recognition of predominantly three types of sleep abnormalities: insomnia, excessive sleepiness, and nightmares, and it was not until the nineteenth century that specific sleep disorders, such as nar- colepsy, began to be recognized. Differentiation between the causes of sleep disorders reached a peak in the past 50 years following the development of technology for the investiga- tion of sleep.

Early Sleep Diagnoses

Most of our current knowledge of ancient Egyptian medicine derives from the Chester Beatty and the Georg Ebers papyri, written around 1350–1600 BC, but they contain little infor- mation on sleep disorders other than dreams [1, 2].

M. Thorpy ()
111 East 210th Street, Bronx, NY 10467, USA e-mail: thorpy@aecom.yu.edu

The Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA

One of the first books published on sleep was The Phi- losophy of Sleep by Robert MacNish in 1830 [3]. MacNish listed several sleep disorders including sleeplessness, night- mares, sleepwalking, and sleep talking, and other authors in the nineteenth century mentioned hypnagogic hallucina- tions, somnambulism, wakefulness, and somnolence includ- ing narcolepsy. Dana in 1884 reviewed the topic of excessive sleepiness and discussed 50 patients and classified the disor- ders into three categories based on the possible underlying cause: (1) epileptoid state, (2) hysteroid sleeping state, and (3) “puzzling nature” cases not due to the prior two causes [4].

In the early twentieth century, two comprehensive books on sleep had a major influence on the development of sleep disorders medicine: Pieron’s Le Problème Physiologique du Sommeil and Sleep and Wakefulness by Nathaniel Kleitman in 1939 (updated in 1963 to contain 4337 references) [5, 6]. These books were the first to mention many different sleep disorders.

Collins in his book Insomnia: How to Combat It in 1930 described three classes of “poor sleepers” [7]. The first class had great difficulty falling asleep which was due to many causes but mainly related to anxiety and worry. In this cat- egory, he included “night terrors” predominantly occurring in children. The second class were those who had severe drowsiness in the evening and an early-morning awaken- ing which he thought was due predominantly to “autotox- ins” or arteriosclerosis in the elderly. His description most equates with the current diagnostic category of “advanced sleep phase syndrome.” The third class he described as those who sleep an adequate amount of hours at night but have severe daytime sleepiness. Gillespie had a greater listing of sleep disorders in his book Sleep, also published in 1930 [8]. He discussed insomnia, narcolepsy, sleep–wake rhythm disturbance, hypnagogic hallucinations, somnolence, sleep paralysis, night terrors, somnambulism, nocturnal enuresis, nocturnal epilepsy, and “sleep pains.”

Interestingly, many authors in the nineteenth century and the first part of the twentieth century described patients who

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_23, 183 © Springer Science+Business Media, LLC 2015

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M. Thorpy

slept for months or even years before returning to full alert- ness, often called “protracted sleep,” a condition still not understood or even included in modern-day sleep classifica- tions. However, in the second half of the twentieth century, sleep classification was established with greater detail and accuracy.

Evolution of Specific Diagnoses

Narcolepsy and Other Hypersomnias

Westphal first described a patient with narcolepsy in 1877, but it was Gelineau in 1880 who described astasia (cata- plexy) in detail and coined the term “narcolepsy” [9, 10]. Following Gelineau’s description in the late nineteenth cen- tury, narcolepsy was brought to general recognition in 1926 by the Australian-born neurologist William John Adie [11]. There were many attempts to distinguish true narcolepsy, or as Adie called it “idiopathic narcolepsy,” from secondary causes of narcolepsy. Adie used the term “pyknolepsy” for alternative causes of sleepiness. Wenderowic in 1924 used the terms “genuine narcolepsy,” “hypnolepsy” for mainly postencephalitic sleepiness, and a symptomatic “hypnoid state” for other causes [12]. Lhermitte in 1930 called narco- lepsy “paroxysmal hypersomnia” to distinguish it from pro- longed hypersomnia [13]. Wilson (1928) and Daniels (1934) regarded narcolepsy as “true narcolepsy” if accompanied by cataplexy [14, 15].

Henneberg in 1916 first used the term “cataplectic inhibi- tion” which was subsequently called “cataplexy” by Adie in 1925 [16]. Prior to that, cataplexy had been called “astasia” by Gelineau [10].

Critchley and Hoffman in 1942 created the term Kle- ine–Levin syndrome to describe adolescents with periodic hypersomnia and megaphagia [17]. Menstrual hypersom- nia, another form of recurrent hypersomnia associated with menstruation, was first reported by Lhermitte and Dubois in 1941 [18].

Idiopathic hypersomnia, a disorder of excessive sleepi- ness that was distinguished from narcolepsy, was recognized by Roth in 1976 [19]. He recognized two forms, one with a long nocturnal sleep period and another with a normal noc- turnal sleep duration.

The invention of the EEG led to the creation of polysom- nography (PSG) that has greatly aided the development of sleep classifications.

Parasomnias

The term “parasomnias” was coined by Roger in 1932 [20]. Roger classified the sleep disorders into three groups: the hypersomnias, the insomnias, and the parasomnias.

Kleitman (1939) recognized that the parasomnias in- cluded: nightmares, night terrors, somniloquy, somnambu- lism, grinding of the teeth, jactations, enuresis, delirium, nonepileptic convulsions, and personality dissociations [6]. Broughton in 1968 developed the classification of the “arousal disorders” that consisted of confusional arousals, night terrors, and sleepwalking [21].

Insomnia

Throughout the years, it was always recognized that in- somnia could be both idiopathic as well as “secondary” to psychological stress or other medical disorders. Primary in- somnia was regarded as a form of insomnia that was not sec- ondary to other medical or psychiatric disorders. In the late 1970s, insomnia became recognized as a symptom rather than a diagnosis, and treatment was directed to the under- lying physical or psychological causes. A large number of different types of insomnia were recognized. The concept of a conditioned insomnia (psychophysiological insomnia) was first presented in the Diagnostic Classification of Sleep and Arousal Disorders (DCSAD), and subsequently became rec- ognized as a common form of primary insomnia [22].

In the 2000s, it became clear that it was difficult to deter- mine whether some disorders were causative of the insomnia or whether they were just coincident with the insomnia. The concept of “comorbid insomnia” was promoted at a National Institutes of Health (NIH) State of the Science conference held in 2005. By 2012, despite the many causes of insomnia, it was recognized that pathophysiologically only one type of insomnia existed and the sole diagnosis “insomnia disorder” was promulgated.

Sleep-Related Breathing Disorders

Following the reports of snoring, sleepiness, and obesity in the nineteenth century, Sir William Osler referred in 1906 to Dickens’ description of Joe [23]. Charles Burwell in 1956 brought general recognition to obstructive sleep apnea syn- drome, which he called the “Pickwickian syndrome” [24].

23 Evolution of the Classification of Sleep Disorders

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Circadian Rhythm Sleep Disorders

Circadian rhythm sleep disorders were recognized in the late 1970s, partly due to recognition of the chronobiological fea- tures of “jet lag” and “shift work.”

The atypical, sleep-onset insomnia called the “delayed sleep phase syndrome” was discovered by Weitzman and colleagues in 1981 [25]. The converse situation, “advanced sleep phase syndrome,” was described in 1979 [26]. The “non-24-h sleep–wake disorder” was first described in a blind person [27].

Modern Sleep Classification Systems International Classification of Diseases

ICD-9-CM In 1967, the eighth revision of the International Classification of Diseases listed very few sleep disorders [28]. The main list of sleep disorders was in the Mental Dis- orders section 306 “Special symptoms not elsewhere clas- sified” that listed hypersomnia, insomnia, nightmare and sleepwalking in a subsection entitled “Specific disorders of sleep.” Section 780 “Symptoms and ill-defined conditions” under the subcategory “Disturbance of sleep” listed only “Inversion of sleep rhythm.” Cheyne Stokes respiration was indexed under “Dyspnoea” and Pickwickian syndrome was indexed under “Obesity not specified as of endocrine ori- gin.”

The North American version of the International Clas- sification of Diseases (ICD-9-CM) in 1980 contained an expanded listing of the disorders included under the major sleep disorder headings in the World Health Organization’s ninth revision of the International Classification of Diseas- es, the ICD-9, first published in 1977 [29, 30]. The sleep disorder diagnoses in ICD-9-CM are organized under two major headings: “The specific disorders of sleep of non- organic origin” (ICD #307.4) and “The sleep disturbances” (ICD #780.5). Subdivisions of these two ICD-9-CM catego- ries were partly based upon the headings and disorders of the 1979 Association of Sleep Disorders Centers (ASDC) DCSAD [22].

ICD-10-CM The ICD-10 was introduced in Europe in 1993 (Table 23.1). The USA revised version, ICD-10-CM, is expected to be implemented on October 1, 2015, and includes a nearly complete listing of the sleep disorders that are contained in the ICSD-2 (Table 23.2) [31]. The disorders are in two main sections: F51 in the “Mental, Behavioral and Neurodevelopmental disorders,” subsection “Behavioral syndromes associated with physiological disturbances and physical factors,” and G47 in the “Diseases of the nervous

Table 23.1 ICD-10 (1993) F51 Nonorganic sleep disorders

F51.0 Nonorganic insomnia
F51.1 Nonorganic hypersomnia
F51.2 Nonorganic disorder of the sleep–wake schedule F51.3 Sleepwalking (somnambulism)
F51.4 Sleep terrors (night terrors)
F51.5 Nightmares
F51.8 Other nonorganic sleep disorder
F51.9 Nonorganic sleep disorder, unspecified

G47 Sleep disorders

G47.0 Disorders of initiating and maintaining sleep (insomnias) G47.1 Disorders of excessive somnolence (hypersomnias) G47.2 Disorders of the sleep–wake schedule
G47.3 Sleep apnea

G47.4 Narcolepsy and cataplexy G47.8 Other sleep disorder G47.9 Sleep disorder unspecified

Table 23.2 ICD-10-CM outline (proposed 2015)

F51 Sleep disorders not due to a substance or known physiological condition

F51.0 Insomnia not due to a substance or known physiological condition
F51.01 Primary insomnia (idiopathic insomnia)
F51.1 Hypersomnia not due to a substance or known physiological condition

F51.3 Sleepwalking (somnambulism)
F51.4 Sleep terrors (night terrors)
F51.5 Nightmare disorder (dream anxiety disorder)
F51.8 Other sleep disorders not due to a substance or known physi- ological condition
F51.9 Sleep disorder not due to a substance or known physiological condition, unspecified (emotional sleep disorder NOS)

G47 Sleep disorders

G47.00 Insomnia, unspecified
G47.01 Insomnia due to medical condition
G47.09 Other insomnia
G47.1 Hypersomnia
G47.19 Other hypersomnia
G47.2 Circadian rhythm sleep disorders
G47.3 Sleep apnea
G47.4 Narcolepsy
G47.5 Parasomnia
G47.6 Sleep-related movement disorders
G47.8 Other sleep disorders
G47.9 Sleep disorder, unspecified (sleep disorder NOS)

Restless legs syndrome (G25.81) Sleep deprivation (Z72.820) NOS not otherwise specified

system,” subsection “Episodic and paroxysmal disorders.” The classification is in development and may reflect changes expected in the ICSD-3.

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DSM of the American Psychiatric Association

DSM-II In 1968, in the second American Psychiatric Asso- ciation’s Diagnostic and Statistical Manual (DSM-II), the only category for sleep disorders was the entry “Disorder of Sleep” [32].

DSM-III In DSM-III (1980), the only two disorders of sleep included sleepwalking (somnambulism) and sleep ter- rors (pavor nocturnus) which were classified in the section entitled “Other Disorders with Physical Manifestations.” DSM-III-R (1987) included an expanded listing of sleep dis- orders in a separate section entitled “sleep disorders” [33]. It included disorders of at least 1 month in duration that were classified into two groups: the dyssomnias and the parasom- nias. The dyssomnias were defined as disorders where the predominant disturbance is in the amount, quality, or tim- ing of sleep. The parasomnias were defined as an abnormal event occurring during sleep. The categories were deter- mined by interrater reliability using a structured interview. The dyssomnias consisted of three main disorders: insomnia disorder, hypersomnia disorder, and sleep–wake schedule disorder. The parasomnias consisted of: nightmare disorder, sleep terror disorder, and sleepwalking disorder.

The revision of the American Psychiatric Association’s DSM-III was under way when the ICSD was in development in the late 1980s. DSM-III-R contained an abbreviated list of sleep disorders that served the purposes of the overall DSM- III-R classification but was not compatible with the ICSD.

DSM-IV The DSM-IV, published in 1994, included addi- tional sleep disorders in part based on the ICSD (Table 23.3) [34]. A major section entitled “Primary Disorders” included

Table 23.3 DSM-IV (1994) Primary sleep disorders Dyssomnias

Primary insomnia
Primary hypersomnia Narcolepsy
Breathing-related sleep disorder Circadian rhythm sleep disorder Dyssomnias NOS

Parasomnias

Nightmare disorder Sleep terror disorder Sleepwalking disorder Parasomnia NOS

Sleep disorders related to another mental disorder
Secondary sleep disorders due to an axis III condition Substance-induced sleep disorders
DSM diagnostic and statistical manual, NOS not otherwise specified

in the dyssomnia category: primary insomnia, primary hypersomnia, narcolepsy, breathing-related sleep disorders, and circadian rhythm sleep disorder. Another category under parasomnias lists: nightmare disorder, sleep terror disorder, and sleepwalking disorder, as in DSM-III-R. A second major section listed “sleep disorders related to another mental dis- order,” and there was an “other sleep disorders” category.

The process of revising the DSM-IV to produce DSM-V was initiated in 2010 and was implemented in 2010.

Diagnostic Classification of Sleep and Arousal Disorders

The Association of Sleep Disorder Centers (ASDC) classi- fication committee, chaired by Howard Roffwarg, produced the DCSAD in 1979. It ushered in the modern era of sleep di- agnoses and became the first classification to be widely used internationally (Table 23.4) [22]. The classification was pro- duced by both the ASDC and the Association for the Psycho- physiological Study of Sleep (APSS) and was published in the journal Sleep. The development of DCSAD began with a workshop on “Nosology and nomenclature of the sleep dis- orders” in 1972 at the APSS annual meeting.

The DCSAD classification consisted of four major cat- egories: (A) the Disorders of Initiating and Maintaining Sleep (DIMS), (B) the Disorders of Excessive Somnolence (DOES), (C) the Disorders of the Sleep-Wake Schedule (DSWS), and (D) the Parasomnias. The first two categories were more of a differential diagnosis listing. However, some disorders, such as the sleep-related breathing disorders, could produce symptoms of both insomnia and excessive sleepiness, and the circadian rhythm sleep disorders could produce both symptoms. Many disorders were listed twice, once in each symptom category. The parasomnia listing was long and did not have subcategory organization. By the mid 1980s, a revised classification system was needed.

Table 23.4 DCSAD outline (1979)
(A) Disorders of initiating and maintaining sleep

(B) Disorders of excessive somnolence
(C) Disorders of the sleep–wake schedule
(D) Parasomnias
DCSAD diagnostic classification of sleep and arousal disorders

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The International Classification of Sleep Disorders

ICSD-I The ICSD, produced by the American Sleep Dis- orders Association in association with the European Sleep Research Society, the Japanese Society of Sleep Research, and the Latin American Sleep Society, was developed as a revision and update of the DCSAD (Table 23.5) [35]. This revision was necessitated by the description of many new disorders and the further development of information on many of the originally described disorders. Classifying the disorders by pathophysiological mechanism was preferred.

The ASDC initiated the process of revising the DCSAD classification in 1985 by establishing an 18-member Diag- nostic Classification Steering Committee under the chair- manship of Michael Thorpy. The first meeting of this group was convened in July 1985 at the Annual Meeting of the ASDC in Seattle. A detailed questionnaire was developed and distributed to members of the Clinical Sleep Society (CSS) in the USA and to sleep specialists around the world to determine the usefulness of the first edition of the clas- sification and to assess the potential usefulness of a number of proposed changes. Members representing the European Sleep Research Society, the Japanese Society of Sleep Re- search, and the Latin American Sleep Society and the Clini- cal Sleep Society were involved in the ICSD development of the individual disorders.

Every entry in the DCSAD was assessed for content and relevance in the practice of sleep disorders medicine. The questionnaire respondents regarded the original classifica- tion highly and the majority of the individual diagnostic entities were considered appropriate and relevant to clini- cal practice. However, opinions differed on both the overall classification structure and some of the individual diagnostic entries.

Table 23.5 ICSD-1 outline (1990) (1) Dyssomnias

Intrinsic sleep disorders Extrinsic sleep disorders Circadian rhythm sleep disorders

(2) Parasomnias

Arousal disorders
Sleep–wake transition disorders
Parasomnias usually associated with REM sleep Other parasomnias

(3) Medical/psychiatric sleep disorders

Associated with mental disorders Associated with neurological disorders Associated with other medical disorders

(4) Proposed sleep disorders

ICSD international classification of sleep disorders, REM rapid eye movement

Of the four main DCSAD diagnostic categories, section (C), “the Disorders of the Sleep–Wake Schedule,” now called the “Circadian Rhythm Sleep Disorders,” was the most fa- vored grouping, probably because of its pathophysiological consistency due to the underlying chronophysiological basis.

The survey indicated that clinicians required more diag- nostic information about respiratory and neurological disor- ders, so those sections were expanded. In addition, integra- tion of childhood sleep disorders into the overall classifica- tion system was recommended. A separate childhood sleep disorders classification was considered, but this may have produced an artificial distinction between the same disorder in different age groups.

A classification for statistical and epidemiological pur- poses required that each disorder be listed only once. Orga- nization on the basis of symptomatology was unsatisfactory because many disorders could produce more than one sleep- related symptom. The final structure was organized more pathophysiologically and less symptomatically. However, as the pathology is unknown for the majority of the sleep disor- ders, the classification was organized, in part, on physiologi- cal features: a pathophysiological organization.

The ICSD-I grouped the sleep disorders into four major sections. Section (1), the dyssomnias, included those dis- orders that produced a complaint of insomnia or excessive sleepiness. The dyssomnias were further subdivided, in part along pathophysiological lines, into the intrinsic, extrinsic, and circadian rhythm sleep disorders. Section (2), the para- somnias, included those disorders that intruded into or oc- curred during sleep but did not produce a primary complaint of insomnia or excessive sleepiness. Section (3) was the medical/psychiatric sleep disorders. Section (4) comprised the proposed sleep disorders, developed in recognition of the new and rapid advances in sleep disorders medicine. New disorders were being discovered, and some question- able sleep disorders had been more clearly described. The inclusion of these disorders encouraged further research to determine whether they were specific disorders in their own right or whether they were variants of other already classi- fied disorders.

The subdivisions of the dyssomnias, intrinsic and extrin- sic sleep disorders, divided the major causes of insomnia and excessive sleepiness into those that were induced primarily by factors within the body (intrinsic) and those produced pri- marily by factors outside of the body (extrinsic). This group- ing of the sleep disorders initially had been proposed by Na- thaniel Kleitman in his extensive monologue on the sleep disorders that was published in 1939 [6].

The medical/psychiatric sleep disorders comprised the medical and psychiatric disorders commonly associated with sleep disturbance. The use of the terms medical and psychi- atric was not ideal, but was preferred to the ICD-9 use of the terms organic and nonorganic. Most medical and psychiatric

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disorders can be associated with disturbed sleep or impaired alertness, so only those disorders with major features of dis- turbed sleep or wakefulness, or those commonly considered in the differential diagnosis of the primary sleep disorders, were included in this section.

The ICSD-I consisted of disorders primarily associated with disturbances of sleep and wakefulness, as well as disor- ders that intrude into, or occur during, sleep. The classifica- tion provided a unique code number for each sleep disorder so that disorders could be efficiently tabulated for diagnos- tic, statistical, and research purposes. The primary aim of the text was to provide useful diagnostic information. Diagnos- tic, severity, and duration criteria were presented, as well as an axial system where clinicians could standardize presenta- tion of relevant information regarding a patient’s disorder.

The axial system, similar to the system used in DSM, was developed to assist in reporting appropriate diagnostic information, either in the clinical summaries or for database purposes. The first axis, axis A, contained the primary diag- noses of the ICSD, such as narcolepsy. The second axis, axis B, contained the names of the procedures performed, such as polysomnography, or the names of particular abnormalities present on diagnostic testing, such as the number of sleep- onset rapid eye movement (REM) periods seen on multiple sleep latency testing. The third axis, axis C, contained ICD- 9-CM medical diagnoses that were not sleep disorders, such as hypertension.

A brief text revision of the ICSD-I was produced in 1997 and called The International Classification of Sleep Disor- ders: Revised [36]. This revision did not change the overall structure or names of the disorders but mainly involved up- dating the text.

ICSD-2 In 2005, the American Academy of Sleep Medi- cine developed a second edition of the ICSD, called ICSD-2 (Table 23.6) [37]. The classification was divided into eight

main sections: (1) insomnia, (2) sleep-related breathing dis- orders, (3) hypersomnias of central origin not due to a circa- dian rhythm sleep disorder, sleep-related breathing disorder, or other cause of disturbed nocturnal sleep, (4) circadian rhythm sleep disorders, (5) parasomnias, (6) sleep-related movement disorders, (7) isolated symptoms, apparently normal variants and unresolved issues, and (8) other sleep disorders. There were two appendices: Appendix A: Sleep Disorders Associated with Conditions Classifiable Else- where; and Appendix B: Other Psychiatric and Behavioral Disorders frequently encountered in the Differential Diagno- sis of Sleep Disorders. The ICSD-2 contained the majority of the diagnoses included in ICSD-I. However, the severity and duration criteria and the axial system of ICSD-I were not included in ICSD-2.

In 2011, the process was initiated to revise the ICSD-2 to produce ICSD-3. Major changes are likely, based on a better understanding of the pathophysiology of sleep disorders, al- though the major group headings are unlikely to change. There will be change in the individual disorders some of which will be listed as subtypes. The ICSD-3 was published in 2014 [38].

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Table 23.6

ICSD-2 outline (2005)

1. Insomnia
2. Sleep-related breathing disorders
3. Hypersomnias of central origin not due to a circadian rhythm sleep disorder, sleep-related breathing disorder or other cause of disturbed nocturnal sleep
4. Circadian rhythm sleep disorders
5. Parasomnias
6. Sleep-related movement disorders
7. Isolated symptoms, apparently normal variants and unresolved issues
8. Other sleep disorders
Appendix A: Sleep disorders associated with conditions classifiable elsewhere
Appendix B: Other psychiatric and behavioral disorders frequently encountered in the differential diagnosis of sleep disorders
ICSD international classification of sleep disorders

23 Evolution of the Classification of Sleep Disorders 189

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of sleep disorders, 3rd ed. Davien: IL: American Academy of Sleep Medicine, 2014.

History of Epidemiological Research in Sleep Medicine

Markku Partinen

Epidemiological studies on sleeping habits and sleep disor- ders date back to the beginning of the last century. The earli- est studies included clinical case series or simple descriptive surveys about the occurrence of different sleep-related phe- nomena. Recent epidemiological research includes modern epidemiological methods. Sleep epidemiology, as we can understand it now, is defined as a discipline of how to study the occurrence of phenomena of interest in the field of sleep.

The word “epidemiology” is derived from epi (upon), demos (people), and logos (discourse or study). Originally, epidemiologists studied mainly infections and diseases of epidemic proportion. Modern applications of epidemiol- ogy include the study of chronic diseases, evaluation of the health status of populations, and effect of different determi- nants (genetic and environmental) on different outcomes. In- crease of computational power enables complicated methods that a researcher could just dream about some 30 years ago. In the beginning of the 1980s, a time-sharing system was used in huge mainframe computers (at that time, IBM domi- nated the computer manufacturing companies). Sometimes, it took a week or more to have results of a set of tables with chi-square values. Instructions were given by punched cards, which were invented by Herman Hollerith in 1884 at the Massachusetts Institute of Technology (MIT), Boston.

Early Studies

The oldest epidemiological sleep studies are from the end of the eighteenth century. Clement Dukes from England studied sleep need in young children [1]. Other early stud- ies are those by Claparède [2] from France and Camp from Michigan [3]. Approximately 80–100 years ago, young chil-

M. Partinen ()
Department of Clinical Neurosciences, University of Helsinki, Helsinki, Finland
e-mail: markpart@me.com

Helsinki Sleep Clinic, VitalMed Research Centre, Helsinki, Finland

dren slept 10.5–13.5 h, 15-year-olds 9–10 h, and adults be- tween 7 h 25 min and 8 h 23 min. These figures do not differ significantly from those in the present day. Women slept a little longer than men. In 1931, Laird published a large study of 509 men of distinction. Sleep disturbances increased with age, as they do at present. At the age of 25 years, about 90 % of men slept well, but by the age of 95 everybody had some sleeping problems. On an average, more than 70% of men of distinction reported some difficulty in going to sleep, and more than 40 % reported awakening during the night [4].

The number of epidemiological studies increased in the 1960s. In these studies, the average length of sleep varied between 7 and 8 h. In Scotland, 2446 subjects aged over 15 were studied. Of the older subjects in the age group 65–74 years, 18 % complained of awakening before 5 a.m. This de- creased to 12% after the age of 75. Less than 10% of men aged 15–64 years complained of disturbed sleep. In the age group 65–74 years, disturbed sleep was a complaint in 25 % of men. In women, the respective percentage was 43 % [5].

Increase of Epidemiological Studies During Recent Years

In the beginning of 1970, less than 50 publications could be found in PubMed using the following Mesh terms: (“Epidemiology”[Mesh] OR prevalence OR incidence) AND (“Sleep Disorders”[Mesh] OR “Sleep Disorders, Cir- cadian Rhythm”[Mesh] OR “Snoring” OR “Sleep Apnea Syndromes”[Mesh] OR “Sleep Apnea, Obstructive”[Mesh] OR “Sleep Apnea, Central”[Mesh] OR “insomnia” OR “pa- rasomnia”) and limiting the publications to original human studies. The number of epidemiological publications started to grow faster at the end of the 1980s. In 1990, already 110 studies were published and the figure increased to more than 300 in 2001. Starting from 2008, more than 1000 epidemio- logical original articles on sleep have been published each year.

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_24, 191 © Springer Science+Business Media, LLC 2015

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Pioneers of Sleep Epidemiology in the USA

Excellent articles on individual differences of sleep length were published by Wilse B Webb in Science [6, 7] and also in the classical book Sleep and Dreaming (edited by Ernest Hartmann) in 1970 [8]. Webb as well as Hartmann belong to the pioneers of sleep research. Webb can be considered a pioneer in sleep epidemiology. He has always emphasized the need for using proper methods and criteria. Among many other things, he also investigated short and long sleepers. “Short sleepers” slept less than 5.5 h per night and “long sleepers” slept more than 9.5 h per night [6, 7]. Webb was the first to correlate sleep recording findings with sleep length and stated that short sleepers had reduced amount of stage 2 and rapid eye movement (REM) sleep than average sleep- ers or long sleepers [6, 7]. Webb studied sleep in the elderly as well as effects of shift work, and he always had strong opinions. A case in point is his letter to the editor of Sleep “Opinion Polls and Science” where he questioned the opin- ion polls as scientific evidence (something that I fully agree with). In general, opinion polls have very little to do with sci- entific epidemiology. All sleep researchers doing or planning to do epidemiological studies should read Webb’s works and verify what he had written about a certain topic.

Edward Bixler started sleep epidemiological studies in the 1970s and he continues to carry on excellent studies [9, 11–13]. He started to work in collaboration with Anthony Kales who is best known for the classic Rechtschaffen and Kales (R&K) scoring system published in 1968 [10]. One of the early classic studies on the prevalence of insomnia is the Los Angeles metropolitan study in 1979 [9]. It was a well-done population-based survey on 1006 individuals that was designed as a sleep epidemiological study. The preva- lence of insomnia was 42.5 %. Nightmares were reported by 11.2%, 7.1% complained of excessive sleepiness, 5.3% re- ported sleep talking, and 2.5 % had sleepwalking. Insomnia was a major complaint amongst older women and those with lower educational and socioeconomic status [9]. Edward Bixler published several landmark studies on the epidemiol- ogy of insomnia, parasomnias and sleep apnea. Already in the beginning of 1980s, he emphasized that the criteria of clinically significant sleep apnea differ by age. His studies also showed a strong correlation between obesity and sleep apnea, and that sleep apnea in postmenopausal women is as common as in men [11–13].

Epidemiology of Snoring and Sleep Apnea

In 1980, Elio Lugaresi and his collaborators published the first results of the San Marino epidemiological population- based survey in the journal Sleep [14]. It was the first large population-based study on snoring and about the association

of snoring with cardiovascular disease. Also, other sleep disorders were surveyed. The Neurological Clinic of Bolo- gna, Italy, is one of the great schools in clinical and clinical– epidemiological sleep research. Prof. Lugaresi and Giorgio Coccagna were among the first persons together with Henri Gastaut to describe obstructive sleep apnea, which they called hypersomnia with periodic breathing. Also, Lugaresi organized the first international symposium “The Rimini Symposium on Hypersomnia and Periodic Breathing” in 1972. Christian Guilleminault introduced the term “sleep apnea” later, in 1975, soon after he had moved from France to work with William Dement at Stanford, USA.

Shortly after the San Marino studies, the first population- based epidemiological studies on the prevalence of snoring and sleep apnea were published from USA (Sonia Ancoli- Israel, Daniel Kripke, Edward Bixler), Finland (Markku Partinen, Tiina Telakivi), Germany (Jörg Hermann Peter, Thomas Podszus), Israel (Peretz Lavie), Sweden (Thorarinn Gislason), and Denmark (Poul Jennum). Thorarinn Gislason is working presently in his hometown of Reykjavik in Ice- land, and he is leading genetic and epidemiological studies in collaborations with Allan Pack at the University of Penn- sylvania in Philadelphia, USA. Investigators from Iceland are in a unique position for genetic studies because the ge- netic roots can be traced back to the AD 800s. Unfortunately, the Icelandic population is isolated, and replication studies in other populations have been often negative. Poul Jennum leads the Danish group of sleep researchers. Using the reg- istries that are unique in all Nordic countries, he recently published excellent papers on economical issues of different sleep disorders.

Prevalence of Sleep Apnea

The prevalence of sleep apnea figures varied, depending on the gender and age, between 1 and 6% which agreed with the results of the Wisconsin population-based study that was published in 1993 by Terry Young and collaborators [15]. The first Wisconsin Sleep Cohort study of 602 employed men and women was published in the New England Journal of Medicine. Four per cent of men and 2% of women met the minimal diagnostic criteria of obstructive sleep apnea syndrome. These are the most commonly cited prevalence figures of sleep apnea although they are valid only for an employed population. As has been shown later by Bixler, sleep apnea is about as common in postmenopausal women as in men of the same age [13]. Sleep apnea is very com- mon in elderly people, but the effect on mortality is lower in elderly than in middle-aged people [16, 17]. New studies are warranted. The occurrence of sleep apnea increases with body weight, and with increasing prevalence of obesity sleep apnea has been increasing more and more. This means that the Young figures from 1993 are probably outdated [18].

24 History of Epidemiological Research in Sleep Medicine

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Sleep and Cardiovascular Disease

Markku Partinen and Michel Billiard were students of Pierre Passouant from Montpellier, France. Partinen studied medi- cine in France and he became interested in sleep when he was preparing for a special certificate of neurophysiology with Passouant. In 1976, after his return to Finland, he start- ed preparing his doctoral thesis [19] on sleep epidemiology. A few years later, he started to collaborate with Markku Ko- skenvuo and Jaakko Kaprio who had been working at the University of Helsinki with the Finnish twin cohort. Ques- tions of snoring and more questions on sleep were added to the surveys. A U-type association was found, for the first time between sleep length and occurrence of coronary heart disease [20]. This finding has since been replicated in several other studies. The association of habitual snoring with arte- rial hypertension as well as the association between snor- ing, sleep apnea and myocardial infarction were reported for the first time by Partinen and collaborators in 1983 [21, 22]. Since that time, the Finnish group continued reporting on genetic and different environmental effects on sleep [23, 24] and publishing further studies on snoring, sleep apnea, and cardio- and cerebrovascular disease [25–27]. These early re- sults have been confirmed later by several other groups.

Type 2 Diabetes and Sleep Apnea

An association between sleep apnea and type 2 diabetes was reported for the first time by Japanese investigators in 1991 [28]. Soon, Finnish researchers found that the severity of sleep apnea was related to the degree of insulin resistance [29]. The association of sleep apnea with type 2 diabetes was recognized widely including the diabetes research commu- nity [30, 31].

Mortality and Morbidity in Patients Diagnosed with Sleep Apnea

The first convincing studies showing that mortality is in- creased in untreated sleep apnea were published by two groups in 1988 [32–34]. Since then, many other studies have shown an association between sudden death, [35] myocar- dial infarction, stroke, and sleep apnea. The best studies have been prospective studies [36–45].

Narcolepsy

Narcolepsy studies were initiated in Montpellier, France, and at Stanford University, USA. The prevalence of narcolepsy has been studied in many countries. The prevalence of nar-

colepsy is about 30 per 100,000 people [46–50]. The high- est figures are from Japan and the lowest are from Israel. In France, the early epidemiological studies were conducted mainly in Montpellier. Pierre Passouant, teacher of Michel Billiard, organized the First International Symposium on Narcolepsy in La Grande Motte in 1975 together with Wil- liam Dement and Christian Guilleminault. Passouant was one of the pioneers of clinical sleep medicine, including epidemiological understanding, together with William De- ment, Christian Guilleminault, Yasuo Hishikawa, and Yutaka Honda.

Insomnia

Insomnia is the most common sleep disorder. It is very im- portant and more difficult to treat than sleep apnea. Socio- economically, insomnia poses more economic burden than sleep apnea. Several USA groups dominated this field but Europeans have also published many important epidemio- logical studies on insomnia. The Swedish (Jerker Hetta, Gunnar Boman, and many others), British (Kevin Morgan and others), and Norwegians (Reidun Ursin, Björn Bjorvatn, and others) have been active together with Finnish, French and German researchers. Sleepiness is an important issue in occupational medicine and in traffic. In these areas, the most important studies were conducted by Pierre Philip from France and Torbjörn Åkerstedt from Sweden. As for epi- demiological studies on narcolepsy, many Europeans have been involved in pioneering studies, including Yves Dauvil- liers from Montpellier, Christer Hublin from Finland, and the Swiss colleagues.

The first international meeting on epidemiology of sleep/ wake disorders was organized in Milano Marittima, Italy, in May 1982 (Fig. 24.1). The proceedings of the excellent meeting were published in the book Sleep/Wake Disorders: Natural History, Epidemiology, and Long-Term Evolution, edited by Christian Guilleminault and Elio Lugaresi.

History of Other Epidemiological Studies

Other European names in the early history of epidemiology of sleeping habits, insomnia, and sleep apnea include Heikki Palomäki (stroke), John Stradling (neck circumference, risk factors, hypertension), Neil Douglas (RCTs, cognition, etc.), Erkki Kronholm (sleep length, insomnia), and Claudio Bas- setti (stroke) among many others. Talking about history of cardiovascular studies on sleep apnea in Europe, one cannot forget Marburg (Germany). Jörg Hermann Peter was a pio- neer in that field, and he organized several important meet- ings on the topic before he passed away in January 2010. Some of the studies that originated in Marburg are now being

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M. Partinen

Fig. 24.1 The first international meeting on epidemiology of sleep/wake disorders was orga- nized in Milano Marittima, Italy, in May 1982. Milano Marittima 1982. Bill Dement and Elio Luga- resi are in the middle

continued in Gothenburg, Sweden, by Ludger Grote and Jan References Hedner. One of the pioneers in the area of narcolepsy and

hypersomnias had been Prof. Bedrich Roth from Prague (Czech Republic). He was born in 1919 and he passed away in 1989. He published his first monograph on narcolepsy in 1957. His blue book on hypersomnias with epidemiological data remains a classic. Sonia Nevsimalova and Karel Sonka are continuing his pioneering work.

Several US groups, in addition to Bixler and Young, have conducted excellent epidemiological studies. One important researcher is Maurice Ohayon who is a psychiatrist. He be- came more and more interested in sleep epidemiology after moving from France to Canada. The first epidemiological study using the so-called Sleep-EVAL system was published in 1996 [51]. Since that time, he has published several cross- sectional studies on the occurrence of different sleep disor- ders.

There are many other Asian, European, and US col- leagues who have conducted epidemiological studies in dif- ferent areas. The list of researchers would be too long, and I have listed only some people who have been important in the history of sleep medicine during its development mainly in the 1980s to the 1990s. I apologize to all of those whose names are missing. Happily, more and more people are in- terested in sleep epidemiology. With the advent of efficient computers and good registries, studies changed from simple descriptive ones to well-planned case–control, prospective, and multivariate analytic studies of different associations and risk factors.

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24 History of Epidemiological Research in Sleep Medicine 195

14. Lugaresi E, Cirignotta F, Coccagna G, Piana C. Some epidemio- logical data on snoring and cardiocirculatory disturbances. Sleep. 1980;3:221–4.

15. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badar S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328:1230–5.

16. Ancoli-Israel S, Klauber MR, Stepnowsky C, Estline E, Chinn A, Fell R. Sleep-disordered breathing in African-American elderly. Am J Resp Crit Care Med. 2000;152:1946–9.

17. Bliwise DL, Foley DJ, Vitiello MV, Ansari FP, Ancoli-Israel S, Walsh JK. Nocturia and disturbed sleep in the elderly. Sleep Med. 2008;10:540–8

18. Partinen M, Hublin C. Epidemiology of sleep disorders. In: Meir Kryger TR, Dement WC, editors. Principles and practice of sleep medicine. 5 edn. St. Louis: Elsevier Saunders; 2011. p. 694–715.

19. Partinen M. Sleeping habits and sleep disorders on Finnish men before, during and after military service. Ann Med Milit Fenn. 1982;57:1–96.

20. Partinen M, Putkonen PT, Kaprio J, Koskenvuo M, Hilakivi I. Sleep disorders in relation to coronary heart disease. Acta Med Scand. 1982;660:69–83.

21. Partinen M, Kaprio J, Koskenvuo M, Langinvainio H. Snoring and hypertension: a cross-sectional study on 12808 Finns aged 24–65 years. Sleep Res. 1983;12:273.

22. Partinen M, Alihanka J, Lang H, Kaliomaki L. Myocardial infarc- tion in relation to sleep apneas. Sleep Res. 1983;12:272.

23. Partinen M, Eskelinen L, Tuomi K. Complaints of insomnia in dif- ferent occupations. Scand J Work Environ Health. 1984;10:467–9.

24. Partinen M, Kaprio J, Koskenvuo M, Putkonen P, Langinvainio H. Genetic and environmental determination of human sleep. Sleep.
1983;6:179–85.

25. Partinen M, Palomäki H. Snoring and cerebral infarction. Lancet.
1985;ii:1325–6.

26. Koskenvuo M, Kaprio J, Partinen M, Langinvainio H, Sarna S,
Heikkilä K. Snoring as a risk factor for hypertension and angina
pectoris. Lancet. 1985;1:893–6.

27. Koskenvuo M, Kaprio J, Telakivi T, Partinen M, Heikkilä K, Sarna
S. Snoring as a risk factor for ischaemic heart disease and stroke in
men. Br Med J. 1987;294:16–9.

28. Katsumata K, Okada T, Miyao M, Katsumata Y. High incidence of
sleep apnea syndrome in a male diabetic population. Diabetes Res
Clin Pract. 1991;13:45–51.

29. Tiihonen M, Partinen M, Närvänen S. The severity of obstructive
sleep apnoea is associated with insulin resistance. J Sleep Res.
1993;2:56–61.

30. Tuomilehto H, Peltonen M, Partinen M, Seppa J, Saaristo T,
Korpi-Hyovalti E, et al. Sleep-disordered breathing is related to an increased risk for type 2 diabetes in middle-aged men, but not in women—the FIN-D2D survey. Diabetes Obes Metab. 2008;10:468–75.

31. Foster GD, Sanders MH, Millman R, Zammit G, Borradaile KE, Newman AB, et al. Obstructive sleep apnea among obese patients with type 2 diabetes. Diabetes Care. 2009;32:1017–9.

32. He J, Kryger M, Zorick F, Conway W, Roth T. Mortality and apnea index in obstructive sleep apnea. Chest. 1988;94:9–14.

33. Partinen M, Jamieson A, Guilleminault C. Long-term outcome for obstructive sleep apnea syndrome patients. Mortality. Chest. 1988;94:1200–4.

34. Partinen M, Guilleminault C. Daytime sleepiness and vascu- lar morbidity at seven-year follow-up in obstructive sleep apnea patients. Chest. 1990;97:27–32.

35. Seppala T, Partinen M, Penttila A, Aspholm R, Tiainen E, Kauki- anen A. Sudden death and sleeping history among Finnish men. J Intern Med. 1991;229:23–8.

36. Ancoli-Israel S, Kripke DF, Klauber MR, Fell R, Stepnowsky C, Estline E, et al. Morbidity, mortality and sleep-disordered breath- ing in community dwelling elderly. Sleep. 1996;19:277–82.

37. Javaheri S, Parker TJ, Liming JD, Corbett WS, Nishiyama H, Wexler L, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation. 1998;97:2154–9.

38. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. New Engl J Med. 2000;342:1378–84.

39. Kaneko Y, Floras JS, Usui K, Plante J, Tkacova R, Kubo T, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. New Engl J Med. 2003;348:1233–41.

40. Campos-Rodriguez F, Pena-Grinan N, Reyes-Nunez N, De la Cruz- Moron I, Perez-Ronchel J, De la Vega-Gallardo F, et al. Mortality in obstructive sleep apnea-hypopnea patients treated with positive airway pressure. Chest. 2005;128:624–33.

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The Insomnias: Historical Evolution

Suresh Kumar and Sudhansu Chokroverty

Introduction

To paraphrase David Parkes [1], insomnia can be called by different names just like Wordsworth’s [2] cuckoo (“O Cuckoo! Shall I call thee Bird, or but a wandering Voice?”) because insomnia is thought to be a symptom of many dis- eases (medical, psychiatric, and others). For an understand- ing of insomnia, one should begin by studying the inhabit- ants of the ancient world and the civilization of the Indus (India), Yangtze (China), the Euphrates (Middle East) [1], and Egypt gradually progressing through to modern indus- trialized and contemporary culture. The term insomnia is derived from Latin meaning literally a total lack of sleep. But from a practical standpoint it is the relative lack of sleep, non-restorative, or inadequate quality of sleep which is rel- evant. Insomnia is really “hyposomnia” meaning a decrease in duration or depth. Henry Cockeram while working on the dictionary of “hard English words” in the early 1620s [3] used the term insomnia synonymous with the word “watch- ing” meaning want of power to sleep.

Developmental Milestones of Insomnia in the Ancient Time

Insomnia

Since ancient times sleep and sleep disorders have been mentioned time and again with particular relevance to sleeplessness and various therapies available for it. Ancient

S. Chokroverty ()
JFK New Jersey Neuroscience Institute, 65 James Street, Edison, NJ 08818, USA
e-mail: schok@att.net

S. Kumar
Department of Neurology, Sree Balajee Medical College and Hospital, Chrompet, Chennai, India

Chennai Sleep Disorders Centre, Chennai, India

trea tises on medicine and surgery have existed as early as 400 BC ca. and have been the forerunners to the present-day modern texts. One such ancient treatise is Charaka Samhita. The Advaita Vedanta written in Sanskrit (ca. 5000 BC) talks about sleep and wakefulness and the different states were termed avasthas; avasthatraya—the three states, namely waking state ( jagrat), dream sleep ( swapna), and dreamless sleep ( sushupti; see also Chap. 4). The Vedanta further de- scribes that all human beings without any exception experi- ence all these three states on a daily basis [4]. The vedas, furthermore, elaborate the presence of a fourth state which is described as a state of true awakening. This is defined as a state where there is no interruption by the waking state and is termed “turiyam” or the fourth state. Any disruption of the three states would lead to unsatisfactory sleep and awakening. The vedas also point out that disruption of the peace of mind by stressors can disrupt the natural process of these three states and lead to sleeplessness. The vedas at that time had pointed out the basis of sleep and in fact went on to describe dreamless, and dreaming, motionless sleep which is similar to features of rapid eye movement (REM) sleep. They also described the probable psychophysiological con- cept of insomnia without directly mentioning it as insomnia.

Ayurvedic medicine existed several thousands of years before Christ. Ayurveda considers sleep to be one of three pillars of health. Ayurveda, a Sanskrit word means the knowledge for a long life ( Ayu means longevity and Veda means knowledge or science). Ayurvedic medicine is a sys- tem of traditional Indian medicine (a form of complementary or alternative medicine) practiced from mid- to second mil- lennium BC to contemporary time. During the Buddhist pe- riod (ca. 300 BC to AD 1000), the knowledge of Ayurvedic medicine spread to far West and East. This ancient system of medicine is being taught along with the allopathic medicine in many universities and colleges throughout India now.

Traditional Chinese medicine (TCM), existing also since many thousands of years before Christ, approaches insomnia in a different way than Western medicine (see also Chap. 5). TCM using the concept of “root and branch” views insom-

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_25, 197 © Springer Science+Business Media, LLC 2015

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nia symptoms as the “branches” and the root of the disease as an imbalance of the fundamental substances (e.g., Chi, Yin, Yang, blood, Jing, Shen) or major organ systems (e.g., heart or liver). According to the TCM concept originating from Shamanism and later Taoism, a wandering spirit or Shen disturbance can manifest most commonly as insomnia symptoms. TCM practitioners often combine acupuncture and Chinese herbal medications (e.g., Suan Zao Ren or sour date seed) for treating insomnia. A popular herb, Yi-Gen San has been approved for the treatment of insomnia in Japan. It is interesting to note that this same herb has been reported to be effective in the treatment of three cases of REM sleep behavior disorder [5].

In Western culture, one finds reference to insomnia, prob- ably for the first time in ancient Greeks in the pre-Hippocratic Epidaurian tablets. According to the Greco-Roman concept, the people’s lives were controlled by gods and goddesses [6]. The goddess of the night (Nyx) had two sons, namely, Hyp- nos (the god of sleep) and Thanatos (the god of death). The Greek god Hypnos is often symbolized to hold a poppy flower in the hand with a field of poppies in front of his house [3]. It is described that in ancient Greece, if a person had issues regarding sleeplessness, he would need to visit the sanato- rium of Asclepios (the Greek god of medicine) where he would receive the treatment with soothing music, rest, and meditation. This is reminiscent of the cognitive behavioral and relaxation therapies of modern time [7]. The present-day therapy like valerian root was already used in the ancient Greek period for the treatment of sleeplessness. For exam- ple, the ancient Greek physician Dioscorides prescribed va- lerian root as a sedative. Hippocrates (400 BC) mentioned about sleep and sleep-related issues in his writings (Corpus Hippocraticum) [8]. In the Egyptian civilization, medical pa- pyri from the Edwin Smith papyrus, the Ebers papyrus, and Kahun papyrus described the use of opium as a treatment for insomnia [9]. It is stated that the first-century BC Greek phy- sician Heraclides of Taras, who lived in Alexandria, Egypt, recommended opium as the treatment of choice for insom- nia [10]. The Indian philosophy describes Nidra Devi as a goddess of sleep and chanting her verses mentioned in the religious book (Chandi path or reading) induces sleep [11].

Aristotle offered the first scientific approach in his writ- ings around 350 BC enumerating the most comprehensive theories of sleep. Three essays in the collection known as Parva Naturalia (on sleep and waking, on dreams, and on divination through sleep) analyzed the genesis of sleep as well as the concept of dreams [12–14]. Quoting Beare’s translation “Likewise it is clear that [of those either asleep or awake] there is no animal which is always awake or always asleep, but that both these affections belong [alternately] to the same animal. For if there be an animal not endowed with sense-perception, it is impossible that this animal should ei-

ther sleep or wake; since both these are affections of the ac- tivity of the primary faculty of sense-perception.” Aristotle stated that no being can remain always awake or asleep per- manently. Again quoting Beare’s translation “Finally, if such affection is sleep, and this is a state of powerlessness arising from excess of waking, and excess of waking is in its origin sometimes morbid, sometimes not, so that the powerlessness or dissolution of activity will be so or not; it is inevitable that every creature which wakes must also be capable of sleep- ing, since it is impossible that it should continue actualizing its powers perpetually.” Aristotle mentioned that excess of waking would make you powerless and tried to explain the intricate balance between sleep and wakefulness.

Insomnia is mentioned in several places in the Bible (see also Chap. 6) to emphasize the severity, associated loneli- ness, anxiety, and guilty conscience as well as illnesses caus- ing sleeplessness [15]. An example in the Psalms is: “I lie awake, I am like a lonely bird upon a roof” (102:8). The Bible also mentions physical activity as a treatment for in- somnia. The importance of getting enough sleep at night has also been emphasized in Qur’an and the Islamic literature (see also Chap. 3) [16].

Evolution of the Concept of Insomnia
from the Nineteenth to Twenty-first Century

Frank in 1811 mentioned agrypnia (meaning insomnia) as one of the seven classes of sleep disturbance [17]. A search of the literature clearly shows that publications on the topic of insomnia dominated the field of sleep research since 1870. For a description of historical evolution of insomnia and its treatment in the nineteenth and early twentieth centu- ries, the readers are referred to Chap. 12 by Schulz and Sal- zarulo. Macfarlane [18] in 1890 wrote the definitive text of the nineteenth century defining insomnia as “loss of sleep.” It is interesting to note that Macfarlane considered insomnia as a symptom and not a disease, a view still hotly debated in this century.

Contemporary sleep medicine defines insomnia as an inability to fall asleep or maintain sleep associated with an impairment of daytime functioning. International classifica- tion of sleep disorders (ICSD-3) [19] classified insomnia into three categories. It can be associated with medical, psy- chiatric or psychological factors, environmental causes, or ingestion of medication. The term secondary insomnia used in the first National Institute of Health (NIH) consensus de- velopment conference in 1983 has been replaced by the term comorbid insomnia in the later NIH consensus conference in 2005 [20] as the cause-and-effect relationship has not been determined. The Diagnostic and Statistical Manual of the American Psychiatric Association (1994; DSM-IV) classi-

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fied insomnia into primary insomnia and that related to med- ical or mental disease or to substance abuse or dependency. DSM-V (published in 2013) recommends the term “insom- nia disorders” replacing “primary insomnia” and “insomnia associated with medical or mental diseases” [21]. According to the Center for Disease Control (CDC) of the USA, 70 mil- lion Americans suffer from chronic insomnia. The lack of a standard definition of insomnia hampered epidemiological studies and limited research on sleep quality. Depending on the definition, up to 30% of the population in the Western countries may experience insomnia symptoms and insomnia may be persistent in 10 % [22]. Insomnia diagnosis is based on subjective reports (sleep questionnaires and sleep diaries) rather than objective data derived from polysomnographic (PSG) findings. In any case, there appears to be a remarkable discrepancy between PSG and subjective measures. Eding- er et al. published research diagnostic criteria for insomnia [23]. Longitudinal studies of the general population in the Western countries suggested high prevalence with varying degrees of persistence with rates varying from 40 to 69% and the incidence rates of 3.9 to 28.8 % [22]. In a longitudi- nal study (mean follow-up of 5.2 years) of Chinese adults, the researchers in Hong Kong led by Y. K. Wing found an incidence rate for insomnia symptoms and insomnia syn- drome (additional daytime symptoms) of 5.9 %, whereas the persistence rate of insomnia syndrome was 42.7 and 28.2 % for insomnia symptoms [24].

Some major advances in insomnia research occurred in the last half of the twentieth and twenty-first century. Some examples of these include long-term consequences of chron- ic insomnia, relationship between insomniac and psychiat- ric disorders, new understanding about pathophysiology of insomnia, and advances in the treatment. First, one must understand that insomnia is a 24-h disease and is not just sleep deprivation. Sleep deprivation is endemic in our mod- ern industrialized society. Average sleep duration in human has decreased by 1.5–2 h in the course of the last 55 years, which may be partly responsible for adverse metabolic and hormonal effects, and increasing incidence of obesity and type 2 diabetes mellitus in the society [25]. Function of sleep, however, remains a mystery but we have enough evi- dence to show that sleep plays an important role in homeo- static mechanism with restitution of sleep, thermoregulation, immune control, and tissue repair, as well as memory con- solidation [26]. Even one night of sleep deprivation impairs hippocampal function resulting in inadequate memory pro- cessing [27]. Jenkins and Dallenbach’s experiment in 1924 [28] proved that memory retention was better after a night of sleep and this was later supported by behavioral and func- tional magnetic resonance imaging (fMRI) studies by Stick- gold and Walker [29]. An early observation by Kripke et al. [30] in 1979 of increased risk of death from coronary arterial disease, cancer, and stroke in those who sleep less than 4 h

(also those who sleep more than 10 h) was later confirmed [31], but remains controversial without resolving cause and effect and because of the confounding factor of medication ingestion. However, short-term consequences, such as exces- sive daytime sleepiness, mood disorder, irritability, impaired work efficiency and absenteeism, accidents at work and home, and falls in the elderly, and long-term (remains de- batable) consequences, such as increased mortality and mor- bidity (e.g., obesity, type 2 diabetes mellitus, hypertension, and other adverse cardiovascular consequences, psychiatric disorders, and memory impairment, have been reported in patients with chronic insomnia [32]. Obstructive sleep apnea (OSA) is an additional comorbidity and up to 50 % of OSA patients may suffer from moderate to severe insomnia [33]. There is a clear bidirectional relationship between insomnia and depression [34]. In 1969, Winokur et al. [35] reported that 100 % of their sample of 1257 patients with depression had comorbid insomnia and these observations have been subsequently confirmed in many reports [34].

Significant advances have been made in the last decade of the twentieth and current century in our understanding of the pathophysiology of chronic insomnia. There are many models and theories proposed. Various models focused on primary insomnia rather than comorbid insomnias as the latter represent heterogeneous conditions. Richardson [36] proposed four physiological models: (1) disruption of the sleep homeostat; (2) disruption of the circadian clock; (3) disruption of intrinsic sleep–wake state mechanisms; and (4) disruption (hyperactivity) of extrinsic “override” systems (e.g., stress response mechanisms). A detailed discussion of these models is beyond the scope of this chapter but avail- able data favor the involvement of dysfunctional extrinsic stress response systems. Physiological hyperarousal remains the contemporary theory inspired by studies undertaken ear- lier by Monroe [37], Kales [38], Adam [39], and coinves- tigators, Bonnet and Arand [40] and continuing with Perlis [41], Vgontzas et al. [42], and other investigators [36]. Perlis [41, 43] and coinvestigators have provided a comprehensive review of the hyperarousal theory. The sustained hyper- arousal throughout 24 h explains the persistence of chronic primary insomnia. The hyperarousal theory is based on the evidence of physiologic arousal with increased autonomic activity (e.g., elevated heart rate and body temperature), sympathetic arousal (measured by heart rate variability), ac- tivation of neuroendocrine (e.g., hypothalamo–pituitary–ad- renal [HPA] and neuroimmunological axes), and heightened cortical arousal (e.g., increased beta and gamma frequency electroencephalography (EEG) activity at sleep onset and during non-REM (NREM) sleep with the higher high-to-low frequency ratio in the fast Fourier transformation (FFT) of the EEG signals, and altered brain metabolism as evidenced by the positron emission tomographic (PET) scan findings of heightened neural activation in brain areas subserving

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arousal and emotion during sleep in insomnias) [41, 43–46]. The increased production of cortisol and interleukin-6 in patients with chronic insomnia support the activation of the HPA and neuroimmunological axes [42]. The finding of a reduction in hippocampal volume [47] in insomnias and the experimental observations of impaired neurogenesis in the hippocampus following sleep loss in rats [48] support cogni- tive deficits and impaired memory consolidation in patients with chronic insomnia. Finally, using a sophisticated immu- nohistochemical method (Fos activation indicating neuro- nal activation), Cano et al. [49] produced a stress-induced insomnia model in rats to show simultaneous activation of both sleep-promoting and arousal-related brain regions simi- lar to the observations in human insomniacs of simultaneous fatigue throughout the day and an inability to “de-arouse” on attempting to sleep.

Evolution of Insomnia Treatment
from the Ancient Time to Twenty-First Century

Natural remedies to promote sleep and as a treatment for sleeplessness were popular in the ancient time with the use of chamomile (medicinal herb in the form of tea). St John’s Wort and mandragora (mandrake tree) as sleeping aid have a history of use over 2400 years for various disorders includ- ing sleeplessness. Ayurvedic medicine, the oldest compre- hensive medicinal system of India, describes the use of yoga and “ashwagandha” to cure insomnia [49a]. Ashwagandha, also known as Withania somnifera in Latin or “Indian win- ter cherry” or “Indian ginseng,” contains steroidal lactones, anaferine, and heterogonous alkaloids, which reduce the pro- duction of cortisol. Ashwagandha promotes a calm state of mind by its restorative action in the nervous system, which counteracts tension and high blood pressure. This brings the body to a state of equilibrium, making the body to relax dur- ing stress and fatigue thus restoring sleep to insomnia pa- tient. Likewise, “brahmi,” also known as Bacopa Monnieri in Latin, was also used in the ancient times to promote sleep. The current concept is that “brahmi” increases the levels of serotonin and bacosides.

Insomnia treatment includes pharmacological therapy using hypnotic medications and non-pharmacologic treat- ment using lifestyle and behavior modifications. In the nineteenth and twentieth centuries, hypnotic medications had been used frequently for insomnia (see also Chap. 12). As mentioned earlier, opium was first used as a hypnotic in Egypt (ca. 1000 BC). From the ancient time until the nine- teenth century, alcohol, opium, or a dilute solution of the active ingredient in the opium poppy seed, morphine, was the ingredient for sleeping medications. Morphine may have

been named after Morpheus (the god of dream and the son of Greek god of sleep Hypnos and the equivalent Italian god of sleep Somnus). In the nineteenth century, bromides, chlo- ral hydrate, and paraldehyde were used as hypnotics, which were later superseded by barbiturates in the beginning of the twentieth century. Benzodiazepines replaced barbiturates in the second half of the twentieth century followed later in the past decade of the twentieth century by imidazopyridines, the non-benzodiazepine GABAA receptor agonists (popular- ly known as Z drugs: zolpidem, zopiclone, including eszopi- clone, and zaleplon). Over-the-counter (OTC) medications (all containing antihistamines) and alcohol are frequently used by the public presently as nonprescription aids for in- somnia. Other prescription drugs currently used as hypnotics include antidepressants (Trazodone and Mellaril (Elavil) in particular); however, at the 2005 NIH state-of-the science consensus conference [20], these medications were discour- aged to be used as hypnotics.

The role of non-pharmacological treatment for insomnia was clearly evident even in the nineteenth century in the form of sleep hygiene, and the other measures (e.g., behav- ioral therapy) were mentioned in the twentieth century (see also Chap. 12). As early as 1880s, hydrotherapy (e.g., baths, showers, wraps, warm douching) was used for sleeplessness [50, 51].

Spielman’s 3P (predisposing, precipitating, and perpet- uating factors) model of insomnia [52] paved the way for modern cognitive behavioral therapy for insomnia (CBT-I; see also Chaps. 58 and 60). CBT-I basically consists of five components [53–58]: (1) sleep hygiene measures [56]; (2) stimulus control therapy (SCT) of Bootzin [57]; (3) sleep restriction therapy (SRT) of Spielman [58]; (4) progressive muscle relaxation (PMR); and (5) cognitive therapy (CT). Later a web-based (internet-based intervention) CBT treat- ment was introduced in a 2012 publication [59]. The two main goals of the treatment for chronic insomnia advocated by the American Academy of Sleep Medicine (AASM) are to improve the quality of sleep and to improve the next-day impairment of function [60]. AASM guidelines recommend CBT for chronic primary as well as comorbid insomnias. Non-pharmacological intervention is shown to be superior to hypnotic treatment alone in a head-to-head comparison [61] and CBT is considered the treatment of choice for chronic insomnia [62]. Combined behavioral and pharmacological treatment may be needed in some patients but many unre- solved issues remain in this approach [63, 64]. Comorbid insomnia including comorbid depression and insomnia re- quires a treatment for both the primary condition and insom- nia itself. It is generally agreed that acute insomnia should be treated with short-term hypnotic medications during the stressful situation triggering acute insomnia to prevent the development of chronic insomnia.

25 The Insomnias: Historical Evolution 201

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Part VII Neurological Sleep Disorders

Narcolepsy–Cataplexy Syndrome and Symptomatic Hypersomnia

Seiji Nishino, Masatoshi Sato, Mari Matsumura and Takashi Kanbayashi

Introduction

In this chapter, the clinical and pathophysiological aspects of idiopathic and symptomatic narcolepsy–cataplexy syndromes and hypersomnia (or excessive daytime sleepi- ness, EDS) are discussed. Although no systematic epide- miological study has been conducted, available data suggest that hypersomnia (both idiopathic and symptomatic) is common but under-diagnosed; both types of hypersomnia significantly reduce the quality of life (QOL) of the subjects. Narcolepsy–cataplexy type 1, narcolepsy without cataplexy (a prototypical hypersomnia) type 2, and idiopathic hyper- somnia (a primary hypersomnia not associated with rapid eye movement [REM] sleep abnormalities) are three major idiopathic hypersomnias [1], but substantial clinical over- lap among these disorders has been noted, as each disorder is currently diagnosed by mostly sleep phenotypes and not by biologically/pathophysiologically based tests. Similarly, symptomatic hypersomnia is a heterogeneous disease entity and the biological/pathophysiological mechanisms underly- ing symptomatic hypersomnia are mostly unknown.

Recent progress for understanding the pathophysiology of EDS particularly owes to the discovery of narcolepsy genes (i.e., hypocretin receptor and peptide genes) in animals in 1999 and the subsequent discovery in 2000, of hypocretin ligand deficiency (i.e., loss of hypocretin neurons in the brain) in idiopathic cases of human narcolepsy–cataplexy. The hypocretin deficiency can be clinically detected by ce- rebrospinal fluid (CSF) hypocretin-1 measures; low CSF hypocretin-1 levels are seen in over 90% of narcolepsy–

S. Nishino () · M. Sato · M. Matsumura
Stanford University Sleep and Circadian Neurobiology Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 3165 Porter Drive, RM1195, Palo Alto, CA 94304, USA
e-mail: nishino@stanford.edu

T. Kanbayashi

Department of Neuropsychiatry, Akita University, Akita, Japan

cataplexy patients. Since the specificity of the CSF finding is also high (no hypocretin deficiency was seen in patients with idiopathic hypersomnia), low CSF hypocretin-1 levels have been included in the third revision of the international classifications of sleep disorder as a positive diagnosis for narcolepsy–cataplexy [1].

Narcolepsy–cataplexy is tightly associated with human leukocyte antigen (HLA) DQB1*0602. Hypocretin defi- ciency in narcolepsy–cataplexy is also tightly associated with HLA positivity, suggesting an involvement of immune- mediated mechanisms for the loss of hypocretin neurons. However, the specificity of HLA positivity for narcolepsy– cataplexy is much lower than that of low CSF hypocretin-1 levels, as up to 30% of the general population shares this HLA haplotype.

The prevalence of primary hypersomnia, such as narco- lepsy and idiopathic hypersomnia, is not high at 0.05 and 0.005%, respectively, but the prevalence of symptomatic (secondary) hypersomnia may be much higher. For example, about several million subjects in the USA suffer from chronic brain injury, and 75 % of those people have sleep problems, and about half of them claim sleepiness [2]. Symptomatic narcolepsy has also been reported, but the prevalence of symptomatic narcolepsy is much smaller, and only about 120 cases have been reported in the literature in the past 30 years [3]. The meta-analysis of these symptomatic cases indicates that hypocretin deficiency may also partially explain the neurobiological mechanisms of EDS associated with symp- tomatic cases of narcolepsy and hypersomnia [3].

Anatomical and functional studies demonstrate that the hypocretin systems integrate and coordinate the multiple wake-promoting systems, such as monoamine and acetyl- choline systems to keep subjects fully alert [4], suggesting that understanding of the roles of hypocretin peptidergic sys- tems in sleep regulation in normal and pathological condi- tions is important, as alternations of these systems may also be responsible not only for narcolepsy but also for other less well-defined hypersomnias.

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_26, 205 © Springer Science+Business Media, LLC 2015

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Since a large majority of patients with EDS are currently treated with pharmacological agents, new knowledge about the neurobiology of EDS will likely lead to the development of new diagnostic tests as well as new treatments and man- agements of patients with hypersomnia with various etiolo- gies.

This chapter focuses on pathophysiological mechanisms and nosological aspects of idiopathic and symptomatic hypersomnia. For the treatments of these conditions, refer to more specific publications available [5–8].

Symptoms of Narcolepsy

Excessive Daytime Sleepiness

EDS and cataplexy are considered to be the two primary symptoms of narcolepsy, with EDS often being the most dis- abling symptom. The EDS most typically mimics the feeling that people experience when they are severely sleep-deprived but may also manifest itself as a chronic tiredness or fatigue. Narcoleptic subjects generally experience a permanent back- ground of baseline sleepiness that easily leads to actual sleep episodes in monotonous sedentary situations. This feeling is most often relieved by short naps (15–30 min), but in most cases the refreshed sensation only lasts a short time after awaking. The refreshing value of short naps is of consider- able diagnostic value. Sleepiness also occurs in irresistible waves in these patients, a phenomenon best described as “sleep attacks.” Sleep attacks may occur in very unusual cir- cumstances, such as in the middle of a meal, a conversation, or riding a bicycle. These attacks are often accompanied by microsleep episodes [9], where the patient “blanks out.” The patient may then continue his or her activity in a semicon- scious manner (writing incoherent phrases in a letter, speak- ing incoherently on the phone, etc.), a phenomenon called automatic behavior [9–11]. Learning problems and impaired concentration are frequently associated [9–13], but psycho- physiological testing is generally normal.

Sleepiness is usually the first symptom to appear, fol- lowed by cataplexy, sleep paralysis, and hypnagogic halluci- nations [14–18]. Cataplexy onset occurs within 5 years after the occurrence of daytime somnolence in approximately two-thirds of the cases [15, 17]. Less frequently, cataplexy appears many years after the onset of sleepiness. The mean age of onset of sleep paralysis and hypnagogic hallucinations is also 2–7 years later than that of sleepiness [14, 19].

In most cases, EDS and irresistible sleep episodes persist throughout the lifetime although they often improve after re- tirement (possibly due to better management of activities), daytime napping, and adjustment of nighttime sleep.

Cataplexy

Cataplexy is distinct from EDS and pathognomonic of the disease [20]. The importance of cataplexy for the diagnosis of narcolepsy has been recognized since its description [21, 22] and in subsequent reviews on narcolepsy [23, 24]. Most authors now recognize patients with recurring sleepiness and cataplectic attacks as a homogeneous clinical entity, and this is now shown to be tightly associated with hypocretin defi- ciency (see the section on the pathophysiology of the dis- ease). Cataplexy is defined as a sudden episode of muscle weakness triggered by emotional factors, most often in the context of positive emotions (such as laughter, having good cards at card games, the pull of the fishing rod with a biting fish, and the perfect hit at baseball), and less frequently by negative emotions (most typically anger or frustration). All antigravity muscles can be affected leading to a progressive collapse of the subject, but respiratory and eye muscles are not affected. The patient is typically awake at the onset of the attack but may experience blurred vision or ptosis. The attack is almost always bilateral and usually lasts a few sec- onds. Neurological examination performed at the time of an attack shows a suppression of the patellar reflex and some- times presence of a Babinski’s sign.

Cataplexy is an extremely variable clinical symptom [25]. Most often, it is mild and occurs as a simple buckling of the knees, head dropping, facial muscle flickering, sagging of the jaw, or weakness in the arms. Slurred speech or mutism is also frequently associated. It is often imperceptible to the ob- server and may even be only a subjective feeling difficult to describe, such as a feeling of warmth or that somehow time is suspended [24, 25]. In other cases, it escalates to actual episodes of muscle paralysis that may last up to a few min- utes. Falls and injury are rare and most often the patient will have time to find support or will sit down while the attack is occurring. Long episodes occasionally blend into sleep and may be associated with hypnagogic hallucinations.

Patients may also experience “status cataplecticus.” This rare manifestation of narcolepsy is characterized by subin- trant cataplexy that lasts several hours per day and confines the subject to bed. It can occur spontaneously or more often upon withdrawal from anticataplectic drugs [16, 26, 27].

Cataplexy often improves with advancing age. In rare cases, it disappears completely but in most patients it is bet- ter controlled (probably after the patient has learned to con- trol their emotions) [14, 28].

Sleep Paralysis

Sleep paralysis is present in 20–50 % of all narcoleptic sub- jects [17, 29–31]. It is often associated with hypnagogic

26 Narcolepsy–Cataplexy Syndrome and Symptomatic Hypersomnia

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hallucinations. Sleep paralysis is best described as a brief inability to perform voluntary movements at the onset of sleep, upon awakening during the night, or in the morning. Contrary to simple fatigue or locomotion inhibition, the pa- tient is unable to perform even a small movement, such as lifting a finger. Sleep paralysis may last a few minutes and is often finally interrupted by noise or other external stimuli. The symptom is occasionally bothersome in narcoleptic sub- jects, especially when associated with frightening hallucina- tions [32].

Whereas EDS and cataplexy are the cardinal symptoms of narcolepsy, sleep paralysis occurs frequently as an isolated phenomenon, affecting 5–40% of the general population [33–35]. Occasional episodes of sleep paralysis are often seen in adolescence and after sleep deprivation, thus preva- lence is high for single episodes.

Hypnagogic and Hypnopompic Hallucinations

Abnormal visual (most often) or auditory perceptions that occur while falling asleep (hypnagogic) or upon waking up (hypnopompic) are frequently observed in narcoleptic sub- jects [36]. These hallucinations are often unpleasant and are typically associated with a feeling of fear or threat [29, 32]. Polygraphic studies indicate that these hallucinations occur most often during REM sleep [29, 37]. These episodes are often difficult to distinguish from nightmares or unpleasant dreams, which also occur frequently in narcolepsy.

Hypnagogic hallucinations are most often associated with sleep attacks and their content is well criticized by the patient. The hallucinations are most often complex, vivid, dream-like experiences (“half sleep” hallucinations) and may follow episodes of cataplexy or sleep paralysis, a feature that is not uncommon in severely affected patients. These hallu- cinations are usually easy to distinguish from hallucinations observed in schizophrenia or related psychotic conditions.

Other Important Symptoms

One of the most frequently associated symptoms is insom- nia, best characterized as a difficulty to maintain nighttime sleep. Typically, narcoleptic patients fall asleep easily, only to wake up after a short nap and are unable to fall back asleep again for before an hour or so. Narcoleptic patients do not usually sleep more than normal individuals over the 24-h cycle [38–40], but frequently have a very disrupted night- time sleep [38–40]. This symptom often develops later in life and can be very disabling.

Frequently associated problems are periodic leg move- ments [41, 42], REM behavior disorder, other parasomnias [43, 44], and obstructive sleep apnea [42, 45, 46].

Narcolepsy was reported to be associated with changes in energy homeostasis several decades ago. Narcolepsy patients are frequently (1) obese [47, 48], (2) more often have insu- lin-resistant diabetes mellitus [47], (3) exhibit reduced food intake [49], and (4) have lower blood pressure and tempera- ture [50, 51]. These findings, however, had not received much attention since they were believed to be secondary to sleepiness or inactivity during the daytime. More recently, however, it was shown that these metabolic changes may be found more specifically in hypocretin-deficient patients [52, 53], suggesting a direct pathophysiological link. Additional research in this area is warranted to clarify this association.

Narcolepsy is a very incapacitating disease. It interferes with every aspect of life. The negative social impact of nar- colepsy has been extensively studied. Patients experience impairments in driving and a high prevalence of either car- or machine-related accidents. Narcolepsy also interferes with professional performance, leading to unemployment, frequent changes of employment, working disability, or early retirement [54–56]. Several subjects also develop symptoms of depression, although these symptoms are often masked by anticataplectic medications [10, 54, 57].

Neurobiology of Wakefulness

In order to help in the understanding of the neurobiology of hypersomnia, we will discuss current understandings of the neurobiology of wakefulness. Sleep/wake is a complex physiology regulated by brain activity, and multiple neu- rotransmitter systems such as monoamines, acetylcholine, excitatory and inhibitory amino acids, peptides, purines, and neuronal and nonneuronal humoral modulators (i.e., cytokines and prostaglandins) [58] are likely to be involved. Monoamines are perhaps the first neurotransmitters recog- nized to be involved in wakefulness [59], and the monoami- nergic systems have been the most common pharmacological targets for wake-promoting compounds in the past years. On the other hand, most hypnotics target the γ-aminobutyric acid (GABA) ergic system, a main inhibitory neurotransmit- ter system in the brain [60].

Cholinergic neurons also play critical roles in corti- cal activation during wakefulness (and during REM sleep) [58]. 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)-con- taining locus coeruleus (LC) neurons, serotonin (5-HT)- containing raphe neurons, and histamine-containing

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tuberomammillary neurons (TMN), are wake active and act directly on cortical and subcortical regions to promote wakefulness [58]. In contrast to the focus on these wake- active monoaminergic systems, researchers have often underestimated the importance of dopamine (DA) in pro- moting wakefulness. Most likely, this is because the firing rates of midbrain DA-producing neurons (ventral tegmen- tal area [VTA] and substantia nigra) do not have an obvious variation according to behavioral states [61]. In addition, DA is produced by many different cell groups [62], and which of these promote wakefulness remains undetermined. Nev- ertheless, DA release is greatest during wakefulness [63], and DA neurons increase discharge and tend to fire bursts of action potentials in association with significant sensory stimulation, purposive movement, or behavioral arousal [64]. Lesions that include the dopaminergic neurons of the VTA reduce behavioral arousal [65]. Recent work has also identified a small wake-active population of DA-producing neurons in the ventral periaqueductal gray that project to other arousal regions [66]. People with DA deficiency from Parkinson’s disease are often sleepy [67], and DA antago- nists are frequently sedating. These physiologic and clinical evidences clearly demonstrate that DA also plays a role in wakefulness.

Wakefulness (and various physiologies associated with wakefulness) is essential for the survival of creatures and thus is likely to be regulated by multiple systems, each hav- ing a distinct role. Some arousal systems may have essential roles for cortical activation, attention, cognition, or neu- roplasticity 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 sys- tems with differential roles coordinating in line. Similarly, the wake-promoting mechanism of some drugs may not be able to be explained by a single neurotransmitter system.

Basic Sleep Physiology and Symptoms of Narcolepsy

Since narcolepsy is a prototypical EDS disorder and since the major pathophysiology of narcolepsy (i.e., deficient in hypocretin neurotransmission) has recently been revealed, the discussion of neurophysiological aspects of narcolepsy will help for a general understanding of neurobiology in EDS.

Narcolepsy patients manifest symptoms specifically relat- ed to the dysregulation of REM sleep [68]. In the structured, cyclic process of normal sleep, two distinct states—REM and three stages (S1, S2, S3) of non-REM (NREM) sleep— alternate sequentially every 90 min in a cycle repeating four

to five times per night [69]. As electroencephalography (EEG) signals in humans indicate, NREM sleep, charac- terized by slow oscillation of thalamocortical neurons (de- tected as cortical slow waves) and muscle tonus reduction, precedes REM sleep when complete muscle atonia occurs. Slow-wave NREM predominates during the early phase of normal sleep, followed by a predominance of REM during the later phase [69].

Notably, sleep and wake are highly fragmented in narco- lepsy, and affected subjects could not maintain long bouts of wake and sleep. Normal sleep physiology is currently understood as dependent upon coordination of the interac- tions of facilitating sleep centers and inhibiting arousal cen- ters in the brain, such that stable sleep and wake states are maintained for specific durations [69]. An ascending arousal pathway, running from the rostral pons and through the mid- brain reticular formation, promotes wakefulness [69, 70]. As discussed earlier, this arousal pathway may be composed of neurotransmitters (acetylcholine, NE, DA, excitatory amino acids), produced by brainstem and hypothalamic neurons (hypocretin/orexin and histamine) and also linked to muscle tonus control during sleep [69, 70]. Whereas full alertness and cortical activation require coordination of these arousal networks, effective sleep requires suppression of arousal by the hypothalamus [70]. Narcolepsy patients may experience major neurological malfunction of this control system.

Narcoleptics exhibit a phenomenon termed short REM sleep latency or sleep-onset REM period (SOREMP), in which they enter REM sleep more immediately upon fall- ing asleep than normal [68]. In some cases, NREM sleep is completely bypassed and the transition to REM sleep oc- curs instantly [68]. SOREMS are not observed in idiopathic hypersomnia.

Moreover, intrusion of REM sleep into wakefulness may explain the cataplexy, sleep paralysis, and hypnagogic hallu- cinations, which are symptoms of narcolepsy. Significantly, whereas paralysis and hallucinations manifest in other sleep disorders (sleep apnea syndromes and disturbed sleep pat- terns in normal population) [71], cataplexy is pathogno- monic for narcolepsy [68]. As such, identifying cataplexy’s unique pathophysiological mechanism emerged to be poten- tially crucial to describing the pathology underlying narco- lepsy overall.

Discovery of Hypocretin Deficiency and Postnatal Cell Death of Hypocretin Neurons

The significant roles, first of hypocretin deficiency and sub- sequently of postnatal cell death of hypocretin neurons as the major pathophysiological process underlying narcolepsy with cataplexy, were established from a decade of investigation in both animal and human models. In 1998, the simultaneous

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discovery of a novel hypothalamic peptide neurotransmitter by two independent research groups proved pivotal [72, 73]. One group called the peptides “hypocretin” because of their primary hypothalamic localization and similarities with the hormone “secretin” [73]. The other group called it “orexin” after observing that central administration of these peptides increased appetite in rats [72]. These neurotransmitters are produced exclusively by thousands of neurons, which are lo- calized in the lateral hypothalamus, and project broadly to specific cerebral regions and more densely to others [74].

Within a year, Stanford researchers identified an autoso- mal recessive mutation of hypocretin receptor 2 (Hcrtr 2) re- sponsible for canine narcolepsy characterized by cataplexy, reduced sleep latency, and SOREMPs, using positional clon- ing of a naturally occurring familial canine narcolepsy model [75]. This finding coincided with the observation of the nar- colepsy phenotype, characterized by cataplectic behavior and sleep fragmentation in hypocretin-ligand-deficient mice (prepro-orexin gene knockout mice) [76]. Together, these findings confirmed hypocretins as principal sleep/wake- modulating neurotransmitters and prompted investigation of the hypocretin system’s involvement in human narcolepsy.

Although screening of patients with cataplexy failed to implicate hypocretin-related gene mutation as a major cause of human narcolepsy, narcoleptic patients did exhibit

low CSF hypocretin-1 levels [77] (Fig. 26.1). Postmortem brain tissue of narcoleptic patients assessed with immuno- chemistry, radioimmunological peptide assays, and in situ hybridization revealed hypocretin peptide-loss and unde- tectable levels of hypocretin peptides or prepro-hypocretin RNA (Fig. 26.1). Further, melanin-concentrating hormone (MCH) neurons, located in the same brain region [78], were observed intact, thus indicating that damage to hypocretin neurons and its production is selective in narcolepsy, rather than due to general neuronal degeneration.

As a result of these findings, a diagnostic test for narco- lepsy based on clinical measurement of CSF hypocretin-1 levels for detecting hypocretin ligand deficiency is now available [1]. Whereas CSF hypocretin-1 concentrations above 200 pg/ml almost always occur in controls and pa- tients with other sleep and neurological disorders, concentra- tions below 110 pg/ml are 94 % predictive of narcolepsy with cataplexy [79] (Fig. 26.2). As this represents a more specific assessment than the multiple sleep latency test (MSLT), CFS hypocretin-1 levels below 110 pg/ml are indicated in the International Classification of Sleep Disorders (ICSD)-3 as diagnostic of narcolepsy with cataplexy [1].

Moreover, separate coding of “narcolepsy with cataplexy” (type 1) and “narcolepsy without cataplexy” (type 2) in the ICSD-3 underscores how discovery of specific diagnostic

Fig. 26.1 Hypocretin deficiency in narcoleptic subjects. a CSF hypocretin-1 levels are undetectably low in most narcoleptic subjects (84.2%). Note that two HLA DQB1*0602-negative and one familial case have normal or high CSF hypocretin levels. b Prepro-hypocretin transcripts are detected in the hypothalamus of control (b) but not in narcoleptic subjects (a). Melanin-concentrating hormone ( MCH) tran- scripts are detected in the same region in both control (d) and narcolep- tic (c) sections. c Colocalization of IGFBP3 in HCRT cells in control and narcolepsy human brain. Upper panel: e Distribution of hypocretin cells and fibers in the perifornical area of human hypothalamus. f In

control brains, HCRT cells and fibers were densely stained by an anti- HCRT monoclonal antibody (red fluorescence: VectorRed), while in narcolepsy brains, staining was markedly reduced. Lower panel: HCRT immunoreactivity (g: red fluorescence) and IGFBP3 immunoreactivity (h: green fluorescence; Q-dot525) and a composite picture (i) arrows indicate HCRT cells colocalized with IGFBP3). Note: nonneuronal au- tofluorescent elements. f and fx, fornix. Scale bar represents 10 mm (a–d), 500 mm in (e and f), 100 mm in g, h, and i (from [78] and [81]). CSF cerebrospinal fluid, HLA human leukocyte antigen, HCRT hypo- cretin, IGFBP3 insulin-like growth factor-binding protein 3

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Fig. 26.2 CSF hypocretin-1 levels in individuals across various con- trol and sleep disorders. Each point represents the crude concentration of hypocretin-1 in a single person. The cutoffs for normal (>200 pg/ mL) and low (<110 pg/mL) hypocretin-1 concentrations are shown. Also noted is the total number of subjects in each range, and the percent- age human leukocyte antigen (HLA)-DQB1*0602 positivity for a given group in a given range is parenthetically noted for certain disorders.

criteria now informs our understanding of narcolepsy’s no- sology; narcolepsy with cataplexy, as indicated by low CSF hypocretin-1, appears etiologically homogeneous and dis- tinct from most patients with narcolepsy without cataplexy, exhibiting normal hypocretin-1 levels [79]. Further, the po- tential of hypocretin receptor agonists (or cell transplanta- tion) in narcolepsy treatment is currently being explored, and CSF hypocretin-1 measures may be useful in identifying appropriate patients as candidates for a novel therapeutic op- tion, namely hypocretin replacement therapy.

Soon after the discovery of human hypocretin deficiency, researchers identified specific substances and genes, such as dynorphin and neuronal activity-regulated pentraxin (NARP)

Note that control carrier frequencies for DQB1*0602 are 17–22% in healthy control subjects and secondary narcolepsy, consistent with con- trol values reported in whites (see Table 64.3). In other patient groups, values are higher, with almost all hypocretin-deficient narcolepsy being HLA DQB1*0602 positive. The median value in each group is shown as a horizontal bar. (Updated from previously published data [79])

[80] and most recently, insulin-like growth factor-binding protein 3 (IGFBP3) [81], which colocalizes in neurons con- taining hypocretin. These findings underscored selective hypocretin cell death as the cause of hypocretin deficiency (as opposed to transcription/biosynthesis or hypocretin pep- tide processing problems), because these substances are also deficient in postmortem brain HLA of hypocretin-deficient narcoleptic patients [80, 81]. Further, these findings, in view of the generally late onsets of sporadic narcolepsy compared with those of familial cases, suggest that postnatal cell death of hypocretin neurons constitutes the major pathophysiologi- cal process in human narcolepsy with cataplexy.

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A large kindred with familial narcolepsy (12 affected members) has been reported in Spain [82]. Affected mem- bers do not exhibit any symptoms suggesting symptomatic cases of narcolepsy and were diagnosed as familial idiopath- ic narcolepsy–cataplexy. The family includes a pair of dizy- gotic twins concordant for narcolepsy–cataplexy in the third generation; the distribution of the disorder indicates an au- tosomal-dominant transmission of the disease-causing gene. Hor et al. recently performed linkage analysis and sequenced coding regions of the genome (exome sequencing) of three affected members with narcolepsy and cataplexy and had identified a missense mutation in the second exon of myelin oligodendrocyte glycoprotein (MOG) [82]. A c.398 C > G mutation was present in all affected family members but ab- sent in unaffected members and 775 unrelated control sub- jects [82]. Affected members were hypocretin deficient, but association with HLA DQB1*0602 was not observed [82]. The mutation may secondarily induce hypocretin deficiency with or without immune-mediated mechanisms. MOG has recently been linked to various neuropsychiatric disorders and is considered as a key autoantigen in multiple sclero- sis (MS) and in its animal model, experimental autoimmune encephalitis [83]; thus autoimmune mechanisms may also be involved in these cases. However, even if autoimmune

mechanisms are involved in these cases, it is possible that the primary target for the immune attack is not the hypocretin system. These results also suggest the heterogeneity of etiol- ogy of idiopathic narcolepsy–cataplexy.

How Does Hypocretin Ligand Deficiency Cause the Narcolepsy Phenotype?

Since hypocretin deficiency is a major pathophysiological mechanism for narcolepsy–cataplexy, how the hypocretin ligand deficiency can cause the narcolepsy phenotype is dis- cussed.

Hypocretin/Orexin System and Sleep Regulation

Hypocretins/orexins (hypocretin-1 and hypocretin-2/orexin A and orexin B) are cleaved from a precursor prepro-hypo- cretin (prepro-orexin) peptide [72, 73, 84]) (Fig. 26.3). Hypocretin-1 with 33 residues contains four cysteine resi- dues forming two disulfide bonds. Hypocretin-2 consists of 28 amino acids and shares similar sequence homology especially at the C-terminal side but has no disulfide bonds

Fig. 26.3 a Structures of mature hypocretin-1 (orexin A) and hypocre- tin-2 (orexin B) peptides. b Schematic representation of the hypocretin (orexin) system. c Projections of hypocretin neurons in the rat brain and relative abundance of hypocretin receptor 1 and 2. a The topology of the two intrachain disulfide bonds in orexin A is indicated in the above sequence. Amino acid identities are indicated by shaded areas. b The actions of hypocretins are mediated via two G-protein-coupled receptors named hypocretin receptor 1 ( Hcrtr 1) and hypocretin recep- tor 2 ( Hcrtr 2), also known as orexin-1 ( OX1R) and orexin-2 ( OX2R) receptors, respectively. Hcrtr 1 is selective for hypocretin-1, whereas Hcrtr 2 is nonselective for both hypocretin-1 and hypocretin-2. Hcrtr 1 is coupled exclusively to the Gq subclass of heterotrimeric G proteins, whereas in vitro experiments suggest that Hcrtr 2 couples with Gi/o, and/ or Gq. (adapted from Sakurai (2002). c Hypocretin-containing neurons

project to these previously identified monoaminergic and cholinergic and cholinoceptive regions where hypocretin receptors are enriched. The relative abundance of Hcrtr 1 versus Hcrtr 2 in each brain structure was indicated in parenthesis (data from Marcus et al. 2001). Impair- ments of hypocretin input may thus result in cholinergic and monoami- nergic imbalance and generation of narcoleptic symptoms. Most drugs currently used for the treatment of narcolepsy enhance monoaminergic neurotransmission and adjust these symptoms. VTA ventral tegmental area, SN substantia nigra, LC locus coeruleus, LDT laterodorsal teg- mental nucleus, PPT pedunculopontine tegmental nucleus, RF reticular formation, BF basal forebrain, VLPO ventrolateral preoptic nucleus, LHA lateral hypothalamic area, TMN tuberomammillary nucleus, DR dorsal raphe, Ach acetylcholine, Glu glutamate, GABA γ-aminobutyric acid, HI histamine, DA dopamine, NA noradrenalin, 5-HT serotonin

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(a linear peptide) [72]. There are two G-protein-coupled hypocretin receptors, Hcrtr 1 and Hcrtr 2, also called orexin receptor 1 and 2 (OX1R and OX2R), and distinct distribution of these receptors in the brain is known. Hcrtr 1 is abundant in the LC while Hcrtr 2 is found in the TMN and basal fore- brain (Fig. 26.3). Both receptor types are found in the mid- brain raphe nuclei and mesopontine reticular formation [4].

Hypocretins-1 and -2 are produced exclusively by a well- defined group of neurons localized in the lateral hypothala- mus. The neurons project to the olfactory bulb, cerebral cortex, thalamus, hypothalamus, and brainstem, particularly the LC, raphe nucleus, and to the cholinergic nuclei (the laterodorsal tegmental and pedunculopontine tegmental nu- clei) and cholinoceptive sites (such as pontine reticular for- mation) [74, 84]. All of these projection sites are thought to be important for sleep regulation.

A series of recent studies have now shown that the hypo- cretin system is a major excitatory system that affects the activity of monoaminergic (DA, NE, 5-HT, and histamine) and cholinergic systems with major effects on vigilance states [84, 85]. It is thus likely that a deficiency in hypocre- tin neurotransmission induces an imbalance between these classical neurotransmitter systems, with primary effects on sleep-state organization and vigilance.

Many measurable activities (brain and body) and com- pounds manifest rhythmic fluctuations over a 24-h period. Whether or not hypocretin tone changes with zeitgeber time was assessed by measuring extracellular hypocretin-1 levels in the rat brain CSF across 24-h periods, using in vivo dialy- sis [86]. The results demonstrate the involvement of a slow diurnal pattern of hypocretin neurotransmission regulation (as in the homeostatic and/or circadian regulation of sleep). Hypocretin levels increase during the active periods and are highest at the end of the active period, and the levels decline with the onset of sleep. Furthermore, sleep deprivation in- creases hypocretin levels [86].

Recent electrophysiological studies have shown that hypocretin neurons are active during wakefulness and reduce the activity during slow-wave sleep [87]. The neuro- nal activity during REM sleep is the lowest, but intermittent increases in the activity associated with body movements or phasic REM activity are observed [87]. In addition to this short-term change, the results of microdialysis experiments also suggest that basic hypocretin neurotransmission fluctu- ates across the 24-h period and slowly builds up toward the end of the active period. Adrenergic LC neurons are typi- cal wake-active neurons involved in vigilance control, and it has been recently demonstrated that basic firing activity of wake-active LC neurons also significantly fluctuates across various circadian times [88].

Several acute manipulations such as exercise, low glu- cose utilization in the brain, and forced wakefulness increase hypocretin levels [85, 86]. It is therefore hypothesized that a

build up/acute increase of hypocretin levels may counteract homeostatic sleep propensity that typically increases during the daytime and during forced wakefulness [89].

Hypocretin/Orexin Deficiency and Narcoleptic Phenotype

Human studies have demonstrated that the occurrence of cataplexy is closely associated with hypocretin deficiency [79]. Furthermore, the hypocretin deficiency was already ob- served at very early stages of the disease (just after the onset of EDS), even before the occurrences of clear cataplexy. Oc- currences of cataplexy are rare in acute symptomatic cases of EDS associated with a significant hypocretin deficiency (see [3]); therefore, it appears that a chronic and selective deficit of hypocretin neurotransmission may be required for the occurrence of cataplexy. The possibility of involvement of a secondary neurochemical change for the occurrence of cataplexy still cannot be ruled out. If some of these changes are irreversible, hypocretin supplement therapy may only have limited effects on cataplexy.

Sleepiness in narcolepsy is most likely due to the diffi- culty in maintaining wakefulness as normal subjects do. The sleep pattern of narcoleptic subjects is also fragmented; they exhibit insomnia (frequent wakening) at night. This frag- mentation occurs across 24 h, thus, the loss of hypocretin signaling is likely to play a role in this vigilance stage stabil- ity (see [90]), but other mechanism may also be involved in EDS in narcoleptic subjects. One of the most important char- acteristics of EDS in narcolepsy is that sleepiness is reduced and patients feel refreshed after a short nap, but this does not last long as they become sleepy within a short period of time. Hypocretin-1 levels in the extracellular space and in the CSF of rats significantly fluctuate across 24 h and build up toward the end of the active periods [89]. Several manipu- lations (such as sleep deprivation, exercise, and long-term food deprivation) are also known to increase the hypocretin tonus [86, 89]. Thus, the lack of this hypocretin build up (or increase) caused by circadian time and by various alerting stimulations may also play a role for EDS associated with hypocretin-deficient narcolepsy.

Mechanisms for cataplexy and REM sleep abnormali- ties associated with impaired hypocretin neurotransmission have been studied. Hypocretin strongly inhibits REM sleep and activates brainstem REM-off LC and raphe neurons and REM-on cholinergic neurons as well as local GABAnergic neurons. Therefore, disfacilitation of REM-off monoaminer- gic neurons and stimulation of REM-on cholinergic neurons mediated through disfacilitation of inhibitory GABAnergic inert neurons associated with impaired hypocretin neuro- transmission are proposed for abnormal manifestations of REM sleep.

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Considerations for the Pathophysiology of Narcolepsy with Normal Hypocretin Levels

There are debates about the pathophysiology of narcolepsy with normal hypocretin levels. Over 90 % patients with nar- colepsy without cataplexy show normal CSF hypocretin levels, yet they show apparent REM sleep abnormalities (i.e., SOREMS). Furthermore, even if the strict criteria for narcolepsy–cataplexy are applied, up to 10 % of patients with narcolepsy–cataplexy show normal CSF hypocretin levels. Considering the fact that occurrence of cataplexy is tightly associated with hypocretin deficiency, impaired hypocretin neurotransmission is still likely involved in narcolepsy–cat- aplexy with normal CSF hypocretin levels. Conceptually, there are two possibilities to explain these mechanisms: (1) specific impairment of hypocretin receptor and their down- stream pathway and (2) partial/localized loss of hypocretin ligand (yet exhibit normal CSF levels). A good example for (1) is Hcrtr-2-mutated narcoleptic dogs; they exhibit normal CSF hypocretin-1 levels [91] while having a full-blown nar- colepsy. Thannickal et al. recently reported one narcolepsy without cataplexy patient (HLA typing was unknown) who had an overall loss of 33 % of hypocretin cells compared to normal, with maximal cell loss in the posterior hypothala- mus [92]. This result favors the second hypothesis, but stud- ies with more cases are needed.

Idiopathic Hypersomnia: A Hypocretin Nondeficient Primary Hypersomnia

With the clear definition of narcolepsy (cataplexy and dis- sociated manifestations of REM sleep), it became apparent that some patients with hypersomnia suffer from a different disorder. Bedrich Roth was the first in the late 1950s and early 1960s to describe a syndrome characterized by EDS, prolonged sleep, and sleep drunkenness, and by the absence of “sleep attacks,” cataplexy, sleep paralysis, and hallucina- tions. The terms “independent sleep drunkenness” and “hy- persomnia with sleep drunkenness” were initially suggested [93], but now this syndrome is categorized as idiopathic hy- persomnia (1). Idiopathic hypersomnia should therefore not be considered synonymous with hypersomnia of unknown origin.

In the absence of systematic studies, the prevalence of idiopathic hypersomnia is unknown. Nosologic uncertainty causes difficulty in determining the epidemiology of the disorder. Recent reports from large sleep centers reported the ratio of idiopathic hypersomnia to narcolepsy to be 1:10. [94]. The age of onset of symptoms varies, but it is

frequently between 10 and 30 years. The condition usually develops progressively over several weeks or months. Once established, symptoms are generally stable and long lasting, but spontaneous improvement in EDS may be observed in up to one quarter of patients [94].

The pathogenesis of idiopathic hypersomnia is unknown. Hypersomnia usually starts insidiously. Occasionally, EDS is first experienced after transient insomnia, abrupt changes in sleep–wake habits, overexertion, general anesthesia, viral illness, or mild head trauma [94]. Despite reports of an in- crease in HLA DQ1,11 DR5 and Cw2, and DQ3, and de- crease in Cw3, no consistent findings have emerged [94].

The most recent attempts to understand the pathophysi- ology of idiopathic hypersomnia relate to the investigation of potential role of the hypocretins. However, most studies suggest normal CSF levels of hypocretin-1 in idiopathic hypersomnia [79, 95].

Nosological and Diagnostic Considerations of Major Primary Hypersomnias

Narcolepsy–cataplexy, narcolepsy without cataplexy, and idiopathic hypersomnia are diagnosed mostly by sleep phe- notypes, especially by the occurrences of cataplexy and SOREMPS (Fig. 26.4; ICSD-3). Discovery of hypocretin deficiency in narcolepsy–cataplexy was not only a break- through but also brought a new nosological and diagnos- tic uncertainty of the primary hypersomnias. Up to 10% of patients with narcolepsy–cataplexy show normal CSF hypocretin-1 levels (Fig. 26.4). As discussed above, altered hypocretin neurotransmissions may still be involved in some of these cases. However, up to 10 % of patients with narco- lepsy without cataplexy instead show low CSF hypocretin-1 levels, suggesting a substantial pathophysiological over- lap between narcolepsy–cataplexy and narcolepsy without cataplexy, and the hypocretin-deficient status (measured in CSF) does not completely separate these two disease condi- tions (Fig. 26.4). Similarly, concerns about the nosology of narcolepsy without cataplexy and idiopathic hypersomnia should also be addressed. Since patients with typical cases of idiopathic hypersomnia exhibit unique symptomatology, such as long hours of sleep, no refreshment from naps, and generally resistance to stimulant medications, the patho- physiology of idiopathic hypersomnia may be distinct from that of narcolepsy without cataplexy. However, current di- agnostic criteria are not specific enough to diagnose these disorders, especially since the test–retest reliability of num- bers of SOREMS during MSLT has not been systematically evaluated.

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Fig. 26.4 Nosological and diagnostic considerations of major primary hypersomnias. Narcolepsy–cataplexy, narcolepsy without cataplexy, and idiopathic hypersomnia are diagnosed by the occurrences of cata- plexy and SOREMPS. Pathophysiology-based marker and low CSF hypocretin levels are included in the ICSD-3 for the positive diagnosis for narcolepsy–cataplexy. However, up to 10 % of patients with narco- lepsy–cataplexy show normal CSF hypocretin levels. In contrast, up to 10% of patients with narcolepsy without cataplexy show low CSF

CSF Histamine and GABAA Receptor Modulator in Narcolepsy and Hypersomnia

Although pathophysiology of hypocretin nondeficient hyper- somnia is largely unknown, neurochemical changes in these disease conditions, namely reduced CSF histamine contents and increased activity of GABAA receptor modulator in the CSF, have been reported recently by two groups [96–98].

Histamine is one of these wake-active monoamines [99], and low CSF histamine levels are also found in narcolepsy with hypocretin deficiency [96, 97]. Since hypocretin neu- rons project and excite histamine neurons in the posterior hypothalamus, it is conceivable that impaired histamine neu- rotransmission may mediate sleep abnormalities in hypocre- tin-deficient narcolepsy. However, low CSF histamine levels were also observed in narcolepsy with normal hypocretin levels, and in idiopathic hypersomnia, decreased histamine neurotransmission may be involved in a broader category of EDS than in hypocretin-deficient narcolepsy [97]. Since CSF histamine levels are normalized in EDS patients treated with wake-promoting compounds, low CSF histamine levels may be a new state marker for the hypersomnia of central

hypocretin-1 levels. These results suggest a substantial pathophysi- ological overlap between narcolepsy–cataplexy and narcolepsy without cataplexy. Similarly, a substantial overlap likely exists between narco- lepsy without cataplexy and idiopathic hypersomnia, as these disorders are diagnosed by the occurrences of SOREMS (two or more). However, the test–retest reliability of detecting number of SOREMS in these con- ditions has not been systematically evaluated

origin, and functional significances of this finding should further be studied further [97].

Ryer et al. recently reported that activities of substance in CSF that augments inhibitory GABA signaling are enhanced in hypersomnia [98]. The authors demonstrated that in the presence of GABA (10 μM), CSF can stimulate GABAA receptor function in vitro (measures of GABAAR-mediated chloride currents in recombinant pentameric human GAB- AAR-expressed cultured cells). Interestingly, stimulations of GABAA receptor function by CSF from hypersomno- lent patients (idiopathic hypersomnia with and without long sleep, long sleepers and narcolepsy without cataplexy) are significantly enhanced compared to those by CSF from con- trol subjects (84.0 vs. 35.8 %) [98]. This bioactive CSF com- ponent had a mass of 500–3000 Da and was neutralized by trypsin. Flumazenil, a benzodiazepine receptor antagonist, reversed the enhancement of GABAA signaling by hyper- somnolent CSF in vitro, and flumazenil normalized vigi- lance in all seven hypersomnolent patients who underwent the drug challenge [98]. The authors conclude that a natu- rally occurring substance in CSF augments inhibitory GABA signaling, revealing a new pathophysiology associated with

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EDS. These results are especially interesting, as GABAAR has never been targeted for the treatment of hypersomnia. It is still unknown if these changes are primary or second- ary to the changes in other neurotransmitter systems. It is also critical to test whether the same change is observed in hypocretin-deficient narcolepsy–cataplexy.

Although these new findings are interesting as they are some of the first biomarkers for idiopathic hypersomnia, and these finding may lead to the development of new treatments for somewhat treatment-resistant hypersomnia. However, these markers do not discriminate the types of hypersom- nia, and similar changes were observed in various types of hypersomnia.

Symptomatic Narcolepsy and Hypersomnia

Symptoms of narcolepsy can sometimes be seen during the course of a neurological disease process. In such instances, the term “symptomatic narcolepsy” is used, implying that the narcolepsy is a symptom of the underlying process rather than idiopathic. For these cases, the signs and symptoms of narcolepsy must be temporally associated with the underly- ing neurological process.

In the ICSD-3, narcolepsy with or without cataplexy asso- ciated with neurological disorders is classified under “narco- lepsy due to medical condition.” The criteria for “narcolepsy due to medical condition” is similar to those for “narcolepsy with cataplexy” and “narcolepsy without cataplexy,” and the diagnostic criteria include (A) the patient must have a com- plaint of EDS occurring almost daily for at least 3 months. (B) One of the following must be observed: (i) A definite history of cataplexy. (ii) If cataplexy is not present or is very atypical, polysomnographic monitoring performed over the patient’s habitual sleep period followed by an MSLT must demonstrate a mean sleep latency on the MSLT of less than 8 min with two or more SOREMPs. (iii) Hypocretin-1 levels in the CSF are less than 110 pg/mL (or 30 % of normal con- trol values). In addition, (D) a significant underlying medical or neurological disorder must be accountable for the EDS and/or cataplexy, and (E) the hypersomnia is not better ex- plained by another sleep disorder, mental disorder, medica- tion use, or substance use disorder [1]. As mentioned earlier, EDS without cataplexy nor other REM sleep abnormalities is also often associated with these neurological conditions, and is defined as symptomatic cases of EDS (ICSD-3: hy- persomnia due to medical condition).

We therefore define “symptomatic narcolepsy” as cases that meet these criteria (if MSLT data were not available, equivalent polygraphic REM sleep abnormalities were also taken into consideration). In addition, an association with a significant underlying neurological disorder that accounts for the EDS and a temporal association (narcolepsy onset

should be within 3 years if the causative diseases are “acute” neurologic conditions) are required [100].

Hypocretin Involvements in Symptomatic Narcolepsy and EDS
Discovery of hypocretin ligand deficiency in idiopathic nar- colepsy has also led to new insights into the pathophysiol- ogy of symptomatic (or secondary) narcolepsy and EDS. In a recent meta-analysis, 116 symptomatic narcolepsy cases reported in the literature were analyzed [3]. As sev- eral authors have previously reported, inherited disorder ( n = 38), tumors ( n = 33), and head trauma ( n = 19) are the three most frequent causes for symptomatic narcolepsy. Of the 116 cases, ten cases are associated with multiple sclerosis (MS), one with acute dissemi- nated encephalomyelitis, and relatively few (n=6) with vascular disorders, 4 with (n = 4 encephalitis, one with degeneration (n = 1), and three cases in one family with heterodegenerative disorder (autosomal- dominant cerebellar ataxia w/ deafness, (ADCA-DN)., Al- though it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, literature review reveals numerous unquestionable cases of symptomatic narcolepsy [3]. These include cases that are HLA negative and/or late onset and cases where the occurrence of narcoleptic symptoms paral- lels the rise and fall of the causative disease.

It is important to figure out what mechanisms and which brain sites are involved in the occurrence of symptomatic narcolepsy, especially in relation to the hypocretin system. Although it is not simple to discuss the mechanisms uni- formly for symptomatic narcolepsy associated with vari- ous genetic disorders, analysis of symptomatic narcolepsy with tumor cases clearly showed that the lesions most often (about 70% of cases) involved the hypothalamus and adja- cent structures (the pituitary, suprasellar, or optic chiasm; Fig. 26.5). The fact that impairments in the hypothalamus are noted in most symptomatic cases of narcolepsy also suggests a possible involvement of impaired hypocretin neurotrans- mission in this condition.

CSF hypocretin-1 measurement was also conducted in these symptomatic narcolepsy and EDS cases, and reduced CSF hypocretin-1 levels were noted in most cases with vari- ous etiologies [3]. EDS in these cases is sometimes reversible with an improvement of the causative neurological disorder or hypocretin status, thus suggesting a functional link between hypocretin deficiency and sleep symptoms in these patients.

Low CSF hypocretin-1 concentrations were also found in some immune-mediated neurological conditions, namely subsets of Guillain-Barré syndrome [101], Ma2-positive paraneoplastic syndrome [102], and MS/neuromyelitis op- tica (NMO) [3], (see below) and EDS are often associated with the patients with low CSF hypocretin-1 levels.

It should be addressed that Winkelmann et al. recently identified three additional ADCA-DN kindreds [103]. With

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Fig. 26.5 Hypothalamic involve- ment in symptomatic narcolepsy. a Category of neurologic diseases associated with symptomatic nar- colepsy; b Brain lesions involved in symptomatic cases with narcolepsy associated with brain tumor. One hundred and thirteen symptomatic cases of narcolepsy are included. The percentage of each neurologic category (with cataplexy [CA]/with sleep-onset rapid eye movement periods [SOREMP]) is displayed. a Tumors, inherited disorders, and head trauma are the three most frequent causes.

b Analysis of cases of symptom- atic narcolepsy with tumor clearly shows that the lesions most often were in the hypothalamus and adjacent structures (the pituitary, suprasellar, or optic chiasm)

exome sequencing in five individuals from three ADCA-DN kindreds, DNA (cytosine-5)-methyltransferase1 (DNMT1) was identified as the only gene with a mutation found in all five affected individuals [103]. DNMT1 is a widely ex- pressed DNA methyltransferase maintaining methylation patterns in the development and mediating transcriptional re- pression by direct binding to histone deacetylase 2 (HDAC2) [104].

Based on the available information of crystallographic structures of the DNMT1 [101], the authors speculate that the identified mutations likely affect DNA binding, recogni- tion, or the interaction with other proteins in the DNMT1– HDAC2 complex, causing insufficient CpG methylation and gene silencing in some cases, resulting in the occurrences of ADCA-DN. As the penetrance of the disease is high in the kindred and affected subjects exhibit clear-cut narcolepsy, it is important to further explore the mechanisms of occur- rences of narcolepsy–cataplexy in these kindreds.

EDS Associated with MS/NMO: A New Clinical Entity for Autoimmune-Mediated Hypocretin- Deficient Hypersomnia

Of note, Kanbayashi et al. recently encountered seven cases of EDS occurring in the course of MS patients initially diag- nosed with symmetrical hypothalamic inflammatory lesions with hypocretin ligand deficiency [106] that contrasts with the characteristics of classic MS cases (Fig. 26.6) (Fig. 26.7).

Symptomatic narcolepsy in MS patients has been report- ed from several decades ago. Since both MS and narcolepsy 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 [107]. However, the discovery of the selective loss of hypothalamic hypocretin neurons in narcolepsy rather indicates that narcolepsy coin- cidently occurs in MS patients when MS plaques appear in the hypothalamic area and secondarily damage the hypocre- tin/orexin neurons. In favor of this interpretation, the hypo- cretin system is not impaired in MS subjects who do not ex- hibit narcolepsy [108]. Nevertheless, it is also the case that a subset of MS patients predominantly shows EDS and REM sleep abnormalities, and it is likely that specific immune- mediated mechanisms may be involved in these cases.

CSF hypocretin measures revealed that marked (≤ 110 pg/

ml, n = 3) or moderate (110–200 pg/ml, n = 4) hypocretin de- ficiency was observed in all seven cases [102]. Therefore, four cases met with ICSD-3 criteria [1] for narcolepsy due to medical condition, and three cases met with the hypersom- nia due to medical condition. Interestingly, four of them had either or both optic neuritis and spinal cord lesions, shar- ing the clinical characteristics of NMO. HLA was evaluated in only two cases (case 2 and case 4) and was negative for DQB1*0602. Repeated evaluations of the hypocretin status were carried out in six cases, and CSF hypocretin-1 levels returned to the normal levels or significantly increased with marked improvements of EDS and hypothalamic lesions in all six cases. Since four of them exhibited clinical charac-

26 Narcolepsy–Cataplexy Syndrome and Symptomatic Hypersomnia

217

Fig. 26.6 MRI findings (FLAIR or T2) of MS/NMO patients with hypocretin deficiency and EDS. A typical horizontal slice including the hypothalamic periventricular area from each case is presented. All cases were female ( f) and age ( y) listed in the parenthesis. * met with ICSD-3 criteria for narcolepsy due to medical condition, and ** met with ICSD-3 criteria for hypersomnia due to medical condition. All cases were initially diagnosed as MS. Cases 3–7 exhibited optic

terization of NMO, anti-AQP4 antibody was evaluated and it was found that three out of seven cases were anti-AQP4 antibody positive, thus being diagnosed as NMO-related dis- order [106].

AQP4, a member of the aquaporin (AQP) super family, is an integral membrane protein that forms pores in the mem-

neuritis and/or spinal cord lesions and cases 4, 5, 7 are seropositive for anti-AQP4 antibody and thus being diagnosed as NMO. CSF hypocre- tin levels are listed below the MRI image. Modified from [102]. MRI magnetic resonance imaging, FLAIR fluid attenuation inversion recov- ery, MS multiple sclerosis, NMO neuromyelitis optica, EDS excessive daytime sleepiness, CSF cerebrospinal fluid

brane of biological cells [109]. Aquaporins selectively con- duct water molecules in and out of the cell, while preventing the passage of ions and other solutes and are known as water channels. AQP4 is expressed throughout the central nervous system, especially in periaqueductal and periventricular re- gions [109, 110] and is found in nonneuronal structures such

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as astrocytes and ependymocytes, but is absent from neu- rons. Recently, the NMO-IgG (Immunoglobulin G), which can be detected in the serum of patients with NMO, has been shown to selectively bind to AQP4 [111].

Since AQP4 is enriched in periventricular regions in the hypothalamus where hypocretin-containing neurons are pri- marily located, symmetrical hypothalamic lesions associated with reduced CSF hypocretin-1 levels in our three NMO cases with anti-AQP4 antibody might be caused by the im- muno-attack to the AQP4, and this may secondarily affect the hypocretin neurons.

However, the other four MS cases with EDS and hypocre- tin deficiency were anti-AQP4 antibody negative at the time of blood testing. This leaves a possibility that other antibody- mediated mechanisms are additionally responsible for the bilateral symmetric hypothalamic damage causing EDS in the MS/NMO subjects. There is also a possibility that the four MS cases whose anti-AQP4 antibody was negative could be NMO, since anti-AQP4 antibody was tested only once for each subject during the course of the disease, and the assay was not standardized among the institutes [106]. It is thus es- sential to further determine the immunological mechanisms that cause the bilateral hypothalamic lesions with hypocretin deficiency and EDS, and their association with NMO and AQP4. This effort may lead to establishment of a new clini- cal entity, and the knowledge is essential to prevent and treat EDS associated with MS and its related disorders. It should also be noted that none of these cases exhibited cataplexy, contrary to the nine out of ten symptomatic narcoleptic MS cases reported in the past [3]. Early therapeutic intervention with steroids and other immunosuppressants may thus pre- vent irreversible damage of hypocretin neurons and prevent chronic sleep-related symptoms in these recent cases.

Conclusion

The chapter described the current understanding of patho- physiology of EDS with various etiologies.

The recent progress for understanding the pathophysiol- ogy of EDS particularly owes itself to the discovery of hypo- cretin ligand deficiency in human narcolepsy. Hypocretin deficiency can be clinically detected as low CSF hypocre- tin-1 level, and low CSF hypocretin-1 levels have been in- cluded in the ICSD-3 as a positive diagnosis for narcolepsy– cataplexy.

Symptomatic narcolepsy has also been reported, but the prevalence of symptomatic narcolepsy is much smaller. The meta-analysis of these symptomatic cases indicates that hypocretin deficiency may also partially explain the neuro- biological mechanisms of EDS associated with symptomatic cases of narcolepsy.

Although the prevalence of primary hypersomnia such as narcolepsy and idiopathic hypersomnia is not high, that of symptomatic EDS is considerably high, and the patho- physiology of symptomatic EDS likely overlaps with that of primary hypersomnia.

The pathophysiology of hypocretin nondeficient narco- lepsy is debated, and the pathophysiology of idiopathic hy- persomnia is largely unknown, but hypocretin deficiency is not likely to be involved in this condition. Of interest, de- creased histaminergic neurotransmission is observed in nar- colepsy and idiopathic hypersomnia, regardless of hypocretin status. Another study reported that activities of substances in CSF that augment inhibitory GABA signaling are enhanced in hypersomnias with various etiologies. Functional signifi- cances of these new findings (if this mediates sleepiness or passively reflects sleepiness) need to be evaluated further.

Although much progress was made regarding the patho- physiology of EDS, these new knowledges are not yet incor- porated into the development of new treatments, and further research is critical.

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Idiopathic Hypersomnia

Sona Nevsimalova

The history of idiopathic hypersomnia which is distinct from narcolepsy is much shorter, and its biological background is less known than that of narcolepsy–cataplexy. The term idio- pathic hypersomnia ( die idiopathische chronische Schlaf- sucht ) was rst used in 1829 by Henrich Bruno Schindler for excessive daytime sleepiness of undetermined origin [1]; however, the description was more suggestive of narcolepsy.

The first author to identify the clinical differences be- tween narcolepsy and other types of hypersomnia was Bed- rich Roth, a Czech neurologist, neurophysiologist, and sleep researcher (Fig. 27.1). In 1956, he published a detailed de- scription of difficulties in awakening—sleep drunkenness, recognized later as a leading clinical symptom of idiopathic hypersomnia [2]. He identified sleep drunkenness as a symp- tom (inertia connected with prolonged nocturnal sleep), as a syndrome (characterized by patients suffering from pro- longed nocturnal sleep, marked difficulty awakening, and daytime sleepiness), and as an independent nosological en- tity. In that paper, he described 20 patients with sleep drunk- enness mostly of the independent form (11 patients). The disease usually began in younger age (between 15 and 33 years); the patients often had positive family history (5 out 11 families) and showed features of depression. The most characteristic symptom consisted of prolonged deep noctur- nal sleep accompanied by sleep drunkenness during awaken- ing, and prolonged daytime naps generally lasting for 1–3 h or more, but occasionally less. Roth found a secondary cause in two cases (ischemic changes along the borderline between the mesencephalon and diencephalon in one case, and post- traumatic etiology in the other). Sleep drunkenness was also noted in 6 out of 127 narcoleptic patients. This made him suspect the existence of a gradual successive transition from narcolepsy to independent hypersomnia with sleep drunken- ness. He found a combination of these entities even in dif-

S. Nevsimalova ()
Department of Neurology, 1st Faculty of Medicine, Charles Univer- sity, Katerinska 30, 128 00 Prague 2, Czech Republic
e-mail: snevsi@LF1.cuni.cz; sona.nevsimalova@lf1.cuni.cz

ferent members of the same family. Only one of his cohort of 20 patients suffered from nocturnal epilepsy in combina- tion with sleep drunkenness during awakening and sleep pa- ralysis while falling asleep. The paper also included the first electroencephalography (EEG) description of sleep drunk- enness—sleep activity alternating with alpha rhythm.

Beginning in the early 1950s, Prof. Roth systematically extended his clinical studies of patients with daytime som- nolence, and in 1957, he clinically analyzed a cohort of 248 cases [3]. These were divided into two groups: 155 cases of narcolepsy and 93 cases of different types of hypersomnia. The latter cases were classified as: (1) functional type (50 cases), in which pathological sleep was not induced by any known disease, (2) cases of organic origin (29 patients) de- termined by some known underlying disease, and (3) sleepi- ness with post-dormital drunkenness (14 cases), specified later as the idiopathic form of hypersomnia with sleep drunk- enness.

The discovery of rapid eye movement (REM) sleep [4–6] gave impetus to polysomnographical (PSG) studies of pa- tients with daytime somnolence, previously regarded as narcolepsy. Dement et al. [7] were the first to suggest that patients affected by excessive diurnal somnolence, but not accompanied by signs of REM sleep, and symptoms of cata- plexy, hypnagogic hallucinations, or sleep paralysis, should be considered to be suffering from hypersomnolence other than narcolepsy.

At that time, Bedrich Roth had no opportunity to study nocturnal sleep recordings in Prague. That was why he de- cided to accept an invitation from Allan Rechtschaffen to visit his sleep laboratory in Chicago and examine patients with sleep drunkenness in the USA. The birth of a new clini- cal entity supported by PSG findings seemed rather amusing there. When Bedrich Roth arrived, everybody in the USA believed that this disease existed only in Prague. However, Roth arranged a short interview in the local television ex- plaining the clinical symptoms of the disease (long noctur- nal sleep with difficulty awakening and long-lasting daytime naps) and asked TV viewers for cooperation. Everybody in

S. Chokroverty, M. Billiard (eds.), Sleep Medicine, DOI 10.1007/978-1-4939-2089-1_27, 223 © Springer Science+Business Media, LLC 2015

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Fig. 27.1

According to clinical data analyzing 451 patients, 200 were diagnosed with idiopathic narcolepsy, 78 with symptomatic narcolepsy, 47 with hypersomnia with organic basis, and 114 with hypersomnia without organic basis (31 of whom with sleep drunkenness), 2 with independent cataplexy, and 10 with independent sleep paralysis. Hypnagogic hallucinations and vivid, terrifying dreams were frequent in narcolepsy, es- pecially in those suffering also from cataplexy and/or sleep paralysis. In hypersomniac patients, these symptoms were rare. Polygraphic examination of 75 daytime recordings with 215 awakenings showed that 97.4% of patients awakened during paradoxical sleep reporting dreams; 80 % of them had experienced vivid dreams with a strong affective component and visual and acoustic perceptions. During synchronous sleep, dreams were reported in 34 % of awakenings, usually with vague content. Vivid dreams occurred in only 10 % of awakening during synchronous sleep, and these came mostly from within 10 min before or after paradoxical sleep.

Although the first description of a familial occurrence of hypersomnia was reported in Roth’s monograph [3], it was only rarely mentioned in later publications. In 1968, Bonkalo [12] described two siblings with a pure form of hypersomnia. A larger material was published in the early 1970s again by the Czech authors [13–14]. They wrote a genealogical study of the families of 30 patients with hypersomnia and 100 pa- tients with narcolepsy. Idiopathic hypersomnia was found to run in the families of more than one third of the cases. The existence of transition from hypersomnia to isolated narco- lepsy in patients with heredofamilial occurrence showed a pathogenetic relationship of these disturbances. According to the authors, transfer of the hereditary predisposition to- wards hypersomnia and isolated narcolepsy is most probably of an autosomal dominant type, while in narcolepsy with cataplexy and other symptoms of sleep dissociation, a multi- factorial type of heredity was supposed.

In 1976, Prof. Roth published a review of 642 person- ally observed cases including 368 cases of narcolepsy and 274 cases of hypersomnia [15]. The largest group of hyper- somniac patients consisted of so-called functional hyper- somnias (213 cases). These were divided into a group with short sleep cycle (191 cases) and another with long sleep cycle (22 cases). The author distinguished two main forms of short-sleep-cycle hypersomnia: (a) idiopathic monosymp- tomatic form (71 cases), marked solely by excessive daytime sleepiness with long naps, and (b) idiopathic polysymptom- atic form (103 cases), in which daytime sleepiness was ac- companied by prolonged nocturnal sleep and usually also by awakening difficulties (sleep drunkenness or sleep inertia). The rest of functional short-cycle hypersomnias were pa- tients with neurotic hypersomnia (5 cases) and hypersomnia with disorders of breathing during sleep (12 cases). How- ever, nocturnal polygraphic recordings were made only in

Prof. Bedrich Roth reading polysomnographic recording. He was born on March 23, 1919, and died on November 4, 1989, a few days before the Czech Velvet revolution

the Chicago team was really surprised to see, exactly then and there, the TV show lineup of people waiting to be ex- amined by Bedrich Roth. After a clinical interview, he chose ten patients and the first PSG findings of this ailment were published [8] in patients with idiopathic hypersomnia who underwent PSG recording for two nonconsecutive nights. The organization of sleep was completely normal except for its long duration (12 h or more). The percentage of REM and nonrapid eye movement (NREM) sleep was normal, as was the periodicity of the sleep cycles, the number of which was simply increased. These findings were later published [8].

Three years later, a complete clinical description of hy- persomnia with sleep drunkenness (58 cases), enriched by long-term nocturnal monitoring (9 cases), appeared in the lit- erature [9] giving a clear picture of this clinical entity. Sleep drunkenness was characterized by difficulty awakening ac- companied by confusion, disorientation, poor motor coordi- nation, slowness, and repeated dosing off. Patients reported that these symptoms occurred almost every morning, and nearly all reported abnormally prolonged sleep. Of 58 cases of hypersomnia with sleep drunkenness, 52 were apparently idiopathic and 6 were possibly symptomatic of organic brain disturbance. A familial history of the disorder was found in 36 % of the idiopathic cases. No specific EEG or PSG abnor- malities were noted except for relatively increased heart and respiratory rates and extended sleep.

In the late 1960s, the Prague school focused on the patho- physiology of narcolepsy and different types of hypersomnia [10]. Narcolepsy seemed to be associated with REM sleep disturbances and in most instances also with disturbances in NREM sleep, whereas hypersomnia was regarded as involv- ing exclusively the NREM system. The authors assumed that most of the independent narcolepsy cases (without cataplexy) had a mechanism similar to that in hypersomnia patients. This hypothesis was supported also by study of dreams [11].

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a minority of these cases, which is why the last mentioned group may have been underdiagnosed.

In the first diagnostic classification of sleep disorders [16], idiopathic hypersomnia was referred to as idiopathic central nervous system (CNS) hypersomnia as one of the dis- orders of excessive somnolence. The distinction between the two forms proposed by Roth was left out.

In a monograph Narcolepsy and hypersomnia, published one year later [17], Roth described a carefully selected group ( n = 167) of idiopathic hypersomnia patients. He character- ized this disease as a short-cycle “functional” hypersomnia, not caused by known organic brain disease or by metabolic or toxic condition or of psychogenic origin. Its clinical pic- ture included a short sleep onset and frequently prolonged nocturnal sleep with difficulty awakening in the morning, and accompanied by psychological and autonomic dysfunc- tion including sexual disturbances. Two forms of short-cycle functional hypersomnia—monosymptomatic and polysymp- tomatic—have a chronic course and severe socioeconomic impact. He drew attention to its relationship to idiopathic narcolepsy, especially the monosymptomatic form, without cataplexy and other disassociated sleep dysfunction. For the treatment, he recommended central stimulants similar to those for narcolepsy. This excellent book served as the most important textbook for physicians and sleep researchers for a long time, as well as for the patients suffering from daytime sleepiness.

In 1981, Roth et al. [18] published a detailed study of neu- rological, psychological, and polygraphic findings in sleep drunkenness. Eight patients with idiopathic hypersomnia and eight controls were tested after normal sleep duration (patients 12 h, controls 8 h), and after sleep deprivation (pa-

Fig. 27.2 A group of sleep researchers organizing the Symposium on Narcolepsy and Hypersomnia in honor of Prof. Roth in 1988. From the left side: Peter Geisler, Michel Billiard, Roger Broughton, Sona Nevsimalova, Bedrich Roth, Christian Guilleminault, and David Parkes

tients after 8 and 6 h, controls after 4 and 0 h of nocturnal sleep). A state of sleep drunkenness, characterized by “mi- crosleep” in polygraphic recording, was found in 19 of the patients, but only once in the controls. Clinically prominent features included cerebellar signs, hyporeflexia or areflexia, signs of vestibular involvement, and fine and gross motor dysfunction. The authors presumed that sleep drunkenness develops as a result of chronic relative sleep deprivation in those patients, whose sleep requirements are greater than in normal individuals.

Figure 27.2 illustrates a group of sleep researchers or- ganizing a Symposium on Narcolepsy and Hypersomnia in Prague in honor of Prof. Roth.

A detailed description of nocturnal sleep as well as Mul- tiple Sleep Latency Test (MSLT) results comparing different disorders of excessive daytime somnolence (EDS) came from the Stanford group in the early 1980s [19]. The largest group in a 100-patient cohort consisted of narcoleptic patients (41 with cataplexy, 5 without cataplexy). The rest of the EDS pa- tients formed a rather heterogeneous group: idiopathic CNS hypersomnia (17), EDS associated with psychological and/ or psychiatric problem (18), irregular sleep pattern (5), in- sufficient (disturbed) nocturnal sleep (4), abuse of stimulant drugs (3), neurological conditions (2). In five patients, EDS was associated with no objective abnormality. The authors found a clear intergroup difference in the nocturnal as well as daytime polygraphic examinations. Narcoleptics showed more severe EDS with a shorter MSLT latency and presence of sleep-onset rapid eye movements (SOREMs) (at least two, although their number varied even in the same patient) as compared with others. REM latency during the night was shorter; they had fewer REM segments and more awaken-

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ings and myoclonic jerks during sleep. In the MSLT, narco- leptics had a mean sleep latency of 3.3 min (standard devia- tion (SD)±3.3), patients with idiopathic CNS hypersomnia 6.5 min (SD±3.2), and patients with psychological distur- bances and those with no objective abnormalities 10.6 min (SD±5.2) and 10.9 min (SD±3.9), respectively. Based on these data, the authors concluded that a mean sleep latency of 5.5 min and less indicates pathological sleepiness which was found in the majority of narcoleptic patients. A value between 6 and 10 min is a “gray area,” typical of idiopathic CNS hypersomnia, and mean sleep latency of 10 min and more indicates that pathological sleepiness is unlikely.

Later data [20–21] supported the hypothesis that nar- colepsy and idiopathic CNS hypersomnia are distinct syn- dromes with characteristic sleep/wake patterns, EDS symp- toms, REM sleep abnormalities, and associated pathophysi- ological events. Idiopathic CNS hypersomnia patients sleep longer than narcoleptics, enter REM sleep later at night, have more NREM stages 3 and 4, experience fewer and briefer awakenings at night, and are not as sleepy during the day. Sleep apnea and periodic leg movements are less frequent in idiopathic CNS hypersomnia than in narcolepsy. The duality of the two conditions was verified also in human leukocyte antigen (HLA) studies [22]. While narcoleptic patients were invariably associated with HLA-DR2 positivity, idiopathic hypersomnia patients showed an increase of HLA-Cw2, DR5, and B27 antigens. However, Honda et al. [23] found that nearly half the patients suffering from essential hyper- somnia (34 patients) had a higher frequency of HLA-DR2. Essential hypersomnia was defined by the following criteria: (a) at least a 6-month history of recurrent daytime napping occurring almost daily, (b) absence of cataplexy, and (c) ab-

Fig. 27.3 Differences in the number of quotations listed by PubMed in the last decades. Narcolepsy and idiopathic hypersomnia are correlated

sence of other disorders with daytime somnolence such as sleep apnea.

During the past 30 years, the term idiopathic hypersom- nia has been given a variety of clinical labels including id- iopathic central nervous hypersomnia or hypersomnolence, functional hypersomnia, mixed or harmonious hypersomnia, and hypersomnia with automatic behavior, and rarely the term was mistaken for NREM narcolepsy. In contrast to nar- colepsy, much less interest was shown to this clinical entity over the years (Fig. 27.3).

The 1990 International Classification of Sleep Disor- ders (ICSD-1) [24] defined idiopathic hypersomnia as a presumably CNS-based disorder associated with a normal or prolonged major sleep episode and excessive sleepiness consisting of prolonged (1–2 h) episodes of NREM sleep. The difficulty waking up in the morning and the distinction between the two forms, as proposed by Roth, were not part of the definition. Narcolepsy and hypersomnia were includ- ed in a subgroup of dyssomnias—disorders which give rise to insomnia, excessive sleepiness, and eventually both—and referred to as intrinsic sleep disorders, induced primarily by factors within the body.

The clinical significance of idiopathic hypersomnia as an independent clinical entity was questioned. In 1993, Guil- leminault et al. [25] suggested that a nonnegligible propor- tion of subjects previously diagnosed with idiopathic hyper- somnia have upper airway resistance syndrome. The clinical features of narcolepsy and idiopathic hypersomnia were seen as substantially overlapping [26]. The same center [27] re- viewed clinical and laboratory information on 42 subjects with idiopathic hypersomnia and obtained detailed follow- up evaluation on 28 of them. Only less than one third of the

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subjects had “classic” idiopathic hypersomnia with nonim- perative sleepiness, long unrefreshing naps, prolonged night- time sleep, difficulty awakening with sleep drunkenness, and prominent mood disturbances. More than one third of the subjects under study had clinical features similar to those of narcolepsy without cataplexy or some other symptoms of ab- normal REM sleep. They had short refreshing naps and no problems on awakening. The remaining one third exhibited intermediate clinical characteristics. The authors concluded that idiopathic hypersomnia is a rare syndrome, in which clinical heterogeneity suggests a variable or multifactorial pathogenesis. In ten patients, they were able to identify pos- sible etiological factors—such as viral illness, head trauma, and primary mood disorder. Association with viral illness at the onset of the disease has been reported by other authors as well [28].

In the past two decades, a great deal of progress in the field of research into idiopathic hypersomnia has been made, thanks to Prof. Billiard. He was the first to resurrect Roth’s idea of polysymptomatic and monosymptomatic forms of idiopathic hypersomnia [29]; he recommended continuous ad lib recordings of abnormally long major sleep episode as well as long nonrefreshing naps. According to PSG data, idiopathic hypersomnia could also be clearly distinguished from other types of hypersomnia, particularly those associ- ated with mood disorder [30]. A few years later, examining a cohort of 23 subjects, he introduced the terms complete and incomplete forms of idiopathic hypersomnia. Detailed clini- cal, PSG, and immunogenetic data were reported. A strong familial predisposition was found; however, no association with HLAs was observed [31]. Billiard et al. [32] suggested in an excellent review that idiopathic hypersomnia is not a pathological entity in itself, but rather a consequence of chronic sleep deprivation in very long sleepers. The reasons that its pathophysiology is poorly known lie in: (1) the ab- sence of clear clinical and PSG criteria, as well as (2) the ab- sence of a natural animal model comparable with the canine model of narcolepsy.

In 2002, a revision of ICSD-1 was initiated, and Emmanu- el Mignot was appointed chairman of the Task Force on “Hy- persomnia of Central Origin, not due to a circadian rhythm sleep disorder, sleep related breathing disorders or other cause of disturbed nocturnal sleep” [33]. In the final version of ICSD-2 [34], two distinct entities appeared: (1) idiopathic hypersomnia with long sleep time and (2) idiopathic hyper- somnia without long sleep time. Idiopathic hypersomnia with long sleep time was characterized by EDS lasting at least 3 months, prolonged nocturnal sleep (more than 10 h), docu- mented by interview, actigraphy or sleep logs, and difficulty waking up in the morning or at the end of naps. Nocturnal polysomnography can help exclude other types of EDS and demonstrate a short sleep latency and prolonged sleep pe- riod (> 10 h). MSLT following overnight polysomnography

shows the mean sleep latency of less than 8 min and fewer than 2 SOREMs. Idiopathic hypersomnia without long sleep time differs from the previous clinical entity by the length of the major sleep episode (longer than 6 h but less than 10 h) and by the absence of difficulty waking up in the morning.

Although this classification responds much better to the clinical description of idiopathic hypersomnia, many ques- tions remain unanswered [33]: Are idiopathic hypersomnia with long sleep time and idiopathic hypersomnia without long sleep time two forms of the same condition or two dif- ferent conditions? Is there a pathophysiological relationship between narcolepsy without cataplexy and idiopathic hyper- somnia?

In their study of 160 narcoleptics, Vernet and Arnulf [35] found 29 (18 %) long sleepers (more than 11 h) with symp- toms combining the disabilities of both narcolepsy (severe sleepiness) and idiopathic hypersomnia (long sleep time and unrefreshing naps). In the authors’ view, this group may represent a transitional clinical entity with multiple arous- al system dysfunctions. The same authors [36] compared 40 hypersomniacs with and 35 without long sleep with 30 healthy matched controls. Hypersomnia patients had greater fatigability and higher anxiety and depression scores, 24% suffered from hypnagogic hallucinations, and 28 % had sleep paralysis. Sleep drunkenness was present in 36 % and unre- freshing naps in 46%. They were more frequently evening types as shown also in previous data [37]. MSLT latencies were normal (>8 min) in 71% hypersomniacs with long sleep time and even longer than 10 min in half of the pa- tients. The authors concluded that MSLT is an inadequate method for the diagnosis of hypersomnia with long sleep time. They recommended at least 24-h monitoring for the verification of idiopathic hypersomnia similar to the sugges- tion by Billiard and Dauvilliers previously [38]. The patients also showed some subjective symptoms besides excessive sleepiness, particularly attention and memory deficit [39].

Possible common features of narcolepsy, especially the type without cataplexy, and idiopathic hypersomnia are hotly debated currently [40–41]. In contrast to narcolepsy, which is characterized by an abnormal propensity to fall asleep, id- iopathic hypersomnia with long sleep time is noteworthy for the patients’ inability to terminate sleep. On the other hand, idiopathic hypersomnia without long sleep time seems to be more like narcolepsy without cataplexy with the excep- tion of REM sleep propensity in MSLT, a feature typical for narcolepsy [42]. However, using repeated MSLT tests in the same subject, we can obtain quite different results. Conse- quently, more research into the pathophysiology and into the predisposing factors of idiopathic hypersomnia is desirable. Genetic studies using genome-wide analysis and other mod- ern methods of molecular genetics can clarify the differences and similarities between these clinical entities.

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