The Clinical and Scientific Basis of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome Byron M. Hyde, M.D. - PDFCOFFEE.COM (2024)

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The Nightingale Research Foundation Review of

The Clinical and Scientific Basis of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome* Byron M. Hyde, M.D. Medical and Scientific Editor • Jay Goldstein, M.D. Director, Chronic Fatigue Syndrome Institute, Anaheim, California, USA Intellectual and Conceptual Advice •

Paul Levine, M.D. NIH, Bethesda, Maryland, USA Editorial Advice

* Also known as Post-Viral Fatigue Syndrome and Chronic Fatigue and Immune Dysfunction Syndrome

The Nightingale Research Foundation

Front Cover Illustration: The boy whose portrait is on the cover comes from a province in Canada where none of the demonstrated physiological brain scanning techniques is accessible. The brain images represented are from different patients and simply illustrate different investigative techniques. Back Cover Illustration: The Nightingale Research Foundation symbol is "Tiger in Kew Gardens" by Beryl Cook. Reproduced from the original painting, courtesy of Beryl Cook and with the assistance of Portal Gallery, London, England.

For Nightingale Research Foundation: Production Editor: Bonnie Cameron Copy Editor: Anne Duncker Communications: Lydia Neilson Project Administrator: Laurie Wilson Assistant Editor: Glenn Sheskay

Published by The Nightingale Research Foundation simultaneously in Ottawa, Ontario, Canada and Ogdensburg, New York State, USA Library of Congress Catalog Card N u m b e r 92-064489 Canadian Cataloguing in Publication Data Main entry under title: The Nightingale Research Foundation review of the clinical and scientific basis of myalgic encephalomyelitis/chronic fatigue syndrome "...proceedings of the Cambridge Easter Symposium on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome."-Foreword. "Also known as post-viral fatigue syndrome and chronic fatigue and i m m u n e dysfunction syndrome". Includes indexes. ISBN 0-9695662-0-4 1. Myalgic encephalomyelitis-Congresses. 2. Chronic fatigue syndrome-Congresses. I. Hyde, Byron M. II. Goldstein, Jay A. III. Levine, P.H. (Paul H.) IV. Nightingale Research Foundation. V. Cambridge Easter Symposium on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (1990: Cambridge University). VI. Title. VII. Title: The Clinical and scientific basis of myalgic encephalomyelitis/ chronic fatigue syndrome. RB150.F37N44 1992

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C92-090416-5

Copyright © 1992 by The Nightingale Research Foundation, 383 Danforth Avenue, Ottawa, Ontario, Canada K2A 0E1 FAX:(613) 729-0825 and Box 310,602 State Street, Ogdensburg, N e w York, 13669 USA No part of this book may be reproduced by any mechanical, photographic, or electronic process, or in the form of a phonographic recording, nor may it be stored in a retrieval system, transmitted, or otherwise copied for public or private use, without the written permission of the publisher. Printed and bound in Canada This text is printed on acid free paper manufactured by an environmentally friendly process. This book was created on a Macintosh Ilci, donated by Apple Canada, assembled in Microsoft Worddonatedby Microsoft Corporation and was formatted in Aldus PageMaker, donated by Aldus Canada.

Magnetic R e s o n a n c e I m a g i n g (MRI) This large colour accentuated sagittal MRI brain scan is t h a t of a 17 year-old girl who was a top academic student in grade 8 when she was involved in an apparently minor MVA t h a t was followed by contact with an infectious mono-like illness. She then developed a typical severe M.E./CFS-like clinical picture. Six years later, she still suffers from significant CNS dysfunction with intellectual and physical abilities far below her previous norm. A cluster of UBOs or punctuate anomalies can j u s t be seen in the transverse (horizontal) cut (Figure 1) of the same girl's brain. These anomalies are located in the posterior part of the left anterior lobe. Figure 2 represents an enlargement of the pathological area, clearly demonstrating two clusters of UBOs. These lesions appear to be in the pre-motor cortex or in the somato-motor cortex, the area responsible, in part, for muscle control. This girl has been confined to a wheelchair for much of the past several years. The QEEG scan indicated contre coup type injury.

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The Clinical and Scientific Basis ofM.E.

Dr. J o h n Richardson M.B., B.S.

/ CFS

Dedication

Dr. J o h n Richardson M.B., B.S. Over the years he has listened to them, learned from them and done his best to help them during the long period when many physicians were simply dismissing these patients' problems as conversion hysteria or anxiety neurosis.

This book is not only dedicated to my friend and mentor, Dr. John Richardson, but it owes its very existence to him. John Richardson was born in Shildon, County Durham, England in 1915. His was a talented musical family and, like his parents, he obtained an excellent musical education. His grandfather was a renowned violinist, his father an equally accomplished organist and his mother a gifted soprano. When John was a boy, he was taught the elements of music and, by the age of 14, he had become the local church organist. He learned the art of organ building from Edwin Taylor, organist and choirmaster for St Mary's in Darlington, Yorkshire and went on to build five pipe organs. He could easily have made his living as a professional musician. He has composed symphonies and played for the Princess of Wales in Balmoral Castle. An avid horticulturist, he grows semi-tropical fruits in his large greenhouse beside his home, Belle Vue House in Ryton, overlooking Hadrian's Wall and the River Tyne.

(2) When I started my study of M.E./CFS in 1985,1 was assisted by many kind, notable and brilliant physicians and researchers in Australia, Britain, Canada, Japan, Iceland, New Zealand, and the United States of America. Many took me into their homes and gave me not only an understanding of the disease process of M.E./CFS but also kindness and friendship. John Richardson, over several visits, spent days with me, going minutely over his research, his correspondence and intellectual storehouse of knowledge. As in all things, John Richardson went far beyond the expected. I was a poor Telemachus but he was a unique Mentor. (3) This book and the Cambridge Symposium were to be the joint work of an informal association of British physicians who meet under the title of the EME or the Epidemic Myalgic Encephalomyelitis Study Group. However, death and illness struck down many of the notables in their group and the enormous necessary work in England was not done. Up to the day of the symposium, we were led to believe that significant fund raising, delegates and staffing would be forthcoming from the second group of British organizers who took up the task from the EME. In the end, none of this anticipated assistance arrived, only unpaid accounts. In the midst of this trying and difficult experience, John Richardson and his Newcastle Research Group rose to the challenge, and helped fund some of the costs. John Richardson insisted that the show should go on and it did. Without John Richardson's determination and equitable personality, there would not have been a Cambridge Symposium. Without that Symposium this book would never have been written.

John Richardson's medical career started prior to the second world war when he decided to study physical medicine and attended the University of Edinburgh. When the war broke out in 1939, he joined the Royal Air Force and saw service in Germany. In 1941, he married Margaret Naseby. They have four children, David, Margaret, June and Gillian. Dr. Richardson remained in the services until after the war when he attended Newcastle University and obtained his M.B. Dr. Richardson, a very young energetic 75 year-old, still practises full-time medicine. His wife Margaret would prefer that he not fly around over the moors in the WWI Tiger Moth. As part of his general practice, he started to see patients with M.E./CFS in 1953. Since then, he has been compassionately examining, diagnosing and treating M.E./CFS patients on a continual basis for longer than any physician alive today.

At 10 p.m., on one of my last visits to his home, and after listening to him discuss the cardiac findings in M.E./CFS patients for several hours, Dr. Richardson turned to me and asked if I was up to doing one or two house calls. With the top of his BMW down, we sped off into the night, over the moors and dodging wandering sheep to visit some of his bedridden M.E./CFS patients. He reminded me of a unique person in a series of books that I had read as a child. The books were based upon The Flying Yorkshireman, a country man who did not resemble a hero but who always came through when the going was difficult.

This book is dedicated to Dr. John Richardson for the following three reasons: (1) When I first hammered on the doors of the Faculty of Medicine at the University of Toronto, I did not know Dr. John Richardson, but had I, he would have been my physician role model. He has the most ceaselessly inquisitive and scientific mind, but he takes care of his patients like the good Samaritan.

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The Clinical and Scientific Basis of M.E. / CFS

Adult QEEG/BEAM Scan, QSI Medical Corporation

The QEEG, Quantitative Electro-Encephalo-Gram, is a computer driven EEG t h a t produces an easily read two dimensional colour coded print of electrical brain activity. The above QEEG scan was performed at the QSI Medical Corporation headquarters in Toronto. The patient is a 42 yearold respiratory technologist who has been house-bound and severely disabled for over six years. This high quality inexpensive QEEG scanner offers several benefits in brain imaging. It is painless and non-invasive. It provides considerably more information than a classical EEG yet is easily read by any trained technologist or physician. The electrical asymmetry of the above scan immediately suggests the underlying pathology; the abnormal activity in the X view indicates both left and right abnormalities in the motor cortex. The electrical abnormality in the A view is situated in the left posterior parietal area of auditory and visual comprehension, consistent with this patient's clinical pathology.

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The Clinical and Scientific Basis of M.E. / CFS

P h o t o n E m i s s i o n T o m o g r a p h y - PET S c a n These PET scan images of a 34 year-old patient of Dr. Byron Hyde were provided by Dr. Stephen Lottenberg, University of California at Irvine. These images demonstrate significant mid-brain changes. This young lawyer has never returned to work during the past ten years after becoming brain disabled with CFS following an incapacitating viral infection. To date, the PET scan is the only brain imaging tool that has been shown to demonstrate adequately sub-cortical physiological injury.

hill Max 0. 0 14. 0 30. 0 46.0 63.

Child SPECT S c a n In the horizontal SPECT brain images in this section, we have adhered to the illogical but standard protocol that the right side of the SPECT image represents the left side of the brain and vice versa. The upper part of the SPECT scan logically represents the frontal (anterior) part of the brain. Except for the MRI pages, the coloured brain imaging techniques in this text represent physiological brain function rather than anatomical features. This HMPAO SPECT scan was provided by Dr. Michael Goldberg of Tarzana, California. The scan was performed by Dr. Ismael Mena with a Shimadzu brain dedicated SPECT unit at UCLA Harbor, California.

These scans are of an 8 year-old boy with M.E./CFS. There is a marked decreased perfusion in the left posterior parietal lobe, the area of the angular gyrus and the area responsible for visual and auditory comprehension. The right cerebellum is also deficient. This quiet, withdrawn child has developed considerable learning difficulty as well as balance problems and nystagmus.

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The Clinical and Scientific Basis of M.E. / CFS

Child SPECT S c a n These Xenon-133 and HMPAO SPECT scans of a 10 year-old M.E./CFS girl patient were provided by Dr. Michael Goldberg of Tarzana, California. The scan was performed by Dr. Ismael Mena with a Shimadzu brain dedicated SPECT unit at UCLA Harbor, California.

The three Xenon scans demonstrate marked decreased perfusion in the right frontal and right posterior parietal lobes. This decreased cerebral blood flow was found to fluctuate around 50 ml/min/lOOg or approximately half of the normal expected blood flow. There is also a marked decrease in perfusion of the cerebellar region.

The ten HMPAO scans reveal the details of bilateral decreased frontal perfusion, more extreme on the right, as well as a bilateral temporal hypoperfusion. There is a decrease in both posterior parietal lobes, more extreme in the right lobe. There is hypoperfusion of the right medial lobe of the cerebellum. There may also be decreased perfusion of the basal ganglia. It is possible that this child may have multiple problems including marked emotional volatility under stress, ataxia or nystagmus problems and a learning disability for comprehending both visual and auditory information.

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The Clinical and Scientific Basis of M.E. / CFS

The N e g a t i v e E f f e c t s of E x e r c i s e on an M.E./CFS D y s f u n c t i o n a l B r a i n These Xenon SPECT scans of a 37 year-old female M.E./CFS patient and the concept were provided by Dr. J a y Goldstein of Anaheim, California. The technical expertise is t h a t of Dr. Ismael Mena, UCLA Harbor, California.

24 H o u r s P o s t - E x e r c i s e Resting State Images 1,2 and 3, represent the abnormal resting state of an M.E/CFS brain. There is a perfusion defect in the left inferior frontal lobe as well as the right and left posterior parietal lobes. Immediate Post-Exercise State Images 4, 5 and 6 represent the immediate post-exercise function of the brain of the same patient. There is a significant decrease in perfusion of the right and left frontal lobes and the right and left posterior parietal lobes. An occipital perfusion defect is starting to appear. The functional resting defects noted in images 1, 2 and 3 have become aggravated. 24 Hours Post-Exercise State Images 7 , 8 and 9illustrate the severely decreased brain perfusion of the same patient 24 hours after the brain has been stressed by physical exercise. This 24 hour delayed effect may explain much of the M.E./CFS dysfunction t h a t occurs the day after exercise or other stress factors. The pathological brain changes demonstrated in 1,2 and 3 were exaggerated by normal physical activity. Similar dysfunctional images could probably be produced in an M.E./CFS patient as a result of sleep deprivation, a secondary infectious state, cognitive, sensory or emotional factors. A normal healthy patient will probably exhibit increased brain perfusion after similar modest exercise. See Dr. Goldstein, Addendum I, showing common stress pathway.

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The Clinical and Scientific Basis of M.E. / CFS

Adult SPECT S c a n These HMPAO SPECT scans of a 35 year-old pilot were provided by Dr. Byron Hyde. This scan was performed by Dr. Jean Leveille at Hotel Dieu Hospital in Montreal, employing a SX300 Picker.

After a significant febrile illness in June 1990, this 35 year-old pilot developed chronic headaches, difficulty in concentration, a marked loss of energy and inability to exercise. He has developed nystagmus. His reading skills have markedly decreased and he has developed emotional lability that occurs after any physical, cognitive or emotional stress factors. He had no significant disability or illness before falling ill in June 1990. SPECT scans performed at Hotel Dieu in Montreal demonstrate marked abnormalities of perfusion in the left posterior parietal lobe, together with decreased perfusion of the left frontal region. He also has a decreased perfusion in the area of the right motor cortex. These SPECT findings are consistent with the clinical description.

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Foreword This text is the work of The Nightingale Research Foundation, a charitable foundation located in Ottawa, Canada and incorporated in 1988 to conduct and assist research into the cause and cure of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (M.E./CFS) and to serve as an educational institution, for the Canadian public, physicians, nurses, teachers and their professional societies. Our Foundation is named after Florence Nightingale, who fell ill with an infectious disease during her service in the Crimean War. She then developed a disease process that was indistinguishable from M.E./CFS. Despite her severe disability, she went on to reform both public health and health care, helping to bring medicine and particularly the care and treatment of the ill patient into the twentieth century. This text that provides a basis of general information for clinicians and researchers interested in M.E./ CFS was initiated by the Cambridge Easter Symposium on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. The Symposium was held at Cambridge University, England in April 1990. The Symposium was international in scope and brought together, for the first time, researchers from around the world who were contributing to the growing body of scientific information regarding this disease process. Had it not been for the efforts of Dr. John Richardson, his Newcastle Research Group and Nightingale staff, the Symposium would have never been held. Without the constant confidence of our supporters and the rugged and continued determination of Nightingale's staff, this text could never have been completed. We have attempted to obtain material in every area of M.E./CFS knowledge, but we have not always been successful. Some information is under copyright and could not be released. Some promised material just never arrived. Scientific knowledge of M.E./CFS is growing so rapidly that we were not always able to keep up with all of the explosive changes in information. To compensate for some of the omissions, Nightingale staff have written review chapters only when an appropriate contributor was not available or the chapter was delayed. These review chapters represent Nightingale's opinions and are not necessarily those of the clinicians and researchers mentioned. Furthermore, in a few cases, we have requested and obtained permission from certain prestigious journals to reproduce works of historical significance. Due to the sheer length of some of the original manuscripts, it was necessary for us to reproduce some of the authors' work in abstract form. For historical purposes, we have attempted to obtain photographs of all of the leading M.E./CFS experts, past and present, who have contributed so much to our knowledge of this disease process. The dimensions and quality of the photographs received were not always uniform. Consequently, the size and the quality of the photographic reproduction is in no way related to the importance of the paper or the author. Some photographs were obtained through the kind assistance of the authors' friends, colleagues and secretaries, as well as medical and newspaper archives to whom we extend our appreciation. This text has come to represent much of our historical, clinical and scientific knowledge of M.E./CFS. We believe that this reference work will provide a welcome and exciting addition to our knowledge of a most fascinating disease process. The Board of Directors The Nightingale Research Foundation June 1992

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The Clinical and Scientific Basis of M.E. / CFS

Preface

Unravelling the Enigma This book attempts to outline, with broad strokes of the brush, the extent of an infectious illness, which affects both the immune and central nervous systems. This infectious illness has occurred in numerous well documented epidemics since the 1934 epidemic in the Los Angeles County General Hospital, magnificently described by Gilliam1 in 1938. Since that date, well over 50 similar clusters or epidemics2 have appeared in the medical literature under a plethora of names. David Bell was right to title his book about this disease process "The Disease of a Thousand Names3". For the purpose of this book I will refer to the disease as M.E./CFS, a fence-sitting title for Myalgic Encephalomyelitis / Chronic Fatigue Syndrome. It is not our intention to suggest M.E./CFS as yet another name. We could have equally tacked on the term PVFS or Post Viral Fatigue Syndrome, a term that, in England, has now partially replaced CFS as a generic term, or CFIDS, a term coined by the epidemiologist, Dr. Seymour Grufferman, and used by many of the U.S. patient groups. At The Nightingale Research Foundation in Ottawa, Canada, we have stuck with the name Myalgic Encephalomyelitis because there have been at least 10 names used in the literature since we started looking at this disease process in 1984 and we are simply tired of trying to keep up with the name changes. We have also tried to avoid the term "fatigue". Fatigue is immeasurable and largely indefinable. Fatigue is a normal phenomenon as well as being associated with almost all chronic disease states. Fatigue, which is simply one of the common features of healthy life and disease, neither defines M.E./CFS nor clarifies the illness. The term "fatigue" does cause disparagement to those who study this serious debilitating illness and those who suffer from it. It is an error to name a disease after just one of its many symptoms.

occur in hospitals and residential schools. In the hospitals, there has been a predilection for the disease to attack chiefly the staff '4 5 rather than the patients. In residential schools, the illness seems to have attacked both staff and students. 6 From the very first well-documented 1934 epidemic1, the question has arisen concerning the relationship of both an infective agent and immunization as a cause of this illness. Unfortunately, immunization has become one of the holy of holies and it is almost totally excluded from discussion in the literature as a cause of disease. Part ofthis may well be the close association of governments to immunization. It is my understanding that part of the problem that Assistant Surgeon General Gilliam of the United States faced in the publication of his report, and the reason for the four-year delay in publication, was the fact that the authorities were not willing to let it be known that this epidemic may have been spread to the staff by the use of human serum in immunization procedures. 7 It takes no great leap of imagination to note that hospital staff continue to be significantly more immunized than their patients and that both teachers and students enjoy a much higher immunization rate than the general public. It is these very groups that are most numerically afflicted by M.E./CFS. It is not my intention to attack immunization. I would not live happily in a world without immunization. Immunization, as a public health benefit, has not only saved countless millions from death and chronic disability, but has also saved governments fortunes and allowed armies to be assembled in vast numbers. One does not suggest with impunity that immunization is a cause of disease. Yet I am strongly suggesting that governments spend more money on research relating to immunization and its consequences than they are presently doing. Immunization is a two edged sword and the relationship between M.E./CFS, infection and immunization has never been seriously studied.

It has always been known by investigators that these epidemics of M.E ./CFS tended merely to highlight the same disease activity in the general public in the epidemic area. At first, these epidemics tended to

Since 1979, there has been an enormous but poorly

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B. Hyde, MD

Preface

Incidence of n e w c a s e s of M.E. / CFS per year 20 mal limits in the face of a chronic infectious stress. The resulting loss of normal internal homeostasis arises from the fact that a chronic viral infection provokes reactive changes in these peptides with a consequent pathophysiological changes and autonomic dysregulation.

180—d

These powerful excitatory and inhibitory mechanisms for rapid physiological adjustment work well with short term stressors. Frequently, these mechanisms shut down the biological system allowing for compensatory adjustments of the homeostatic mechanisms. When the stressor is an infectious agent, the messenger mechanisms stimulate compensating immune reactions to rid the body of this infectious stressor and ultimately return the individual to a normal homeostasis. 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 year

By definition, chronic infections have managed to escape these initial compensatory immune mechanisms. However, the neurochemical homeostatic events continue to be employed uselessly and to the detriment of the organism. This modulatory biochemical complex, biologically derived over the millenium to assist the organism, destabilizes the autonomic neuronal outflow and the individual can no longer function systemically within normal limits. Two theories of viral cause have been proposed.

documented increase in cases of M.E./CFS amongst the general public8. These increases compounded slowly until the late Summer of 1984 when it appears that a critical mass was reached and a veritable explosion of M.E./CFS occurred. Numbers, however, did not drop as one would expect after an epidemic period, but rather appear to have continued to rise in ever-increasing numbers. Although one of the infectious causes may represent a newly discovered virus, the illness that we are describing is not new. Thomas Sydenham, the father of English medicine, described a similar disease spectrum as Muscular Rheumatism in 168114. But from 1681 to the present time, what has been described is always the same. This disease has usually closely followed the patient's contact with an environmental stimulus and usually this stimulus has been an infectious disease.

The Retrovirus Concept Dr. Paul Cheney believes that the present epidemic9, starting in 1979, represents a new disease process caused by the emergence of an entirely new retroviral infection. His views should be taken seriously, for, if he is correct, the new retrovirus, first noted by Dr. Michael Holmes in New Zealand on July 23rd 198610, isolated and further clarified by Drs Paul Cheney and Elaine DeFreitas at the Wistar Institute in 199011 may be pivotal in our understanding of M.E./CFS. Is it the same as the second retrovirus successfully grown and whose structure was further elucidated by Dr. John Martin in The Los Angeles County Hospital?12 If so, it will bring us full circle to that first epidemic in 1934.

A Loss of Homeostasis In terms of its major dysfunction, M.E./CFS represents an acute change in the balance of neuropeptide messengers, and due to this, a resulting loss in the ability of the central nervous system (CNS) to adequately receive, interpret, store and recover information. This dysfunction also results in the inability of the CNS to consistently programme and achieve normal, smooth end organ response. The problem is one of maintaining systemic functioning within nor-

The Enterovirus Concept In 1958, it was pointed out by Dr. Bjorn Sigurdsson 15 that both the patients who had fallen ill with Akur-

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The Clinical and Scientific Basis ofM.E. / CFS

eyri disease in 1948, (another synonym for M.E./ CFS.), and also the healthy population from the same area, failed to succumb to a paralytic poliomyelitis epidemic that swept Iceland during that period. Later, when the same Akureyri population were first immunized against poliomyelitis, it was observed that this population responded with a much higher seroconversion than the non-Akureyri population of Iceland. This is one of the reasons why many researchers feel that there is a cross-over effect between M.E./CFS and the closely related poliomyelitis-enterovirus family and, indeed, that M.E./CFS is caused by an enteroviral infection. One personal observation that I can make is that, since the introduction of poliomyelitis immunization in 1954-56, and until 1979, there appears to have been a decrease both in poliomyelitis and M.E./CFS epidemics reported. This is only a cursory observation since no funding has been available to investigate these occurrences. It is not generally realized, but in the 1954-56 period, M.E./CFS itself changed abruptly. I have made the point of examining many patients who were affected with M.E./CFS prior to 1956 and who suffered a paralytic association along with the typical symptom picture of M.E. / CFS. For all purposes, post-1956 M.E./CFS patients have been spared overt paralysis. One can only conclude that poliomyelitis immunization may have somehow spared many subsequent M.E./CFS patients the paralytic features common in earlier epidemics. Again, one has to question the rise of Post-Polio Syndrome. Since 1881, when the first paralytic poliomyelitis epidemic was described, occurring on the north central Swedish/Norwegian border16, there has been no clearly described body of information that discusses Post-Polio Syndrome. Post-Polio Syndrome began clearly to surface around 1979 and only received its name duringthe same period17 when M.E./ CFS also catapulted into public attention. Lauro Halstead writes that "...prior to 1980 the name (postpolio syndrome) did not exist and without a name it was not possible to talk or write about it." It is most curious for an epidemic disease such as paralytic poliomyelitis, that had been around since 1881, to suddenly spawn a major new manifestation. There is no difference in the clinical picture between these

two disease syndromes except that in Post-Polio Syndrome there has been a clear observation of an earlier paralytic poliomyelitis illness. Yet, when we at Nightingale question patients with M.E./CFS who were born prior to 1955, we find that over a third of them had a parent, sibling or house resident who was paralysed with poliomyelitis. Poliomyelitis was a scourge, but it was just not that common. Are many M.E./CFS patients simply post-polio patients who had contracted a subclinical case of poliomyelitis years earlier? Is M.E./CFS in part simply a poliomyelitis variant? Physicians do not understand paralytic poliomyelitis as well as they should, nor as well as they think they do. We do not know why, when a poliovirus epidemic swept through a town, infecting and immunizing the vast majority of the population without even giving them a minor cold, only a few in that same population with the same virus fell ill, died or were paralysed. Did some of those individuals who fell ill and died with poliomyelitis have an immune dysfunction problem? Did some of them harbour a subclinical chronic virus infection that had previously injured their immune system? We still do not understand the cause of Encephalitica Lethargica 18 or of the major changes in that disease from the time it appeared in 1915 until 1934, when for all intents and purposes it disappeared 19 , curiouslyin thesameyearthatM.E./CFSappeared. One cannot but be impressed by the similarity of the sleep dysfunctions and associated pain syndromes and the inability, until now, to isolate a causative agent in both M.E./CFS and Encephalitica Lethargica. Who is right about the cause of M.E ./CFS, the British researchers who believe we are dealing with a persisting enteroviral infection or the American and New Zealand scientists who believe they have found a new and explosive retrovirus that has provoked such severe disability in so many hundreds of thousands of children and adults in the world today? The clinicians and scientists in this book may not yet have all of the answers, but like the discoverers of the New World, they have mapped out the bold features of the terrain.

Byron Hyde, M.D., Editor The Nightingale Research Foundation, Ottawa, Canada

Preface

B. Hyde, MD

References 1. Gilliam A.G. Epidemiological Study of a n Epidemic, Diagnosed as Poliomyelitis, Occurring Among the Personnel of The Los Angeles County General Hospital During The Summer of 1934, Public Health Bulletin No. 240, April 1938, The United States Public Health Service.

11. DeFreitas E., HilliardB., Cheney P., BellD.etal. Evidence of Retrovirus in Patients With Chronic Fatigue Immune Dysfunction Syndrome, Presented at the 11th International Congress of Neuropathology, Kyoto, Japan, September 4, 1990. (see CFIDS Chronicle, September 1990).

2. see this book, Review of Epidemics.

12. Personal communication with Dr. John Martin, Novemberl991 concerning further decoding of virus structure.

3. Bell D. The Disease of a Thousand Names, First Edition, Possard Publications, Lyndonville, New York. 4. The medical staff of the Royal Free Hospital, An Outbreak of Encephalomyelitis in the Royal Free Hospital Group, London, in 1955, Br. Med. J., 1957; 2:895-904. 5. Shelokov A., Havel K , Verder E., Welsh W. Epidemic Neuromyasthenia, An outbreak of poliomyelitis-like illness in student nurses. N.E.J.M., 1957; 257:345-55. 6. Hyde B., Bergmann S. Akureyri Disease, Forty Years Later. Lancet, 1988;1191-2. 7. Conversation between A. Gilliam and Alexis Shelokov reported to B. Hyde by A. Shelokov, 1988, 1991. 8. Cheney P. Kalamazoo Symposium, Oct 19, 1991.

13. Personal communication Dec 1991 with co-worker, Dr. David Bell. 14. Sydenham, T. The Works of Thomas Sydenham, M.D. (translation from the Latin edition of Dr Greenhill by R.G. Latham M.D.), Vol 1, London, Sydenham Society (1847). 15. Sigurdsson B., Gudnadottir M., Petursson, G. Response to Poliomyelitis Vaccination, The Lancet, 1,370-371, Feb. 1958. 16. Bergenholtz, noted in Wickman, Ivan, (translation Maloney, W.) Acute Poliomyelitis (Heine-Medin's Disease), The Journal of Nervous and Mental Disease Publishing Company, (1913). 17. M u n s a t , T. P o s t - P o l i o S y n d r o m e ; ButterworthHeinemann, Halstead, Lauro, Chapter 3, pg 24, (1991).

9. Cheney P. Kalamazoo Symposium, Oct. 19, 1991.

18. Von Economo C. (translation.Newman, K.O.) Encephalitis Lethargica; its sequelae and treatment. London (1931).

10. Holmes M. The Cambridge Symposium on Myalgic Encephalomyelitis (M.E.), Lady Mitchell Hall, Cambridge University, England, April 9-12, 1990.

19. Brain W. Russell. D i s e a s e s of the Nervous System, pg. 428-438, Oxford Medical Publications, Second Edition, (1940). 20. Nightingale Research Foundation, unpublished figures

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The Clinical and Scientific Basis of M.E. / CFS

In Appreciation This text would not have been possible without the financial help, support and services of the following individuals, associations and corporations. Nor could we have succeeded without our staff, the majority whom have donated their time and talents without any thought of financial remuneration, and others who have worked long hours for very modest wages. I would like to single out three of our staff. First, Lydia Neilson who, despite her illness, and in addition to being our principal fund raiser, has always been there to help those who despaired of life. Somehow, in her weakness she found strength and was able to use this strength to help others. Also this book would never have been completed were it not for the tireless efforts of our Production Editor, Bonnie Cameron, whose organizational abilities and technical ingenuity made this book possible. Attempts to coordinate the work of so many clinicians and researchers scattered across the globe has been daunting. The administrative excellence of Laurie Wilson has been invaluable during the preparation of this text. I would like in particular to acknowledge one individual, Kim Bechthold, whose companies and Principal Patrons, Genmark Corporation of San Francisco and BioCapital Corporation of Toronto, came to the rescue of both the Symposium and this book, ensuring their success. This was and is equally true of an anonymous Alberta family whose son and brother was ill and the Hobin family of Barry Hobin and Associates, Architects of Ottawa. Without their considerable and timely financial assistance we would not have succeeded in this venture. I would also like to thank and acknowledge, Dr. Henry Eisenberg from Syracuse, New York, Dr. Charles Poser, Beth Israel Hospital, Harvard, and Sandra Gwyn who were responsible for my taking up this challenge, Dr. Jay Goldstein in California, Dr. John Richardson in England and Dr. Peter O. Behan in Glasgow, whose ideas have greatly influenced this work, and my wife, Maureen O'Neil and my private secretary, Margaret O'Neill, who put up with me throughout this period. My thanks also go out to those thousands who are not mentioned here, whose modest donations and letters of encouragement have inspired us to complete our mission and make this publication available to all who might benefit from its existence. Byron Hyde M.D.

Principal Patrons

Patrons

BioCapital Corporation, Ontario An Anonymous Alberta Family Province of Ontario Royal Canadian Legion, Montgomery Branch Apple Canada Bell Northern Research Newcastle Research Group,G.B. Department of Health and Welfare, Canada G.W. Cadbury Trust, Great Britain Corel Systems Corporation Royal Bank of Canada Barry Hobin and Associates, Architects G. & P. Chilton & clients of Midland Walwyn Genmark Corporation, California

The Hon. H. Perrin Beatty Canadian Life and Health Insurance Ass. Clare Francis, Great Britain Goldberg, Shinder, Gardner & Kronick Miriam Gallacher, Ontario Brian and Donna Haley, BC Kim Harvey, BC IBM Canada Adrienne Kowalski, BC John and Pauline Perry Power Corporation, Quebec Richard & Donald Purcell, Ontario Dr. Gerald Seguin, Ontario Donna Sinclair, BC

xiv

Acknowledgements

M.E./CFS Associations & Support Groups I would like to laud Marc Iverson, President of the CFIDS Association and Publisher of the CFIDS Chronicle in Charlotte, North Carolina, who without any prior medical training, and although desperately ill, has managed to produce the best continuous source of medical information on M.E./CFS anywhere in the world. The efforts of Marc Iverson and his staff must truly be one of the most remarkable contributions to modern American medical history. The following support groups or their members have been instrumental in the success of this book. Many of them also raised considerable funds that enabled us to stay solvent during this period. Alberta M.E./CFS Associations, including Calgary, Edmonton, High Prairie, Lethbridge, Peace River & Red Deer Associations; British Columbia M.E. Society, and, Victoria, Comox, Vernon, Kelowna support groups; Ontario M.E. Support groups in Burlington, Chatham, Collingwood, Hamilton-Wentworth, KitchenerWaterloo, London, Orillia, Oshawa, Ottawa, Quinte-Bellville, St. Catharines Australia New South Wales M.E. Association; Great Britain, M.E. Action Campaign; New Zealand, ANZYMES Association; South Africa South Africa M.E. Association; USA, CFIDS Association, North Carolina Association, Massachusetts Association and their members

Principal Benefactors

Significant Assistance

Air Canada; Bell Canada; Canadian Airlines; Cybermedix Laboratories, Ontario; Miss Patricia Hession; Janet & Golden Lang Of Golden Colour Laboratories, Ontario; the Crout Family; National Printers, Ontario; Margaret Siebrasse, Quebec; Taggart Family Trust, Ontario; Phyllis & Cyril Putt, BC; Paul and Sue-Ellen Roache, Australia

Mary Pamela Allen, BC.; Walter Bick, Bicks Pickles; Barbara & Peter Burke, Dr. Song Yin Cai, Philippe Cassidy, Omelan Chabursky, Brian Child, Joan Cotsworth, BC; Warren Foster, BC; Ron & Marie Foxcroft, Deirdre Franklin, Les Filles de la Sagesse D'Ottawa, Gwendolyn Hancock, Mr. & Mrs. Houghton, Elizabeth Howson, Dorothy Jackson, BC Beverley & Peter Jones, Kelowna Elks Club, BC; Joyce Lang, BC; J.R. MacDonald, Que; McAlpine &Hordo,B.C Beatrice McPhatter, BC W.H.Merril, Mrs. C. Palumbo, Lucielle Parizeau, Pfizer Canada Inc., Roy Postlewhite, Sarah Pouliot, Christie Richards, Washington D.C.; H.A. Schnurr,BC Lily Smith, Dr. Graeme Taylor, Earl Trouten, Troco Limited, Ontario; Pamela Turriff, BC; Robert & Susan Vadeboncoeur, Quebec; George D. Willits, Miriam Wright, The Estate of Evelyn F. Wright, Dr. Lydia Wu, Max Wyman, BC

Benefactors If not otherwise mentioned, those following are from Ontario: An Anonymous Ontario Family; PaulBeatty; Milus Bollenberghe Topps Watchorn, Ontario; Burroughs Welcome Pharmaceuticals, Canada; Bristol M y e r s Pharmaceuticals, Canada; CUPE Canadian Union of Postal Workers; Dan Can Electric, Terry Deutscher, Robert Dingman, Alberta; Ferano Construction; Andre Gagnon, General Scrap Iron, Alberta HEM Pharmaceuticals, Philadelphia, Louise Matte-Lewis and Family and Friends, Patricia Muster, BC; Sean O'Sullivan, Reliable Services, Scotia Pharmaceuticals, Nova Scotia; Smith Kline and French Pharmaceuticals, Canada Sun Life of Canada, William & Irene Turriff, BC, Essence Vida, BC

Financial Assistance Sylvia Abbott, BC; Hazel Bain; Jean Baird; Collins Barrow, Alberta; Peter Bell, BC; E.G. Bernard, BC; Susan Best; Paul Bilodgau; Blackburn Properties; Brian Blackwell, BC; Chad Blackwood, BC Arthur Blair; Sylvia Boivin, BC; J e a n Booth,

XV

The Clinical and Scientific Basis of M.E. / CFS

Cambridge Symposium Support Staff

BC;Elizabeth Borek; Susan Botting; Alice Brodie; George Bruce; Butler Research; Gillian Canning, Quebec Larry Corless,AB; W.E. Couling, BC; Sally Coulter; Cathy Clemens; George W. Clemens; Dr. R. J.Conklin,BC; ReneDesormeaux; Dr. LarryDobson; Beryl Farr, Nancy Finn, AB; Barbara Fitzgerald; Bozena Frydova, B.C.M. Garamszeghy; John & Mildred Garlick; Dr. Lorna Guiou; Dr. David Gotlib, Drs Eva & Paul Groff; Dan and Shirley Gilbert, Alberta; Robert and Mary Gilhuly; Novella Gouldsborough, MB Grief Containers, Niagara Falls; Kenneth Gross; Ross Hall; Theresa Iverson, BC; Mabel Kung, Mr & Mrs Guy Launay, Leduc Cleaners, Alberta Loeb Inc., Luxors Gifts Ltd., BC; Jennifer Lynch, Judge W.E. MacLatchy, Maureen Madigan, Anita Manstan, A1 Martin, Carolyn Matthews, Mary Percival Maxwell, Mr & Mrs J. Mendel, Quebec; Merck Sharp & Dohme Research, Terling Park, Great Britain; Susan Mertens, BC; Metropolitan Toronto Police; R.E. Miller; Mollenhayer Construction Ltd; Lorraine Molloy; MDS Laboratories, Canada; Frank Mrack, Saskatchewan; Betty Miller; Dr. Brian MyhillJones, B.C.; Brian Newby, Alberta; Jack Newby, Alberta; John H. Newton, BC Marion Oades; Ontario Secondary School Teachers' Federation, Brian Orshinsky, Saskatchewan Frank Palumbo; G.R. Pauling, Alberta M.Petre Family; Raymond & Margaret Philips, BC; Rebecca Pratt; Darlene Quartermain; Lorna Quion; Dr. R.J. Richards; B.G. Robertson; Royal Canadian Legion, Strathcona Branch; Roussel Canada, Barbara Russell, BC; Mrs. J.M. Samuel, New Mexico; Richard Sandborn; Lois Schneider, AB; AlanShiff; Margaret Shouldice; Lloyd Singer; Sino Acupuncture Clinic, Marcia Smith; Robert McCallum, Stiefel Canada Inc, Frank Stoelzle, BC; Syntex Inc. Canada, Susan Tarras, BC; Dr. Lary Turner; UpJohn Pharmaceuticals Canada, Nico Van Duyvenbode; Jean and Rick Van Loon; Miroslava Vintor, BC; Jane Wallace, Saskatchewan Esther Wallner BC, David Ward, BC Dan Watts; H.O Westra, BC, Ruby Wilkins; Joan Wright; Sarah Wright; Wyeth Limited, Canada

We would particularly mention Valerie Oades Gamache who was the principal individual responsible for bringing the Symposium together and for all of the final detailed organization. I would also like to mention Ann Frampton who was able to recover a part of the funds held by the British organizers and ensure that they were paid to the British creditors. Jim Brook, Claire Comeau, Borys Chabursky, Marc Chuma, Anne Duncker, Ann Frampton, Valerie Gamache, Toni Jeffreys, Abdul Khan Grimshaw, Raymonde Guilbault, the late Martin Lev, Margaret O'Neill, Joan Rothery, Helen Urwin

Specialist and Associate Nightingale Staff Matthew Allen, Brenda Barsellotti, Ikbal Boga, Judy Cameron, Borys Chabursky, Dianne Delaney, Denise Dinsley, Valerie Gamache, Armett E. Hill, P. Kanagaretnam, Peggy Kitcher, Jill Peters, Sharyn Robertson, Michel Rochon, Glenn Sheskay, Robert Towsley Finally, I should like to mention and thank our honorable board, past and present, who supported us in this work. Past and Present Honorary Board The Hon. Monique Begin, P.C. The Hon. Guy Charbonneau The Hon. David Crombie, P.C. Dr. Josephine Flaherty Arnell Goldberg, Q.C. Dr. Gilles Hurteau Dr. Antoine D'lorio Dr. John Last The Hon. Martin O'Connell, P.C. Joan Pennefather Since we have so many people to thank, we may have inadvertently omitted some names. Naturally our thanks also go out to these people.

Principal Nightingale Staff Bonnie Cameron, Anne D u n c k e r , R a t n a Kanagaretnam, Lydia Neilson, Margaret O'Neill, Kathrine Tatsis, Laurie Wilson

Byron Marshall Hyde, Chairman Danielle Dougall, Vice President

xvi

The N i g h t i n g a l e R e s e a r c h F o u n d a t i o n R e v i e w of

The Clinical and Scientific Basis of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Contents Magnetic Resonance Imaging (MRI)

i

Dedication:

ii

Dr. John Richardson

iv-viii

Brain Imaging Illustrations

ix

Foreword Preface:

X

Unravelling the Enigma

xiv

In Appreciation

SECTION 1

SECTION 2

A ROAD MAP TO M.E. / CFS / PVFS / CFIDS

Chapter 1: The Disease of a Thousand Names

3

Chapter 2: The Definitions of M.E./CFS, A Review

5

Chapter 3: A Description of Patients Borys Chabursky, Byron Hyde, M.D., Anil Jain, M.D.

19

Chapter 4: General Information, Post Infectious, Acute Onset M.E. / CFS Byron Hyde, M.D., Sheila Bastien, Ph.D, Anil Jain, M.D.

25

Chapter 5: Clinical Observations of CNS Dysfunction in Post-Infectious, Acute Onset M.E. / CFS Byron Hyde, M.D., Anil Jain, M.D.

38

Chapter 6: M.E. / CFS: The Physical Signs of Disease Byron Hyde, M.D., Anil Jain, M.D.

66

OPENING REMARKS OF THE HONORARY CHAIRMEN

Chapter 7: Myalgic Encephalomyelitis, Then and Now, An Epidemiological Introduction, A. Melvin Ramsay, M.B., Betty Dowsett, M.B.

81

Chapter 8: M.E., The Epidemiological and Clinical Observations of a Rural Practitioner, John Richardson, M.B., B.S.

85

xvii

SECTION 3

OPENING REMARKS OF SOME OF THE CHAIRMEN

Chapter 9: The Myalgic Encephalomyelitis Syndrome, John Murdoch, M.D., Ph.D: New Zealand

SECTION 4

Chapter 10: "Spasmophilia" and/or "Myalgic Encephalomyelitis" Henri Rubinstein, M.D.: France

100

Chapter 11: Tapanui Flu (A quest for a diagnosis) Peter Snow, M.B., ChB, FRNZCSP: New Zealand

104

Chairman

J.E. Banatvala, MA., M.D., MRCP, FRCPath: England

107

Chairman

Alan Smith, M.D.: South Africa

108

AN HISTORICAL REVIEW OF M.E. / CFS LIKE DISEASE

Chapter 12: Myalgic Encephalomyelitis (Chronic Fatigue Syndrome): An Historical Perspective, Byron Hyde, M.D.

SECTION 5

SECTION 6

95

111

THE TWENTIETH CENTURY HISTORY OF M.E. / CFS

Chapter 13: The 1934 Los Angeles County Hospital Epidemic, A.G. Gilliam, M.D., reviewed by Byron Hyde, M.D.

119

Chapter 14: The Clinical Syndrome Variously Called Benign Myalgic Encephalomyelitis, Iceland Disease and Epidemic Neuromyasthenia, E.D. Acheson, D.M., MRCP

129

Chapter 15: Epidemic Neuromyasthenia - Clinical Syndrome? Donald A. Henderson, M.D., MPH and Alexis Shelokov, M.D.

159

Chapter 16: A Bibliography of M.E./CFS Epidemics Public Domain

176

THE EPIDEMIOLOGY AND METHODOLOGY OF M.E. / CFS

Chapter 17: Epidemiolgic and Immunologic Findings in Clusters of Chronic Fatigue Syndrome, Seymour Grufferman, M.D., Dr. PH

189

Chapter 18: Epidemiologic Aspects of CFS / M.E. Paul H. Levine, M.D.

196

xviii

CHILDREN AND STUDENTS WITH M.E. / CFS

SECTION 7

Chapter 19: Children with M.E./CFIDS: Overview and Review of the Literature, David S. Bell, M.D., FAAP

209

GENERAL REVIEW

SECTION 8

Chapter 20: A Multidisciplinary Approach to Investigating and Treating Patients with Chronic Fatigue Richard H.T. Edwards, Ph.D., FRCP

219

Chapter 21: A Review of M.E. / CFIDS / PVFS in America, Anthony Komaroff, M.D.

228

Chapter 22: Post-Viral Fatigue Syndrome Research in Glasgow, A Review, Nightingale Research Foundation

235

EVALUATING THE M.E. / CFS PATIENT

SECTION 9

SECTION 10

Chapter 23: How do I Diagnose a Patient with Chronic Fatigue Syndrome?, Jay Goldstein, M.D.

247

Chapter 24: The Evaluation of Adults with Chronic Fatigue: A Review of Laboratory and Psychological Findings Dedra Buchwald, M.D.

253

Chapter 25: Chronic Fatigue of Nasal Origin: Possible Confusion with Chronic Fatigue Syndrome Alexander Chester III, M.D., FACP

260

THE INFECTIOUS ORIGINS OF M.E. / CFS

Chapter 26: Possible Role for Epstein-Barr Virus (EBV) in the Chronic Fatigue Syndrome (CFS), James Jones, M.D.

269

Chapter 27: Detection of Viral Related Sequences in CFS Patients Using the Polymerase Chain Reaction, W. John Martin, M.D., Ph.D

278

Subsection A The Enteroviral Theories Chapter 28: Myalgic Encephalomyelitis (M.E.) - A Persistent Enteroviral Infection?, E.G. Dowsett, M.B., A.M. Ramsay, M.B. et al

285

Chapter 29: Virology Laboratory Diagnosis of Chronic Fatigue Syndrome Bernadette McLaughlin, M.D.

292

Chapter 30: The Immunosuppressive Effects of Group B Coxsackievirus Infections, Mauro Bendinelli, M.D., Ph.D., Donatella Matteuci, BS

298

xix

Chapter 31: Evidence of Chronic Enterovirus Infection in M.E., James F. Mowbray, FRCP

304

Chapter 32: Chronic Enterovirus Infection in Patients with PVFS, Galal Yousef, M.D. et al

310

Subsection B The Retroviral Theories

SECTION 11

SECTION 12

Chapter 33: A Retrovirus Aetiology for CFS?, Michael J. Holmes, M.D.

319

Chapter 34: Viral Infection in CFS Patients, W. John Martin, M.D., Ph.D

325

Chapter 35: The Search for a Retrovirus in CFS/CFIDS, Elaine DeFreitas, Ph.D, Hiroshi Terunuma, M.D., Ph.D.

328

Chapter 36: The Search for a Retrovirus in M.E./CFS, A Review Byron Hyde, M.D.

330

THE SKELETAL MUSCLE AS TARGET

Chapter 37: Molecular Virology of Muscle Disease: Persistent Virus Infection of Muscle in Patients with Postviral Fatigue Syndrome Leonard C. Archard, PhD, Louise Cunningham, Ph.D.

343

Chapter 38: Neuromuscular Abnormalities in Patients with CFS, Carolyn L. Warner, M.D. et al

348

Chapter 39: An Account of 100 Muscle Biopsies in Epidemic M.E., David Doyle, M.D.

352

Chapter 40: Whole Body and Muscle Protein Synthesis in Myalgic Encephalomyelitis, David Halliday, M.D., P.J. Pacy, M.D.

357

Chapter 41: Exercise Testing in Patients with Chronic Fatigue Syndrome David McCluskey, M.D., M. Riley, M.D.

364

THE HEART AS TARGET Chapter 42: Cardiac and Cardiovascular Aspects of M.E./CFS, A Review Byron Hyde, M.D., Anil Jain, M.D.

SECTION 13

375

NEUROLOGY Chapter 43: The Differential Diagnosis Between Multiple Sclerosis and Chronic Fatigue Postviral Syndrome, Charles M. Poser, M.D.

387

Chapter 44: Neurological Features of M.E., Russell J.M. Lane, M.D.

395

Chapter 45: CFS: Limbic Encephalopathy in a Dysfunctional Neuroimmune Network, Jay Goldstein, M.D.

400

XX

SECTION 14

M.E. / CFS AND THE PERIPHERAL NERVOUS SYSTEM Chapter 46: An Historical Review of the Electromyographic Features of Post-Infectious M.E. / CFS, Byron Hyde, M.D., Alberto Marinacci, M.D. and Karl Von Hagen, M.D.

409

414 Chapter 47: Evidence for Organic Disturbance in the Post Viral Fatigue Syndrome: Neurophysiological Studies, Goran A. Jamal, M.D., Ph.D. SECTION 15

SECTION 16

SECTION 17

M.E. / CFS AND CENTRAL NERVOUS SYSTEM INJURY Chapter 48: Magnetic Resonance in the Diagnosis of M.E./CFS, A Review, Byron Hyde, M.D., Royce Biddle, M.D. Thomas McNamara, M.D.

425

Chapter 49: Study of Cerebral Perfusion by NeuroSPECT in Patients with CFS, Ismael Mena, M.D., Javier Villanueva-Meyer, M.D.

432

Chapter 50: Multi-modality Sensory and Auditory Cognitive Event-Related Potentials in M.E. and M.S., Deepak Prasher, M.D., and Leslie Findley, M.D.

439

NEUROPSYCHOLOGICAL CHANGES IN M.E. / CFS

Chapter 51: Patterns of Neuropsychological Abnormalities and Cognitive Impairment in Adults and Children, Sheila Bastien, Ph.D

453

Chapter 52: The MMPI as an Aid to CFS Diagnosis, Linda Iger, Ph.D

461

Chapter 53: Is There a CFS Dementia?, Curt A. Sandman, Ph.D

467

Chapter 54: Physical and Psychosocial Functioning in Chronic Fatigue Syndrome, Diane L. Cookfair, Ph.D et al

480

PSYCHIATRY IN M.E. / CFS

Chapter 55: Depression / Somatization Explanations for the Chronic Fatigue Syndrome: A Critical Review, Donald G. Dutton, Ph.D

491

Chapter 56: The Psychiatric Status of Patients with the Chronic Fatigue Syndrome, Ian Hickie, M.D. et al

509

xxi

SECTION 18

FOOD INTOLERANCE IN M.E. / CFS

Chapter 57: The Role of Food Intolerance in CFS, Robert Loblay, M.D., Ph.D., Anne R. Swain, Ph.D SECTION 19

SECTION 20

SECTION 21

521

IMMUNOLOGY

Chapter 58: Immunological Abnormalities in Patients with CFS, Andrew Lloyd, M.D. et al

541

Chapter 59: Recent Developments in Immunological Aspects of CFS Sudhir Gupta, M.D., Ph.D.

545

Chapter 60: Host Factors Affecting the Course and Outcome of Viral Disease, Roger M. Loria, Ph.D. (See also Chapter 74: The Role of Thymic Infections, Nathan Trainin, M.D. and Chapter 28: M.E. - A Persistent Enteroviral Infection, Betty Dowsett, M.D.)

551

Chapter 61: Abnormalities of Natural Killer (NK) Cell Numbers and Function in Patients with Chronic Fatigue Immune Dysfunction Syndrome (CFIDS), Hugh Pross, M.D., Ph.D, FRCPC

566

BLOOD CELL CHANGES

Chapter 62: Opioid-Mediated Monocyte Dysfunction in the CFS, Jesus Prieto, M.D. et al

575

Chapter 63: Paired, Age, Sex and Ethnically Matched Studies of Peripheral Blood Leucocyte Profiles in Early CFS, Michael Holmes, M.D. et al

585

Chapter 64: Working Towards a Diagnostic Aid in CFS: Analysis of Peripheral Blood Leucocyte Profiles by Radial Plot, John Cross, Ph.D et al

592

Chapter 65: The Role of Nondiscocytic Erythrocytes in the Pathogenesis of M.E. / CFS, Len O. Simpson, Ph.D.

597

Chapter 66: Differentiation Between M.S. and M.E., E.J. Field, M.D., FRCP

606

NEW INVESTIGATION TECHNIQUES

Chapter 67: Biochemical Defects in the 2-5A Synthetase/RNAse L Pathway Associated with CFS with Encephalopathy, Robert J. Suhadolnik, Ph.D et al

613

Chapter 68: Evidence for T-Cell Activation by Soluble IL-2-R and T8-R in the Chronic Fatigue Syndrome, Paul R. Cheney, M.D., Ph.D (See also Chapter 64: Working Towards..., John Cross, Ph.D)

618

xxii

SECTION 22

SECTION 23

TREATMENT

Chapter 69: Intravenous Immunoglobulin Therapy in Patients with CFS, Andrew Lloyd, M.D. et al

625

Chapter 70: Essential Fatty Acid Therapy for M.E., Michael D. Winther, M.D.

628

Chapter 71: Clinical Improvements Obtained with Ampligen in Patients with Severe CFS and Associated Encephalopathy, Daniel L. Peterson, M.D. et al

634

Chapter 72: Immunological Therapy with Transfer Factor, Andrew Lloyd, M.D. et al

639

Chapter 73: The Florence Nightingale Disease: A Multisystem Experiment of Nature: A 50 Patient Five Year Analysis, H. Hugh Fudenberg, M.D.

641

Chapter 74: The Role of Thymic Hormones in Viral Infections Nathan Trainin, M.D. et al ( See also Chapter 23: How I Diagnose..., Jay Goldstein, M.D.)

654

FIBROSITIS / FIBROMYALGIA

Chapter 75: Fibrositis / Fibromyalgia Syndrome, I. Jon Russell, M.D., Ph.D

SECTION 24

663

CONCLUSIONS

Summary

693

Addendum I - Jay A. Goldstein, M.D.

695

Addendum II - Linda Iger, Ph.D

697

Addendum III - Harvey Moldofsky, M.D.

698

Addendum IV - David C. Poskanzer, M.D., M.P.H.

699

Addendum V - Alfredo A. Sadun, M.D., Ph.D, Pravin U. Dugel, M.D.

700

Addendum VI - Bjorn Sigurdsson, M.D., Ph.D

704

Index of Clinicians, Researchers and Associates

706

Index

712

Index of Photographs

724

xxiii

Section 1

A Road Map to M.E. / CFS / PVFS / CFIDS

G.Parish, MB, D.Bell, MB, B.Hyde, MB, H. Rubinstein,

MB

The Bisease of a Thousand

Names

Chapter 1

The Disease of a Thousand Names The following descriptive names have been compiled from the work of Dr. Gordon Parish, Dr. David S. Bell, Dr. Henri Rubinstein and Dr. Byron Hyde. The following represent just a few of the names that have been given to this protean illness: The Poliomyelitis Names: A disease resembling or simulating poliomyelitis; atypical poliomyelitis; abortive poliomyelitis, encephalitis simulating poliomyelitis; encephalitis resembling poliomyelitis; postpolio syndrome; posterior poliomyelitis, sensory poliomyelitis. Postpolio syndrome is considered by the medical community to be an indisputable entity. Unlike M.E./CFS there is no physician who doubts its existence. However, postpolio syndrome symptomology is identical to that of M.E./CFS. The only difference is that, in postpolio syndrome, there is clear evidence of paralytic poliomyelitis in the patient concerned. Curiously, no note was ever made of postpolio syndrome except in the recent medical literature, despite the fact that poliomyelitis has been in existence as an epidemic disease since 1881 when the first epidemic of poliomyelitis occurred in Sweden. The rise in postpolio syndrome closely parallels the increasing incidence of M.E./CFS observed since 1979. It is our opinion at Nightingale that postpolio syndrome is no more than M.E./CFS [in an individual with previous history of clinical poliomyelitis.] Names based upon location: Iceland disease, Akureyri disease, Coventry disease, Tapanui flu, Otago mystery disease. Royal Free disease, Lake Tahoe mystery disease, Lyndonville chronic mononucleosis, the English disease;

Bacterial names: Chronic brucellosis, Chronic lyme disease;

Neuromyasthenia-names: Neuromyasthenia, Neurasthenia, Epidemic neuromyasthenia, Epidemic pseudo myasthenia, Sporadic postinfectious neuromyasthenia, Neurocirculatory asthenia;

Immune based names: Chronic immune activation syndrome, CIAS, Chronic immune dysfunction syndrome, CIDS, Low natural killer cell syndrome (Japan), Multiple chemical sensitivity syndrome, Ecological disease, Allergic fatigue syndrome, Antibody negative lupus, Antibody negative lyme disease, Chronic activated immune dysfunction syndrome, CAIDS, Chronic fatigue and immune dysfunction syndrome, CFIDS, Naxalone-reversible monocyte dysfunction syndrome (NRMDS);

Combined virus/symptom names: Post-viral fatigue syndrome, PVFS, Persistent viral fatigue syndrome;

Myalgic Encephalomyelitis names: Myalgic encephalomyelitis, benign encephalomyelitis, benign myalgic encephalomyelitis, benign subacute encephalomyelitis, epidemic myalgic encephalomyelitis or encephalomyelopathy, acute infective encephalomyelitis, epidemic diencephalomyelitis, lymphoreticular encephalomyelopathy;

Epstein-Barr Virus based names: Chronic Epstein-Barr virus syndrome, CEBV, Chronic active Epstein-Barr virus infection, CAEBV, Virus epidemic in recurrent waves, Chronic mononucleosis, Familial chronic mononucleosis, Chronic infectious mononucleosis, Chronic active Epstein-Barr virus infection, Chronic mononucleosis-like syndrome;

Myalgia type names: Epidemic malaise, persistent myalgia following sore throat. Damadian's ache, Myofascial syndrome, Muscular rheumatism, Fibromyalgia syndrome, Fibromyositis, Fibrositis, Epidemic myositis, Lymphocytic meningo encephalitis with myalgia and rash, Syndrome polyalgique idiopathique diffus (S.P.I.D.); (The Fibromyalgia names are based upon a symptom complex seen in M.E., Lupus, Rheumatoid arthritis and several other non-associated illnesses.)

Hypothalamic Names: Epidemic vegetative neuritis, Neurocirculatory asthenia, vasoregulatory asthenia, vasomotor instability, vasomotor neurosis, Habitual chronic hyperventilation syndrome;

Personal names: Da Costa's Syndrome, Beard's disease;

The Atypical Names: Atypical multiple sclerosis, Atypical migraine;

Symptom based names: Chronic fatigue syndrome, CFS, La Spasmophilic, (France), Raggedy Ann Syndrome, the English sweats, Effort syndrome, Tetanie chronique idiopathique;

Media names: Yuppie flu, Yuppie plague; Miscellaneous names: Soldier's heart, Epidemic vasculitis syndrome.

3

The Clinical and Scientific Basis of M.E. / CFS

Myalgic Encephalomyelitis (M.E.) Many readers may not understand the significance of the above term that has been used in Great Britain for many years to describe this disease process. My refers to muscle and algic to pain. Encephalo refers to brain, myel to spinal cord and itis denotes inflammation. The name Myalgic Encephalomyelitis is consistent with our knowledge of the disease process except for the suffix itis; there is no evidence of active inflammation. A pathologically more appropriate name would be Myalgic Encephalomyelopathy - opathy simply referring to the fact that there is pathology.

4

B. Hyde, MD

The Definitions of M.E. / CFS, A Review

Chapter 2

Andrew Lachlan

Wallis

This damaged photograph of Dr. Andrew Lachlan Wallis was sent to us by the N.S.W. Australia, Medical Board. It is the sole photograph that we have been able to recover of Dr. Wallis, who registered in N.S.W. in 1958 and then appears to have disappeared. Dr. Wallis' thesis outlines guidelines for the diagnosis of adults that have not been improved upon. Dr. Wallis was the first to describe M.E. / CFS in large numbers of children and was the first to define the illness in children. He was the first to describe the microscopic brain pathology in M.E. /CFS.

The Definitions of M.E./CFS, A Review B. Hyde, M.D. (Please see Chapter 5 for Dr. Hyde's photograph and curriculum

vitae.)

Under "define", two of the examples given in the Third Edition of the Shorter Oxford English Dictionary are: (a) To determine the boundary or limits of. (b) To set forth the essential nature of. Yet one of the problems facing physicians and researchers interested in M.E. / CFS, is that the perception of the limits and boundaries of the disease varies greatly in relation to the prejudices of those who describe the disease. Some apparently reasonable physicians insist that no children are affected by M.E. /CFS, that no infectious agent is apparent, and that there are no physical signs. I hope that this text will put an end to such naive objections. An Adequate Definition The Clan War The formation of an adequate definition of a disease appears to be an easy task. It is not. Rheumatoid arthritis has been redefined every few years for most of this century and still researchers are far from satisfied. The problem is simply that if you know the exact cause, the method of acquiring and the pathophysiology of a disease, one does not need a definition.

M.E./CFS finds itself in a fierce clan war between biochemical, subcellular, brain imaging and virological scientists who are challenging the centuries-old imaginative world of psychiatry. Frequently the psychiatric theory proponents are not even psychiatrists but traditionalists who have learned their subject well and have lost their ability to look again. Many skins will be bruised before this conflict has ended.

5

The Clinical and Scientific Basis of M.E. / CFS

If we have a definitive test for a specific disease, there is little need for definition, only the need of a good historian or a good checklist. One of the biggest problems with M.E./CFS is that researchers are so much at each other's throats that an excellent definition is beyond reasonable consensus. But from what we do know, we should be able to build a reasonable working definition.

Wallis' Variations Seen in Children (1) Depression: This often occurred with weeping tendencies, and appeared early. There were four cases severe enough to warrant psychiatric inpatient treatment. (2) Loss of energy: This occurred in all but the mildest cases and frequently persisted.

Early attempts to define M.E./CFS consisted of simple symptom check lists, sometimes mixed in with insights from the particular epidemic under examination. One such check list stands out above all others and that is the working definition ofA. L. Wallis of the epidemic M.E./CFS illness that occurred in 1955 in Cumberland in England It is particularly useful as it is also the first definition to demonstrate some of the specifics of M.E./CFS in children.

(3) Retardation of thought process: Work involving abstract thought was difficult to perform in all with protracted illness or recurrences. Serial seven test was poorly performed, often with errors, often starting the test well and then getting bogged down. (4) Impairment of thought process: This was a common feature, and the contents of papers or magazines read only a few minutes earlier could not be recollected.

The Wallis Descriptive Definition for Adults (1) A systemic illness with relatively low fever or subnormal temperatures.

(5) Impairment of memory: Recent retention and recall: Items of work to be done or purchases to be made had to be listed as memorising proved unreliable.

(2) Marked muscle fatigability. (3) Mental changes with impairment of memory, changes in mood, sleep disorders and irritability or depression.

(6) Disorders of sleep: Inversion of sleep rhythm was common with nightmares in children. Hallucinations on waking occurred in 6 cases.

(4) Involvement of the autonomic nervous system resulting in orthostatic tachycardia, coldness of the extremities, episodes of sweating or profound pallor, sluggish pupils, bowel changes and frequency of micturition, possibly as a result of a lesion of the hypothalamus.

(7) Behaviour disorders: Temper tantrums were frequent in young children. In older children unsociability and lack of attention and effort on return to school was frequent. If behaviour was checked, children tended to weep. Persistent Traits in Children

(5) Diffuse and variable involvement of the central nervous system, leading to ataxia, weakness and/ or sensory changes in a limb, nerve root or a peripheral nerve.

(1) Nocturnal enuresis (2) Disobedience at school and at home (3) Unmotivated acts of aggression (4) Facile lying in normally truthful children (5) Rapid changes in mood

(6) Muscular pain, tenderness and myalgia, and (7) Recurrence in some patients over a period of several years.

It is interesting to compare these findings with those quoted by Behan and Behan over 30 years later in children with sporadic M.E./CFS. Apparently the Behans had not seen the manuscript published by

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The Definitions of M.E. / CFS, A Review

B. Hyde, MD

In 1959, Henderson and Shelokov, writing in the New England Journal of Medicine, describe a check list of the acute findings of M.E./CFS or what they called Epidemic Neuromyasthenia.

Wallis when they wrote these findings in the CRC Reviews.

Behan and Behan, Ten Findings in Children with PVFS (post-viral fatigue syndrome)

The Henderson and Shelokov Summary

(1) There is anxiety and clinging dependency. (2) There is reluctance to attend school. (3) There is lack of interest in playing games with other children. (4) There is lassitude. (5) Sleep pattern is disturbed. (6) Nightmares and irritability are common. (7) A significant amount of body weight may be lost. (8) In some cases such severe weakness occurs that the child is confined to a wheel chair for several months. (9) Nearly all affected children are diagnosed first as hysterical, with depression or "parental over-involvement". (10) When forced to attend school and take part in physical exercises, this has been followed by disastrous deterioration in the clinical condition, with overwhelming exhaustion and weakness supervening.

(1) Fatigability, malaise, prodromal sore throat (2) Muscle weakness, cramps, spasms and twitches (3) Bursting headache, neck pain, eye pain (4) Irritability, depression, lack of concentration, emotional instability, impaired mentation (5) Visual problems, photophobia, diplopia (6) Dizziness, nausea, cutaneous sensory changes (7) Urinary, menstrual difficulties Of the 23 features mentioned in this summary, the vast majority can be attributed to an acute CNS injury and 17 of the features could only be attributed to a CNS or muscle pathology. In the Henderson Shelokov list, fatigue is only one of 27 notations and is not elevated to special status. As with Gilliam and later Wallis, the urinary and menstrual difficulties are mentioned.

Comments:

The first and only attempt to date to systemize M.E./ CFS in the form of a useful working definition was made in 1988 by a United States Government researcher, Dr. Gary Holmes and his learned team. Their definition was a good start. Yet all of these researchers had believed that Epstein-Barr virus was the cause of what they called Chronic EpsteinBarr Syndrome and this was perhaps one of their collective difficulties. However, a review of the literature on M.E./CFS epidemics would have revealed that the epidemic disease they described had an incubation period of as little as 4-5 days and that EBV had an incubation period of 30-50 days. This failure to return to the literature haunts the very basis of their definition.

Wallis studied these M.E./CFS children and adults for a period of approximately two years and then apparently left for Australia; Behan and Behan had the advantage of studying these children for years. These traits may persist chronically. Wallis points out that this disease in part represents a hypothalamic injury and that the disease is characterized by a subnormal temperature after the prodromal period of three or four days. These findings of subnormal variability are described in every welldocumented M.E/CFS epidemic. It is unfortunate that the CDC diagnosis did not benefit from a review of this literature.

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The Clinical and Scientific Basis of M.E. / CFS

The CDC Definition This article is reprinted with the kind permission from Holmes et al, Chronic Fatigue Syndrome: A Working Case Definition. Ann Intern Med. 1988; Vol. 108, Number 3: pages 387-389.

Chronic Fatigue Syndrome: A Working Case Definition Gary P. Holmes, M.D.; Jonathon E. Kaplan, M.D.; Nelson M. Gantz, M.D.; Anthony L. Komaroff, M.D.; Lawrence B. Schonberger, M.D.; Stephen E. Straus, M.D.; James F. Jones, M.D.; Richard E. Dubois, M.D.; Charlotte Cunningham-Rundles, M.D.; Savita Pahwa, M.D.; Giovanna Tosato, M.D.; Leonard S. Zegans, M.D.; David T. Purtilo, M.D.; Nathaniel Brown, M.D.; Robert T. Schooley, M.D.; andlrenaBrus, M.D.; Atlanta, Georgia; Worcester and Boston, Massachusetts, Bethesda, Maryland; Denver, Colorado; New York and Manhasset, New York; San Francisco, California; and Ohama, Nebraska The chronic Epstein-Barr virus syndrome is a poorly defined symptom complex characterized primarily by chronic or recurrent debilitating fatigue and various combinations of other symptoms, including sore throat, lymph node pain and tenderness, headache, myalgia, and arthralgias. Although the syndrome has received recent attention, and has been diagnosed in many patients, the chronic Epstein-Barr virus syndrome has not been defined consistently. Despite the name of the syndrome, both the diagnostic value of Epstein-Barr virus serologic tests and the proposed causal relationship between Epstein-Barr virus infection and patients who have been diagnosed with the chronic Epstein-Barr virus syndrome remain doubtful. We propose a new name for the chronic Epstein-Barr virus syndrome - the chronic fatigue syndrome - that more accurately describes this symptom complex as a syndrome of unknown cause characterized primarily by chronic fatigue. We also present a working definition for the chronic fatigue syndrome designed to improve the comparability and reproducibility of clinical research and epidemiologic studies, and to provide a rational basis for evaluating patients who have chronic fatigue of undetermined cause. [MeSH Terms; axilla; chronic disease; depression; Epstein-Barr virus; fatigue; fever; lymph nodes; memory disorders; neck, pharyngitis. Other indexing terms; chronic Epstein-Barr virus syndrome; chronic fatigue syndrome; sore throat]

The Chronic Epstein-Barr virus syndrome, also known as chronic mononucleosis or chronic mononucleosis-like syndrome, is a syndrome of unknown cause that has been the subject of interest in both medical and popular literature, particularly since 1985. As it was described 14 in four groups of patients, the syndrome consists of a combination of nonspecific symptoms - severe fatigue, weakness, malaise, subjective fever, sore throat, painful lymph nodes, decreased memory, confusion, depression, decreased

ability to concentrate on tasks, and various other complaints - with a remarkable absence of objective physical or laboratory abnormalities. The syndrome was linked in these and other reports to Epstein-Barr virus, because many, but not all, of the patients had Epstein-Barr virus antibody profiles that suggested reactivation of latent infection. Reference laboratories soon began to advertise Epstein-Barr virus serologic tests for use in the diagno-

From the Division of Viral Disease, Centers for Disease Control, Atlanta, Georgia: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Laboratory of Clinical Investigation, National Institutes of Health, Bethesda, Maryland: Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado: Atlanta Medical Association, Atlanta, Georgia; Department of Medicines, Mount Sinai Medical Center, New York, New York: Department of Pediatrics, North Shore University Hospital, Manhasset, New York; Division of Biochemistry and Biophysics. Food and Drug Administration, Bethesda, Maryland; Department of Psychiatry, University of San Francisco School of Medicine, San Francisco, California, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, and Department of Medicine, Beth Israel Medical Center, New York, New York.

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The Definitions of M.E. / CFS, A Review

sis of the chronic Epstein-Barr virus syndrome 5 . Although reliable data are not available, indications are that the syndrome has been diagnosed commonly by physicians, often on the basis of poorly defined diagnostic criteria. Since late 1985, the Division of Viral Diseases, Centers for Disease Control has responded to several thousand telephone and mail requests for information about the chronic EpsteinBarr virus syndrome, both from physicians and from patients in whom the syndrome has been diagnosed. Judgingfrom the inquiries received, many physicians appear to have based their diagnoses on little more than the presence of detectable serum Epstein-Barr virus antibody titers.

Epstein-Barr virus syndrome without implying a causal relationship with Epstein-Barr virus. Because of the nonspecific nature of the symptoms and the lack of a diagnostic test, researchers have had difficulty devising a case definition for the chronic Epstein-Barr virus syndrome. When definitions have been described, they have differed greatly among the various published studies, making direct comparisons of the study results difficult. We have organized an informal working group of public health epidemiologists, academic researchers, and clinicians, to develop a consensus on the salient clinical characteristics of the chronic Epstein-Barr virus syndrome and to devise a definition for the chronic fatigue syndrome that will be the basis for conducting future epidemiologic and clinical studies. Because the syndrome has no diagnostic test, the definition at present is based on signs and symptoms only. This definition is intentionally restrictive, to maximize the chances that research studies will detect significant associations if such associations truly exist. It identifies persons whose illnesses are most compatible with a possibly unique clinical entity; persons who may have less severe forms of the syndrome or who have less characteristic clinical features may be excluded by the new definition.

More recent studies 6 7 have cast doubt on the diagnostic value of positive Epstein-Barr virus serologic results and on the proposed relationship between Epstein-Barr virus infection and patients who have been diagnosed with the chronic Epstein-Barr virus syndrome. Although some statistically significant associations between positive Epstein-Barr virus serologic tests and illnesses diagnosed as the chronic Epstein-Barr virus syndrome were identified in one study using age-, sex-, and race-matched controls6, the serologic associations between the syndrome and cytomegalovirus, herpes simplex virus types 1 and 2, and measles virus were as strong as or stronger than the association with Epstein-Barr virus. EpsteinBarr virus serologic results in this study were also found to be poorly reproducible, both within and among laboratories, leading to the conclusion that the results of these tests are not directly comparable unless they have been done in parallel.

The chronic fatigue syndrome is currently an operational concept designed for research purposes that physicians must recognize not necessarily as a single disease but as a syndrome - a complex of potentially related symptoms that tend to occur together - that may have several causes. Periodic reconsideration of conditions such as those listed under major criteria, part 2, should be standard practice in the long-term follow-up of these patients.

With the apparent lack of correlation between serum Epstein-Barr virus titers and the presence of chronic fatigue symptoms, it is premature to focus research and diagnostic efforts on Epstein-Barr virus alone. Many public health officials and clinicians are concerned that a diagnosis of the chronic Epstein-Barr virus syndrome may not be appropriate for persons with chronic fatigue who have positive Epstein-Barr virus serologic tests, and that definable occult diseases may actually be the cause of symptoms such as fatigue, weakness, and fever. It is also inappropriate to use a name for the syndrome that implies a specific causal agent. We, therefore, propose a new name the chronic fatigue syndrome - that describes the most striking clinical characteristic of the chronic

Case Definition for The Chronic Fatigue Syndrome A case of the chronic fatigue syndrome must fulfill major criteria 1 and 2, and the following minor criteria: 6 or more of the 11 symptom criteria and 2 or more of the 3 physical criteria; or 8 or more of the 11 symptom criteria. Major Criteria 1. New onset of persistent or relapsing, debilitating

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The Clinical and Scientific Basis of M.E. / CFS

fatigue or easy fatigability in a person who has no previous history of similar symptoms, that does not resolve with bedrest, and that is severe enough to reduce or impair average daily activity below 50% of the patient's premorbid activity level for a period of at least 6 months.

erythrocyte sedimentation rate; antinuclear antibody; thyroid-stimulating hormone level; HIV antibody measurement; and intermediate-strength purified protein derivative (PPD) skin test with controls. If any of the results from these tests are abnormal, the physician should search for other conditions that may cause such a result. If no such conditions are detected by a reasonable evaluation, this criterion is satisfied.

2. Other clinical conditions that may produce similar symptoms must be excluded by thorough evaluation, based on history, physical examination, and appropriate laboratory findings. These conditions include malignancy; autoimmune disease; localized infection (such as occult abscess); chronic or subacute bacterial disease (such as endocarditis, Lyme disease, or tuberculosis), fungal disease (such as histoplasmosis, blastomycosis, or coccidioidomycosis), and parasitic disease (such as toxoplasmosis, amebiasis, giardiasis, or helminthic infestation); disease related to human immunodeficiency virus (HIV) infection; chronic psychiatric disease, either newly diagnosed or by history (such as endogenous depression; hysterical personality disorder; anxiety neurosis; schizophrenia; or chronic use of major tranquilizers, lithium, or antidepressive medications); chronic inflammatory disease (such as sarcoidosis, Wegener granulomatosis, or chronic hepatitis); neuromuscular disease (such as multiple sclerosis or myasthenia gravis); endocrine disease (such as hypothyroidism, Addison disease, Cushing syndrome, or diabetes mellitus); drug dependency or abuse (such as alcohol, controlled prescription drugs, or illicit drugs); side effects of a chronic medication or other toxic agent (such as a chemical solvent, pesticide, or heavy metal); or other known or defined chronic pulmonary, cardiac, gastrointestinal, hepatic, renal, or hematologic disease.

Minor Criteria Symptom Criteria To fulfill a symptom criterion, a symptom must have begun at or after the time of onset of increased fatigability, and must have persisted or recurred over a period of at least 6 months (individual symptoms may or may not have occurred simultaneously). Symptoms include: 1. Mild fever - oral temperature between 37.5°C and 38.6°C, if measured by the patient - or chills. (Note: oral temperatures of greater than 38.6°C are less compatible with chronic fatigue syndrome and should prompt studies for other causes of illness.) 2. Sore throat. 3. Painful lymph nodes in the anterior or posterior cervical or axillary distribution. 4. Unexplained generalized muscle weakness. 5. Muscle discomfort or myalgia.

Specific laboratory tests or clinical measurements are not required to satisfy the definition of the chronic fatigue syndrome, but the recommended evaluation includes serial weight measurements (weight change of more than 10% in the absence of dieting suggests other diagnoses); serial morning and afternoon temperature measurements; complete blood count and differential; serum electrolytes; glucose; creatinine, blood urea nitrogen, calcium, phosphorus; total bilirubin, alkaline phosphatase, serum aspartate aminotransferase; serum alanine aminotransferase; creatine phosphokinase or aldolase, urinalysis; posteroanterior and lateral chest roentgenograms; detailed personal and family psychiatric history;

6. Prolonged (24 hours or greater) generalized fatigue after levels of exercise that would have been easily tolerated in the patient's premorbid state. 7. Generalized headaches (of a type, severity, or pattern that is different from headaches the patient may have had in the premorbid state). 8. Migratory arthralgia without joint swelling or redness. 9. Neuropsychologic complaints (one or more of the following: photophobia, transient visual scotomata, forgetfulness, excessive irritability, confusion, difficulty thinking, inability to concentrate, depression). 10

B. Hyde, MD

The Definitions of M.E. / CFS, A Review

10. Sleep disturbance (hypersomnia or insomnia).

2. Nonexudative pharyngitis.

11. Description of the main symptom complex as initially developing over a few hours to a few days (this is not a true symptom, but may be considered as equivalent to the above symptoms in meeting the requirements of the case definition).

3. Palpable or tender anterior or posterior cervical or axillary lymph nodes. (Note: lymph nodes greater than 2 cm in diameter suggest other causes. Further evaluation is warranted.) Acknowledgements: The authors thank Mrs. Josephine M. Lister for manuscript preparation.

Physical Criteria Physical criteria must be documented by a physician on at least two occasions, at least 1 month apart.

Requests for reprints should be addressed to Gary P. Holmes, M.D.; Division of Viral Diseases, Center for Infectious Diseases, Centers for Disease Control; Atlanta GA, 30333.

1. Low-grade fever - oral temperature between 37.6°C and 38.6°C or rectal temperature between 37.8°C and 38.8°C (See note under Symposium Criterion 1.)

References 1. Tom M, Morag A, Ravid Z, et al. Prolonged atypical illness associated with serological evidence of persistent Epstein-Barr virus infection. Lancet. 1982; 1:61-4.

4. Straus SE, Tobato G, Armstrong G, et al. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med. 1985:102:7-16.

2. DuBoisRE, Seeley JK, B r u s l , e t a l . Chronic mononucleosis syndrome. South Med J. 1984; 77:1376-82.

5. Merlin TL, Chronic Mononucleosis: pitfalls in the laboratory diagnosis. Hum Pathol. 1986:17:2-8.

3. Jones JF, Ray CG, Minnich LL, et al. Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies. Ann Intern Med. 1985:102:1-7.

6. Holmes GP, Kaplan JR, Stewart JA, Hunt B, Pimsey PF, Schonberger LB. A cluster of patients with a chronic mononucleosis-like syndrome: is Epstein-Barr virus the cause? JAMA. 1987:287:2297-2302. 7. Buchwald D, Sullivan JL, Komaroff AL. Frequency of "chronic active Epstein-Barr virus infection" in a general medical practice. JAMA. 1987:287:2303-7.

end of document

Comments on the above paper many illnesses by calling fatigue the primary characteristic, the authors necessitated the elimination of hundreds of other diseases. To truly follow the criteria set out by the CDC definition probably makes M.E./CFS the most expensive illness to investigate of any known disease. Fatigue is not an object, it is simply a modifier in search of a noun.

The first criticism of this paper is that it takes one symptom of disease, fatigue, and elevates it to an unrealistic importance. The first sentence states t h a t "The chronic E p s t e i n - B a r r syndrome is...characterized primarily by chronic or recurrent debilitating f a t i g u e . . Y e t the problem with fatigue is that it is neither specific, definable nor scientifically measurable. Fatigue is both a normal and a pathological feature of every day life. Every normal person gets fatigued. Fatigue is a common feature of much major psychiatric disease and major medical disease. Since fatigue is such an integral part of

Also, taking fatigue as the flagship symptom of a disease not only bestows the disease with a certain Rip Van Winkle humour, but it removes the urgency of the fact that the majority of M.E./CFS symptoms

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The Clinical and Scientific Basis of M.E. / CFS

Palpable or tender anterior or posterior cervical or axillary lymph nodes, (not to exceed 2 cm.) M.E./CFS: Patients suffer from cutaneous hypersensitivity, they tend to lose weight during the early months of disease making normal lymph nodes more apparent. I know of no M.E./CFS expert who would care to stake his reputation on his ability to distinguish any difference in the lymph nodes of 10 M.E./ CFS patients from those of 10 normal controls. These tender points more likely represent fibromyalgia points than sensitive lymph nodes.

are in effect CNS symptoms. Interestingly, CNS dysfunction was not part of the CDC exclusion list. Was this an oversight or were the authors suggesting that M.E./CFS was a CNS dysfunction? That would have made a lot of sense, since to most physical M.E./ CFS scientists and clinicians, M.E./CFS represents a major attack on the CNS by the chronic effects of a viral infection. This relationship of the systemic features of M.E./CFS to CNS dysfunctions are only beginning to be explored in this text. The second criticism is illustrated in the seven references all of which refer to Epstein-Barr and five of which refer back to the authors of the CDC paper. It is unusual in a scientific paper to attempt to prove one's points by primarily citing oneself. I mentioned earlier that there were many expert American M.E./ CFS clinicians and historians that were not called upon or referred to. Had they been heard, many of the following errors would have been avoided.

These three features are all important in infectious mononucleosis (glandular fever), a disease associated with EBV; they are not important in M.E./CFS. I can only wonder if these authors, all published in the field of this herpes virus, and with the help of their patients, all attempting to prove their illness, did not confuse the two illnesses of mononucleosis and M.E./CFS.

Low-grade fever: There may be fever in the first few days of the prodromal period but the predominant temperature abnormality is one primarily of subnormal and marked diurnal variability.

The third criticism is the exclusion of certain diseases. For example, thyroid dysfunction with an early increase of TSH, and ovarian- uterine dysfunction, both related to a primary possible hypothalamic injury are a real part of the inception or consequences of M.E./CFS and should not be excluded. To exclude certain patients with bladder, GIT, cardiac, pulmonary and certain other endocrine dysfunctions that have started after the M.E./CFS illness started, may be equivalent to removing some of the systemic side effects patients with this illness incur.

Non-exudative pharyngitis: There may be pharyngitis in the first few days of the prodromal period and patients complain of dryness and irritation of the pharynx but there is no publication on consistent cultured bacterial or viral pharyngitis beyond that generally found in a normal population.

The Oxford Guidelines This British paper was developed developed in Oxford England by 21 invited clinical and scientific researchers. Six other individuals were invited but did not attend. Of those present, eight were in psychiatry or psychology as was the Chair, Dr. Sharpe. Another six were research scientists. Non-psychiatric clinicians in attendance, who spend at least half of their working day with M.E./CFS patients were few. Reprinted with the kind permission of The Journal of the Royal Society of Medicine, MC Sharpe et al, A Report - Chronic Fatigue Syndrome: Guidelines for Research, JRSM Volume 84, February 1991, pp 118-121.

A Report Chronic Fatigue Syndrome: Guidelines for Research Keywords: chronic fatigue syndrome; research; definition

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The Definitions of M.E. / CFS, A Review

Authors Dr. M.C. Sharpe MRC Psych Clinical Lecturer, Department of Psychiatry, University of Oxford

Dr. VR Preedy PhD Research Biochemist, Department of Biochemistry, King's College Hospital, London

Dr. L.C. Archard PhD Senior Lecturer, Department of Biochemistry, Charing Cross and Westminster Medical School, London

Dr. AP Smith PhD Research Psychologist, Department of Psychology, University of Sussex Dr. DG Smith MB General Practitioner, Horndon-On- TheHill, Essex

Professor J.E. Banatvala MD Professor of Virology, Department of Virology , St. Thomas' Hospital Medical School, London

Dr. DJ Taylor DPhil MRC Staff Scientist, MRC Biochemical and Clinical Magnetic Resonance Unit, John Radcliffe Hospital, Oxford

Dr. L.K. Borysiewicz FRCP Wellcome Trust Senior Lecturer, Department of Medicine, University of Cambridge Professor A.W. Clare MD. Trinity College, Dublin

Dr. DAJ Tyrrell MD Director, MRC Common Cold Unit, Harvard Hospital, Salisbury

Clinical Professor of Psychiatry,

Dr. S Wessely MRCPsych Wellcome Training Fellow in Epidemiology, Institute of Psychiatry, London

Dr. A. David MRCPsych MRC Training Fellow, Institute of Psychiatry, London

Dr. PD White MRCPsych Senior Lecturer, Department of Psychological Medicine, St. Bartholomew's Hospital, London

Professor RHT Edwards FRCP Professor of Medicine, Department of Medicine, University of Liverpool

Other signatories who contributed to the guidelines but who were unable to attend the meeting

Dr. KEH Hawton DM Consultant Psychiatrist, Department of Psychiatry, University of Oxford

Professor PO Behan MD Professor of Neurology, Department of Neurology, University of Glasgow

Professor HP Lambert MD. Emeritus Professor of Microbial Disease , St. George's Hospital Medical School, London Dr. RJM Lane MD Consultant Neurologist, Regional Neurosciences Center, Charing Cross Hospital, London

Dr. F Clifford Rose FRCP Director, Academic Unit of Neuroscience, Charing Cross and Westminster Medical School, London

Dr. EM McDonald MRC Psych Research Psychiatrist, Institute of Psychiatry, London

Professor TJ Peters FRCP Professor of Clinical Biochemistry, Department of Biochemistry, King's College Hospital, London

Professor J F Mowbray FRCP Immunopathology, Department of Immunopathology, St. Mary's Hospital Medical School, London

Dr. PG Wallace MRCGP Head of Research Unit, Department of General Practice, St. Mary's Hospital Medical School, London

Dr. DJ Pearson FRCP Senior Lecturer, Department of Medicine, University of Manchester

Professor DA Warrell FRCP Professor of Tropical Medicine and Infectious Diseases, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford

Dr. TEA Peto MRCP Consultant Physician, Department of Infectious Diseases, John Radcliffe Hospital, Oxford

Dr. DJM Wright MD Consultant Microbiologist, Department of Microbiology, Charing Cross Hospital, London

Introduction The principal lack of agreement concerns definition of the clinical syndrome to be studied. A number of clinical syndromes have been described, all apparently referring to similar groups of patients, but differing sufficiently to preclude comparison of published studies. The various names used include epidemic neuromyasthenia 1 , idiopathic chronic fatigue and myalgia syndrome 2 , benign myalgic encephalomyelitis 3 , chronic infectious mononucleosis4, Royal Free disease5, postviral fatigue syndrome 6 , fibrositisfibromyalgia7'8, and chronic fatigue syndrome 9 .

Patients who present with a principal complaint of disabling fatigue of uncertain cause have received much attention in recent years. Correspondingly there has been an increasing amount of research into this problem. The findings have however often been contradictory. Resolution of these contradictions depends on the ability to compare research studies, but such constructive comparison has rarely been possible. This is largely because research has been carried out by investigators trained in different disciplines, using different criteria to define the condition. Whilst such an eclectic approach is to be welcomed, agreement on case definition, and assessment methods is necessary if progress is to be made.

An attempt to address the problem of case definition was made by Holmes and colleagues in 19889, who

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The Clinical and Scientific Basis of M.E. / CFS

The Guidelines

chose the name chronic fatigue syndrome (CFS) because it is descriptive and free from unproven etiological implications. They also proposed an operational definition for the syndrome. Although a welcome advance, this definition proved to be unsatisfactory in practice. 1011 Other definitions e.g. by Lloyd and colleagues12 are also unsatisfactory 13 , and have not been widely accepted.

The following guidelines were agreed. Symptoms A preliminary research glossary is appended. This comprises definitions for symptoms and suggestions for their description. Signs There are no clinical signs characteristic of the condition, but patients should be fully examined, and the presence or absence of signs reported.

Additional sources of difficulty have arisen from inadequate and poorly described sampling procedures, choice of comparison groups, shortcomings in study design and measures of poor or unspecified reliability.14

Syndromes

In an attempt to remove these obstacles to progress, a meeting of research workers with a known interest in the field was convened. The format of the meeting was modelled on the MRC (Medical Research Council) workshop on Alzheimer's disease.15

Two broad syndromes can be defined: Chronic fatigue syndrome (CFS) (a) A syndrome characterized by fatigue as the principal symptom.

Aims

(b) A syndrome of definite onset that is not life long.

The aim of the meeting was to seek agreement amongst research workers on recommendations for the conduct and reporting of future studies of patients with chronic fatigue. Specifically we set out to agree on which patients should be included, how such studies should be approached, and on the minimal data that should be reported.

(c) The fatigue is severe, disabling, and affects physical and mental functioning. (d) The symptom of fatigue should have been present for a minimum of 6 months during which it was present for more than 50% of the time. (e) Other symptoms may be present, particularly myalgia, mood and sleep disturbances.

Procedure The meeting (attended by all those listed at the beginning of the paper) was held at Green College, Oxford, on 23 March 1990, and chaired by Professor Anthony Clare. It was restricted to invited research workers, all of whom had studied patients with CFS. The disciplines represented included biochemistry, general medicine, general practice, imaging, immunology, infectious diseases, microbiology, neurology, physiology, psychiatry, and psychology.

(f) Certain patients should be excluded from the definition. They include: (i) Patients with established medical conditions known to produce chronic fatigue (e.g. severe anaemia). Such patients should be excluded whether the medical condition is diagnosed at the presentation or only subsequently. All patients should have a history and physical examination performed by a competent physician.

Before the meeting all participants (and several others who were unable to attend) were circulated with a questionnaire, and their responses were used to draw up an initial discussion document which formed the basis of discussion during the meeting. Points on which agreement was reached were recorded and a draft ofthis paper circulated to participants.

(ii) Patients with a current diagnosis of schizophrenia, manic depressive illness, substance abuse, eating disorder or proven organic brain disease. Other psychiatric disorders (including depressive illness, anxiety disorders and hyperventilation syndrome) are not necessarily reasons for exclusion.

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The Definitions of M.E. / CFS, A Review

Post-infectious fatigue syndrome (PIFS)

Study design

This is a subtype of CFS which either follows an infection or is associated with a current infection (although whether such associated infection is of aetiological significance is a topic for research).

The design of studies must be chosen with regard to the hypothesis being tested. Both cross-sectional and longitudinal designs may be useful; the former to establish associations, and the latter to demonstrate temporal sequence (eg of infection and symptoms).

To meet research criteria for PIFS patients must (i) fulfil criteria for CFS as defined above , and (ii) should also fulfil the following additional criteria: (a) There is definite evidence of infection at onset or presentation (a patient's self-report is unlikely to be sufficiently reliable). (b) The syndrome is present for a minimum of 6 months after onset of infection. (c) The infection has been corroborated by laboratory evidence.

Longitudinal single case designs that examine correlations of relevant variables with fluctuations in symptom severity may be useful. Measurements All measures (both clinical and laboratory based) should be reliable, valid and reproducible between centres. Reliable measures of subjective fatigue and of disability are lacking and require development. When reporting studies the reliability of all measures should be assessed and specified whenever possible.

In reporting studies it should be clearly stated which of these two syndromes is being studied. The degree of disability should be measured and stated. The criteria and method used to exclude subjects from study must be clearly described and the degree of examination and investigation specified. All patients should be assessed for associated psychiatric disorder and the results of this assessment reported.

Glossary This glossary provides provisional definitions of the principal symptoms and suggests how they may be described. Each symptom is considered as follows:

Sampling

(i) A description of the symptom (what it is). (ii) What it is to be distinguished from (what it is not). (iii) Criteria for rating its presence. (iv) Additional description.

The way in which the patient sample was obtained should be clearly described. In particular it is essential to know whether the sample was recruited from primary care or from secondary referral centres. Because of the risk of introducing bias at this stage the use of random samples or consecutive referrals is preferred.

Fatigue (i) When used to describe a symptom this is a subjective sensation and has a number of synonyms including, tiredness and weariness. A clear description of the relationship of fatigue to activity is preferred to the term fatiguability. Two aspects of fatigue are commonly reported: mental and physical. Mental fatigue is a subjective sensation characterized by lack of motivation and of alertness. Physical fatigue is felt as a lack of energy or strength and is often felt in the muscles.

Comparison Groups The term comparison group is preferred to control group. The precise choice of comparison groups should be determined by the hypothesis being tested. In the current state of knowledge multiple comparison groups may be required as there are pitfalls in the sole use of 'healthy' or 'normal' selected controls. Suggested comparison groups include patients with neuromuscular disorder, patients with conditions causing inactivity, and patients with depressive disorder. The method used to obtain the comparison group should be clearly specified.

(ii) Fatigue as a symptom should be distinguished from low mood and from lack of interest. The symptom of fatigue should not be confused with impair-

15

The Clinical and Scientific Basis of M.E. / CFS

ment of performance as measured by physiological or psychological testing. The physiological definition of fatigue is of a failure to sustain muscle force or power output. (iii) To be regarded as a symptom, fatigue must: (a) be complained of; (b) significantly affect the person's functioning; (c) should be disproportionate to exertion; (d) should represent a clear change from a previous state; and (e) be persistent or, if intermittent, should be present more than 50% of the time. (iv) The symptom should be described as follows: (a) severity: mild, moderate, or severe; (b) frequency: continuous or intermittent. If intermittent the proportion of the time present; (c) relation to activity: it should be stated whether the fatigue is greatly increased by minor exertion and whether it occurs at rest. Disability (i) This refers to any restriction of lack (resulting from loss of psychological or physiological function) of ability to perform an activity in the manner or within the range considered normal for a human being (i.e. things people cannot do in the areas of occupational, social, and leisure activities because of their illness16).

(iii) To be regarded as a symptom the mood disturbance should be (a) complained of; (b) should represent a significant change from a previous state; and (c) should be relatively persistent or recurrent. Judgements of the appropriateness of mood disturbance are unreliable and should be avoided. (iv) The symptoms should be described as follows: (a) type: depressed mood, anhedonia, anxious mood, emotional lability, irritability; (b) severity: standard scales are available to assess the severity of depressed mood and anxiety. In addition it should be determined whether the patient's disorder is sufficient to meet operational diagnostic criteria for major depressive disorder, generalized anxiety disorder or panic disorder according to a recognized psychiatric classification, e.g. the current edition of the Diagnostic and Statistical Manual of the American Psychiatric Association, DSM-III-R 17 ; (c) duration and frequency of the mood disturbance should be reported. Myalgia (i) This refers to the symptom of pain or aching, felt in the muscles. (ii) It should be distinguished from feelings of weakness and from pain felt in other areas such as joints.

(ii) Disability (e.g. inability to walk) should be distinguished from impairment of function (e.g. weak legs) and from handicap (e.g. unable to work).

(iii) The myalgia should be (a) complained of; (b) be disproportionate to exertion; (c) be a change from a previous state; (d) should be persistent or recurrent.

(iii) There should be a definite and persistent change from a previous level of functioning and it is desirable to seek supportive evidence from an informant.

(b) degree of disability.

(iv) The symptom should be described as follows: (a) severity: mild, moderate, or severe; (b) frequency and duration; (c) relation to exertion: if after exertion the time of onset relative to the exertion and duration should be described.

Mood

Sleep

(iv) The disability should be described as follows: (a) area of disability (i.e. occupational, social, leisure, self-care);

disturbance

(i) The term mood disturbance has been used to include depression, loss of interest and loss of pleasure (anhedonia), anxiety, emotional lability and irritability.

disturbance

(i) The symptom of sleep disturbance refers to a subjective report of a change in the duration or quality of sleep. (ii) Sleep disturbance should be distinguished from feelings of daytime fatigue or tiredness. (iii) The sleep disturbance should

(ii) These phenomena should be distinguished from each other.

16

B. Hyde, MD

The Definitions of M.E. / CFS, A Review

(iii) The criteria for rating its presence.

(a) be complained of; (b) not simply be a response to external disturbance; (c) be a change from a previous state; (d) be persistent.

(iv) Additional information, e.g. severity. Conclusions

(iv) The symptom should be described as follows: (a) type: hypersomnia or increased sleep; insomnia or reduced sleep (which should be further described as either difficulty getting off to sleep, early waking, or subjectively disturbed or unrefreshing sleep); (b) severity: the amount of change in duration of sleep should be quantified in hours. Other

The contributors hope that these guidelines will provide a basis for fruitful research studies, and for inter-disciplinary collaboration essential to this field of research. The guidelines are preliminary and will undoubtedly require further refinement and revision. The authors would welcome comments and suggestions.

symptoms M C Sharpe University Department of Psychiatry Warneford Hospital, Oxford 0X3 7JX

Many other symptoms may be present and should be recorded as follows: (i) The definition used.

Acknowledgments: The convenors wish to thank all the participants and Professor Anthony Clare for his chairmanship. They also wish to thank Duphar Pharmaceuticals, Dr. Peter White and Professor Michael Gelder, for financial support.

(ii) Symptoms should be carefully distinguished from one another.

References 9. Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome a working case definition. Ann Intern Med 1988; 108:387-9.

1. Henderson DA, Shelokov A. Epidemic neuromyastheniaclinical syndrome? N Engl J Med 1959;260:757-64. 2. Byrne E. Idiopathic chronic fatigue and myalgia syndrome (myalgic encephalomyelitis); some thoughts on nomenclature and aetiology. Med J Aust 1988;148:18-82.

10. Manu P, Lane TJ, Matthews DA. The frequency of the chronic fatigue syndrome in patients with symptoms of persistent fatigue. Ann Intern Med 1988; 109:554-6.

3. Galpine JF, Brady C. Benign myalgic encephalomyelitis. Lancet 1957;757-8.

11. Komaroff A, Geiger A. Does the CDC working case definition of chronic fatigue syndrome (CFS) identify a distinct group? Clin Res 1989; 37:778A.

4. Isaacs R. Chronic Infectious mononucleosis, Blood 1948;3:858-61.

12. Lloyd AR, Wakefield A, Boughton C, Dwyer J. What is myalgic encephalomyelitis? Lancet 1988;i:1286-7.

5. The medical staff of the Royal Free Hospital. An outbreak of encephalomyelitis in the Royal Free Hospital Group London, in 1955. BMJ 1957;2:895-904.

13. David A, Wessely S, Pelosi A. Myalgic encephalomyelitis or what? Lancet 1988;ii:100-l.

6. BehanPO. Behan WMH, Bell EJ. The postviral fatigue syndrome- an analysis of the findings in 50 cases. J Infect 1985;10:211-22.

14. David A, Wessely S, Pelosi A. Post viral fatigue: time for a new approach. BMJ 1988;296:696-8. 15. Wilcock GK, Hope RA, Brooks DN, et al. Recommended minimum data to be collected in research studies on Alzheimer's disease. J Neurol Neurosurg Psychiatry 1989;52:693-700.

7. Pritchard C. Fibrositis and the chronic fatigue syndrome. Ann Intern Med 1988; 106:906. 8. YunusMB. Fibromyalgia syndrome: new research on an old malady. BMJ 1989; 298:474-5.

17

The Clinical and Scientific Basis of M.E. / CFS

16. World Health Organization. International classification of impairments, disabilities and handicaps. Geneva: WHO, 1980.

17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, revised 3rd edn. Washington DC: APA, 1987.

end of document

Comments This Oxford paper appears to me to serve a single purpose and that is to introduce the term, post-infectious fatigue syndrome as an acceptable term under which to publish. The term chronic EpsteinBarr disease was rarely used in the United Kingdom and in general they still tend to disdain the "Americanism" Chronic Fatigue Syndrome. In attempting to both rubber-stamp and clarify the term CFS they simply added confusion to the already too complicated CDC definition. It is my opinion that their definition shows no new insight into the disease process. The authors state that the syndrome is not lifelong. There is no evidence or basis for such a categorical statement. We have seen ample evidence of lifelong CNS dysfunction in M.E./CFS.

to work as a vociferous lobbyist for the unsupported position that CFS patients get better if you tell them that nothing is wrong with them. Behan Definition Please see Chapter 22, Post-Viral Fatigue Syndrome Research in Glasgow. Conclusion It is a tragedy that clinicians and scientists who spend the majority of their time studying M.E./CFS patients have not put together a short, usable working definition with subgroups. These would include: (1) a short working definition for researchers and clinicians

Reviewing the many eminent physicians present at this workshop, it is my observation that it includes only two medical participants who routinely may spent up to 50% or more, of their time, investigating M.E./CFS patients.

complemented by: (2) a definition relating to children and adolescents, (3) an inexpensive epidemiological definition.

Since this definition has appeared, the Behan group in Glasgow, certainly the most productive, the best financed and most important M.E./CFS clinical and research group in the U.K., has only published under the term PVFS or post-viral fatigue syndrome, yet another name.

Until we have a better understanding of the infectious etiology and the pathophysiology of M.E./CFS or a resolute marker, a perfect definition will elude even the most knowledgable. In the meanwhile, it is clear that if CNS dysfunction were utilized as the primary feature of the disease, the list of disease exclusions would be considerably and economically shortened. It is hard to avoid the fact, that the majority of symptoms given in each and every one of these definitions, Wallis, HendersonShelokov, CDC and Oxford, lean heavily on CNS dysfunction or CNS symptoms as the primary system involved.

The National Institute of Health Definition The NIH definition update workshop held in the Spring of 1990 has yet to be published. Certainly improvements have been made in the CDC definition at this workshop. However, those that organized this meeting appear to have made a deliberate attempt to avoid inviting any American scientists who engaged in neuropsychological or physiological brain mapping and evaluation of M.E./CFS patients. A disproportionate part of that meeting was taken up by one physician, who in my recollection, appeared

M.E./CFS is a systemic disease with many systemic features, but it is characterized primarily by CNS dysfunction, of which fatigue is only one of many components.

18

B. Chabursky, B. Hyde, MD, A. Jain, MD

A Description of Patients who Present with a Presumed Diagnosis of M.E. / CFS

Chapter 3

Borys Chabursky with Dr. Daniel Peterson

A Description of Patients w h o Present w i t h a Presumed Diagnosis of M.E./CFS Borys Chabursky, Byron Hyde, MD, Anil Jain, MD Borys Chabursky is a student at the University of Toronto. He is in the third year of a four year undergraduate specialist programme in Pharmacology and Toxicology. He has worked for the Nightingale Research Foundation as the National Director of Fund Raising and is a member of the media relations team for the National Society for Fund Raising Executives, Toronto chapter. He has also done research work with Dr. Hyde in Ottawa, Dr. Ryll in Sacramento and Dr. Mildon in Toronto. He has published in the CFIDS journal. Additionally, Borys worked for several pharmacies doing marketing, public relations and business development. (Please see Chapter 5 for Dr. Hyde's photograph and curriculum vitae. Please see Chapter 4 for Dr. Jain's photograph and curriculum vitae.)

Since 1985, we have collectively seen and examined over 6,000patients who have arrived at The Nightingale Research Foundation, either self -diagnosed or referred as possible M.E./CFS patients. The following represents some ofour observations concerning individuals who may or may not actually suffer from M.E. / CFS. (2) a chronic disease process involving a low-grade encephalopathy resulting from either a persistence of the viral infection or the chronic metabolic effects of the initial destabilizing infection. This process may be the result of one or more infectious agents and involves a primary or secondary immune dysfunction.

It is our belief that M.E./CFS may represent two superimposed disease processes: (D a dynamic disease process involving a postencephalitic viral provoked injury followed by a variable recovery process. It is those patients that do not recover to their previous or adequate level of function that we come to know as suffering from chronic M.E. /CFS disease.

It is also our belief that M.E./CFS represents a major acquired CNS dysfunction in which the brain func19

The Clinical and Scientific Basis of M.E. / CFS

tion undergoes a metabolic alteration. We believe that the CNS is diffusely injured at several levels and that these areas include the cortex, the limbic system, the basal ganglia, the hypothalamus and areas of the spinal cord and its appendages. This persisting multilevel CNS dysfunction defines the nature of the disease process. Most physicians first see M.E./CFS patients once they have become chronic and their disease process relatively static. Although the diversity and extreme nature of the dysfunctions tends to decrease once the patient's disease is chronic, the ongoing disabling features may be sufficient to create persisting major work and school disability.

This short summary gives us a checklist of academic attainment, loss of schooling, geographical changes and major illnesses, major family illnesses, immunizations, school and work record. The summary provides us with a useful clothes horse to act as a frame for more precise questions. We also ask for the patient's report cards and work record to assess both lost schooling and academic achievement. The report card often gives a better social and medical understanding than physicians' records. We place great store in the history of the patient from birth. When we look at the history of the disease we are interested in the type of onset, the environment of the onset of illness and how the disease process unfolds.

Techniques of History Taking One of the first questions that we ask a prospective M.E./CFS patient is: How did your illness begin? and frequently the patient replies, "with a flu-like illness". If you ask the patients what they mean by a flu-like illness, a multitude of descriptions ensue. It is the symptom picture that we wish to discover rather than a name that in itself can suggest different diseases to different people.

Although we, as many physicians, have difficulty with the CDC definition guidelines 1 , all physicians should have a CDC checklist as well as their own. The patient's profile should be checked off to conform with legal requirements. Discussion of these findings

We also ask the patient to supply us with a typed, year by year summary of major life events from birth to the present time. Since many M.E./CFS patients will reply with dozens, sometimes hundreds of pages of history, we ask them to limit the description for each year from one to three sentences.

It is most unusual for an acutely ill patient to approach us in an attempt to fraudulently seek compensation. On the contrary, most of these patients want an instant magic pill so that they can return to work immediately and are not happy when we do not have that magic potion. Fraud is not likely to be missed if the physician is knowledgeable of the patient and of

D i s e a s e s M a s q u e r a d i n g a s M.E./CFS We have discovered in those patients who present at our office with a possible diagnosis of M.E./CFS, that the morbidity of perhaps as many as 25% may arise from one of the following illnesses: Multiple Sclerosis Rheumatoid illness or lupus (SLE) Thyroid illness Sarcoma Renal or Liver Localized and Metastatic malignancies disease Brain tumours, including astrocytomas, gliomas Infectious illnesses including: Transverse Myelitis Toxoplasmosis Myopathic illnesses, including: AIDS myasthenia gravis Lyme Disease (Borrellia burgdorferi) mitochondrial myopathies Tuberculosis post-infectious polymyositis Brucellosis Vitamin B 12 Deficiency Disorders Various psychiatric and social-psychiatric states including: Pernicious aenemia Anxiety neurosis Vegetarianism and intentional dietary deprivation Uncomplicated Endogenous or Reactive Depression Intestinal disease associated with or independent of M.E./CFS Psychopathic Personality Disorder Schizophrenia and other psychiatric disease.

20

B. Chabursky, B. Hyde, MD, A. Jain, MD

A Description of Patients who Present with a Presumed Diagnosis of M.E. / CFS

the disease process. Almost all acutely ill adult patients suffer from work related deprivation anxiety. In chronically ill patients, other factors come into play. We have had a small but interesting group of HIV positive patients who do not tell us they are HIV positive and may be even delusional, insisting that they have M.E./CFS. They are often phobic and then never return when told they are HIV positive. All patients should be checked for HIV and questioned as to sexual activity and intravenous drug use. All patients presenting with M.E./CFS who fit into the guidelines should have the immediate benefit of a MRI. In areas of state supported medicine, this may at times represent a difficulty. These MRI tests should be ordered with specific understanding of localization of M.S., M.E./CFS UBOs (unidentified bright objects) and other space occupying lesions. This may save a later legal action against the attending physician and may, in a few cases, result in the discovery of a treatable lesion.

Few patients with M.E./CFS present or continue as chronic depression. Despite this, we do diagnose severe depression in this group and have investigated patients who have succeeded in committing suicide. We almost always refer the few patients with severe depression for psychiatric assistance. These may be the only M.E./CFS patients that psychiatrists ever see, supporting the belief held by some psychiatrists that M.E./CFS is essentially a depressive illness. As many as 20% of all women with typical chronic M.E./CFS illness will eventually develop thyroid abnormalities. Thyroid disease is not necessarily an exclusion of M.E./CFS. M.E./CFS or M.E./CFS-like illnesses The British and others utilize the name Post-Viral Fatigue Syndrome because, among other reasons, they believe the American term, Chronic Fatigue Syndrome, is too open to misinterpretation. However, it is not just the American name but the definition that may be too unfocused.

CT scans are definitely not useful for M.E./CFS patients and sometimes serve little purpose for M.S. patients. If anything, CT scans play a negative role in the investigation of an M.E./CFS patient, since, once the physician finds that it is normal, there is a tendency to tell the patient there is nothing wrong with the brain. The treating physician, as well as the radiologist, should learn to read the MRI.

The name Post-Viral Fatigue Syndrome would suggest that the triggering illness is the cause of the disease process. That may not be the case. M.E./CFS can start acutely or insidiously, but, when it starts acutely after an observed triggering infection, it is much easier to diagnose. But the reason that the Acute Onset form is easier to diagnose is not due to the infectious start but rather the explosive symptoms that are more often observed following an Acute Onset form.

MRI lesions, called UBO's can often be found in M.E./ CFS patients, particularly in the first year of illness. These lesions may be mistaken for early M.S. They are only rarely larger than 1 cm in length and less in width. 2 M.E. patients may also have oligoclonal banding 3 in the spinal fluid in the first six months and thus be misdiagnosed as M.S.

Nor are Acute and Insidious Onset M.E. / CFS necessarily different diseases. Frequently, in one family an Acute Onset and an Insidious Onset will occur within the same time frame. At times, a patient with an earlier Acute Onset appears to trigger an insidious onset in a new contact.

M.E./CFS patients maybe misdiagnosed as suffering from rheumatoid disease. This is particularly true in children. The knees, ankles and elbows may be dramatically swollen but are not red or hot or internally ankylosed. A typical M.E./CFS patient will have a classical lupus rash in the submaxillary region, considerable pain and often be incorrectly diagnosed as "a rheumatoid waiting to happen". Frequently the sedimentation rate is 0-5 in this group, unusual for a true rheumatoid.

We recognize several clinical entities within the collectivity of these terms, all obscured by these general diagnostic names. They are as follows: (1) Acute Onset M.E./CFS is characterized by brain and physical dysfunction, immediately after:

21

The Clinical and Scientific Basis of M.E. / CFS

(a) an apparent infectious triggering agent,

This form of M.E. /CFS is often incomplete. The onset symptoms are frequently less dramatic and fewer in number than an Acute Onset Type. They tend to resemble the chronic pattern seen one or more years after the start of an Acute Onset M.E./CFS.

(b) an infectious disease in close family member or partner, (c) a specific immunization(s), or transfusion(s), (d) a traumatic incident, eg: automobile accident, surgery.

In this group, by definition, an infectious triggering episode is never discovered. Not infrequently, other family members may have or have had M.E./CFS. A detailed history reveals that they frequently have had previous similar episodes that they omitted to discuss. They may well represent recurrent bouts of a previous acute onset illness that started in early childhood and is not remembered. A detailed life history, as noted above, is important to document in this group.

The Acute Onset Group can frequently tell you the hour, day and year when the illness started. The onset is frequently dramatic and they can usually be diagnosed within two weeks of the onset of their illness. The Acute Onset Group frequently contains a subgroup that may represent a significantly delayed reaction and is as follows: (2) D e l a y e d Acute Onset M.E./CFS

This large insidious group has been poorly investigated and rarely appears in the literature.

There is no difference from the Acute Onset M.E./ CFS in its characteristics, however, M.E./CFS follows:

(4) P u r e F a t i g u e S y n d r o m e without any evidence of brain or physical dysfunction, depression or other psychiatric disturbance.

(a) Mononucleosis-Like Illness: Six months to two years earlier, an infectious mononucleosis-like illness occurred that may have persisted with marked prostration for two or more months followed by a complete clinical recovery.

This fourth group of Pure Fatigue Syndrome is quite curious and appear regularly. They are not M.E./ CFS. The patient arrives in our office with the following complaint. "Doctor, I am tired all of the time. I am tired when I wake up. I am tired when I run my 5 or 10 or 20 miles everyday. I don't have any appreciable muscle pain or cognitive problem but just this fatigue."

(b) Encephalitis: Six months to two years earlier, an encephalitic illness occurred, severe in nature but of very short duration, usually less than one week of prostration, followed by a complete clinical remission without any persisting sequellae.

This group tends to have no obvious psychiatric history. They tend to have active full-time jobs. They tend to have normal family lives. They tend to be fairly positive persons, anxious and concerned with their job and health. The few that have been tested by SPECT have normal brain imaging. We don't know what to make of this patient group.

(c) Subclinical Poliomyelitis: Many years earlier, when in childhood, the individual had a parent, sibling or close contact who had paralytic poliomyelitis. The M.E./CFS patient never demonstrated any poliomyelitis-like illness. This Delayed Acute Onset Group may be the same group as the post-polio patients but who had suffered a subclinical case of poliomyelitis. Up to one third of adult M.E./CFS patients may fit into this group.

Although it is most rare to find any pathology in this group, they should not be treated in a cavalier manner since they may represent a single area brain lesion. One such patient that we investigated fell into this group. He was referred to a neurologist who sent the patient home telling him that he simply suffered from depression. He was not depressed. However, the patient died of a brain tumour two years later.

(3) Insidious Onset M.E./CFS This group tends to slowly ease themselves into the spectrum of M.E./CFS illness. Clinically they are difficult to diagnose when not associated with an epidemic.

22

B. Chabursky, B. Hyde, MD, A. Jain, MD

A Description of Patients who Present with a Presumed Diagnosis of M.E. / CFS

(5) Pure Muscle or Fibromyalgia Illness with pain and fatigue but without any evidence of brain exhaustion or dysfunction, depression or psychiatric disturbance. A recent symposium on CFS at the NIH in 19914, concluded that Fibromyalgia was a symptom of several disease processes, and that Fibromyalgia Syndrome was a synonym for CFS. We believe there is a third process of pure Fibromyalgia Illness without any other apparent attached disease process. This group must be distinguished from Fibromyalgia Syndrome, that is simply a synonym for M.E./CFS. It must be this group, the Pure Muscle or Fibromyalgia Illness Group, that recover w h e n exercised. In our experience, exercising M.E./CFS or Fibromyalgia Syndrome patients results in an increasing disability of both cognitive and muscular strength.

siderably disabled for an extended period of time, sometimes in excess of two years. They have, after considerable difficulty, justifiably obtained disability insurance, but now are partially or, in a few cases, completely recovered. This fairly large subgroup has certain common characteristics. They have largely lost self-confidence both as to their intellectual and physical capacities. Most of these individuals have, in the past, improved and returned to work or school only to fall ill again with a recurrence of their disease process. Now, seemingly recovered, they wish to return to work but they are frightened to lose their hard-earned disability pension, fall ill again and be left both disabled and without any income. The Employer's Perspective: Often their employer does not want them back.

(6) Post-Varicella i n d u c e d B r a i n D y s f u n c t i o n They have been replaced with another employee who is adequately filling their old job and who can be depended upon.

Varicella (chicken pox) is well-known as a cause of brain and systemic injury in prenatal and very early childhood, giving rise to deafness, and other sensory and cardiac defects. Varicella can cause up to 19% death rate in adults over the age of 20s or persisting major central nervous and systemic illness in adults. This process should be distinguished from M.E./CFS. To our knowledge, no one has studied and published the post-encephalitic brain injuries in this group of individuals using QEEG, SPECT and PET scanning techniques. Post-Varicella brain and muscle dysfunction, as well as post Herpes Zoster fatigue syndrome, should not be confused with the M.E./CFS group since they probably represent a specific postencephalitic brain and cellular injury. It cannot be concluded that their brain and muscle defects are the same as those of M.E./CFS patients.

The employer is very concerned that the patient is contagious. Concerned that the illness is of a psychiatric nature, the employer is frightened and apprehensive about psychiatric patients and possible emotional confrontation. Often this group may have been excellent and productive workers, but, having fallen ill with M.E./ CFS, attempted to continue to work with disastrous consequences to the employer and employee. The excellent work is forgotten and the irregular work pattern and productivity are remembered. The employer is concerned about legal repercussions, filling out forms, accident policies and the views of other employees.

(7) Post-Hepatitis B Fatigue Syndromes

Some employers rehire these M.E./CFS patients simply to fire them, and thus prevent any loss of costeffective company insurance package.

This is a separate disease entity and should not be included as part of M.E./CFS. (8) Post-Recovery M.E./CFS Group

Many of these patients feel that they are strong enough to return to part-time jobs but, if they do, they

This group have definitely suffered a moderate or severe case of typical M.E./CFS, and have been con-

23

The Clinical and Scientific Basis of M.E. / CFS

They represent a major problem for disability insurance and the government employment offices to solve. However, there is little chance of immediate help from either Government or insurance companies since both have been studiously blind to the reality of M.E./CFS. Physicians, insurance companies and governments have been largely inept in dealing with this sociological work crisis. Why then should an employer take in a potential problem?

will not qualify for long-term disability insurance benefits and they will, in addition, lose their previous insurance benefits or access to them thus losing all access to a disability net. Summary We are concerned about the delayed group that may represent a significant number ofM.E./CFS patients. Do these cases represent an earlier infection that provokes a chronic immune injury? This could set the individual up for the triggering infection that will eventually result in M.E./CFS.

It is obvious that the prospective diagnosis of M.E./ CFS attracts many individuals who are ill and undiagnosed. In the course of our study ofM.E./CFS we have seen innumerable very disabled children with rheumatoid disease and others with disease resembling Encephalitica Lethargica. Because they do not conform to clear-cut diagnostic criteria they have been abandoned in their wheel chairs and forgotten in their homes. To abandon our jurisdiction is neither what physicians were trained to do nor what governments were elected to do.

We are very concerned that some of these M.E./CFS patients may harbour an insidious malignancy. We have seen this occur infrequently but often with disastrous results. Even when a patient has a confirmed diagnosis ofM.E./CFS, re-evaluation should be an annual event to rule out such eventualities. We are concerned with the Post-Recovery Group.

References 4. Schluederberg A. Workshop on the Definition and Medical Outcome Assessment of CFS in Research,. National Institute of Allergy and Infectious Diseases, Bethesda, March 18-19, 1991.

1. Holmes G., Kaplan J., Gantz N. et al. Chronic fatigue syndrome; A working case definition. Annals of Internal Medicine, 108, 387-389. 2. Biddle R. See chapter 48 this text.

5. Gordon JE. Chicken pox: An epidemiological review. Am. J. Med Sci 1962; 244: 362-389

3. Poser C. See chapter 43 this text.

24

B. Hyde, MD, Sheila Bastien, PhD, A. Jain, MD

Post-Infectious, Acute Onset M.E. / CFS, General

Information

Chapter 4

Anil Jain

General Information Post-Infectious, Acute Onset M.E./CFS (Post-Viral Fatigue Syndrome) Byron Hyde, MD, Sheila Bastien, PhD, Anil Jain, MD Dr. Jain received his Bachelor of Sciences from the University of Ottawa. Subsequently, he graduated in Medicine from the Faculty of Medicine, University of Ottawa in 1985. He then completed his internship from the Ottawa General Hospital. Following this, he worked in Family Practice and in the emergency department at the Springdale Hospital in Springdale, Nfld., Canada for two years. Over the last four years, Dr. Jain has dedicated the majority of his practice for diagnostic evaluation and treatment of thousands of patients suffering from M.E. / CFS in North America. He is presently the clinical Director of the Nightingale Research Foundation (Canada) on M.E. (Please see Chapter 5 for Dr. Hyde's photograph and curriculum vitae. Please see Chapter 51 for Dr. Bastien's photograph and curriculum vitae.) In the previous chapter we discussed several of the non-psychiatric disabling syndromes that we have encountered at The Nightingale Research Foundation. This chapter reviews the general information concerning Acute Onset M.E. / CFS and, in particular, the form that is triggered or caused by an apparent infectious illness. This is the same entity as Post-Viral Fatigue Syndrome. As explained in the previous chapter, this is an arbitrary clinical classification based upon the form of onset. This arbitrary classification has been made by researchers in order to narrow the disease range down to a manageable and similar group. i.e. at the Initial Stage, and some appear to skip this early period and fall ill at the level resembling the Early Chronic Stage where there is a blunting or obscurity of many of the symptoms but not necessarily of the disability.

Using the type of onset, i.e. Post-Viral Fatigue Syndrome1 as a defining technique, is a far from perfect way to subdivide the various forms of M.E ./CFS. If we define the disease by symptom picture, some patients seem to start at the beginning of this process,

25

The Clinical and Scientific Basis of M.E. / CFS

ery or rebound to the previous decreased level of function.

M.E. / CFS Stages (1) Initial Stage (2) Recuperation Stage

(3) Early Chronic Stage (4) Late Chronic Stage

(3) Neuropsychological and reactive psychiatric changes.

Clinically, there are three forms of this disease. The first is a complete form where the patient runs through the four stages, starting at the Initial Stage. This is the pattern one sees regularly with PostInfectious, Acute Onset M.E./CFS. It is relatively easy to diagnose and does not require a waiting period of 6 months. 2 The second is the Insidious Onset M.E./CFS that usually starts with the blunted symptom picture seen in the Chronic Stages and thus represents a more clinically difficult diagnosis. To make matters worse, as in all diseases, the entire symptom picture is not always present in any one patient, thus making the clinical diagnosis of incomplete forms difficult or clinically impossible to diagnose. A similar problem exists in the diagnosis of rheumatoid disease processes.

Post Infectious, Acute Onset M.E./CFS Post-Viral Fatigue

Variable expression of the above disease pattern exist, are common, and can be explained by injury to different functional areas of the central nervous system. The most common incomplete expression is the non-myalgic form. This symptom variability is quite comprehensible if the physician realizes that M.E./CFS, like paralytic poliomyelitis, can injure certain areas of the CNS while missing others.

Incubation Period 1 The incubation period has been well documented in various epidemics 1 and also in some of the more recent sporadic cases of M.E. /CFS. The documented incubation period of the triggering disease is probably about 5-6 days, but varies from 4 to 154,5,6,7,8,9 days. However, the role of the triggering infection is not understood. Are we measuring the incubation period of the triggering disease or of the actual M.E./ CFS disease. Are they the same or different diseases?

Syndrome.

Known Incubation Period of M.E./CFS. This chronic disease process is characterized by the acute onset of:

1934 Los Angeles* 1948 Akureyri epidemic* 1955 Royal Free epidemic* 1955 Cumberland epidemic 1955 Massachusetts epidemic 1965 Texas epidemic** 1984 Labour Day Montreal cluster* 1984 Ontario cluster

(1) Obvious central nervous system (CNS) and muscle dysfunction accompanied by a plethora of strange, frightening and unstable symptoms. The CNS symptoms and dysfunctions include: cognitive sensory sleep motor and frequently pain dysfunction.

4-7 days4 5-10 days5 5-6 days6 5-7days7 5 days8 21 days9 7-10 days10 5 days11

* multiple examples documented ** This 21 day period is not a true incubation period since Dr. Leon-Sotomayor discounts the prodromal period or triggering infection as being different from the actual disease process. This 21 day period would closely associate with our own observations in which there is the initial infectious incident followed by a pause then the gradual development of the full blown features of the illness. This period can take up to 21 days.

(2) Rapid fatigue, shut-down or exhaustion of muscle and CNS functions after no apparent cause or after minor:

Incubation Period 2

physical intellectual sensory or

The incubation period 1, mentioned above, relates to the incubation period of either the epidemic disease or the triggering disease. This does not explain the

infectious interaction, and associated with an unusually slow rate of recov-

26

B. Hyde, MD, Sheila Bastien, PhD, A. Jain, MD

Post-Infectious, Acute Onset M.E. / CFS, General

apparent delayed association that we have documented all too frequently of an infectious mononucleosis-like disease or an encephalitic process that preceded the actual M.E./CFS illness by a variable period, usually from 6-24 months. Nor does it explain the frequent association of an M.E./CFS patient with an earlier close contact with a paralytic poliomyelitis patient 11 .

Information

most unusual for the two disease processes to display exactly the same clinical spectrum. At the same time, we have many cases of individuals in the same family who have fallen ill at significantly different time periods. It is not known if this indicates transmission of a chronic infectious illness, if we are observing a latent infection with spurts of infectivity as note by Wallis16 or if we are merely observing late expression of the disease process in which all parties were infected at the same proximate time. We have a few instances in which several generations in the same family have developed the illness. In the Mercy San Juan Hospital epidemic17, the illness seems to have been passed down through as many as five related and unrelated non-sexual, casual contacts.

Transmission of Infection The major mode ofinfectivity appears to be by airborne or respiratory route4,13. There is no evidence in the literature that the infection was waterborne or that potables were the cause of the illness. Bodies of water, or sewage may, however, sustain the causative infectious agent.

Attack Rate

It is not known if the triggering or prodromal disease is the cause of M.E./CFS or if the triggering disease is a convenient non-specific destabilizing virus that provides the ultimate injury to a pre-existing destabilized immune system.

Population at risk

No. of Cases

Los Angeles 1934 Student Nurses 401 65 Graduate Nurses 891 73 Attendants 266 5 Orderlies 318 5 Akureyri epidemic 5,21 6,887 465 high school and university students ages 10-14 46 9 ages 15-19 231 66 11 ages 20-24 56 Royal Free Hospital 6 3,500 292 Men 950 27 Women 2,550 265 Nurses 800 149 Cumberland epidemic 7 Orton region

It is not known if M.E./CFS in any one individual is caused by: (a) a single unique virus, (b) one or more families of viruses (c) a virus that requires a particular immune window or breakdown in order to create a persisting virus infection (d) or if M.E./CFS operates in an AIDS-like system with one virus that immobilizes the immune system and another infectious agent that causes the disabling illness.

Attack Rate per 100

16.2 8.2 1.9 1.6 6.75 5.1 28.6 19.6 8.3 2.8 10.4 18.6 13.9 19.8

*E ventually 1116 case were documented in the Akureyri epidemic giving a considerably larger attack rate for the general population of 6,887 of 16.2 rather than 6.75

Although the Lake Tahoe epidemic in 1984 appears to have been first documented in a girls' high school basketball team14, there is also an anecdotal story from the Lake Tahoe epidemic, that 5 unrelated men all fell ill with M.E./CFS after having slept with the same prostitute 15 . This prostitute was visiting from Africa. There is no mention of sexual transmission of M.E./CFS in the literature. We have countless cases documented in our files where one spouse with M.E./ CFS has had long-term repeated sexual contact with an existing or new spouse without transmission of the illness. We have had a few cases of apparent rapid transmission to a new sexual partner. However, it is

Degree of Infectivity During the first few weeks of the Initial Stage, M.E./ CFS appears to be infective but highly selective within clusters and epidemics. During the Recovery and Chronic Stages, M.E./CFS does not appear to present a significant infective risk. Wallis states that "the level of infectiousness is fairly high as shown by the numbers of families where secondary attacks had occurred subsequent to the primary illness."18

27

The Clinical and Scientific Basis of M.E. / CFS

ability within the same epidemic both in degree of illness, symptoms, myalgic or non-myalgic forms, chronicity and even form of illness manifested.

Period of Infectivity Clinically, it would appear that the main period of infectivity ofM.E./CFS occurs in the period preceding the overt illness and during the early days of the Initial Stage. In most cases, the chronic phases of this disease do not appear to be particularly infective.

In the August 1984 North Carolina orchestra M.E./ CFS epidemic20, it appears that the orchestra broke down into three groups:

Education In a very few (a) one with M.E./CFS clusters and inPost Grad Degree (b) one with an assumed dividual cases acquired immune dysthe disease in• Post Grad Degree function but no observfectivity appears Q BA/BSc able disease Some College to continue for • S o m e High School Education (c) and one with no ob• High School Graduate many months, E3 Some College servable disease and no e.g. (a) Four inobservable i m m u n e dividuals in an dysfunction. open lesbian Some High School Education community in The group with no M.E./ Ontario fell ill CFS but observable with both acute Professionals immune dysfunction, onset and in• Professionals White Collar within five years manisidious onset 0 Management fested a considerably M.E./CFS. This • Blue Collar larger number of mairregular series • White Collar lignancies than would of new illness be anticipated. involved new sexual partners In an August 1984 Onand casual dintario cluster 1 1 seven ner contacts in Management which there was family members fell ill neither kissing with presumably the nor other sexual (From work of Sheila Bastien, PhD) same virus infection. Occupation contact. Fomites were shared, e.g.(b) In the Mercy San Juan Hospital Five members of the same household came down with epidemic17 infectivity was followed through 5 new a tracheobronchitis and two with Bornholme's disgenerations of contacts. One can only surmise that ease and no tracheobronchitis. Those that fell ill with we may be dealing with two different infectious Bornholme's disease then developed M.E./CFS. The processes. Wallis states that the time of maximum tracheobronchitis started in mid-August and perinfectivity appeared to be at or about the time of sisted for up to six weeks and preceded the cases of initial onset of symptoms. Recurrences of symptoms M.E./CFS by one week. of the disease became a well-marked feature, and, at that time, contacts would develop the typical disease, In this epidemic, one case of M.E./CFS was totally suggesting, therefore, that the host was again cleared within one year and another has become infectious.19 chronic. Twenty days a f t e r f a l l i n g ill with tracheobronchitis and no M.E./CFS, that individual kissed a non-family member and that outside person fell ill within 5 days with M.E./CFS. This illness was a typical acute onset form but was self-limiting after two months.

Variability of Disease Expression There is little in the literature of variable expression of illness but there appears to be considerable vari-

28

B. Hyde, MD, Sheila Bastien, PhD, A. Jain, MD

Post-Infectious, Acute Onset M.E. / CFS, General Information

During the Akureyri epidemic5 in northern Iceland, during the same epidemic period, approximately 5 children fell ill with Parkinson's disease 21 as an apparent result of the Akureyri epidemic. These children eventually died of Parkinson's disease.

that work in psychiatric institutions and nursing teachers seem to be particularly singled out. In the teaching professions, teachers who work in schools for the disabled appear to be particularly at risk. It has been suggested that these individuals represent a group of high contact with a potentially ill public and are thus exposed to more infectious illness. This is true. However, these select groups also tend to be the same population that keep their immunizations up to date and, in fact, they may be some of the few adults who routinely receive immunization due to their line of work. Several of the epidemics occurred after the individuals were either exposed to immunization or would have been expected to have been just immunized. These groups that are noted to have a high risk of falling ill with M.E./CFS do not work in occupations where there is higher stress than the average worker. However, they do work in occupations that require higher levels of immunization. This relation to inoculation is also seen in other infectious diseases. It has been observed that there is an increased risk of poliomyelitis occurring after prophylactic inoculation against diphtheria, whooping cough and smallpox. The risk seems greater 8-14 days after the inoculation.29

In any one cluster we have noted some patients with severely disabling disease and some mildly disabling disease, some with pain syndromes and some with no pain syndromes.

Who Falls 111 with M.E./CFS? In the early epidemics, there was an initial preponderance of disease among health care workers in hospitals and in nursing schools4 617 ' 22 . There have been several epidemics among schools5'7,23, that, in the case of the Akureyri and Lake Tahoe epidemics, involved both teachers and students. Historically, there has been a tendency for the staff of institutions to manifest increased disease incidence. There have been several epidemics among military establishments.24'2526 Except for the Akureyri and the 1955 Cumberland, England epidemic7 until 1979, most M.E./CFS disease tended to occur as institutional epidemics. Although there is much early anecdotal talk of M.E./CFS in the community, sporadic M.E./ CFS did not become widespread and appear significantly in the literature until after the apparent increase in 197927. From that time on a steady increase among the general public was observed by several clinicians with 1984 marking an apparent major increase in the numbers falling ill with M.E./CFS 28 .

Racial and Working Class Anomalies Among blue collar workers, we again note the high proportion of individuals who are health care workers. Unlike the consensus in the United States, and despite the relatively low black and native populations in Canada, we have seen several blacks of both African and American origins ill with M.E/CFS. We have seen Mohawk, Woodland Cree and Algonquin native persons with M.E./CFS. Numbers are not large, but consistent with their low relative populations. In Canada there tends to be a much more egalitarian mix of patients with M.E./CFS rather than the higher income, higher educated groups seen in the United States series30. We believe this bias is either a sampling error or may simply represent one of access to physicians.

We have noted M.E./CFS in children from the age of 3 to adults in their late 60's. In children and in adults, there tends to be a marked increase of reported cases of females, with girls and women representing as many as 65-75% of all of the cases. In children, we have found that there seems to be an increased frequency of M.E./CFS in girls in grades 7 and 8 and again in youths in their last year of high school and first year at University.

It is of particular interest that Dr. Luis LeonSotomayor, a Spanish American, observed a significant number of blacks who fell ill in the Texas epidemic. This was described in his book Epidemic Diencephalomyelitis 9 . Also, in the Punta Gorda

We have found a definite occupational bias with teachers, health care workers and social workers significantly affected and to a lesser degree, other professions such as the clergy and lawyers. We have also found that, within the health professions, those

29

The Clinical and Scientific Basis of M.E. / CFS

epidemic in Florida, described by Poskanzer, Henderson et al37, there were a large number ofblacks observed with M.E./CFS. The Punta Gorda epidemic was of particular interest due to the fact that of the some 60 epidemics noted in this book, it was the sole epidemic in which a door-to-door study was involved. The absence of blacks might simply be interpreted as disabled M.E./CFS black patients avoiding a group of white physician researchers. To my knowledge, no black U.S. researcher has been funded to study M.E./ CFS by NIH or CDC. Geographical Distribution One wonders if, as with M.S., there is not a geographical epicentre of M.E./CFS and if there is not an in creased frequency of M.E./CFS in the northern British Isles, particularly in the area north of Hadrian's wall and extending up to the Glasgow area. We also find it curious that, in the some 26 Canadian physicians with M.E./CFS that we have seen from Ontario and Quebec, twenty-one originally came from or worked in Scotland, England and Ireland and of the remaining five, one was from Denmark, one from Belgium and one from Mexico, but of European origin. Only two were born and raised in Canada and one of those was married to a physician with M.E./ CFS who came from Ireland.

The Natural History of M.E./CFS: does not resemble Alzheimer's disease with a cumulative increase in disability until the patient succumbs. M.E. is rarely progressive. does not resemble M.S., although the symptoms may at times be similar, where there tend to be periods of increased activity of the disease process with a stepwise increase in disability. does resemble that of epidemic paralytic poliomyelitis in that these patients show an initial recovery period after which many are left with permanent disability. Anterior or Paralytic Poliomyelitis As with anterior poliomyelitis, the deaths that have been recorded tend to occur early in the first weeks of the disease. There are however, few deaths from M.E./CFS recorded in the literature 731 . Repeat infections of paralytic poliovirus were rare and when they did occur, appeared to have been associated with different polio or other enteroviral types. It is not known if the recurrences of M.E./CFS represent a resurgence of a latent and existing disease or a reinfection with a new viral entity.

Natural History of M.E./CFS The natural history of post-infectious M.E./CFS resembles that of a single infectious injury with an initial rapid period of symptom and disability improvement from the prodromal infection, after which a new disease process sets in from which the patient either recovers or is left with a chronic illness and a decreased level of performance, frequently in the areas of intellectual, neuropsychological, physical and emotional abilities. This decreased level of performance can stabilize at this new level, slowly improve or deteriorate depending upon many physical and psychosocial aspects of support. This new level of functioning is quite variable and may be dependent upon the site and degree of the initial central nervous system injury. It is rare for a patient who has been ill for one year or more to totally recover. It is also rare for the patient to show a progressive deterioration once the Chronic Stage has been reached. We have observed these few exceptions.

30

As with anterior poliomyelitis, M.E./CFS tends to occur as a single isolated event that causes the maximum disability during the first few months and during which period the patients tend to improve. During this early period even patients severely disabled with poliomyelitis or M.E./CFS may significantly recover while some show limited recovery. As with anterior poliomyelitis, there tends to be continued recovery in most M.E./CFS patients after the first acute episode , but any recovery tends to be marginal after two years. Psychosocial dysfunction may aggravate the physical aspects of what would have been a stabilized moderate to severe illness. Rehabilitation in paralytic poliomyelitis usually has to take into account only the physical disability. There tends to be little or no brain dysfunction in classical anterior poliomyelitis, while, in M.E./CFS, brain dysfunction is the defining characteristic of the disease.

B. Hyde, MD, Sheila Bastien, PhD, A. Jain, MD

Post-Infectious, Acute Onset M.E. / CFS, General Information

In poliomyelitis, any physical disability is eventually stabilized and the process of rehabilitation can be affected by modifying the home and work place, structurally assisting the patient with braces, wheel chairs, automobile modifications, and changing the work focus to one more congruent with the physical limitations of the disability.

derstanding of M.E./CFS is the chronically unstable nature of the illness. This lack of stability results both in the patient's lack of dependability in the work place and the patient's increasing loss of confidence in her own abilities. A typical example of an M.E./CFS patient is illustrated by a disease process where there is a lack of stability or dependability of: (a) the central nervous system's functions, (b) the neuropsychiatric behavioural patterns (c) the reactive psychiatric patterns (d) muscle function

Stable Chronic Stage of Poliomyelitis No matter what degree of disability is attained by the paralysed poliomyelitis patient, that patient's condition has one over-riding characteristic, stability. The degree of disability is stable and that stability can be depended upon. It is this expectation and this assurance of stability that allow any serious health, reeducation and work planning.

Thus, even as the patient's physical and CNS functions improve, she may develop a significant loss of confidence in her own ability to perform. Frequently this psychological loss of confidence or ability becomes one of the dominant forces in perpetuating the patient's disability.

Unstable Chronic Stage of M.E./CFS One of the diagnostic principals underlying the un-

A Description of Prior Illnesses, Triggering Infections, and Stages of M.E./CFS

SIGNS OF PRIOR ILLNESS the full blown features of M.E./CFS. (For further details see Chapter 6, M.E./CFS: The Physical Signs of Disease).

We routinely note in our clinic the occurrence of a curious illness that can sometimes be documented three months to two years prior to the prodromal illness. This may present as:

Observed T r i g g e r i n g I n f e c t i o n s (1) a mononucleosis-like illness that causes a period of chronic illness that may last up to six months, or

The most common presentation is that of a minor nonspecific viral-like illness, sore throat, with or without febrile episode. There is frequently diarrhoea and/or gastric pain.

(2) It may resemble an acute encephalitic process. When it occurs as an encephalitic process, the illness is usually very short lasting (2-4 days), very severe with at times an almost comatose patient, a rapid and apparent complete recovery and without other apparent lingering sequellae. The patient will usually state that this had been the worst headache of his life.

There is nothing in the prodomal disease to forewarn of the impending chronic illness. There is a habit of calling this prodromal infection, a flu-like illness but there is no indication that it is an influenza. "Flu" has entered the public domain as a synonym for any unknown minor infection. However, to our knowledge, despite the tens of thousands of cases of M.E./ CFS, only a few physicians have ever attempted to culture, successfully recover this "flu-like" virus and publish their results. Those that have would suggest that influenza is most rare and that enteroviruses may be among the most frequently encountered family of prodromal viruses.

(3) A third type is that of a minor episode that resembles the main chronic M.E./CFS disease. This minor episode tends to last several weeks or even months. During this time, the person rarely misses school or work but is quite unwell. The patient then usually recovers for a brief period only to fall ill with

31

The Clinical and Scientific Basis of M.E. / CFS

We are not in a known Lyme disease area and perhaps, for this reason, have never seen a case of Lyme disease as an onset although we have demonstrated positive Lyme disease tests in approximately 12 chronic M.E./CFS cases.

Disseminated Encephalomyelitis or ADEM. Contrarily, we have frequently observed that there is an aborted recovery. This biphasic character of the disease can also be typical of paralytic poliomyelitis33. Four Stages of Post-Infectious M.E./CFS

Triggering infections include: Acute Onset M.E./CFS can be arbitrarily and profitably subdivided into 4 overlapping stages.

(1) Non-specific viral illness (2) Tracheobronchitis (3) Encephalitic-like illness (4) Bornholme's disease (5) Meniere's syndrome (6) Epidemic conjunctivitis (7) Hand, Foot and Mouth disease in children (8) Undiagnosed forms of hepatitis (9) Infectious Mononucleosis-like disease (10) Myocarditis or pericarditis

Initial Stage: Recuperation Stage: Early Chronic Stage: Late Chronic Stage:

0-6 months 2 weeks-24 months 1-6 years from 6 years on

The Initial Stage 0-6 months

Half of the above list; (4), (6), (7), (8) & (10) could be potentially classifiable as enteroviral infections and, with the exception of Meniere's disease, whose cause is unknown, and infectious mononucleosis, enterovirus infections are known to give rise to all of the above triggering infections. One cannot, of course, be sure if (1), (2) & (3), in M.E./CFS patients are due to enterovirus or other viruses. Despite the now almost universal rejection of EBV as a cause ofM.E./CFS, clinically an infectious mononucleosis-like illness appears in a modest but significant recent number of M.E./CFS histories. Most frequently this illness occurs 6 months to 2 years prior to the onset of M.E./CFS. Less frequently, it occurs just prior to onset ofM.E./CFS.

Initial False Recovery Phase Many M.E./CFS patients will frequently start to improve from the triggering or presenting illness before demonstrating the full-blown features of M.E./ CFS. When it occurs, this recovery phase from the prodromal infection is very short lasting, from a few hours to one or two days, until the actual typical M.E./CFS features become apparent. Drs. Behan make the point that in M.E./CFS "there is no latent period after the initial disease and before the characteristic M.E./CFS symptoms develop,"32 They apparently use this argument to separate M.E./CFS from the auto-allergic reaction that follows a wide variety of different viral diseases known as Acute

32

The Acute Onset M.E./CFS illness frequently declares itself by a dramatic barrage of symptoms following one of several prodromal symptom pictures. These are noted in this chapter as well as by Drs. Behan 32 34 and Luis Leon Sotomayor9. (1) There is usually a significant degree of malaise, or total body discomfort such as one encounters in an acute attack of influenza. This malaise is associated with a rapidly fluctuating temperature change in which the body temperature tends to have a below normal temperature variability that may shoot up to modest elevation of temperature. This peak is often associated with episodes of drenching sweats not necessarily associated with any physical or emotional activity. (2) There is a severe exhaustion or prostration that can assume the proportions of narcolepsy or even Encephalitica Lethargica. The patient can be awoken but soon falls back to sleep. In most patients, this period lasts for a few days to a few months but we have seen cases that have persisted for years. This persistence is particularly noticeable among children and youths. (3) There may be an exacerbation of the prodromal symptoms. (4) There is an alarming fluctuation and variability of symptoms. (5) There is frequently tachycardia with ectopic beats.

B. Hyde, MD, Sheila Bastien, PhD, A. Jain, MD

Post-Infectious, Acute Onset M.E. / CFS, General Information

valve prolapse may be erroneously dismissed as preexisting defects. Even those functions commonly associated with brain function, i.e. memory, emotional control, reading comprehension, aphasia, ataxia and sensory perception will vary as to the degree or completeness of recovery. All this suggests an unequal level of damage, variable location of injury and variable recovery of brain function.

(6) There is frequently marked initial anorexia. (7) The disease process tends to usher in a permanent hypotensive process. However, about 10%, particularly those who had mild hypertension at onset, will react with a malignant type hypertension sometimes resembling a carcinoid syndrome 9 . (8) The patient frequently suffers from irritability, severe anxiety or panic attacks at the start of the disease process. This anxiety is very much related to the great number and inexplicable nature of the symptoms. In some cases this may be associated with hyperventilation. This condition may persist for the duration of the illness.

Some patients will start to recover within two weeks while others may show little recovery until five or six months after onset. We have never seen a patient who has not recovered to some degree from this initial bomb blast of symptoms. Symptom decrease should not be confused with decrease of disability. This period of recovery is variable and is almost always over by one or two years. At that time the patient will either be no longer disabled and back to work, or will be left at various levels of disability according to the variation in the individual disease process. Although most recovered patients will insist that they have completely recovered, on scrutiny many will have returned to work and social activity simply at a reduced level of brain and physical ability.

(9) There is a tendency for the multiple symptoms and signs to come in "storms". In the Initial Stage these storms seem to have a life of their own without any apparent triggering mechanism. In the Recuperation and later stages, the storms may be provoked by unusual but not necessarily excessive activity or association with infectious disease 9 . (10) It may take 3 weeksto 6 months to develop the full symptom picture of M.E./CFS.

Physicians who observe the recovery of one M.E./CFS patient, her return to the work-force or to full-time school, sometimes generalize this recovery into the expectation that all ME./CFS patients will recover and that those that do not, have something morally wrong with them.

Recuperation Stage 2 weeks-24 months, usually 1-12 months The Recuperation Stage is characterized by a decrease in the number and severity of symptoms and symptom storms. The patient also tends to have an amnesic loss of remembrance of these early symptoms. During this period, some patients will rapidly return to normal and any minor permanent disability will be discounted as they return to a usual level of work and social activity. Others will return to work but will have to discount much of their social life due to the severity of on-going features of their disability. There tends to be an uneven return of abilities.

Early Chronic Stage 1-6 years The early chronic stage is characterized by the same features as the Inital Stage. However, rapid shut down or exhaustion of muscle and CNS functions is the chief complaint as the patient attempts to return to normal activity. The CNS cognitive, sensory, sleep, motor, gastric and pain dysfunctions still exist, but exist in a more diffuse but not necessarily less disabling pattern. Insidious onset M.E./CFS has a clinical and symptom spectrum that resembels this early chronic stage as do recurrences.

Some patients may recover most or all of their physical but not their cognitive abilities. This is seen particularly in children. Others may recover their mental abilities but not their physical strengths. Cardiac irregularities, if they occurred, and if they were not associated with myocarditis, tend to return to a normal pattern. Chordae tendinae ruptures that may occur in the Initial Stage and signs of mitral

This Early Chronic Stage is when the physical and medical aspects starts to merge with the psychosocial aspects of the disease, sometimes creating a treat-

33

The Clinical and Scientific Basis of M.E. / CFS

difference in those who adapt and those who do not is not simple. We believe the following factors are important in the individual's success or failure to be rehabilitated.

ment impasse. It is impossible to separate the physical from the psychosocial aspects when rehabilitation is the issue. The social aspects of the disease hinders the improvement of the physical disease and the physical aspects hinder the socio-economic life of the patient. Due to the financial and technical constraints of modern medicine, few general practitioners, internists or psychiatrists are able to cope with the lengthy time involved in the psychosocial aspects of rehabilitation.

Some Factors Affecting Rehabilitation Males with supporting spouse Women without family obligations Pre M.E./CFS intellectual assets Level and type of pre M.E./CFS education Degree and area of CNS injury Social and economic support facilities Family, medical and government support Access to knowledgeable re-education program

This is the stage in which many M.E./CFS speciality physicians first see the M.E./CFS patient. If the patient is unlucky, she will already have been improperly diagnosed by several physicians, may have undergone minor or major surgery or investigative intervention. Marinacci, tongue in cheek, mentions patients from the 1934 epidemic "who had a hysterectomy in 1938, in the hope that the mental symptoms would be relieved, but the procedure was not beneficial."35 At the Nightingale clinic we have rarely seen an adult female patient who had suffered from M.E./CFS for over five years, who has not had either a pelvic intervention or pelvic surgery.

Most of this group will have had a reversal of the initial hypersomnia and will now have a sleep dysfunction that involves non-restorative sleep and features of narcolepsy. To the detriment of earlier phases of sleep pathology, it is this period that sleep pathologists have most investigated. Sleep patterns are interrupted by arousal patterns. Many patients in this stage of illness will not recover sufficiently to either enjoy work or social activities. This early Chronic Stage is marked by major changes in their life pattern. Unstable marriages will become increasingly destabilized and marriage breakdown and divorce will occur. Money reserves will have been liquidated. Many of the social confines of poverty may have set in and the patients, most of whom will have had life and social expectations set at a higher level, will now see those hopes and expectations destroyed. It is difficult for a physician, in a 15 minute visit, to relate to this change, particularly if the patient is still wearing a snappy, wealthy looking $1000 dollar Kenzo suit she had bought five years previously.

It is thus understandable that, due to the multiple interpretations and her failure to show significant improvement, the patient may well have lost faith in her physicians and sought out well meaning and perhaps at times fraudulent individuals who practice what is loosely termed "alternative medicine". Humankind is still quite scientifically primitive. Many people still believe in variations of magic, they just don't use the term magic. It is rare to find an M.E./CFS patient who is not on several vitamins, oriental and perhaps other mystical "curative" agents, loosely called, "natural products". Most do no harm except to the pocket book. Some are dangerous. Inquiry should always be made as some of these " n a t u r a l " products may be l i f e - t h r e a t e n i n g , e.g. germanium.

It is the period when students and youths and some adults will be most prone to suicide.

The Early Chronic Stage is characterized by a fairly unstable level of dysfunction. During this period, most patients continue to show a very slow and uneven period of recovery and readaption to their altered state of CNS, muscle and social function. Recovery should not be confused with adaption. During this same period some patients will adapt to their altered internal environmental circumstances and others will not be able to make the transition. The

The more dramatic features noted in the Initial Phase will have diminished, but the patient will be left with a chronic brain, muscle and social dysfunction. Depending upon the ability of the patient to adapt to her changed circumstances and the area of most brain dysfunction, she may exhibit various levels of social and psychological impairment.

34

B. Hyde, MD, Sheila Bastien, PhD, A. Jain, MD

Post-Infectious, Acute Onset M.E. / CFS, General Information

The Married Male Teacher

tal and social abilities are often equated with eccentricity. He can place more of his executive burdens on his senior staff. If his incompetency becomes too painful, he will frequently be bought out with a considerable financial settlement. A labourer with an active physical job will not be able to keep up with the changes in his altered physical condition.

It is also the period when different social and financial abilities start to direct the course of the disease process. For instance, a disabled male teacher will often be able to return to work. He will have little or no social life. He will depend upon his wife for preparing course work and for marking exams. He will tend to sleep during the lunch break and return home at 4p.m. to sleep until a late dinner and then return to his bed, to sleep until the next morning. He will tend to spend the weekends in bed or in a state of exhaustion, but he will pick up his cheque. He is usually a total loss as a teacher and his relationship with the students will become trying. He will cease to perform many of his physical, intellectual and social functions as a teacher, parent or spouse.

Late Chronic Stage: from 6 years on. There has been no publication and to our knowledge, no research done on the chronic features of disease in M.E./CFS. Without adequate recovery and support, there is an increasing tendency for the patient to become a hermit.

The Married Female Teacher These patients tend to be forgotten. They have adjusted to their altered abilities. They will still show some minor improvements in function, but this is due to their accepting their altered abilities. We rarely see these individuals since they have given up any hope that physicians can be of service to them.

A woman teacher at the same level of disability as her male counterpart will not be able to return to work or assume any other similar or appropriate work. Unlike her male counterpart, she will not be able to sleep in her car during lunch time in the local shopping centre parking lot. Her husband, who will be working, will rarely prepare her course work or mark her students' papers. She will have to return home at four or five p.m. and prepare supper for her children and husband and help her children with their homework. She will have to do the washing and cleaning. Despite the reputed social revolution, many husbands will not take on their share and certainly not their wife's share of the essential household activities. Some do, but it cannot be counted upon in most families. The net effect is that neither the work, home nor social abilities can be met by a mentally and physically exhausted woman with M.E./CFS.

Despite their previous relatively high earning ability, many of these M.E./CFS patients will have become poor, long out of the work force, with no appreciable disability insurance. They frequently have disorganized houses and minds and, unless, they have sufficient social structure, can become street people. They tend to no longer be recognized as having a post-infectious disease process. It is our opinion, that far from M.E./CFS simply being a disease of the upper middle class, many of those that fall ill as children, adolescents and young adults become a significant proportion of the chronic poor.

The Spinster Dr. John Richardson in the Newcastle-Upon-Tyne area in England has found a higher than usual level of retroperitoneal carcinoma 3 6 in this group. Retroperitoneal carcinoma is a very rare disease. He has also noted an apparent decrease in breast cancer. We also have noted what appears to be a lower than normal incidence of breast cancer in M.E./CFS patients.

We find that when a woman can get back to work, she is usually single and does not have children or other obligations. The Senior Executive A senior executive with an excellent executive assistant and secretarial staff can also get through with these work support structures. His changes in men-

There appears to be a recurrence of irregular cardiac rhythms in chronic illness, particularly after 20 years, but this may simply be a feature of aging. 35

The Clinical and Scientific Basis of M.E. / CFS

If M.E./CFS is poorly funded and poorly investigated, this late chronic phase is almost totally devoid of

research and is replete with all of the mythologies that occur when scientific scrutiny is absent.

References 1. Sharpe M.C. et al (1991) A report ...chronic fatigue syndrome: guidelines for research. J. Royal Soc Med 84:118-21.

15. Paul Cheney, M.D., African prostitute, personal communication with Byron Hyde, M.D.

2. Holmes G., Kaplan J., Gantz N. et al. Chronic fatigue syndrome; A working case definition. Annals of Internal Medicine, 1988;108:387-9.

16. Wallis A.L. Idem (7) pages 25-26. 17. Ryll Erich, Chabursky B. 1975 Mercy San J u a n Hospital epidemic, in preparation.

3. See Chapter on Epidemics, this text. 18. Wallis A.L. Idem (7) pages 25-26. 4. Gilliam A.G. Epidemiological Study of a n Epidemic, Diagnosed as Poliomyelitis, Occurring Among the Personnel of The Los Angeles County General Hospital DuringThe Summer of 1934,Public Health Bulletin No. 240, April 1938, The United States Public Health Service.

19. Wallis A.L. Idem (7) page 26. 20. Grufferman S. see abstracts, The Cambridge Symposium on Myalgic Encephalomyelitis (M.E.), The Nightingale Spring 1990;Vol.l,Issue 3:12 16.

5. SigurdssonB.,Siguijonsson J.,SigurdssonJ.H.,Thorkelsson J and Gudmundsson K. (1950) A disease epidemic in Iceland simulating poliomyelitis. American Journal of Hygiene, 1950;52:222-38.

21. Bergmann S. Iceland, personal communication in 1988 with B. Hyde. 22. Shelokov A., Havel K , Verder E., Welsh W. Epidemic Neuromyasthenia, An outbreak of poliomyelitis-like illness in student nurses. NEJM, 1957;257:345-55.

6. The medical staff of the Royal Free Hospital, An Outbreak of Encephalomyelitis in the Royal Free Hospital Group, London, in 1955, Br. Med. J., 1957;2:895-904.

23. Parish J.G. Unpublished review of Lake Tahoe Disease.

7. Wallis A.L. An investigation into a n unusual disease seen in epidemic and sporadic form in a general practice in Cumberland in 1955 and subsequent years, Doctoral Thesis submitted to University of Edinburgh (1957), page 18.

24. Gsell O. Encephalomyelitis myalgic epidemic eine poliomyelitisahnliche krankheit, Schweiz Med Wochenschr (reviews 3 milirary epidemics)1958;88:488-91.

8. Pittsfield, Massachusetts Epidemic. Described by Hyde B.Canada Diseases Weekly Report, Proceedings of a Workshop on Chronic Fatigue Syndrome, J a n 1991, Vol. 17S1E, p. 7 also Hyde B. Bergmann S. Chronic Aspects of Akureyri Disease in Post-Viral Fatigue Syndrome, Jenkins and Mowbray, John Wiley, p.210, (1991).

25. Graybill J., Silva J., O'Brien M., Reinarz J. Epidemic Neuromyasthenia, A Syndrome or a Disease (Lackland Air Force Base, Texas) JAMA 1972; 219:1440-3. 26. Hyde B. M.E. Epidemics in the U.S. Airforce, The Nightingale, The Nightingale Research Foundation 1991; Vol.1 Issue 5, Summer: 15-7 .

9. Leon-Sotomayor Luis. Epidemic Diencephalomyelitis, Pageant Press, 1969, page 13.

27. Preface, this text. 10. Sean O'Sullivan M.D., Donna Rosenthall, September 1, 1984 Montreal Cluster, personal communication with Byron Hyde.

28. Cheney P., Goldstein J., Hyde M. Separate papers read at Kalamazoo Michigan Symposium, Oct. 1991.

11. See this chapter.

29. Wilson G.S. Poliomyelitis and prophylactic inoculation against diphtheria, whooping-cough and small pox, Report of the Medical Research Council Committee on inoculation procedures and neurological lesions. The Lancet, 1956;Dec 15;12231231.

12. Schluederberg A. Workshop on the Definition and Medical Outcome Assessment of CFS in Research, National Institute of Allergy and Infectious Diseases, Bethesda, March 18-19,1991. 13. See Chapter 3, this text, Description of Patients. 14. Daniel Peterson, M.D., Girls' highschool basketball team,' personal communication with Byron Hyde.

36

30. Bastien S. Vancouver Workshop On Research Directions for M.E./CFS, May 1991.

B. Hyde, MD, Sheila Bastien, PhD, A. Jain, MD

Post-Infectious, Acute Onset M.E. / CFS, General

Information

34. Behan P. Diagnostic and Clinical Guidelines for Doctors, a Publication of the Myalgic Encephalomyelitis Association of Great Britain. 1991.

31. Rose J.R. An outbreak of encephalomyelitis in Sierra Leone, Lancet 1957;2:914-6. 32. BehanP.,BehanW. Post-viral fatigue syndrome, a review. CRC Reviews. Cleveland, Ohio:CRC Press, 1988.

35. Marinacci Alberto. Applied Electromyography, chapter. The Value of the Electromyogram in the Diagnosis of Iceland Didease, page 92, Lea & Febiger, 1968.

33. Weinstein Louis. Chapter 188, Principles of Internal Medicine, Ed. Harrison T.R Fourth Edition, pg 1142.

36. Richardson J. Workshop on M.E./CFS in Newcastle, 1989.

37

The Clinical and Scientific Basis of M.E. / CFS

Chapter 5

Byron M. Hyde with his daughter

Dominique

Clinical Observations of Central Nervous System Dysfunction in Post-Infectious, Acute Onset M.E./CFS Post-Viral Fatigue Syndrome Byron Hyde M.D., Anil Jain M.D. Dr. Hyde attended the Haileybury School of Mines and worked as a geophysicist. He then did premedicine in the Faculty of Medicine and University College, University of Toronto, obtaining a degree in chemistry and nutrition. He graduated in Medicine from the University of Ottawa where he was Director and Chief of the International Exchange Program for the Canadian Association of Medical Students and Interns (CAMSI). Dr. Hyde founded the International Summer School in Tropical Medicine. He interned at Hotel Dieu in Montreal, was a resident at St. Justine Hospital in Montreal and to the Ottawa Civic Hospital. He also studied in Munich at the University Kinderklinik and in Paris at the Necker Hospital for Children. He was a research chemist at the Roscoe B. Jackson Laboratory at Bar Harbour, Maine, a leading world laboratory in immunological research. Following this, he was Chief Technician in charge of the Electron Microscope Laboratory in Toronto at the Hospital for Sick Children. This was followed by a similar post at the University of British Columbia. Dr. Hyde has authored a book on Electron Microscopy and two non-medical books. Dr. Hyde has been a physician for 20 years and has performed charitable work as a physician in Laos and the Caribbean. He held the position of Chairman of the Ottawa Community Health Services Association, and is presently Chairman of The Nightingale Research Foundation (Canada) and Chairman of the 1990 Cambridge Easter Symposium and the Workshop on Canadian Research Directions for Myalgic Encephalomyelitis / Chronic Fatigue Syndrome in May 1991, at the University of British Columbia. He has worked exclusively with M.E. / CFS patients since 1985. (Please see Chapter 4 for Dr. Jain's photograph and curriculum Post-Infectious Acute Onset M.E./CFS Post-Viral Fatigue Syndrome

vitae.)

Post-Infectious, Acute Onset M.E./CFS is commonly referred to as Post-Viral Fatigue Syndrome. It is our opinion that the primary cause ofdisability in this disease process is an acquired central nervous system (CNS)

38

B. Hyde, MD, A. Jain, MD

Clinical Observations of Central Nervous System Dysfunction in Post-Infectious,.. .M.E. / CFS

dysfunction. We believe that M.E./CFS represents an acutely acquired, chronic change in the ability of the central nervous system to process, with any dependability, the functions ofreception, interpretation, storage and recovery of information and to programme dependable, normal, smooth end-organ response. Depending upon the patient, we believe a physiological encephalopathy exists in one, but usually several of the cortical areas responsible for motor, sensory, cognitive and emotional function. Those deeper levels of CNS function that are responsible for the coordination of motor, sensory, cognitive, emotional, hormonal and at time rational value judgement may also be physiologically injured. In particular, we believe that there is evidence of subcortical injury to the hypothalamic-pituitary-end organ axis and also to the limbic system, that area responsible for coordination for so many CNS functions. This is not simply theory, but it is based upon an enormous body of clinical information that we discuss in this chapter. Scientific evidence presented in this text is increasingly strengthening this belief. The following clinical observations were made from a review of the literature covering over 6,000 of our patients. Few patients have all of the symptoms and complaints described here, but many will have a large number of these problems. We have seen a few patients with almost all of the symptoms described in this chapter. function in the M.E./CFS patient is from the publications of Alberto Marinacci in the 1950's-1960's2. Marinacci demonstrated that anterior horn cell injuries did occur in M.E./CFS patients, 3 but, unlike in anterior poliomyelitis, these cells were injured, not destroyed. Leon-Sotomayor also s t a t e s , t h a t "Electromyograms done in 20 patients (early in the disease process) showed findings consistent with a patchy denervation-type of polyneuritis most likely caused by a diffuse anterior horn cell injury". 4 The nature of this injury has never, to my knowledge, been investigated further. During the 1950's when Dr. Marinacci examined those recently fallen ill with M.E./CFS, he noted that the spinal cord damage in M.E./CFS was different from that of paralytic poliomyelitis in which there was an irreversible injury to the anterior horn cells. Marinacci found that in M.E./ CFS there was usually reversible damage to these cells. His work suggests that these "recovered" anterior horn cells in some M.E./CFS patients were unstable and could in the future break down as physiological motor units. This is exactly the same concept used to explain post-polio syndrome.

M.E./CFS, like most diseases, has a considerable variability of expression. However, where some chronic diseases such as paralytic poliomyelitis are known essentially by a variable peripheral neurological dysfunction, M.E./CFS is primarily a disease of variable CNS dysfunction, e.g. motor, cognitive, sensory and emotional dysfunction. Although Jamal 1 has demonstrated that motor dysfunction is discernible in M.E./CFS, it is primarily the patient's subjective complaints of physical dysfunction that have been most evident. Most cases of M.E./CFS are studied only when they reach the Chronic Stages. This is understandable, but it is a little like studying chicken pox-varicella one year after the spots have disappeared. As in most viral illnesses, the most florid picture occurs early in the disease. In that manner, the disease process of M.E./CFS most similarly imitates a poliomyelitis infection rather than that of a known retrovirus. It is possible that this disease process exists, due to a preceding viral injury of the immune system and what we are describing is the effect of a superimposed acute viral injury that the faulty or damaged immune system has failed to overcome.

Marinacci notes that on electromyography, during the first two weeks of the acute stage of M.E./CFS, only polyphasic normal amplitude motor units are found. After three weeks one starts to detect scattered fibrillation and positive sharp waves. This is further evidence for the concept of prodromal injury, minor recovery, onset of major illness that we sometimes see in M.E./CFS.

CNS D y s f u n c t i o n i n M.E./CFS Central nervous system dysfunction can be divided into: Brain dysfunction Spinal cord and root ganglia dysfunction Anterior Horn Cell Injury

Sporadic Cases

The little that we do know about spinal cord dys-

In the chronic stages of this 1950's group, high 39

The Clinical and Scientific Basis of M.E. / CFS

Hospital, when first examined by electromyogram 14 -18 years later, still demonstrated isolated polyphasic motor units and a few fibrillation potentials denoting mild persistent injury to the lower motor neurons or radiculopathy. This suggets that epidemic cases may be more severe than sporadic cases. Clinically, we see this motor dysfunction in chronic M.E./CFS patients who are perfectly functional until they shovel snow or do some other exercise that exceeds their normal level of activity. This activity then causes a persistent tremor, fasciculation or twitch in a specific nerve distribution, e.g. ulnar nerve distribution. Duration of this involuntary muscle movement depends upon the individuals limitations and rarely lasts more than a week or two after the provoking incident.

Alberto

In our experience, sporadic onset M.E./CFS tends to be correlated with and results in more insidious onset patients with less dramatic symptoms and less disability than the acute onset forms of M.E./CFS that we see more frequently in epidemics or epidemic years. This would also conform with Marinacci's differences in sporadic and epidemic cases.

Marinacci

polyphasic and some giant motor units developed in a segmental distribution. In mild cases, that accounted for approximately 20% of the patients, these findings rapidly disappeared and there tended to be no reappearance of the M.E./CFS illness. In moderate cases, or approximately 80%, recovery occurred over a period of 18 months. In about 5% of the patients, both the complaints and abnormal electromyographic findings persisted for over 3 years. This more seriously injured group tended to have recurrences of their disability.

Experimental Support Transmission of M.E./CFS to monkeys has been successfully demonstrated, producing CNS and PNS injury in at least two separate sets of experiments. The first was in 19345 where "cross-sections of the spinal cord demonstrated numerous minute haemorrhages in the grey matter". The second was in the 1949-51 Adelaide, Australia epidemic where a radiculitis of the sciatic nerve was demonstrated with small punctate lesions of the myelin sheath. 6

Clinically, in accordance with Marinacci's work, we observe a large number of local neuralgias and muscle spasms early in the disease with a tendency to improvement over several months, suggesting possibly spinal cord and peripheral nervous system involvement early in the disease process.

Human Pathology In Canada, during the 1984 North American pandemic, a physician who fell ill with M.E./CFS ordered his own sural nerve biopsy. Observations of his sural nerve biopsy7 showed inappropriately thin myelin sheaths, loss of large myelinated fibres, mild inflammatory changes and evidence of previous axonal degeneration. Although such lesions would explain some of the acute features such as peripheral muscle spasms, insufficient human biopsy material has been examined to confirm the impression that there is a

Epidemic Cases Dr. Marinacci was able to study approximately 20% of the original 1934 epidemic group. It is interesting that the 20% of the patients who fell ill during the 1934 epidemic at the Los Angeles County General

40

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Clinical Observations of Central Nervous System Dysfunction in Post-Infectious,.. .M.E. / CFS

conductive defect in specific peripheral nerves of many M.E./CFS patients. Since this clinical finding tends to clear in most patients once the disease has reached a chronic phase, it would not be profitable to look for these lesions except in the Acute Stage. Neither the experimental nor the human pathology case cited are sufficient to generalize the findings, but they do indicate the value of further research in these areas.

(CRH), to stimulate the thyroid, adrenal and sex organs. The anterior pituitary produces: Thyroid stimulating hormone (TSH) , thyroid Adrenocorticotropin hormone (ACTH) , adrenals Gonadotrophin hormones , sex glands Although most M.E./CFS physicians are increasingly aware of this endocrine problem in M.E./CFS, it is unfortunately one area that research physicians have avoided until the recent published work of Dr. Demitrack and associates. 9

Acquired Brain Dysfunction in M.E./CFS The process can be categorized under:

Fluid Balance Dysfunction Central Endocrine Dysfunction Fluid Balance Dysfunction TSH Dysfunction Temperature Regulation Dysfunction Sexual Dysfunction Natural Killer Cell Dysfunction Cognitive dysfunction Volition dysfunction Sensory dysfunction tactile dysfunction pain dysfunction auditory dysfunction visual dysfunction proprioceptive dysfunction Seizure activity Hypnagogic dysfunction Sleep disorders Dream disorders Amnesia Motor dysfunction Emotional dysfunction

We routinely observe that there is a metabolic fluid imbalance in M.E./CFS. This is also documented by Gilliam10. Leon-Sotomayor11 also notes this oedema and suggests it is due to loss of vasomotor reflexes and venous pooling in the hands with the development of carpal tunnel syndrome that is more pronounced in the night. Although it can be a chronic feature, clinically, we have noted, particularly in the first few months of illness, that patients tend to have puffy hands and wrists as well as puffy lower extremities and joints. Many women, but also men, have at times marked diurnal weight changes. We know clinically that there is an irregular diurnal and nocturnal output of urine. Dr. Peter Behan has discussed his observations of an unusual fluid output related to a hypothalamic injury. 12 It is interesting to note that water excretion can also be influenced by thyroid hormone dysfunction, which increases urine solute by augmenting both catabolism and the oral intake of foodstuffs. 13

Central Endocrine Dysfunction Thyroid Stimulating Hormone (TSH) Dysfunction

8

Dr. John Richardson has noted that M.E./CFS is, in large part, an injury of the endocrine system functions originating in the hypothalamic and pituitary areas of the lower brain. Most of the hormones of the hypothalamus or pituitary gland cannot be measured directly in a normal laboratory and many others can only be measured by indirect methods that rely on target organ response.

One of the most common endocrinological findings we observe in M.E./CFS is thyroid dysfunction and the first thyroid hormone to show an abnormal pattern is TSH. This was first mentioned by Fudenberg 14 and also by Hyde15 in 1990. All varieties of thyroid disease dysfunction other than malignancy have been observed routinely in M.E./CFS patients at the Nightingale clinic. In our experience, as many as 20% or more of all women who develop M.E./CFS will within five years develop some form of thyroid disease. They should be watched and when indicated, treated for this condition.

The area of the hypothalamic nuclei acts as the master control of much of the endocrine system and, through its actions, the anterior pituitary gland is triggered by the corticotropin releasing hormone

41

The Clinical and Scientific Basis of M.E. / CFS

Temperature Regulation Dysfunction Patients routinely complain of dysfunctional temperature regulation in M.E./CFS. We have noted that a marked fluctuation of body temperature with a lower t h a n normal average temperature is pathognomonic of M.E./CFS patients. This is also described by Gilliam16 who notes that there is "an instability of temperature, with a frequent daily range from 97-99 F. That was much more characteristic of this illness than a real elevation of temperature". We routinely observe patients with severely cold extremities, cyanosis and a visible line demarcating the cold from the area of normal skin temperature. This finding was also illustrated by Dr. LeonSotomayor 17 with photographs of patients with cyanotic discoloration of the knee and foot as well as another showing blotchy appearance of the hands with cyanotic changes over the knuckles and nail beds. The fact that this loss of normal blood flow may be persistent has been indicated by Gilliam18 noting the unequal and slow growth of nails on the hand most affected. M.E./CFS patients frequently develop problems in adapting to both cold and hot weather. They appear unable to regulate their internal thermostats adequately. Sexual Dysfunction Much of the sexual dysfunction seen in the early and even chronic stages of M.E./CFS is probably related to the malaise, the pain syndromes and the chronic exhaustion experienced with the onset of the disease process. However, this does not explain the lack of orgasm in women and men that in some cases becomes chronic, the lack of ability to maintain erection early in the disease and the prolactin abnormalities we sometimes see in women. There is hardly any mention of the sexual dysfunction in the literature, except for mention by Dunnet of loss of libido for many months 19 and Ramsay 20 who describing a woman two years after she fell ill during the London Free epidemic, states "excessive frigidity had made sexual intercourse impossible". We routinely record total cessation of menses, irregular menses, many gynaecological pain syndromes, and infrequently, what appears to be an early, reversible softening of testes.

activity that is particularly striking in the first year of illness in our M.E./CFS patients. Renoux and Renoux have suggested that a left cortex injury can inhibit T cell and specifically natural killer cell activity and that brain lateralization for cognitive processes should be extended to immune recognition. It is of interest that physiological brain imaging suggests that the left cortex is one of the primary areas of injury in M.E./CFS patients. 21 Blood Pressure Regulation M.E./CFS patients routinely suffer from postural hypotension and, in general, their blood pressure measurements tend to be lower than one would expect in the normal public. We believe that this unusually large number of patients with relatively low blood pressures is related to hypothalamic or other changes. Conversely, we have seen a small but significant number of M.E./CFS patients who will develop malignant hypertension with the onset of disease. Some of these will have an almost carcinoid feature with flushing and typical diencephalon seizure state. Others seem to be unable to adjust blood pressure with body activity, resulting in high blood pressure on modest activity and very low pressure when reclining. We believe that, in each of these cases, there may have been an alteration to the hypothalamic nuclei responsible for maintaining normal arterial pressure. Leon-Sotomayor also noted the de nouveau occurrence of hypertension in 10% of his series of 50 patients, "It is conceivable that lesions in the diencephalon could give rise to permanent hypertension, as was observed in five patients reported in the present series".22 Acquired Cognitive Dysfunction Central nervous system dysfunction, and in particular, inconsistent CNS dysfunction is, undoubtedly, both the chief cause of disability in M.E./CFS and the most critical in the definition of the entire disease process. Of the CNS dysfunctions, cognitive dysfunction is one of the most disabling characteristics of M.E./CFS. When this simple fact is understood, it becomes immediately apparent why this is such a devastating disease for children, students and adults, both within and outside the educational system. Today, few adult work situations exist where consistent use of education and developed cognitive skills

Natural Killer Cell Dysfunction There appears to be a loss of natural killer cell

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B. Hyde, MD, A. Jain, MD

Clinical Observations of Central Nervous System Dysfunction in Post-Infectious,.. .M.E. / CFS

Loss of Verbal and Performance Intelligence Quotient

are not necessary to maintain a place in the work force.

"Many of these patients behave stupidly" Marinacci24

Patients can return to work with pain, with muscle spasm, with fatigue, with motor dysfunction, but when the patient consistently has difficulty in making new memories, recalling old memories and coordinating new and old information he becomes of little use in the modern work force. It is the combination of the chronicity, the dysfunctions, and the instability, the lack of dependability of these dysfunctions, that creates "the most chronic of chronic disabilities23." It is these combined acquired, chronic brain and physical dysfunctions that define M.E./CFS.

Patients will freely discuss cognitive dysfunctions but many will be unhappy and unaccepting if they are told that they have lost a significant amount of their verbal and performance I.Q. Admission of I.Q. loss represents a threat to their work and social abilities and to their own sense of identity. Dr. Bastien has observed that the average patient with M.E./CFS may lose approximately 20% of his estimated preillness IQ.25 Some will lose more than this. Past the age of puberty, loss of verbal I.Q. will not be as significant as the loss of performance I.Q. The enquiring observer tends to judge a person's I.Q. not simply by verbal but also by dress and learned cultural responses that tend to blind us from adequately assessing I.Q. It is almost impossible to assess I.Q. loss unless we know the I.Q. of the patient before the illness. Afterthefact, we must rely on group, academic or professional I.Q. expectations.

Some of these acquired cognitive dysfunctions of M.E./CFS are listed in the following table: Acquired Cognitive Dysfunctions in M.E./CFS Loss of Verbal and Performance Intelligence Quotient Dysfunction in Simultaneous Processing Easy distraction Decreased concentration Receptive and expressive dysphasia Reading Comprehension Dysfunction Sequencing Dysfunction Visual Comprehension and Discrimination Discalculia Abstract Reasoning Dysfunction Memory Dysfunction Dysfunction in making new memories Dysfunction in recalling formed memories Immediate and delayed verbal recall Visual Recall Dysfunction Spacial Perception Dysfunction Volition Dysfunction

We can also roughly assess I.Q. loss if we realize that I.Q. is the sum of all of the more visible individual cognitive losses. Dysfunction in Simultaneous Processing Easy distraction Decreased concentration Early in the disease process, patients may be distracted and unable to concentrate simply due to the severe headaches that frequently are associated with the onset26. Others have "noise" in their head that is often described as buzzing and thus mistaken for Meniere's disease or as the sound of the crackle and hissing of a short-wave receiver slightly off of the frequency channel. The symptom storms, the myalgias and the anxieties also make it difficult to concentrate. However, there comes a period in the disease process when these symptom storms settle down and the patient becomes acquainted with his new internal environment and, when that occurs, the primary lack of concentration ability becomes obvious.

Discussion of Acquired Cognitive Dysfunctions All of the following acquired dysfunctions can be readily demonstrated by a knowledgeable neuropsychologist. In the case of an insurance or disability claim, the help of a knowledgeable neuropsychologist may be essential. Testing is also useful for treatment research. However, at the time of writing, many physicians will not have access to such expertise, and the patient may not have funds or adequate insurance to cover this type of investigation. If the physician is familiar with some of the defects, he can make a rough assessment from a careful history.

Most brain functions do not operate separately but have back-up systems. Thus patients with M.E./CFS may be able to understand a single person speaking

43

The Clinical and Scientific Basis of M.E. / CFS

directly to them. However, the same patient may not be able to understand the same conversation from the same person on the telephone. If even slightly tired they may become irritable even with telephone conversations from friends. They have difficulty in concentrating and following the conversation even more than with a face to face conversation. Visual or multisensorial cues are important in M.E./CFS. An M.E./CFS patient may have no difficulty at a dinner party with two or three persons and one table conversation, but with multiple persons and conversations, may not be able to understand a word that is said. In addition she may not even be able to recall the guests and, in extreme cases, may not even recall the dinner party the next day. The same person may have no difficulty and no anxiety walking in the country, but will experience panic in crowds and even more so in a busy shopping centre where she is deluged with multiple discordant sensory information. All individuals tend to concentrate better when the input of information is specific and simple, but a normal individual has the ability to block out extraneous and unwanted information or noise. M.E./CFS patients lose the ability to distinguish noise from required information and tend to shut down all intake after simple fatigue or minimal prolongation of the information signal. This receptive shutdown has alarming connotations for making memories and at times can create danger to the M.E./CFS patient.

totally inappropriate and nonsensical responses that at times can be quite hilarious. This is a most common complaint and tends to improve as the disease progresses unless the patient is fatigued, anxious or experiences sensory storms. 27 These patients will show faulty testing in immediate and delayed verbal recall dysfunction tests. Reading Comprehension Dysfunction Sequencing Dysfunction This dysfunction is closely allied spacially with that of receptive dysphasia, that area is localized in the area of the annular gyrus of the posterior left parietal lobe. The patient can still read, but what she reads is not comprehended nor can it be compared with known information that had previously been stored. This dysfunction is one of the primary cognitive problems encountered by an M.E./CFS patient 28 and plays havoc with any job description or learning ability. Unless she redevelops these skills in a structured retraining programme, even an M.E./CFS patient with a PhD in English can become and remain functionally illiterate. These skills do improve during the recuperation stage but sometimes much is lost. In sequencing dysfunction patients will variously lose the ability to look up phone numbers in a telephone directory or to look for words in a dictionary. They develop problems in retrieving and placing files. Patients not only become confused with restaurant menus, but also find it impossible at times to make any decision. Students tend to have significant troubles with lists of true and false questions.

Receptive and expressive dysphasia

Visual Comprehension and Discrimination Dysfunction

Closely allied to concentration is the difficulty in understanding speech and in speaking. The patients will complain that they were able to hear the spoken words clearly, the words were not garbled, but they made absolutely no sense. These patients had lost the ability to interpret normal language. When the M.E./CFS patient speaks, important elements are frequently left out of the sentence such as the verb or subject. Sometimes the syntax is askew. At times, the patient's reply makes absolutely no sense or does not respond to the question asked. Patients are usually aware of the structural faults in their own conversation and at times become overly conscious of this, but rarely do they tend to be aware of their

Patients will complain routinely of going through a red light. They see it is red, but the significance either does not register or is slow to register. Facial Agnosia It is not unusual for an M.E./CFS patient to develop facial agnosia, e.g. Teachers fail to recognize and associate children's faces with their name. A patient had a dinner party for a business associate and despite sitting beside his associate's wife all night,

44

B. Hyde, MD, A. Jain, MD

Clinical Observations of Central Nervous System Dysfunction in Post-Infectious,.. .M.E. / CFS

different. Patients may relate that they can walk, but they manifest that they are conscious of a dissociation of the mind and the body and that they have to "tell their legs" to. walk. This dissociation is not a psychotic manifestation but is akin to the Olympic runner who has to tell her legs, to push, to build up speed, to pass that person a metre ahead in the race. This dissociation of mind and body function is similar to that encountered in the sleep paralysis observed in the hypnapagogic period. This volition form of mind body dissociation is much more common than is sleep paralysis.

failed to recognize the guest the next day when they met by accident. The guest remarked on the wonderful dinner and the patient neither remembered the person nor could figure out what dinner was being discussed. Such patients can suffer from bouts of "jamais vu". These patients may have difficulty in any manner of visual recall. Discalculia Perhaps the one overriding cognitive dysfunction observed in almost all M.E./CFS patients, irrespective of their prior mathematical abilities, is the development of discalculia.29

If you are walking with an M.E./CFS patient and you stop to observe something in a store window, the M.E./CFS patient will frequently keep on walking. When you ask why they did not stop and wait, they will sometimes tell you that it is just too hard to get their legs moving again. In reality, it may be too hard simply to get their mind to give the command. Stopping, like starting can be a problem for M.E./CFS patients. This stopping and starting problem is a central dysfunction and along with the rigid mask like faces that develop with fatigue, may be similar to that seen in Parkinsonianism. There are other findings similar to those of a physiological Parkinson's disease. Dr. Ichise of the Mount Sinai Hospital in Toronto has observed that SPECT scans routinely show basal ganglia hypoperfusion in M.E./CFS.30

Patients either have difficulty or cannot make small change, add up columns, do serial sevens subtraction. M.E./CFS patients frequently cannot remember even their own phone numbers or combinations although they tend to have less difficulty with touch positions on a touch telephone or touch combination locks. A few exceptional children are able to overcome this problem with mathematics and discalculia. However, in devising an educational programme for most children with M.E./CFS it may be worthwhile to abandon mathematics and related subjects if any hope of salvaging the child's education is to be considered.

Abstract Reasoning Dysfunction Memory Dysfunction Dysfunction in making new memories Dysfunction in recalling formed memories Immediate and delayed verbal recall dysfunction Visual Recall Dysfunction

In the commencement of movement, all individuals have an initial inertia during which time the muscle mass builds up efficiency. Athletes build up to maximum output rapidly, but even in non-athletes the warm up period is relatively short. In M.E./CFS patients, this muscle warm up period seems significantly longer, but it is the "mental warm up period" that is affected in this volition dysfunction. The brain functions of an M.E./CFS patient are often like that of a locomotive, that does not readily make changes in volicity and can only change tracks with deliberation.

These are well discussed within the text of this book.

Proprioceptive Dysfunction

Volition Dysfunction

The patient in the acute stages often has periods of loss of positional sense of the extremities. In the dark, the patient may walk like a person with tabes dorsalis. The patient develops faulty judgement in the position of curbs and which frequently causes twisted ankles.

Confusion with timetables is routine, with the patients routinely showing up at the wrong time or on the wrong day.

This lack of volition is characteristic of M.E./CFS patients yet we cannot find it mentioned in any of the numerous publications. Volition dysfunction can be initially confused with depression but it is quite

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The Clinical and Scientific Basis of M.E. / CFS

Gilliam notes that in case 105, "there was a loss of position sense of the hands and feet".31 Amnesia To our knowledge, long standing amnesia does not occur in M.E./CFS. However, shorter periods do. The patients are regularly lost for seconds, less frequently for minutes and this may provoke panic attacks, particularly if the amnesic attack is associated with disorientation, where the patient, momentarily, neither knows where she is nor who she is. Although it is quite common to lose orientation of place totally, it is extremely rare to lose orientation of person. We have had patients who have lost large parts of the day but this is infrequent. Amnesic patients can, in most cases, be easily cued back to reality. It is extremely rare to observe hallucinations, but these short hallucinogenic bursts tend to be self-limiting occurring at the beginning of the illness and should not necessarily be taken as an indication of a psychotic breakdown. Patients will regularly tell you that they are amnesic and that they cannot remember major elements of the previous day unless they are cued. This is not really amnesia but rather a difficulty to recall past events. Whole periods of recent history appear to have never been imprinted and even with cues the patient cannot recall major incidences. Often they confabulate to obscure the obvious memory loss.

membered tasks without the necessity of multiple sensory clues. An M.E./CFS patient may require multiple sensory clues to perform a given task, e.g. the M.E./CFS patient is the principal driver of an automobile that he has had for 6 years. He knows the position of all of the major controls or functions of the automobile. He then falls ill with M.E./CFS and at night can no longer find the switch for the headlights or the door handle unless the interior lights are on. He has not forgotten where the switch is, since as soon as the light is on, his hand instinctively finds the switch, but he needs an external sensory stimulus to recall specifics of gross memory reserves. Tactile Dysfunction or Apraxia It is the rule for patients to frequently drop things since they cannot gauge the weight of the object, due to loss of normal tactile recognition. Ramsay states that "Many...tend to drop or fail to grasp articles...and the destruction rate of household crockery has in consequence risen alarmingly". 33 They lose the ability to recognize or locate by touch and require visual confirmation to recognize familiar objects, e.g. cannot locate home light switches in the dark. They tend to have poor position discrimination of their extremities and head. Pain Dysfunction In the Royal Free Hospital epidemic, "Spontaneous pain was the commonest sensory manifestation." 34

Absence spells probably account for some of the momentary amnesic losses and failure to make new memories for others.

The quality of pain reception may be significantly impaired. At disease onset, patients have been known to protest due to the unbearable pain provoked by the weight of the bed sheets. The multiple "hit and run" pain storms that frequently torment M.E./CFS patients are undoubtedly in part seizure phenomena but can more clearly be appreciated as dysfunctional pain receptors in either the peripheral or central pain recognition areas. To our knowledge, other than the work of Leon-Sotomayor35, there has been no publication devoted to the origins of the jungle of pain syndromes associated with M.E./CFS. The pain symptoms associated with M.E./CFS will be reviewed separately since it is difficult to ascribe all of these pain phenomena to brain dysfunction or even to be exact as to the pain receptor origins in each case.

Sensory Dysfunction This section is closely associated with the subsection of Cognitive Dysfunction. We have separated it simply due to the occurrence of "sensory storms". Sensory storms were first described by Luis LeonSotomayor as Diencephalon Seizures, a term no longer in vogue.32 Sensory storms were an important and astute observation and seem to have been missed by subsequent writers. The necessity of multiple sensory clues Sensory dysfunction tends to have cumulative effects. For instance, a normal person performs re-

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B. Hyde, MD, A. Jain, MD

Clinical Observations of Central Nervous System Dysfunction in Post-Infectious,.. .M.E. / CFS

Auditory Dysfunction

Sensory Storms

Many different forms of central auditory dysfunction are recognized by patients with M.E./CFS. These include:

Sensory storms are a common feature of post-infectious M.E./CFS. It is essential for the physician to understand the terror that they can provoke in a patient, particularly if that patient has little judgement or support. These storms are likely to occur more frequently during the acute stage where they tend to have no particular triggering factor. The fact is that they often have a life of their own and can create a certain amount of terror or panic when they arise unannounced. Not only are the patients struck with an explosion of sensory phenomena, but they almost invariably develop an accompanying malaise. At worst, the patient feels as if she were going to die. It is possible that such storms may precipitate a suicide attempt. It is important to forewarn the patient that these storms may occur, but are generally short lived and tend to decrease significantly in the chronic stages of disease. In chronic stages, storms can be triggered by and occur after physical, intellectual or infectious stress.

(1) inability to comprehend in the presence of multiple auditory signals, (2) loss of tone perception in which music previously appreciated becomes "flat and boring" (3) discomfort, pain and "noise" associated with hearing a modest decibel sound signal. Part of the associated pain may be in the outer ear and may be due to spasm of the tympanic muscles, as one of the major characteristics of this disease is muscle spasm. (4) and finally, a sudden loss of appreciated sound volume. But perhaps the greatest hearing problem is associated with the difficulty and at times inability to interpret spoken or auditory information. This dysfunction is one of the most central problems of M.E./ CFS and represents physiological injury to the area of the angular gyrus in the region of the left posterior parietal lobe. This same area is responsible for visual i n t e r p r e t a t i o n , a n o t h e r m a j o r problem for M.E./CFS patients.

Leon-Sotomayor describes these storms as very variable in which one, several or all of the following may predominate.

Interference greatly accentuates this auditory dysfunction, e.g. if two or three people are speaking or if there is a radio turned on, the patient frequently has difficulty in interpreting information. Auditory comprehension is usually keyed by the initial transmitted information. The initial information asks the question or outlines the area to be comprehended. Frequently the M.E./CFS patient does not register the initial burst of focusing information and thus cannot make sense of the follow-up information. The M.E./CFS patient is frequently heard to ask, "Can you repeat what you were just saying!" Making sense of new auditory information requires the patient to store short-term information and "to make memories". This simple process often represents a difficulty for the M.E./CFS patient. Luis

47

Leon-Sotomayor

The Clinical and Scientific Basis of M.E. / CFS

Elements

of Sensory

Storms

(a) emotional disturbance, increased nervousness, aggravation of tremors and blepharospasm (b) abrupt or insidious onset with subnormal temperature or low-grade fever (c) pleurodynia (d) diaphragmatic tendinitis (e) abdominal pain ( f ) spotty myalgia and tendinitis, usually over the calves and pectoralis muscle group (g) fibrillatory muscle twitching and muscle jerks; jerking of the muscles is usually more severe during sleep, usually awakening the patient (h) increased bowel movement (i) episodic weakness, shortness of breath and fainting episodes. Orthostatic hypotension, tachypnea and tachycardia are constant findings in the acute stage of the illness (j) episodic sympathetic overactivity followed by neuromyasthenia symptoms (k) abrupt waxing and waning of the symptoms is the most characteristic feature of the illness (I) episodic nervousness, changes in personality, tendency to depression, tremors, nocturnal paresthesias, insomnia, nightmares and carpopedal tunnel syndrome are also characteristic of this condition (m) periorbital tenderness, palpebral swelling, burning and dryness of the eyes (n) abrupt vasomotor changes manifested by conjunctival injection, facial flushing or pallor, acrocyanosis and increased sensitivity to environmental temperatures. Patients can be feeling hot and perspiring one minute and cold and shivering the next. Profuse perspiration can be induced by emotional factors or by minimal physical exertion The clinical picture was also characterized by a high incidence of relapses during the first six months of the illness. The relapse usually presents the same clinical manifestation as the acute attack usually with less severity. Clinical manifestation during the relapses may present as colitis, rheumatoid-like picture, carcinoid syndrome-like picture. Neuromyasthenia, mental depression, irritability, 32 generalized myositis and tendinitis, and fluid retention with facial puffiness were commonly present during relapses.

Visual Dysfunction: (Also see Addendum V, Dr. Sadun) Perhaps one of the most interesting and the most complex of the dysfunctions involves the patients' external and central ophthamological processes. A small number of patients will have no visual complaints but, for the majority who do, there is a considerable collection of visual phenomena. Although most clinicians remark on these findings, there is almost nothing in the literature concerning the opthamological changes. Pain: The patient complains of pain, usually behind but sometimes above the eye. The posterior fundus at times will demonstrate a large cherry red discoloration.36 It is most unusual to demonstrate any optic nerve involvement.

be a ptosis over that eye. A few of these patients demonstrate an Adies pupil with loss of patella reflex. This Adies pupil comes and goes. Latency of Accommodation: The patient will frequently complain of a sluggish or decreased range of accommodation, often described as a slow zoom lens. Patients with previous normal accommodation will, with onset of M.E./CFS, relate that, when changing gaze from near to far objects, their accommodation adjustment is unusually slow to react.

Photophobia: Patients often appear with dark sunglasses. When examined, the patient will frequently demonstrate a contradictory cogwheel dilatation of the pupil rather than the normal pupillar contraction when challenged with a light source. The contrary pupillar reflex tends to be one sided. There may

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B. Hyde, MD, A. Jain, MD

Clinical Observations of Central Nervous System Dysfunction in Post-Infectious,.. .M.E. / CFS

Nystagmus: There is an apparent increased incidence in nystagmus when the patient is asked to look into the upper outer quadrants. Pellew37 describes the variability of this nystagmus, "A patient examined in the morning might have nystagmus, which would disappear at midday, recur later, disappear later and recur the next day." This waxing and waning, this inconsistency in the same patient in the same day is typical of almost all findings ofM.E./CFS.

Night Vision Loss: Patients frequently complain of night vision loss. They stumble in their own homes and at times have a manner of walking that resembles that of tabes dorsalis patients of another era. As in tabes dorsalis, the normal proprioception cannot come into play without a visual reference. Colour Vision: We have had patients complain of colour appreciation changes, of a loss of colour intensity. On examination, we have at times noted onesided and bilateral loss of colour vision. We have had one patient with no history of colour blindness but who developed red green blindness and when verified one year later was normal. We rarely examine patients for colour blindness unless they have a particular complaint. At present, we have no way of telling if this visual variation predated the illness, is a common feature of M.E./CFS or is simply a normal variant.

Double Vision: Patients will complain of double or blurred vision, particularly when tired. This, at times, has been associated with obvious lack of parallelism. External Ophthalmoplegia: Described in the London Free epidemic as "common, usually affecting one or both sixth nerves and occasionally the third nerve".38 We frequently observe failure of the two eyes to track together. Internal Ophthalmoplegia: We regularly observe abnormal contraction and enlargement of the pupil and assume injury of the iris or ciliary muscle (third nerve) dysfunction. It is usually one-sided.

Palpebral Oedema: This is usually one sided and usually on the left side.13

Central Visual Dysfunction Tearing and Dry Eyes: Patients will complain contrarily of inappropriate and excessive tearing and at the same time of lack of sufficient tear formation or excessively dry, irritated and even painful eyes. The excessive tearing is usually short-lived and is replaced by a dryness of the eyes. In effect, all of the mucous membranes tend to dry, including buccal and vaginal, developing a situation that can be mistaken for Sjogren's syndrome.

Visual Comprehension Dysfunction: The primary central visual dysfunction is equivalent to the auditory dysfunction mentioned above. The patient fails to integrate and store visual information in a meaningful way. As mentioned, the single area of major cortical damage in M.E./CFS appears to be in the posterior left parietal lobe20, the area that integrates and interprets visual and auditory sensory information. This dysfunction provokes the following problems:

Tunnel Vision: At times, an M.S. patient with central optic nerve injury will direct her gaze to the peripheral areas. We see the reverse in M.E./CFS patients. Early in the disease process, we infrequently have patients mention that they are looking at the world "through a tunnel". Because it sounds so bizarre, most patients will not describe this for fear that the physician will believe that they are psychiatric patients. This complaint may be associated in some cases with peripheral scotomas, but the presence of scotoma is not sufficient to explain all of the cases. Many patients without describing tunnel vision will mention loss of peripheral vision. Loss of normal peripheral vision represents a frequent problem for a car driver with M.E./CFS.

Reading: Some patients are so damaged that they permanently lose much of their ability to comprehend easily what they read. For most patients, this disability occurs significantly during the initial stage from 0-6 months and then improves to reach a new plateau, subjectively below their previous level. This can be a catastrophe for students or those who depend upon reading for their livelihood. Writing: To write, one must not only have the ability to recall, but also to read and comprehend what one has written. M.E./CFS patients can make ridiculous spelling and grammar errors and fail to notice these

49

The Clinical and Scientific Basis of M.E. / CFS

omissions, e.g. leaving out the verb structures in a sentence, difficulties in spelling or comprehending simple words like "and". There appears to be a cross over effect in which patients have improved writing skills with their non-dominant hand compared to healthy controls. Many of these patients develop a deformed handwriting consistent with that of brain damaged patients. Like many of the symptoms of M.E./CFS, this too waxes and wanes. Early in the disease, there is frequently a rapid deterioration in the handwriting ability over the time it takes to write one or two pages. Distance and Spacial Dysfunction: Human brains interpret distance not only by parallax but by the complex ability to recall, associate and compare appropriate visual and visual memory cues. Perhaps no sensory linked function is so important in the busy urban world. Our depth and speed perception is essential as a guarantee of our safety. These functions, working in tandem, interpret motion, speed and vector. They protect us as much in crossing a road as they protect the integrity of a teacup when we place it upon a shelf. The following problems are frequently mentioned by patients: (a) Jay walking: Inability to jay walk or cross streets without a light, due to loss of ability to judge speed, distance, deceleration and vector. This problem has not only been the cause of patients walking into moving automobiles, fortunately with only their dignity ruffled and a few bruises, but also of the death of one young girl who walked or fell into the path of a train and perished. All of these visual perception problems are aggravated by mind altering medications.

steps seems somehow to confuse the individual's perception. It may be related to height sensing mentioned next. Depth of Field Dysfunction: (a) Height Sensing: Inability to judge the position of the road or floor when either stepping off a curb or descending a stair. Patients have particular problems at the bottom of a moving escalator. Many twisted ankles occur due to this disability. It is common for patients to fall while descending stairs as they not only have problems with distance judgement but also suffer from an associated vertigo. (b) Irregular Walking Surface: Many patients have positional difficulty particularly when walking on fields or unpaved surfaces, since they tend to fatigue particularly easily due to the necessity of concentrating all of their judgement abilities. This problem is exaggerated by lack of adequate light and/ or fatigue. (c) Wall crashing: Patients routinely walk into the door jamb or wall rather than walking through the open door. (d) Mending: Inability to judge position of button holes, threading needles and finger position. (e) Dishes: Patients regularly crash dishes into the shelf, misjudging the shelf position and at times breaking the dish. Reversals:

(b) Traffic motion: This inability to judge the speed and position of cars coming from the side occurs equally with drivers or passengers. This does not seem to bother drivers as much since they tend to lose their lateral vision and don't even see cars from side roads or passing cars. However, it is difficult for drivers of an M.E./CFS passenger who is vociferously demonstrating his inability to judge the deceleration or acceleration of an approaching automobile.

If this occurs, it happens in the first days of the illness and is most infrequent. We are aware of four patients who complained of such short term reversals of vision. In one case, a respirologist complained of leftright reversal. He had fallen ill with Acute Onset M.E./CFS, and, early in the disease, attempted to continue working. While driving home, his view of the road became reversed. Fortunately he ended up in a snow bank. On SPECT and QEEG he had a lesion in the left visual cortex. He has remained severely ill and bed-ridden for the past 4 years. The others all had vertical reversals lasting less than one hour. One case of Dr. John Richardson was hospitalized for one week with a vertical reversal.

(c) Repeating: Sometime, particularly when descending an escalater or a walled staircase, the last step seems to repeat itself and the patient stumbles. This repetitive visualization of identical

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B. Hyde, MD, A. Jain, MD

Clinical Observations of Central Nervous System Dysfunction in Post-Infectious,.. .M.E. / CFS

Clouding: This frequently described phenomenon resembles an opaque or milky film or veil sensation bilaterally covering the field of vision. It is as though the individual had a turtle-like opaque film that covered the eye momentarily. This phenomenon lasts seconds and can recur through the various stages of disease.

Visual-Auditory Dysfunction Television: When most people are ill, they can at least read a book or watch television. In the first few months of disease, M.E./CFS patients have difficulty even watching a T.V. sitcom and following the story line. This combined visual and auditory dysfunction is particularly obvious at this simple level.

Seizure Activity: Two of Britain's leading M.E. /CFS experts take opposing positions regarding seizure activity. We have heard Professor Peter Behan categorically state39 that there is no seizure activity in M.E /CFS while Dr. John Richardson, who has continually followed M.E. / CFS for longer than any living clinician, states that all M.E. / CFS patients by definition have seizure activity. We are totally in agreement with John Richardson. It would be worthwhile for a clinician to briefly review a pictorial view of seizure activity such as that of CIBA's Frank Netter, perhaps the world's best known illustrator of the central nervous system, which clearly indicates these seizure forms.40 utilizing a QEEG scanner i.e. a computer driven EEG.

Our conception of CNS seizure activity has been highly modified since the mid- 1930's by technology. Up to that time seizures were known by their clinical description or by activity stimulated by implanting electrodes or stimulating certain areas of animal and human brains. In the early 1920's, a German scientist, Hans Berger (1873-1941) discovered that human brains produced an electrical activity that could be recorded and measured by an electroencephalogram, or ECG. At that time, clinicians and scientists in their wisdom rejected the possibility that the brain could have such electrical wave activity41 and it was not until the late 1930's that this opinion began to change when two British scientists discovered the same principal. By the early 1940's the revolution was so complete that, if a seizure activity could not be documented by EEG, it was considered to be a form of conversion hysteria. It is easy for a physician to forget that the EEG picks up electrical activity only from the outer 1 mm skin of the upper cortex of the brain and that any central or lower brain activity is not readily accessible to EEG identification.

The appearance of the QEEG (CEEG, BEAM) scan is beginning to modify our concept of seizure activity again. Based upon this new evolving technology, the classification of brain seizures is perhaps about to undergo another revolution. Yet QEEG technology still will not be good enough to measure deep seizure activity. Many of the following clinical seizure observations are still beyond the limit of available technology. During the Initial Stage from 0-6 months, various seizure manifestations occur. EEG changes were documented in 40 of the 48 cases tested from the Royal Free epidemic and Children's Hospital cases by Pampiglione. 42 Although Pampiglione states that these EEG changes tended to persist for years, we have not been able to duplicate those findings with conventional EEG. From personal experience at our clinic, unless one employs a QEEG, the major EEG changes tend to fall off and are difficult to verify after the patient has been ill for 6 months. Using a QEEG, i.e. a computer driven EEG, these abnormalities can be noted for years or perhaps as long as the illness persists.

We routinely refer M.E./CFS patients with obvious seizure activity to neurologists, often in very august institutions, and when the EEG is normal, the neurologist frequently acts in a dismissive manner to the patient and to us, suggesting that this patient suffers from coversion hysteria. Sometimes however, we can record these dismissed cases with seizure activity,

It is our observation that all seizure activity is greater in the Initial Stage (0-6 months) of M.E./CFS and decreases considerably in the recuperation stage (212 months). In the chronic stages, occasional bursts of increased activity may persist.

51

The Clinical and Scientific Basis of M.E. / CFS

We have observed the following seizure activity: Grand Mai Seizure: This occurs rarely and is usually noticed in epidemic situations, e.g.: In a single Gloucester Ontario primary school, reputedly as many as 7 teachers fell ill with typical M.E./CFS during the fall of 1984. In this cluster, one developed typical grand mal seizure. This seizure activity ceased after one year. Absence (Petit Mal) Seizures: Probably all M.E./ CFS patients experience this form of seizure activity. These seizures usually consist of simple episodes usually lasting less than 10 seconds. We have seen these absence spells extended to longer periods in which ambulatory automatism occurs, e.g. A bus driver having left his designated route by several city blocks was awakened by his demonstrative passengers. During this time, the bus driver had unconsciously navigated several busy streets and intersections. We have also noted this behaviour in two cases that extended almost to amnesic lengths, for "several missing hours" in which the patient was not observably "asleep". Frequently the patient is not aware of the existence of these absence spells and a relative or associate must be questioned concerning the history.

Sotomayor35 above, it is the rare M.E./CFS patient that does not experience profuse episodic sweating, flushing or facial pallor. The patient usually complains of the malodorous nature of the sweats. The odour may simply represent a heightened sensitivity with limbic system derangement. The seizure can go beyond this simple description, but when it does, it is seen almost exclusively during the first weeks of the illness. Brain 43 mentions this as a term employed by Penfield, as Diencephalic Autonomic Epilepsy which appears to be due to neural discharge from centres of the hypothalamus. There is flushing of the face, a rise in blood pressure, sweating, dilatation and contraction of the pupils, tachycardia, and retardation of the respiratory rate. Focal Motor Seizures: as noted above. These are frequently noted in the hypnagogic period but can occur at any time during the initial stage. This can involve involuntary movement of both single muscle and/or muscle groups. Neck muscles may go into spasm, twisting the head to one side. Auditory Seizures: These are common and frequently are associated with Menieres Syndrome. The patient has ringing or hissing in the head and may also have associated pain. There is no evidence of external or middle ear disease and although hearing comprehension may be markedly decreased, simple auditory tests are not usually affected.

SIMPLE PARTIAL SEIZURES: These should always be recorded because they may suggest the area of dysfunction. The following seizure activities are routinely recorded. The patient may decline to admit to these if the physician terms them seizures.

Visual Seizures: These are rare outside of the initial and recuperation stages, i.e. 0-24 months. They should not be confused by the peripheral scotomas or photophobia that occur commonly. They are usually described as lightning-like flashes. Very transient microsecond sectional blindness also occurs.

Somatosensory Seizures: The patient complains of tingling or pins and needles in the extremities and face. These can be almost continuous during the first few weeks of illness, can frequently be pressure activated and are sometimes associated with focal motor seizures or single muscle spasm e.g.: left side of the face in one of the branches of the trigeminal nerve. These can be primarily one-sided or bilateral. The most common pattern is that the patient reports diffuse bilateral changes with a marked increase in the left side activity.

COMPLEX PARTIAL SEIZURES: These tend to be episodic, very short-term and frequently dramatic responses. Olifactory Hallucinations: The patient frequently complains of intense and unusual smells that are not apparent to others. This doubtlessly represents a limbic system derangement.

Autonomic Seizures: Described in detail by Leon-

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B. Hyde, MD, A. Jain, MD

Clinical Observations of Central Nervous System Dysfunction in Post-Infectious,.. .M.E. / CFS

Episodic Dysphasia/Dyspagia: The patient has episodic difficulty in maintaining volume of speech. The patient may have spasmodic difficulties of the larynx and upper oesophagus with or without activation by swallowing. This can also be easily triggered by certain foods. These findings tend to occur frequently in some patients, can be quite frightening and have caused laryngeal blocking with certain foods and fatigue.

attacks of tremulousness. They last up to one minute. Sometimes these are so pronounced that the patient feels he is in an earthquake. These can happen day or night but appear more pronounced when the patient is lying down. They tend not to be externally visible and are common even in chronic cases. Psychomotor Attacks: The patient does not lose consciousness but may be amnesic, confused and anxious. This is of short duration, usually persisting for approximately 15 seconds.

Deja Vu/Jamais Vu Episodes: Jamais vu episodes are the more frequent with patients getting lost in their own building or lost driving on a road they normally know well.

Episodic Affective Disorders: Abrupt changes in emotional response frequently triggered by fatigue or multiple sensory input barrages and may consist of inappropriate fear, anxiety, pleasure or happiness.

Uncategorized Seizures: Tremulous Attacks. The patient has subjective

Sleep Dysfunction (also see Addendum

Harvey

Moldofsky)

HYPNAGOGIC & HYPNAPAGOGIC DYSFUNCTION

the respiratory muscles. This paralysis lasts from several seconds to one or two minutes.

Sleep dysfunction is the rule in M.E./CFS but we separate this group as it is so dramatic and different from the usually described sleep dysfunction. This normal dreamlike, delusional period through which the mind passes while falling asleep or awaking is characteristic of several abnormal patterns in M.E./ CFS. This narcoleptic state is common in M.E./CFS.

This form of dysfunction occurs when there is a failure of the normal uniform activation or spread of consciousness and function over the nervous system. The levels concerned with consciousness awaken before the levels concerned with motor function.

Hypnagogic Period (2) Waking Dreams: This could be considered to be the reverse of cataplexy where there is a dissociation of consciousness when the subject is partially awake. At times in childhood, the child may rise from sleep with every evidence of being awake but terrified and still living a dreadful nightmare. At times it takes the comforting parent several minutes to convince the child that this very real experience was simply a dream. Such a state is rarely seen in normal adulthood but exists commonly in M.E./CFS adults and children.

Hypnagogic Myoclonus: Frequent in normal children but rare in adults, these are brusque, sometimes almost violent movements of arms or legs. Sometimes the sleeping partner is kicked or struck while the spouse with M.E./CFS is totally unaware of the incident. They are common in adult M.E./CFS patients. Hypnapagogic Period (1) Sleep paralysis: This cataplexy-like state occurs when the patient awakens and is conscious, but there is a total loss of body tone and an inability to move an arm or leg. This results in a frightening paralysis, as though one had been injected with curare that spared

Thematic Dreams: Usually these dream-like states persist for only a few minutes. However, we have one Chilean patient who awoke, living a dream in which he was a mediator between the Pope and General

53

The Clinical and Scientific Basis of M.E. / CFS

The patient can always be aroused to some extent, may reply rationally, will take food, but cannot be depended upon to stay awake or finish eating any food offered. As soon as the patient is left alone she tends to fall back to sleep.

Pinochet who was still then the Dictator of Chile. This dream state persisted through breakfast and lunch during which time the patient was like an automaton living his dream. Pain Dreams: Another form ofhypnapagogic dream is the pain dream. These hypnapagogic dream states are not common, but they are interesting and we have not seen them described in the literature. They occur in the myalgic form of M.E./CFS. The dream is curious in that it is formless and storyless and consists only of terrible pain localized in one part of the body. One actually dreams of pain. Like any dream, it seems to go on for what appears to be an eternity until the patient awakes fully, only to find that the severe pain persists. This pain can endure for most of the day but is usually over within one or two hours.

The patient tends to lose significant weight rapidly during the initial hypersomnic period. Russel Brain states that hypersomnia is most frequently caused by a dysfunction of the posterior hypothalamus and upper part of the mid brain 43 .

Causes of Insomnia: There is almost no consistent evaluation of sleep dysfunction in the published medical literature although these themes are a frequent topic of conversation among M.E ./CFS clinicians. The following represent our observations. Marked insomnia alternating with episodes of acute narcolepsy is rarely observed in the Initial Stage of the disease process but is the rule in the Recuperation and Chronic Stages of M.E./ CFS. Insomnia is a primary central dysregulation. However, we have noted that when a patient is asked why he doesn't sleep, some of the answers and observations are as follows:

SLEEP DISORDERS Post-encephalitic sleep disorders occur frequently but in M.E./CFS they are the rule and few if any M.E./ CFS patients with a full blown disease escape sleep dysfunction. These sleep disorders with the associated symptoms at times appear uncannily to be taken from a text on encephalitica lethargica. Hypersomnia:

(a) Night Temperature Variation: During normal sleep, the body temperature may fall as much as 2 degrees.44 In M.E. /CFS the patient's temperature is frequently 2 degrees subnormal while awake and one can only wonder if the drop in sleeping temperature is not additive. These patients experience wide variability of temperature, frequently with pronounced sweats while asleep. This unusual nocturnal rhythm disturbs the normal sleep process.

The process starts within days of the illness. It commonly resembles an extension of the short duration hypersomnia associated with an acute viral infection such as influenza. However, in many cases the period of hypersomnia extends so that it resembles that sometimes seen in infectious mononucleosis or, in some cases, encephalitica lethargica. This form of encephalitica lethargica sleep pattern is seen in both adults and children. It appears more dramatic and may even be more common in children. It is difficult to be sure. However, one's heart naturally goes out to children and the anxious parent who is very aware of this situation. The adult who sleeps 18 hours a day at home frequently goes unnoticed unless the patient is in a particular research project. The child who sleeps 18 hours a day becomes the focus of concern.

(b) Night Extremity Hypothermia: Perhaps related to the bradycardia, the extremities, fingers, toes and nose become so cold they start to hurt and this pain awakes the patient. This hypothermia of the extremities also occurs frequently during the day with the onset of environmental cold spells. These patients respond poorly to chilling. (c) Urine Output: Healthy patients decrease urine formation at night, M.E./CFS patients, particularly in the first months, appear to increase urine output. Nocturia is frequently reported in patients

The state of the patient in the hypersomnic state resembles that found in normal sleep. The breathing is normal and does not resemble a comatose state.

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who never previously had to awaken in the night to relieve themselves. The bladder area becomes overly sensitive in the majority of M.E./CFS patients and this pain or spasm also helps to awaken the patient.

these occur day or night but when they occur at night they tend to awaken the patient. (m) Spasm: M.E./CFS's common name in France is Spasmophilie and for good reason since patients frequently have painful spasms associated with their illness. At night, these spasms tend to awaken the patient. While in bed they tend to occur in the foot, the big toe.

(d) Malodorous Sweats: The patient will often complain of the malodorous night sweats associated with this disease. These sweats are more frequent in the Initial Stage. The smell may be real or it may be related to a hypersensitive limbic system.

(n) Light Flashes: These light flashes mentioned as a phenomenon that usually occur during the day, also occur when the patient is asleep. They awaken the patient in the same way that a streak of lightning does.

(e) Nightmares: These vivid colourful and frightening dreams tend to occur primarily during the Initial Stage. The terrifying nature ofthese dreams frequently awakens the patient. They are discussed in greater detail in this chapter.

(o) Causalgia: These intense, short-lived, herpes-like pains, can occur anywhere in the body. Usually they occur during the day, particularly involving the left anterior chest and simulating an acute myocardial incident. When they occur during sleep, they always awaken the patient. This kind of pain is particularly frequent after an active day such as getting out of bed for a physician or hospital visit.

(f) Diurnal Rhythm Inversion: The patient tends to sleep during the day and is unable to sleep during the night. (g) Seizures, Myoclonus and Fasciculations: The abrupt muscular or limb movements wake the patient or the sleeping companion. (h) Sleep Palsies and Paresthesias: These sometimes result in uncomfortable cutaneous sensations that awaken the patient.

(p) Night Headaches: These may be related to cervical spine spasm or can occur as an intense pancephalic exploding headache that occurs during the late night. Frequently these pains awaken the patient at 4 or 5 a.m. Once the patient is out of bed for a few minutes the pain rapidly diminishes and the patient can then fall back to sleep. We have speculated that this may be related to the marked night bradycardia that is known to occur. Holter monitor should be requested.

(i) Fear of Dying: This is just one of many terrifying neuroses that develop due to the initial frightening symptom picture of M.E./CFS. The patients may not have been diagnosed and feel they have some terminal illness. They frequently feel so ill that they assume that this is how one feels just prior to death. This is more than simple malaise and it continues even into the chronic stages of the disease.

(q) Hyperacusis: M.E./CFS patients tend to have marked hypersensitivity to sound and so the patient awakens due to sounds that would otherwise not have disturbed sleep.

(j) Unresolved Conflict or Anger with the Physician: Unresolved conflict is an important component of sleep neurosis. Many patients feel they are abandoned by their physician.

(r) Remembered Sleep Apnia: We have only recorded this in three patients but the patient is frightened and, unlike in cases of classical sleep apnia, the patient remembers the occurrence. This may occur as a hypnapagogic incident, but it tends to occur during the night and not during the normal hypnapagogic period.

(k) Pain on Movement: Some patients are in severe or persistent pain that is worse during the Initial Stage of the illness. Normal sleep movement triggers these pains and the patient awakens. (1) Sensory Seizures or Storms: Referred to by Leon-Sotomayor as diencephalon fits or seizures,

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Narcolepsy: Narcolepsy results from an impaired CNS control of wakefulness and the sleep/wake cycle. To our knowledge, no one has yet published on narcolepsy and the intrusion of REM sleep into the waking state in M.E./CFS but that is simply a question of time and research. Although excellent M.E./ CFS sleep dysfunction studies have been published by Moldofsky, he has only looked at patients in later stages of the disease and neither he nor others have to our knowledge published on any of these fascinating epiphenomena or changes occurring in the early disease stages.

(s) Night Bradycardia and Night Hypotension. Discussed in the following text. (t) Medication Reactions: Patients frequently have adverse reaction to certain medications. Sometimes it is sufficient to awaken the patients or keep them continuously awake. The reaction seldom lasts longer than 24 hours but can be quite frightening to the patient. We have seen this with H2 blocker medications but any medication can provoke this reaction. (u) Cardiac Irregularities: Ectopic or irregular rhythm or heart pain awakens the patient. This tends to occur early in the illness.

Narcolepsy is very common in M.E./CFS. The patient is sleepy much of the day, especially in those periods when normal people also tend to be sleepy, such as after meals. We have noted sleep attacks during the middle of meals, while walking up stairs in an attempt to get to a bed before sleep takes over, where the patient literally lies down and falls asleep at the table or on the stairs. These attacks are usually preceded by an overwhelming desire to sleep.

(v) Ataxia: Patients have awoken due to the sensation that they were in an earthquake. The bed seems to be moving and the patient suffers from marked ataxia. This also occurs less commonly during the day and occurs in short brusque bursts such as an earthquake tremor. At the start of the illness, rarely, these attacks can last for several hours but the episodes rapidly decrease in length as the disease progresses. In recalling this phenomena among the physicians at the Royal Free epidemic, Jane Eden describes these attacks as "what really shook us was the way our beds seemed to lurch and pitch like a coracle crossing a stormy sea. Morning usually brought a calm somewhat tempered by the thought that one must have been imagining it after all."45

M.E./CFS p a t i e n t s are u n u s u a l l y subject to narcolepsy, to sleep attacks, sleep paralysis and hypnagogic and hypnapagogic hallucinations. We have not noted Cataplexy in an M.E./CFS patient.

Dream Disorders It is perhaps incorrect to speak of dream disorders, but there is certainly a change in content, colour and violence of the dreamscapes of M.E./CFS patients. It is also rare for a non-psychiatric physician to take the time to enquire about dreams, but if the question is asked one is told of:

(w) Explosive Stool Loss: Patient awakens having soiled himself and the bedclothes. This occurs only in the Initial Stage. This alphabet of common causes of M.E./CFS insomnia have all been recorded in numerous of our patients.

(a) the intense brightness and colour of dreams; (b) the violence of these dreams; (c) the frequent attack nature of dreams; (d) the frequency of hypnagogic and hypnapagogic dream states; (e) the pain dreams.

Sleep Bradycardia: Similar to sleep apnea in its format except that, instead of a significant decrease of the respiratory rate, in this case it is the significant slowing of the heart below the normal nocturnal decrease. The patient usually awakens during the night due to a significant headache. Once the patient is up for a few minutes, the headache decreases and the patient may return to sleep. These periods are also associated with a marked fall in blood pressure. Holter monitor should be ordered in all M.E./CFS patients.

Leon-Sotomayor suggests that sensory seizures originating in the mid-brain may provoke the unusual dream patterns. 32 As early as 1911, Wickman,46 describing acute poliomyelitis dreams in similar terms and, in 1934, Gilliam,10 describing the dream states

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Clinical Observations of Central Nervous System Dysfunction in Post-Infectious,.. .M.E. / CFS

Courtesy ofRudi Haas, The Egg Carton Zoo

e.g. A male Irish physician had dreams consisting of "murder, bloodshed, mayhem and butchered Caribbean bodies all over the place".

during that first M.E./CFS epidemic, mentions the vivid and increased dream activity. Behan and Behan47 mention that, in their view, sleep disorders are "not accompanied by hypna(pa)gogic hallucinations or sleep paralysis" However, Wallis 48 has noted them in his dissertation, "children continued their dreams on wakening". In our experience, M.E./CFS hypnapagogic dreams are all fairly common features in both children and adults and are worthy of the physician's interest.

e.g. A female social worker described "decapitated heads with blood streaming from their eyes, ears and nose". Curiously, her triggering onset was with epidemic conjunctivitis. e.g. Children dreaming of Pac man-like monsters persistently attacking them.

The M.E./CFS dream is usually an attack dream in which some unseen assailant or inanimate object persists in attacking the patient. The colours are vivid and they are described as being the most brilliantly coloured, the most intense, the most persistently frightening of dreams. Some of the dreams are violent and work related, some explicitly sexual, but never pleasant in nature.

e.g. A secretary in a research laboratory described "My sister had just returned from Africa, thrilled with the boa constrictor she had brought back. However, this large writhing beast, wrapped itself around my neck and arm and threatened to kill me. But I had no sister in reality and I had no knowledge either of anyone coming from Africa or of snakes".

e.g. Rudi Hass, 49 the Austrian artist-photographer suffered from a severe case ofM.E./CFS after falling ill in Africa. This particular case was associated with a triggering attack of what, at the time, was diagnosed as possibly Lhasa Fever or even Apollo fever. He awoke from a dream one morning and, utilising egg cartons, fashioned some of the monsters in his dreams. This is illustrated above.

e.g. A woman writer from Radio Canada related, "It was like Clock-Work Orange. There were toughs breaking into the house. I couldn't call the police because they were part of the group. It was rape and pillage in which I was involved. They broke up and smashed the house. There were people in the dream that were acquaintances. It was like Star Wars, with flashing lights. I awoke huddled in a ball, cringing. My husband was sleeping beside me but the dream continued for another ten minutes and I could not stop it although I was wide awake. The visual part of the dream then stopped, but the terror continued for over an hour."

e.g. An economist would not relate the content of her dreams but to quote her she stated: "My god, they were very ugly, very vivid, very detailed, very coloured, very personal, very oppressive, with dying, death and violence everywhere".

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Pain Syndromes Associated With M.E./CFS Pain syndromes in M.E. / CFS can vary from totally disabling, to occurring only after exercise, to non-existent. When they occur, and that is in over 60% of M.E./CFS patients, the variety of pain syndromes can be legion. The very number of them can cause grave anxiety to the patient and help create skepticism on the part of the physicians who frequently believe that no one in their right mind can have this many symptoms. Physicians have been trained to associate pain with local or referred pathology. They almost never associate or ascribe pain as a central dysfunction. Once they have scrupulously investigated pain for its possible cardiac, surgical or malignant origins they tend to feel impugned if their search has revealed no local pathology and fall back and blame the patient for the pain syndrome by terming it hysteria, conversion hysteria, or somatization . Some of these pain symptoms may result from peripheral nerve and end organ derangement. More likely, the majority of these pain syndromes are manifestations of central pain receptor deregulation or injury. The sheer number of pain syndromes suggest that the amygdala in the limbic system, the right posterior central gyrus of the parietal lobe as well as the posterior tracts of the spinal cord could all be affected. The very chronicity of these pain syndromes cautions physicians from creating a dependence upon narcotics. Muscular Rheumatism, T. Sydenham, 1681 50 head and extremities. The rapid muscle and brain fatigue that is normal in M.E./CFS becomes accentuated.

"The pains are sometimes in one part, sometimes in another; they seldom are attended with fevers. They are less fixed to one spot, are more erratic, and more uncertain. At times it afflicts this or that joint; at times the inward parts only. Here it produces suffering, which suffering goes off when the point again transfers itself outwardly, then it harasses the patient in turns, and prolongs itself to the duration of the most chronic amongst the chronic diseases."

This malaise is often exaggerated or cumulative in association with specific events. It occurs as a rule after any physical exercise that goes beyond the normal everyday work output. Malaise may occur often in place of what would have been an infectious illness, e.g. all of the family comes down with an influenza or simple sore throat and cough. The M.E./ CFS patient may come down with no external symptoms of an infectious illness although one would anticipate such an event since everyone else in the family is ill. The M.E./CFS patient simply develops this terrible malaise, e.g. We see this often when a child in the family falls ill with chicken pox. The healthy adult who is immune, due to an earlier varicella infection, is usually symptom free, - not so the M.E./CFS patient. The M.E./CFS patient develops a severe malaise and not only encounters all of the above problems but often becomes bedridden for no apparent reason unless the physician has seen this varicella effect before.

The t h r e e m o s t i m p o r t a n t M.E./CFS p a i n s y n d r o m e s are the following: (1) Malaise "Malaise has probably occurred in every epidemic described in the literature" 81 . Malaise is accentuated in the Initial Stage and it recurs for as long as the disease process exists. Malaise is almost impossible to describe. It is often referred to as the pain and discomfort that one has during the acute phase of an influenza. However, it is not always the same. The patient feels terrible, feels as though he is about to die. There is no fever as in influenza nor dimming of consciousness that, mercifully, usually occurs in the malaise of a febrile influenza attack. The malaise tends to wander, to wax and wane. It particularly injures the sensory and dulls the cognitive abilities of the brain. The pain seems to originate everywhere, both on and within the chest and abdominal areas,

The patients term these probably infectious equivalents "crashes". Many M.E./CFS patients will inform the physician that since they fell ill with M.E./CFS five years earlier they never once had a typical "cold" or external sign of an upper respiratory infection. They most likely will have had many "crashes".

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(2) Lower Cervical, Upper Dorsal Pain

moderate to severe bilateral pain in the occiput and in the area "behind the eyes". The patients sometimes describe it as a feeling of having been clubbed.

It is the most frequently encountered chronic pain and it tends to continue well into the chronic stages. This is discussed in the text and tends not only to be a persistent form of pain but also possibly triggers the chest wall pains and the chronic occipital pain that so frequently occur in M.E./CFS patients.

Expanding Head Pain: Different from the encephalitic-like pain, it lacks the prostration and fever but is nevertheless a total head pain which the patient describes "as though my head were expanding and blowing up".

(3) Bladder, Genitalia Pain and Discomfort in Women

Ear Pain: This pain is very short lived, lasting at times only for seconds, severe and worse during the Initial Stage. Referred to in England as tensor tympani pain, it consists of a precise needle like pain primarily in one ear. Less frequently, this phenomenon occurs in the nose. The same type of pain occurs very frequently in the bladder area and less frequently in the anus. It occurs as a spasm where there is a potential muscle sphincter.

This also is discussed in the text. However it is the singularly most misdiagnosed pain symptom that leads to sometimes drastic and unnecessary intervention. Since nothing is found on these interventions, the patient is usually blamed as being hysteric or seeking surgery, whereas it is really the physician's ignorance of this almost constant pain association in M.E./CFS. Since this pain at times is associated with interstitial cystitis where a vein in the wall of the bladder mucosa may rupture, this appearance of blood may be incorrectly interpreted as either infectious or more sinister pathology. Nota Bene.

Ophthalmic Pain: M.E./CFS patients frequently complain of photophobia with eye pain or discomfort. Cursory exam will reveal that these patients' pupils expand rather than contract when a penlight is shone into their eyes. The pupil movement tends to be irregular and cogwheel-like.

The following is a review of the common pain syndromes encountered in M.E./CFS patients.

Also, frequently due to the decreased tearing usually present, the patient will have irritated his eyes due to excessive rubbing. These dry eyes should be treated with artificial tears.

These pain syndromes frequently come in "storms" in association with other dysfunctions already noted. Cephalgias and Other Head Area Pain: It may seem unusual to catalogue pains, but they are a principal part of many patients' disability. These too occur in storms and when that occurs they can lead to a diagnosis of panic attack. These cephalgias tend to be more dramatic during the early part of the illness and the intensity of the pain tends to decay with time. With the exception of the encephalitic pain, all of these pain syndromes are fairly common if the patient is affected with a myalgic form of the disease.

Tooth Hypersensitivity Pain: This is common and the patient may develop both heat and cold sensitivity. Spike-like Pain: This is described by Thomas Sydenham 51 in 1681 as Clavicus Hystericus and again by Gilliam in the 1934 epidemic52. Sydenham writes, "Often times, it attacks the exterior of the head, creating intolerable superficial pain; so isolated, however, as for the thumb, laid across, to cover it. Here it keeps fixed. This is the Clavus Hystericus. So boring and so severe as to feel as if an iron nail were being driven in." In the scalp, this site frequently gives rise to an eliptical bolus that can usually be rolled around under the finger. It may be a fibromyalgia equivalent. This severe pain occurs anywhere on the scalp and sometimes the extremities and is described by the patient as a nail being driven into the body. The pain is of moderate duration and maximum intensity, rarely lasting longer than one hour.

Encephalitic Pain: The earliest type of pain, if it occurs, is one of encephalitic intensity with severe prostration. This occurs in only a small percent of patients. Most Common Head Pain: The most common and prominent pain complaints are of dull, persistent,

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already noted, may also be associated with spasm in the oesophagus and duodenal sphincter that we frequently record. These stomach area spasms are so common that a good number of our patients arrive with cimetadine or other H2 antagonist treatment, not for their central effect, but for suspected ulcer disease.

Fibromyalgia Pain: Associated with pain in the typical fibromyalgia sites of the body. The patient can frequently roll a painful, ellipsoid object under the finger, even under the scalp. These are probably not lymph glands. They frequently occur in "sensory storms". They tend to move about the body in any one storm. Both the storm and the pain tends to be wasting.

Both single muscle and muscle groups may be involved. There is, early in the disease, the cramp like kick in the area of the left diaphragm that is described like a baby kicking in a pregnant woman. This frequently arises immediately after eating and often results in the physician ordering an upper GI series. Nothing is found on X-Ray. The spasm of irritable bowel syndrome is common and is discussed elsewhere.

Formifieation: Formification means the movement of ants. This is perhaps one of the most frightening of any of the pain syndromes. Fortunately it is not common. It occurs during the Initial Stage only, and patients have described it as the swarming of bees, buzzing and moving within the head and reaching down into the spinal cord. Patients tend to be terrified with this symptom. When it occurs it may last up to a few hours. It rarely repeats itself more than two or three times. It may be a cause of severe panic and possibly suicide.

We see this spasmodic pain in tendons and have recorded a very few tendon ruptures, usually in athletic individuals early in the disease. This spasmodic pain is frequent in the long strap muscles such as the sternocleidomastoid muscle in the anterior triangle of the neck, the sartorus, the calcaneal (Achilles) tendon and gastrocnemius muscle. When the spasm occurs in the neck, the head is usually turned painfully to that side. In the extremities this can be observed as bunching of tissue, pain and sometimes bruising.

Cervical Pain: There are few M.E./CFS patients, even when the non-myalgic patients are considered, who do not describe the nagging pain in the cervical spine area. The pain tends to be localized from C4 to T3 and can persist even into the chronic phases of the disease. It is perhaps neuralgia from this area that extends itself up into the occiput and down into the anterior and posterior chest wall.

A frequent spasm occurs in the foot and great toe. The great toe is dorsiflexed and frequently the whole foot is in spasm. This also occurs when the patient is in bed. It sometimes awakens the patient who has to get out of bed to massage or stand on the foot. The spasm lasts a few minutes only. In the London Free Epidemic, many somewhat humorous photographs appear in one of the publications demonstrating great toe spasm. Both this and carpal spasm are a common feature of M.E./CFS.

Sore Throat: Many patients will describe recurrent sore throats with M.E./CFS. This is quite distinct from "bacterial pharyngitis" where an obvious infection can be cultured. The most common cause of this discomfort is the associated Sjogren's-like syndrome. The patient has the typical lupus-like rash, dry eyes with decrease in tearing, and a concomitant dryness in the buccal area caused by an apparent decrease in activity of the buccal glands. They have dry mouths and sore throats. It is usually an error to treat these cases with antibiotics.

Chest a n d Abdominal P a i n

"Spasmophilic" Spasm Associated Pain:

Pain in this area can be easily broken down into:

It is this symptom that gives rise to the common French name for M.E./CFS, i.e. Spasmophilic, meaning muscle spasm. Localized spasmodic or tetanic muscle spasm is common in this disease. The muscle sphincters are particularly prone to persistent pain of this type. This spasm, in addition to the areas

Fibromyalgia Pain: This is described under Cephalgias. However the prominent area of pain is on or in the chest wall. The sensitive neck and axillary gland pain often described is probably related to fibromyalgia rather than lymph gland pain

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in most cases. The classical fibromyalgia points are noted although most of the forms are incomplete.

Some patients have an associated myocarditis. Many patients with M.E./CFS have an associated mitral cusp prolapse. This finding is not taken very seriously in North America but either patients with mitral cusp prolapse are particularly prone to falling ill with M.E./CFS or it comes as part of the disease process. Dr. John Richardson has a film of a patient with acute onset M.E./CFS who did not have prolapse prior to falling ill and on open heart surgery was shown to have freshly ruptured chordae tendinae attached to the mitral valves.

Sentinel Point: A sub-variety of fibromyalgia may be the quixotic fusiform swellings that come and go, usually in the left chest and axilla and less commonly in other locations. These swellings can cause intense local pain, occur in "attacks", can be rolled under the finger, and then, after an hour or two, the swelling decreases and the acute pain with it. Although pain can be raised on palpation of this area at any time, moderate residual pain from the "attack" can follow in this area for several days. There is one specific site, usually locate superior and medial to the left nipple, that may occur in patients who have few other fibromyalgia-like points. Early in the disease, frequently the patient will be seen, holding his left chest, often hand under the shirt in a Napoleon fashion. This point is one of the few that has been known to persist for weeks, months and even years. When this point occurs in the designated location in a woman, frequently that woman is biopsied for possible breast malignancy. It occurs less frequently in other areas.

Many patients have left and, less frequently, right diaphragmatic pain with tenderness on palpation. Abdominal pain: In addition to the diaphragmatic pain, about twenty percent of the patients will have an acute or gradual onset of irritable bowel syndrome with all of the discomfort that this implies. Urogenital Pain: But by far the most common abdominal pain occurs in the lower abdomen and particularly the urogenital system as described at the onset of the pain section. This symptom is definitely worse in postpubertal females and is associated with any and every form of menstrual irregularity and cessation. Part of the pain in women is in relation to a typical "perimenstrual" distress syndrome with all the symptoms and changes that occur with that condition.

Causalgia and other Neuralgic Pain: This lancing pain is sharp, severe and brief. The patient usually describes it as like a cattle prod or electric shock. They are not uncommon in Myalgic Acute Onset forms of the disease. They are seen frequently in those patients who start their disease with Borneholme's disease, but can occur independently of this syndrome.

So consistent is this pain area that it is rare to find a woman with chronic M.E./CFS that has not had surgery or at least a cystoscopy and multiple genitourinary exams to evaluate the cause of the pain. Almost all of these women will have been placed on antibiotics for suspected urinary tract infections. The principal element is probably severe muscle spasm. A high degree of interstitial cystitis is seen in this group.

Borneholme's Disease "For this be sure, tonight thou shalt have cramps, Side stitches that shall pen thy breath up." The Tempest, l.ii., W. Shakespeare

Although it occurs considerably less frequently in men, when it does occur it is usually misdiagnosed as prostatism despite the young age of the general population. The patients, both men and women will complain of pain, sometimes excruciating pain, urgency, difficulty in starting and stopping the stream, frequency, incomplete voiding and nocturia. There is also frequently sharp pain in a specific site of the penis. Many males will also describe erectile impotence. When this occurs it is usually only in the early

In addition to those chest pains mentioned, some M.E./CFS patients start their disease as Bornholme's disease, also known as intercostal neuralgia. These patients tend to have a persistence of their chest pain syndrome and the accompanying neuralgia. Perhaps the most succinct description of this disease as a prelude to M.E./CFS appeared in a letter to the editor by J.A. Cotterill in The Lancet, on June 9, 1973. It is well worth reading.

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stages of the disease. Women during the same period will describe failure of sensation and orgasm.

Sigurdsson 53 in which polyarthritis developed after this illness in a number of cases.

Adolescent children will also have urogenital symptoms and they are often associated, even in early teenage, with the onset of bed wetting. It is understandable that physicians will mistake this for urinary tract infection. Serial urinalysis will clarify the non-infective nature of this complaint. Blood should not be considered a necessary sign of infection but of a possible interstitial cystitis or vein rupture in the bladder wall. This symptom will last for weeks to years.

Bone Pain: This pain is described in the bones of the extremities. We don't know if it actually originates in the bone. The pain is so intense that frequently the physician sends the patient for an X-Ray and of course nothing is found. The pain tends to persist into the chronic stages of the disease but is worse in the initial stages. This pain is described as bone breaking as in "break bone fever" or as one encounters in an expanding bone lesion. As severe as it is, it does not persist, rarely lasting longer than two hours. It then rapidly disappears leaving no pain sequelae.

P a i n i n the E x t r e m i t i e s Muscle Pain: One of the old names of M.E./CFS was muscular rheumatism. There are three forms of common muscle pain.

Hypothalamic Dysfunction Pain: Patients will not only complain of severe episodic sweats but also of severe blanching of their extremities, nose, ears, lower arms and hands as well as lower legs and feet. Observation will often reveal a blanched clearly demarcated line separating warm from icy cold tissue. The whitened extremities may persist for hours and can be extremely painful.

(a) The patient complains of feeling as though he had been beaten with an axe handle. He feels bruised and hurt. This pain lingers for several hours and then departs, usually only after the patient has slept. It is sometimes associated with a dull generalized headache as well as an increased inability to concentrate.

Rarely, this also occurs as isolated spots anywhere on the torso or upper extremities. It is quite curious and again a clearly demarcated line can be drawn around the cold spot. This rarely persists longer than an hour. Infrequently, these cold spots turn brown, or bruised the next day as though the patient had been hit by a Lacrosse ball in full flight.

(b) The second pain is very similar to spike-like pain that has been described in the head The patient will describe a severe pain, usually in the main muscle mass in the leg, extensors or flexors. It is described as a nail or as though a knife or arrow had been stuck into the leg although it can occur anywhere. This pain tends to last a few hours and then abate.

A variation of this hypothalamic dysfunction occurs with a complete diencephalon seizure discussed earlier.

(c) The third is associated with particular muscle group use. e.g. When a patient does highway driving for considerable distances, he will frequently develop "foot drop" and associated pain. This usually resolves over a few days. It is also seen in the extensors of the leg and in the shoulder muscles after shopping. Frequently, the painful muscle can be palpated and is hard and swollen.

Periarthritic Pain: This type of pain is sufficiently common to have had several M.E ./CFS patients diagnosed as having incipient rheumatoid arthritis. Since M.E./CFS is routinely associated with a lupus like submaxillary rash and elevated rheumatoid or ANA factors, it is an honest mistake. These patients tend to have low sedimentation rates and the swelling in the joint is never red, nor hot, nor is there ankylosis.

Emotional Dysfunction Of the approximately 60 M.E./CFS epidemics noted in the literature there is not one which does not describe the acute onset of emotional dysfunction. In 1951, Pellew in Australia, 54 described two patients hospitalized at the same time in the same hospital.

The patient routinely indicates the knee and elbow and makes the physician think in terms of an arthritic process, whereas, in most cases, they are dealing with a periarthritis. This is mentioned by

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One had paralytic poliomyelitis and the other M.E./ CFS. After two months, the poliomyelitis patient was almost totally paralysed except that he had some movement in his right great toe. He was described as "the most cheerful patient in the ward". Whereas the M.E./CFS patient over two months totally recovered his muscle power "but was extremely irritable and almost melancholic."

rational decisions. Anatomical and physiological damage to the centres of the brain that affect emotional control should be considered, as injuries to other areas of the brain are considered. One does not have an injury to the motor functions of the brain due to the fact that the patient's mother did not love her or that she had been depressed. One has an injury to the motor functions of the brain due to an infection, or immune injury or other physical and pathological change. Injuries to the areas of the brain affecting emotion are of the same nature as those that affect physical function. It is time for all physicians to put away their emotional copy of the Ebers papyrus and to accept the infectious and immune theory of disease as a cause for much emotional dysfunction.

This abrupt change from a person with a normal emotional control to one of pathological emotional dysfunction is noted in every epidemic. Gilliam, in one of his classical lines, states that "the emotional upsets - varied in degree from relatively slight displays of irritability and impatience to violent manifestations of dislike for people and things formerly liked...crying spells resulting from no known provocation." 55 Sigurdsson notes "complaints of nervous instability, irritability were conspicuously frequent for months after".56

Summary This overload of symptoms and complaints follows an infectious disease in a patient with no previous history of similar episodes. These changes not only cause severe and chronic anxiety even in the most phlegmatic of patients, but also tend to be too much for most treating physicians. It is because of all these unmanageable complaints that the patient becomes more persistent of the physicians time and the physician becomes more frustrated and more skeptical.

Some physicians have jumped upon this emotional dysfunction as an explanation of the entire disease in the same way that some physicians have looked at muscle dysfunction or loss of respiratory control or hyperventilation. M.E./CFS is a diffuse brain dysfunction. There seems to have been a separation of emotional function from that of all other brain functions as far back as 1900 B.C. (Kahun Medical Papyrus)57 and 1550 B.C. (Eber's Papyrus). 68 From that period until the time of Augustine the emotions were considered to reside in a woman's uterus (the hysteria). We noted earlier that this mentality persisted until the 1950's when Marinacci observed that "cases who had a hysterectomy in 1938, in the hope that the mental symptoms would be relieved, but the procedure was not beneficial".59

Passed off for years as hysteria, somatization and anxiety neurosis, this chronic disease state with all of these sensory changes can only be explained in terms of an acute injury to the brain resulting from an infectious or other CNS injury and in a chronic dysfunctional aftermath. We have completed this partial symptom list since, to our knowledge, no such bibliography of M.E./CFS CNS dysfunctions exist in the literature. Patients with an insidious onset may have this symptom picture as well, but much more frequently they will more closely resemble a more blunted chronic stage of M.E. with disability but little of the extremes of sensory and cognitive derangement described here.

Injury to the left frontal lobe and at times both lobes is increasingly documented in QEEG, SPECT and PET scans of the M.E./CFS brain. In 1991, we won a Supreme Court decision in Alberta 60 by demonstrating frontal lobe and limbic system damage in an M.E./CFS patient who had lost the ability to make

References 2. Marinacci Alberto, Applied Electromyography, chapter. The Value of the Electromyogram in the Diagnosis of Iceland Disease, Lea & Febiger, (1968)

1. Jamal G. Hansen S. Journal of Neurology, Neurosurgery and Psychiatry 1985; 48:691-694

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3. Marinacci A.A. and Von Hagen K. Bulletin of the Los Angeles Neurological Society, Vol 30, No 4, part 1, December 1965, page 166-7

20. Ramsay A.M. Encephalomyelitis in North West London, An endemic infection simulating poliomyelitis and hysteria, The Lancet, Dec 14, 1957, page 1197

4. Leon-Sotomayor L., Epidemic Diencephalomyelitis, Pageant Press, 1969, page 85

21. Renoux G. Renoux M. (pg 17-19) Immune modulation agents and their mechanism, R.L. Fenichel and M.A. Chirigos, Marcel Dekker Publisher (1984)

5. Van Wart, R. Courville C, Hall E. (1934) Epidemic of Poliomyeltis in Los Angeles, American Journal of Public Health, Vol 24, Number 12, Dec 1934, 1207-1209 6. Pellew RAA. Clinical description of disease resembling poliomyelitis, seen in A d e l a i d e , 1949-1951, (1951) Med.J.Australia, I, 944-946

22. Leon-Sotomayor L., idem (11), pages 88-89 23. Sydenham, T. The Works of Thomas Sydenham, Latin Edition of Dr Greenhill (translated by R.G. Latham), The Sydenham Society, 1848 24. Marinacci A. Von Hagen K. idem(3) pg 165

7. During the 1984 pandemic a sural nerve biopsy was taken from a Nova Scotia physician suffering from M.E./CFS inDecember 13,1984, reported by Dr King of the Victoria General Hospital, Halifax, Canada. The immuno-fluorescence was reported by Dr T. Ghose

25. BastienS. Loss of verbal and performance I.Q. paper given at Vancouver Workshop on Research Directions, UBC. May 1991, 26. Pellew R.A. A , idem (6) page 944

8. Richardson J. The Cambridge Symposium on Myalgic Encephalomyelitis (M.E.) April 9-12, 1990

27. Leon-Sotomayor L. idem (11) page 15

9. Demitrack M.A. et al. Journal of Clinical Endocrinology and Metabolism, December 1991

28. Goldstein, J. Chronic Fatigue Syndrome and Fibromyalgia Pathogenesis and Treatment, First International Conference, Los Angeles Biltmore, February 1990

10. Gilliam, A.G., Epidemiological Study of an Epidemic, Diagnosed as Poliomyelitis, Occurring Among the Personnel of The Los Angeles County General Hospital D u r i n g T h e Summer of 1934,Public Health Bulletin No. 240, April 1938, The United States Public Health Service, page 15

29. Bastien S. idem (25) Discalculia 30. Itchese, paper given at Vancouver Workshop on Research Directions, UBC. May 1991

11. Leon-Sotomayor L., Epidemic Diencephalomyelitis, Pageant Press, 1969, page 10

31. Gilliam A.G. idem (10) page 15

12. Behan P. Hamilton Ontario Speech, Oct 1991

32. Leon-Sotomayor L., Epidemic Diencephalomyelitis, Pageant Press, 1969, pagesl5-17

13. R. Douglas Collins, Laboratory Diagnosis, J.B. Lippincott, (1968) page 37

33. Ramsay A.M. idem (20) page 1199 34. Medical Staff of the Royal Free Hospital, An outbreak of encephalomyelitis in the Royal Free Hospital Group, London in 1955, British Medical Journal(1957) 2: 895-904

14. FudenbergH.H. Chronic Fatigue Syndrome and Fibromyalgia Pathogenesis and Treatment, First International Conference, Los Angeles Biltmore, Los Angeles Biltmore, February 1990

35. Leon-Sotomayor L.

15. Hyde B.M. Chronic Fatigue Syndrome and Fibromyalgia Pathogenesis and Treatment, First International Conference, Los Angeles Biltmore, Los Angeles Biltmore, February 1990

36. Richardson J. Newcastle-upon-Tyne Symposium, 1989

16. Gilliam, A.G. idem (10), page 23

37. Pellew R.A.A. A Clinical Description of a Disease resembling Poliomyelitis seen in Adelaide 1949-1951, The Medical Journal of Australia, June 30, 1951 pg 944-946

17. Leon-Sotomayor L., idem (11), page 119

38. idem (23) page 896

18. Gilliam idem (11), page 24

39. Behan P. , Hamilton Ontario Speech, October 1991.

19. Dunnet BMJ, 1963,1,1187

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40. Netter F. The CIBA Collection of Medical Illustrations, Vol 1, Nervous System, Part 11 1986, pp 43-45

49. Haas R. Blohm H. Suzuki D. Egg Carton Zoo, Oxford University Press, (1986)

41. BergerHans 1873-1941, (German inventor of EEG), see Isaac Asimov's Chronology of Science and Discovery, Harper & Row, page 504, (1989)

50. Sydenham, T., The Works of Thomas Sydenham (translated from the Latin edition of Dr Greenhill, London (1848) 51. Medical Staff of the Royal Free, idem (34), page 902

42. Pampiglione G., H a r r i s R., Kennedy J., Electroencephalographic investigations in myalgic encephalomyelitis Postgraduate Medical Journal (November 1978) 54: 752-754

52. Gilliam A.G. idem (8)

43. Brain W. Russell, Diseases of the Nervous System, Oxford University Press, second Edition, 1942, page 819

53. Sigurdsson Bjorn et al. A disease epidemic in Iceland simulatingpoliomyelitis, American Journal of Hygiene, vol 52, pp. 222-2238, page 234

44. Brain W. Russell, idem (43) page 831

54. Pellew R.A.A. idem (37) page 945

45. Eden J. We called it the pestilence, World Medicine, June 15, 1977, page 25

55. Gilliam A.G. idem (8) page 24 56. Sigurdsson Bjorn idem (53), page 238

46. Wickman I. Acute Poliomyelitis (1913) The Journal of nervous and Mental Disease Publishing Company, New York.

57. Kahun Papyrus, see introduction, The Papyrus Ebers: the greatest Egyptian medical document, Translated by B. Ebbell, Copenhagen: Levin & Munksgaard, 1937:108

47. Behan P. Behan W. Post viral fatigue syndrome, a review. CRC Reviews. Cleveland, Ohio: CRC Press, 1988

58. Ebers Papyrus, idem (57) 48. Wallis A.L. An investigation into a n u n u s u a l disease seen in epidemic and sporadic form in a general practice in Cumberland in 1955 and subsequent years, Doctoral Thesis submitted to University of Edinburgh (1957).

59. Marinacci A. idem (3) page 163 60. Transcript of Alberta Supreme Court Judgement, August 1991, Appeal, November 1991

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Chapter 6 M.E. / CFS: The Physical Signs of Disease Byron Hyde, MD, Anil Jain, MD (Please see Chapter 5 for Dr. Hyde's photograph and curriculum vitae. Please see Chapter 4 for Dr. Jain's photograph and curriculum vitae.) M.E. / CFS patients may demonstrate a multitude of physical signs both of the prodromal illness and the chronic features of their disease process. Knowledge of these physical signs,along with a good history, often provides sufficient information to make a clinical diagnosis of a complete or classical M.E. / CFS. Increasingly, we are able to support our clinical diagnosis with laboratory tests, brain imaging and neuropsychological testing. When the patient is a poor historian, or if we are dealing with an incomplete form of the disease process, we are increasingly able to lean upon these testing procedures to assist us in making that diagnosis. The problem of supporting a diagnosis with testing procedures is no longer a doubt, it is however often an exercise in access, affordability and frustration for both the patient and physician. This chapter is divided into the following sections: (1) Prior Illness: Frequently patients will note an unusual earlier illness that occurs from 3 months to two years prior to the prodromal illness. (2) Prodromal signs: The prodromal signs result from an acute interaction of the virus and a host that may be immune compromised. This response usually occurs independently of the host's interaction with his external environment. (3) Chronic M.E./CFS signs: These are the characteristic physical signs of M.E./CFS

disease.

SIGNS OF PRIOR ILLNESS We routinely note in our clinic the occurrence of a curious illness that can sometimes be documented usually as having occurred three months to two years prior to the prodromal illness. This may present as:

school or work but is quite unwell. The patient then usually recovers for a brief period only to fall ill with the full blown features of M.E./CFS. 1934 Los Angeles Epidemic

(1) a mononucleosis-like illness that causes a period of chronic illness that may last up to six months, or

This prior illness was noted by Gilliam on several occasions. In one of these he recounts in the case history of a social worker. Case #102 fell ill on July 7 with a severe headache, "never anything like it before". She recovered, returned to work, only to fall ill three months later on October 8 with a severe case of atypical poliomyelitis [M.E./CFS].1

(2) It may resemble an acute encephalitic process. When it occurs as an encephalitic process, the illness is usually very short lasting (2-4 days), very severe with at times an almost comatose patient, a rapid and apparent complete recovery and without other apparent lingering sequellae. The patient will usually state that this had been the worst headache he had had in his life.

"The patient recalled a transient illness, for which he did not at the time seek medical care, often several months earlier, which resembled the systemic or meningeal phase of poliomyelitis."2

(3) A third type is that of a minor episode that resembles the main chronic M.E./CFS disease. This minor episode tends to last several weeks or even months. During this time, the person rarely misses

Gilliam notes that in 25 cases, the systemic or meningeal symptoms occurred so far prior to the time the

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patient reported off duty that there might be considerable error in fixing the dates on which they occurred.3

Clearly, some earlier infectious agent had attacked these patients who all later fell ill with M.E./CFS. Perhaps one of the reasons there was such great difficulty in finding the infecting illness was that the prodromal illness that occurred months and even up to two years after their prior illness was not the complete cause of the patient's final M.E./CFS illness. Was this infection the cause of some latent illness? Was this earlier illness due to a retrovirus?

1948 Akureyri Epidemic In the text, Post-Viral Fatigue Syndrome, Hyde and Bergmann state "When the ten 1948 Akureyri patients were interviewed in May 1988, it was found that three had first fallen ill in 1947. In each case, the disease was of a similar nature, with burning pain in one or more limbs, severe prostration and profound muscular weakness. The illness was short-lived, lasting about two weeks, followed by an apparent complete recovery. The fact that a similar type of disease occurred in three of the ten patients the year before falling seriously ill in 1948 was quite unanticipated."4

SIGNS OF THE PRODROMAL DISEASE The prodromal disease ofM.E./CFS may have considerable variability. However it is not known if M.E./ CFS (a) is caused simply by the prodromal disease virus that contains within its own structure the ability to destabilize the host's immune system and thus create both the acute and chronic illness or (b) the prodromal infection is the final infectious insult, that reaches a destructive disease orbit by riding upon an already destabilized immune system. This earlier immune injury may have, in effect, altered the immune system, thus creating a window though which the prodromal infection, by avoiding the normal immune defenses, could lead to a chronic and possibly hybrid illness.

1949-51 Adelaide Australia Epidemic Pellew notes that "Many patients said that they had been feeling vaguely offcolour forperhaps three months with occasional bouts of headache, associated with lassitude and aches in limbs lasting for two days or so. "5 1955 Royal Free Epidemic Crowley notes that among the late summer Royal Free illness patients "Between March 1 to July there were four cases of infectious mononucleosis-like illness. One woman had a mild transitory [Royal Free] illness in July 1955 that totally resolved. She returned to work and five months later, in December, she fell ill and was hospitalizedwith a mononucleosis-like illness. Six days later her fiance was hospitalized with an encephalitis".6

The possibility of a single virus cause has been suggested by Mowbray 8 who has indicated that potentially any enteroviral persistence may cause M.E./ CFS. This echovirus type 30 and coxsackie B viruses persistence is discussed in considerable detail by Schnurr and Schmidt. 9 Yet Bendinelli, 10 who states that, although coxsackievirus suppresses the immune system in mice and in human cells in vitro, "We know of no evidence that suggest that coxsackievirus (CV) suppresses immunity in humans". He then continues that "There are, however, early observations that concomitant CV infections can lead to unusually severe poliovirus and potentiate certain protozoan and fungal infections".

Eden, a clinical student at Royal Free in 1955 states: "Since early spring some clinical students at the Royal Free Hospital had been having highly unpleasant symptoms. They started of as a sore throat and rather stiff neck. By the way our necks felt, our cervical lymph nodes should have been enlarged. And so they were, but only to the size ofsmall peas. The shivering, aching limbs, aching back, disturbed sleep suggested a high fever but the thermometer obstinately refused to budge above 99." She describes the typical but mild M.E./ CFS like symptoms in some detail. She continued to work for several months when she notes, "The bomb didn't go off until July." She then goes on to describe the start of the severe disabling epidemic.7 (page 25)

Michael Holmes, Elaine DeFreitas and John Martin, 11 all discoverers of the possible role of a retrovirus in M.E./CFS, appear to assume that this retrovirus may be the unique cause of M.E./CFS. It could also be reasonable to assume that such a retrovirus, if it proven to exist, may cause a primary immune injury, similar in manner to the HIV process, that may precede the triggering infection by a considerable period.

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As pointed out by Leon-Sotomayor12 "The acute state of the illness may have several clinical presentations" Leon-Sotomayor then goes on to list 15 different clipical presentations he has observed. He also makes an important statement that "The relapse usually presented the same clinical manifestation as the acute attack but less intense. " 13 This point is important since the onset symptoms and physical findings tend to be echoed throughout the disease process. Different onsets frequently cause somewhat different variants of the central disease picture. Behan and Behan 14 also discuss a more limited list of findings that are included in the Leon-Sotomayor review of the various presentations. We concur with both of these authors on the variability of onset disease.

geographical area it is highly unlikely that there were a multitude of viral causes but rather a multitude of host viral responses. Different viral receptors on the same virus may attach to different organ receptors, and even different brain receptors causing hypothalamus, basal ganglia or limbic system injuries. Clinically, several of the following injuries can occur in any one patient. Many, but not all, of these clinical findings tend to decrease in severity once the disease becomes chronic. Anterior Poliomyelitis Contact One of the very early and curious findings that we have repeatedly observed is an early contact with a poliomyelitis patient. In those adult M.E./CFS patients who were born prior to 1955, that is prior to the introduction of generalized polio immunization, we have observed a striking correlation with poliomyelitis.

It is important to note that all of the findings in the Leon-Sotomayor list originated in the same epidemic. In any one cluster or epidemic we also have observed this variable onset picture, although different epidemics tend to have their own signature of onset and symptom picture. Undoubtedly, part of the differences in description depends upon the observer and what he believes to be important.

In excess of 30% of M.E./CFS patients born before 1955 can give a history of living with a parent, sibling, relative or close friend who had been disabled by paralytic poliomyelitis. Poliomyelitis was just not that common. Are these individuals really post-polio syndrome patients, who had subclinical cases of poliomyelitis?

The physical presentations noted by Leon-Sotomayor are listed in the following table. Since these patients all fell ill during the same epidemic and in the same

PRODROMAL ILLNESS Dr. Leon-Sotomayor has listed the following prodromal illnesses associated with M.E. / CFS.12 CNS Onset (a) Involuntary muscle jerks, carpopedal spasm, myoclonic episodes that may mimic tetanus or strychnine poisoning.

(d) CNS with aseptic meningitis-like picture, Parkinson-like picture, diencephalic fits with chills, cold extremities, pounding of the heart, palpitations, borborygmus, temperature of96-100, changes of respiratory pattern, sinus arrhythmia, diplopia. This "storm" lasts for a few minutes with components persisting for hours.

(b) Psychiatric complaints with hyperventilation syndrome. (c) Neurovegitative (hypothalamic) episodes with fatigue and abrupt fluctuation of blood pressure (90/ 60 to 160/110), both orthostatic and hypertension may be present, tachypnea to shallow breathing, bounding pulse, profuse perspiration.

(e) Thyrotoxic and thyrotoxic-like picture with staring eyes, irritability, palpitations, tremor, increased perspiration, diarrhoea, leukocytosis, weight loss, vasomotor instability, and elevated BMR.

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(f) Postprandial dysporia characterized by palpitations, nausea, perspiration, tremulous feeling mimicking hypoglycemia, carcinoid or dumping syndrome.

M.E./CFS illness by months. We have seen the thyrotoxic picture on several occasions but that tends to occur long after the onset of illness. All of the other forms noted by Leon-Sotomayor and Behan and Behan have been routinely observed by us.

(g) Ophthalmological picture with pain, loss of accommodation, both dryness and burning of the eyes in addition to increased lacrimation, photophobia, blepharospasm,

In addition to the above, we have noted the following prodromal onsets:

Respiratory System Onset

Paralysis and Paresis

(h) Upper respiratory infection, with pharyngitis, earache and with or without, Meniere's-like syndrome

Prior to the mid-1950s and the general introduction of polioimmunization, many of the M.E./CFS cases were permanently paralysed during the initial illness and some recovered from this early paralysis 16 . These paralysed patients were never considered to be poliomyelitis since the persistence of sensory, cognitive and emotional dysfunctions, the waxing and waning of muscle strength and other symptoms were very atypical of classical anterior poliomyelitis. Many M.E./CFS patients were treated as cases of hysterical paralysis 17 . Many M.E./CFS patients were considered to represent a variant of poliomyelitis. With the introduction of immunization and the abrupt cessation of clinical poliomyelitis in the mid-1950s and the continuation of non-paralytic M.E./CFS, few proponents of the infectious origins of M.E./CFS continued to believe that there was any relationship between the two illnesses. One of us (BMH) has personally examined M.E./CFS patients (Akureyri Disease) in Akureyri and in Reykjavik in Iceland, in Canada and the United States, some of whom, despite the passing of almost 50 years, are still paralysed. Except for the paralysis, there is no clinical difference between these two types of patients. It is difficult not to conclude that polioimmunization, which appears to be equally effective against all enteroviral paralysis, may have saved tens of thousands of present day M.E./CFS patients from paralysis. Perhaps "poliomyelitis" epidemics have not stopped, perhaps their cell target has simply changed.

(i) Infection-like illness with chills, malaise, leukeoid reaction and fever. (j) Pulmonary infarction or pneumonia-pleurisy-like symptoms. Genito-Urinary System Onset (k) Genito-urinary complaints with puffiness of the face, palpebral oedema, microscopic haematuria, proteinuria, high specific gravity of urine, oligouria, polyuria, orchitis and oophoritis. Cardiovascular System Onset (1) Cardiovascular complaints with any of the following C.H.F., pericarditis, myocarditis, cardiovascular collapse, cardiac arrhythmia (PAT or PVC) hypertension, orthostatic hypotension. Gastroenteric System Onset (m) Acute abdomen presentation with appendicitislike picture, diverticulitis-like picture, colitis, pancreatitis or cholecystitis-like picture. We have seen only one cardiovascular collapse but Dr. John Richardson has had two cases of cardiovascular collapse with death. Autopsy of one of his patients, a professional football player, who died on the playing field, revealed no cardiac infarct. 15 Our single case involved a pulmonary infarction in which the patient had a cardiac arrest and fortunately was resuscitated. We have seen the meningitis-like picture on many occasions but that tends to precede the

Hand, Foot and Mouth-like Disease (HFM) We have noted this illness on many occasions in M.E./ CFS children and in a significant number of young adults as prodromal illness. Hand, foot and mouth disease is usually associated with coxsackie A16andA5,butalsoA4,7,9 and 10, as

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well as coxsackie B 2, and 5 and enterovirus 71. Except in the case of enterovirus 71, it is reputedly an illness normally seen in children from 1 to 5 years old18. We have never seen this clinical illness associated with M.E./CFS patients under the age of 5. We have documented the illness on several occasions in children usually between the ages of 5 and 14. HFM disease is sometimes misdiagnosed as herpangina. We have also seen HFM disease less frequently in adults as a prodromal or triggering disease of M.E./CFS.

a clinically identical illness, certain of whom remain considerably ill with M.E./CFS at the time of writing. We have encountered others. It is not a frequent prodromal cause, but the individuals who do fall ill tend to persist in their M.E./CFS illness. Reticulo Endothelial System Onset 21 We have rarely seen this form, but it occurred in the 1955 Cumberland, England epidemic described by Wallis 21 and observed on several occasions by Dr. Gordon Parish elsewhere in England 22 In this form, there is marked enlargement of the lymphatic glands, more so in children. The cervical glands were the most commonly enlarged, followed by the inguinal and axillary glands in that order. The spleen and liver were typically involved, enlarged and painful. Jaundice was also seen in some cases. In the London Free epidemic, 10% of the cases had liver enlargement 23 . Crawley states that "More than half the cases then showed varying degrees oflympho-reticular disturbance " 24.

The clinical description is a disease of mild or no fever with sore throat. It is associated with a rash described as small 4 mm macules becoming vesicules in the anterior mouth and lips, located on the palms and fingers, soles and toes and sometimes buttocks. It tends to be associated with malaise, headaches and anorexia. An associated abdominal pain, cough, conjuctivitis, coryza, diarrhoea, pleuritis, nausea/ vomiting, pleuritis, carditis or pneumonia have also been described 18 . We refer to this disease as hand, foot and mouth-/j&e disease since we usually have only the patient's history to go on and have never had a chance to test the fresh vesicles for viral particles that we have seen. There is another difference with the official description, namely that, in the adults, the rash is in the locations noted but more usually described as starting below the knee and below the elbow.

Death Wallis 25 describes the pathological features of one of the few deaths attributable to M.E./CFS that occurred in a developed country. This death occurred in the Cumberland epidemic. The pathological report is of interest. He describes the report of Dr. R. Klein of the Crichton Royal, Dumfries, Scotland,"There are in the entire diencephalon, particularly round the thirdventricle, numerous small haemorrhages, which extend into the adjacent parts of the mid-brain. Similar haemorrhages can be seen in the corpora mamillare and the supra-mammilary nucleus, the haemorrhages are mostly around small vessels, but some are also to be seen in the free tissue"25. It should be noted that this would correspond in size and location to the UBO's identified by Biddle in the Lake Tahoe epidemic 26 . This patient of Dr. Wallis was an abstainer, so an alcoholic encephalopathy was not part of the differential diagnosis. The many suicide deaths usually occur during the recuperative or chronic stages of the disease.

Acute Hemorrhagic Conjuctivitis-Like Disease 1 9 (AHC) This poliomyelitis-like disease is associated with enterovirus 70, coxsackie A24 and hepatitis A (also an enterovirus or enterovirus-like virus). It was pandemic in the tropics in the period 1967-1973 and was associated with paralysis and death 1 9 . It is reputedly not seen in the temperate regions. However, this may be strictly due to the protective polioimmunization in temperate countries. We have seen AHC in three persons who were in Africa during and after this period. We have documented a similar cluster of physicians and health care workers 20 who fell ill with

Delay in Onset of Principal Disease In the London Free epidemic it was noted that when the primary features of the prodromal illness are over, it may take as long as 3 weeks for most of the features ofM.E. / CFS to develop27. Pellew28 notes that some patients

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had no muscular weakness even at two months after onset, then muscular weakness would develop by three months. We concur in this finding and have noted development of certain chronic features of the disease to take up to six months. It is possible that many of the signs and symptoms are present at an earlier date but the patient is often so disabled by exhaustion and bedridden that all of his disease features are not experienced until a certain physical or social activity is reached. Henderson and Shelokov, Chapter 15, this text, note that after the prodromal period and "After a period of days to three or four weeks, there is an abrupt exacerbation of symptoms..." PHYSICAL SIGNS OF CHRONIC DISEASE These physical signs that we and others note all require a more systematic evaluation. The physical signs of chronic disease will be discussed under the following headings.

Chronic M.E./CFS signs: The chronic signs are manifestations of both specific and ongoing host injury that resulted from the prodromal injury, chronic aspects of the disease process and the lack of internal homeostasis that is characteristic of a M.E./CFS patient. The prominence of the physical signs is often dependent on the host's acute interaction with his environment. This host interaction may be sensory, intellectual, physical or strictly relate to an unstable internal homeostasis. These characteristic physical signs of M.E./CFS disease, and the lack of stability or dependability of the hosts internal homeostasis, become more apparent when the host is challenged by these environmental stimuli.

Vital signs Cutaneous Ophthalmalogic Neurologic Genito-urinary Muscular Orthopedic Gastroenteric

Vital Signs Pulse and Heart Rate: Pulse is frequently irregular and bounding during the course of the early prodromal illness. In the early Initial Stage, many patients will have an unusual decrease in resting rate and an unusual increase in activity rate. A Holter monitor is necessary to document many of these features.

As noted in the introduction of this chapter, many of these physical signs can be potentiated by environmental interaction. These interactions can be sensory, intellectual, emotional, physical or related to the failure of the host's normal homeostasis that is pathognomic for M.E./CFS. It is an error to believe that the majority of these signs are related to disuse atrophy or lack of conditioning or that they can be improved by forced physical activity.

There also tends to be a failure of the heart rate to keep up with the physiological requirements of rapidly changing cardiovascular demands. This has been noted by T. Montague. 30 Clinically this can be documented both in orthostatic hypotension and the inability of the heart rate to keep up with a rapid change in demand, e.g. a patient who tries to bound up 5-6 steps from a resting position will frequently experience an unusually slow speed up of heart rate, chest spasm and shortness of breath.

Inconsistency of Signs: Pellew observed that 2 9 , "A patient examined in the morning might have nystagmus which would disappear at midday, recur later, disappear later and recur next day. This on again off again pattern, typical of M.E./CFS, may persist for years although there is a tendency of decrease rather than increase in frequency. Other that this inconsistency, the lack of a normal internal homeostasis, the unusual rapidity of development of cognitive and muscle inconsistency and lack of dependability, the slowness of muscle and cognitive recovery, there are no pathogonomic signs specific to the illness. It is this inconsistency that provokes the major disability of M.E./CFS patients.

We have observed nocturnal bradycardia as measured by Holter monitor. Blood Pressure: The blood pressure may increase or decrease during the first few days of the prodromal period only to fall to a persisting lower than normal blood pressure in chronic patients. As mentioned

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The Clinical and Scientific Basis of M.E. / CFS

earlier, some normotensive patients and perhaps more frequently in patients with pre-existing mild hypertensive disease, one can observe the rapid development of malignant hypertension, sometimes with the appearance of carcinoid syndrome. The carcinoid features tend not to continue but the malignant hypertension when it occurs, tends to persist and to be poorly controllable.

The most common cutaneous changes can be confused with either systemic lupus erythematosus (SLE) or even dermatomyositis (D) but, in our experience, even severe cases of M.E./CFS do not respond to corticosteroids. However, no matter how severe the case ofM.E./CFS may be, we have never seen a case that has been progressive or that has lead to death as in the case of SLE and dermatomyositis.

Temperature: Temperature is sometimes mildly elevated during the first one to three days of the illness. Pellew notes a typical finding 29 "The range of temperature was from just above normal to 102 F, the average being just under 100 F and the duration of fever, with fall by lysis, was short, about three days being usual". This is typical of the prodromal phase.

Facial Features: M.E./CFS patients frequently develop what Dr. Ramsay 34 referred to as the ghastly pallor. This sudden blanching of the face with an almost Parkinsonian mask-like appearance is seen more frequently in the first year of illness but commonly can persist for the life of the illness. It is usual for a fatigued M.E./CFS patient to exhibit a mottled malar erythematous discolouration similar or identical to that seen in systemic lupus. This mottled discoloration also occurs in the area of the sternum.

Once the typical chronic features set in, the normal diurnal temperature changes. First the base temperature is lowered, reaching regularly two degrees below the normal temperature. In addition there is an increase in the normal diurnal variation with swings up to 100°F (37.8°C)31. Gilliam 32 states that " a frequent daily range from 97 - 99 F was much more characteristic of this illness than a real elevation of temperature". Dr. Anne Mildon 33 of Toronto has documented malignant hyperthermia, a very rare condition, in several M.E./CFS patients.

One-sided palpebral oedema in not infrequent and has been described by Leon-Sotomayor 35 . Early in the disease we have observed third nerve injury and mild Horner's syndrome. This does not persist. However misdiagnoses and improper treatment have led to permanent cases of tardif dyskinesia. What is described as painful shotty glands, frequently in the posterior cervical triangle 36 are described very frequently in the literature. However it is difficult to be too impressed with this finding in chronic cases. In chronic cases, neck sensitivity of this nature probably represents fibromyalgia points.

Respiratory Rate: Early in the disease, one may note hyperventilation in M.E./CFS patients. This is not common and is frequently associated with sensory or diencephalonic storms. More frequently we see bouts of shallow breathing after minimal physical activity.

Hands and Feet: Other common cutaneous signs are cold Raynaud's hands. They are often blotchy with cyanotic nail beds. There are frequently liver palms and an engorged or prominent vein that follows the crease of the flexor pollicis brevis muscle on the palm. This muscle mass on the palm adjacent to the thumb is frequently atrophied in chronic cases. All of these have been pointed out by Dr. Ryll in the Mercy San Juan Hospital epidemic of 197537. In the acute disease, the finger tips may be shiny and smooth, the nail beds cyanotic with an almost sclerodermatous appearance. Paul Cheney has noted that there may be a loss of fingerprints in extreme cases. 38 Wilson and Walker 65 discuss similar findings in the 1934 California epidemic. They note "Vasomotor and trophic disturbances were almost constant findings among

CUTANEOUS SIGNS Cutaneous changes are common to most M.E./CFS patients but, like many of the symptoms, they are rarely consistent and tend to wax and wane. They tend to be exaggerated with exercise, sensory stimulation, symptom storms and intellectual activity. A patient who arrives at the physician's office rested, will, after a long interview, tend to begin to manifest an increase in visible cutaneous changes. There may be daily drenching sweats early in the disease that decrease in frequency in the chronic stages.

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M.E. / CFS: The Physical Signs of Disease

times quite painful. Similar features were also noted by Leon-Sotomayor. 39 We have seen this primarily in the neck and hand. We have observed this frequently but not noted associated pain. Carpopedal spasm was noted in the London Free epidemic 40 and is a frequent complaint but rarely observed.

the adult patients. In the cases of more extreme involvement exfoliation of the skin of the affected extremities occurred, followed by glossy atrophy of the skin and atrophy of the subcutaneous tissue." Rarely, there may be a coarse tremor, particularly after activity. These signs tend to be more common in the left hand. Carpopedal spasm is seen frequently.

Raynaud's Disease: This is common in M.E./CFS but we have never seen it go on to ulceration or gangrene. We have seen this involving the fingers, toes, hands and sometimes the ears and nose with pallor and both pain and loss of sensation. It sometimes can involve well circumscribed spots on the extremities or body. The line demarcating normal from pathologically cold skin is often so distinct that it is visible with the eyes and apparent with touch. It can form visible glove and stocking distribution that may lack normal sensation. Acrocyanosis is illustrated by Leon-Sotomayor 41 . However, the cyanotic colour alterations in the hands and feet and the white and numb fingers and toes described by Fog 42 are a more frequent observation. These acute Raynaud's disease changes are visible and appear sometimes without expectation. The patient may complain of severe localized pain in the area.

Comparison of M.E./CFS and SLE 43 4 4 Sign Primary candidate

M.E./CFS young to middle age women

SLE middle age women

Sedimentation rate elevated in 10% SLE Cells Rheumatoid factor

usually 0-5

high

never in approx. 20%

80% 20%

Migratory polyarthritis Arthralgias without objective changes Deforming arthropathy Muscle atrophy and weakness Pericarditis, myocarditis

often

often

usual never

usual can occur

usual occurs, early infrequent

GIT symptoms Sjogren's-like or Sicca Syndrome Thyroid disease

common common

usual occurs late frequent common common

Exacerbation triggered by surgery, trauma, emotional stress, sunlight, non-essential drugs Mottled erythematous maculopapular eruption Malar butterfly Upper chest and neck Telangiectases and ecchymotic spots on hands and feet Thinning and atrophy of skin of finger tips with loss of fingerprints Raynaud's disease Alopecia Patchy oedema Erythema nodosum Purpura Oedematous swelling of face and extremities Response to steroids ASA, NSAIDS

common in women

common

common

common

Alopecia: This is not a common finding but we see from time to time patchy loss of hair. It occurs in the pubic area and also involves body, facial and scalp area hair. Alopecia totalis is very rare. Ophthalmalogic Signs

common common

common common

occurs

occurs

common

common

common occurs common occurs occurs

common common common common common

occurs

occurs

poor

good

We routinely find ophthalmalogical signs. These include; -Conjunctival injection is frequent 4 5 -Palpebral swelling, usually left sided 33 -Sicca Syndrome or pseudo-Sjogren's syndrome with excess tearing and excess drying of the tear and buccal glands is a common chronic feature -Patients regularly complain of photophobia and we regularly note unequal and contrary pupillar reaction to light in chronic patients. 46 During the acute stage of the London epidemic they observed that "the pupils were sometimes unequal, and might be defective in reactions to light and accommodation 46 . External ophthalmoplegia was common." -Movement of the pupil may be irregular or cogwheel -We have seen cases of Adies' pupil with loss of patellar reflex

Vein Engorgement: Dr. Erich Ryll 66 noted engorgement of veins in the Mercy San Juan Hospital epidemic in 1975. He states that these are some-

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The Clinical and Scientific Basis of M.E. / CFS

simply the weight of the sheets creates excessive pain. We have found this common in the Initial Stages but only cutaneous and muscular hyperesthesia are routinely observed in the chronic stages.

-Rapid variation of visual accommodation within one day and with fatigue. Also sluggish accommodation is very common. Both of these tend to settle down in the chronic stages. -A variable and increase in nystagmus is routinely observed -Cherry red posterior fundus early in the disease process that tends to persist for weeks 47 -Loss of night vision -Possible loss of colour vision -External ophthalmoplegia -Diplopia is mentioned in Fog's description of the 1952 Danish epidemic, 42 and in the South African epidemic in 195948 as it is in almost all epidemics.

The nerve distribution most frequently observed in the Akureyri 56 epidemic were the ulnar, axillary, lateral femoral cutaneus, first sacral, fifth lumbar and first thoracic nerves. We also find in both acute and chronic patients these same nerves involved except the area of the first thoracic extends up to the fourth cervical. Fasciculations, tremors and even short spasms of tetanic contraction are common but rarely documented by the physician.

Neurologic Signs Modified Romberg test (with eyes closed) is usually always positive (eyes closed). Hand tremor can occur. Loss of equilibrium and motor weakness are common.

Spinal Fluid Pressure Gilliam notes 57 that "Nearly all cases in which the spinal fluid pressure was recorded showed the fluid to be under increased pressure." This is important since, possibly due to rapid draining of spinal fluid, we have seen at least three iatrogenic cases of brain stem hernia, one in a child, all resulting in permanent injury considerably worse that the original illness.

Neck stiffness, increased and decreased tendon reflexes have been described in the Initial Stage but are infrequent in chronic illness. Loss of abdominal reflexes is sometimes noted in the early disease. Abnormal EEG was noted by Pampiglione in the London Free 49 epidemic and Leon-Sotomayor noted 7 out of 25 abnormal EEGs early in the disease. 50 Although Grand Mai epilepsy is rare, seizure activity is the rule in M.E./CFS. This is discussed in detail in this text in the chapter on CNS dysfunction.

Cardiovascular Signs Early in the disease there tends to be sinus arrhythmia, PVCs, tachycardia. Leon-Sotomayor 58 and Richardson 59 have noted an associated myocarditis and friction rub early in the disease and muffled heart sounds. There appears to be an increased incidence of mitral valve prolapse. Dr. John Richardson 59 has documented sudden cardiac death in the absence of coronary occlusion in athletes early in the disease. This is very rare. Many patients have unrecognized myocarditis and pericarditis early in the disease that one cursory examination may fail to reveal. Dr. Richardson has also commented on the increased incidence of mitral valve prolapse in M.E./CFS 59 .

Involuntary muscle movement is common in the early stages and tremor in later stages. In acute and chronic patients with straight leg raising we frequently note cogwheel movement of the leg. This was observed in the South African epidemic described by Hill 48 who notes "When these muscles were tested against resistance, they contracted in a curious interrupted or cog-like fashion". In the London Free epidemic 51 they observed "apeculiar jerking in a limb on voluntary movement - that was distinctive and characteristic - of this encephalitis., "one nurse developed cogwheel rigidity in the right arm". The Medical Staff of the Royal Free 23 .

Dr. Leon-Sotomayor is perhaps the lone cardiologist to comment extensively on this illness. On ECG, Leon-Sotomayor noted 58 :

Hypoalgesia, and hyperesthesia were observed in the acute stages of the Los Angeles 52 , Akureyri 53 , Adelaide 54 and London 55 epidemics. Sometimes

sinus tachycardia except when recumbent sinus arrhythmia

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M.E. / CFS: The Physical Signs of Disease

PVC or PAC non-specific unstable ST-T wave changes other supraventricular arrhythmias elevation of ST-segments peaking of T waves prominent U waves TU- segment depression High incidence of post-exercise ST segment and T wave abnormalities.

muscle weakness described by most patients. To compound matters still further, most M.E./CFS patients can lift a weight equivalent to what any similar non-M.E./CFS underconditioned person can lift. Are these patients simply unreliable witnesses? How can this conundrum be logically answered? Pain: The first point to note is that non-myalgic M.E./CFS patients generally appear to have much less muscle weakness. Many M.E./CFS patients have inhibition of muscle strength by pain. This pain can either be immediate such that running up six steps or running across an 18 foot road allowance will bring them to a grinding stop. The second is the delayed pain reaction. Particularly in the first months or even years of illness, any modestly prolonged muscle activity may result in a delayed pain syndrome of considerable intensity that may persist for days. This pain may be specific to a particular muscle group and also generalized as a malaise and tends to prevent muscle activity.

Leon-Sotomayor attributes many of these changes to an unstable autonomic influence. Genito-urinary Signs Although chronic exhaustion is probably the leading cause of sexual dysfunction, patients frequently complain of dysparunia and impotence. Frequently, there is a distinct vaginal dryness as there tends to be in all mucous membranes. Pudental pain syndromes are common but rarely any physical signs are seen except for interstitial cystitis with an engorged bladder wall vein or ecchymosis. Genital complaints are less common in men. Early in the disease process nocturia, difficulty in starting and stopping stream, and pain are common. Orchiditis is seen rarely and usually in association with a Bornholme's-like onset. Even quite young male p a t i e n t s may have pseudoprostatitis.

Specific Muscle Group Weakness: The patient may tell the physician that all of his muscles are weak. This is not often true. A review of the epidemics will usually point out that the authors state that only specific muscle groups are affected. Usually these specific muscle groups persist in weakness, although this pain and weakness may wander over time to another group. What the patient is complaining of is more likely heaviness and the feeling of exhaustion and malaise in the muscles.

Marked menstrual changes are common. MUSCULAR-ORTHOPEDIC SIGNS

Loss of Dependability: Another problem that M.E./ CFS patients experience is the increased speed with which some muscles loose their strength and coordination and the slowness of recovery to a comfortable ability. With activity, the patient tends to lose proprioception and position sense, the ability to estimate the position of his limb. He becomes clumsy and incoordinated.

Muscle Strength A few patients will have such profound muscle weakness that they will be confined to a wheel chair or almost permanently in bed. This degree of disability is more common in children than in adults. These adults fortunately are the exception. A very few of these disabled patients will react to weight bearing by convulsive, tetanic convulsions. These sorry patients are usually dismissed as cases of somatization. We believe this may represent a limbic dysfunction.

Incoordination: We see this loss of fine muscle coordination frequently described by patients who have difficulty maintaining legible writing. This is mentioned by Innes 6 0 "His handwriting became less legible".

Most patients will usually relate to the physician t h a t their muscles are weak. Yet, although electrophysiological and microscopic work reveals changes, there is little to account for the profound

Much of the weakness that the patient describes is

75

The Clinical and Scientific Basis of M.E. / CFS

really rapidly developing incoordination. There is a lack of smoothness of muscle movement, particularly for complex muscle tasks and this is most likely a central control fault. This has also been noted by Dr. Bastien in this text. Antagonists and agonist muscle groups may contract at the same time. A patient without pain will have less problem lifting up a child than she will have with small rapid movements of drying many dishes. Place the same patient in the dark and she will frequently lose the ability to coordinate even simple muscle movements. Walking around a mile on a sidewalk may be difficult, but not as difficult as trying to walk 500 feet on uneven ground. The problem is not one of distance but one of poor central coordination, positional dysfunction, poor balance and loss of smooth muscle action. Gilliam 61 states that "Muscle weakness tends to be confined to localized muscle groups and not to the general distribution that would be expected if due to immobilization alone." We too have tended to find specific muscle groups weaker than others. If this is true, then it may not be relevant to test, as is usually done, the same muscle group in every patient for cellular and neuromuscular dysfunction. Thus, testing a single muscle group such as the flexors of the left forearm with a simple muscle task and finding it to have normal function and strength may be akin to testing a poliomyelitis patient, paralyzed from the waist down. No matter how good the researcher's technique may be, the patient will be found to be in perfectly normal muscular strength and health. Shortness of Breath: This is frequently related to diaphragmatic incoordination, pain, or weakness or pain in the chest wall muscles. Some of the exhaustion and weakness experienced by the patient may be due to decrease in function of these muscle groups in which the patient is unable to respond to increased oxygen needs with increased activity.

Polyarthritis: Sigurdsson 62 notes that"polyarthritis developed after this illness in a number of instances". We also find this, but the arthritic involvement is particularly apparent in children and adolescents in the Chronic Stages of M.E./CFS. These cases are frequently misdiagnosed as rheumatoid disease despite lack of supportive rheumatoid tests. This is also discussed by Wilson, Walker 65 in the 1934 epidemic, where they observe, "A unique feature of this (1934 California) epidemic was the occurrence of inflammatory changes in and about the joints, which was observed in 34% of the adult patients in the present series. In 10% there were merely transitory but sharply localized pain and tenderness in the joints." It should be noted that Wilson, Walker were orthopedists, the number of arthritic patients were twelve, and that their series were referred for these specific complaints and did not represent the epidemic as a whole. We routinely see a small number of these cases at Nightingale. A n a e r o b i c Activity: Patients tend to utilise anaerobic muscle activity rather than aerobic activity. This can be readily measured if the correct apparatus is available. Measurement of these features proide a useful diagnostic tool. Gastroenteric Signs Abdominal distress is frequent with pain and appropriate guarding that mimics cholecystitis, gastric and duodenal ulcer and acute appendicitis. We usually note diaphragmatic sensitivity, generally left-sided, early in the disease. Liver and spleen enlargement have been noted. 63 The staff of the London Free also noted that "there was extreme tenderness of the subcostal regions, and attempts at palpation might evoke resentment due to pain." These acute abdomen situations tend to occur early in the disease. There is also a tendency early in the disease for weight loss with anorexia and constipation, whereas in the later stages there is a tendency for weight gain, dietary fanaticism, loose stools and irritable bowel syndrome. The typical irritable bowel syndrome with bloating, rapid diurnal fluid and weight change, colic, heightened gastrocolic reflex or dumping syndrome and severe bowel urgency or even bowel incontinence develops in about 20% ofM.E./CFS patients. Some of this is related to the development of acquired food

Fibromyalgia Points: Fibromyalgia points are commonly tender. Insertions of major tendons are often tender and activity has resulted in infrequent rupture of tendon. These ruptures usually occur in the lower posterior leg. Muscle bunching or spasm can frequently be palpated after minor activity. A stiff painful neck may be common in the Initial Stages.

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M.E. / CFS: The Physical Signs of Disease

sensitivities. Food neurosis is a common finding in this group and it becomes difficult to separate true food sensitivities to the almost religious zeal of dietary mania.

patients have not suffocated to death by the temporary blocking of the larynx by certain foods.

Our most difficult patients have been those with explosive retroperistalsis. Fortunately this is not a common feature of the disease. Hardtke 6 4 points out a much more common problem is the incoordination of the larynx and the oesophagus and it is a frequent complaint of the "need to swallow carefully to avoid choking on liquids". We regularly note this problem with liquids and solids. It is a wonder that some of our

It is frequently stated that there are no physical signs in M.E./CFS. Yet it is rare that we do not encounter numerous physical signs although these are more apparent in the Initial Stage of the disease. In the chronic stages there are also less dramatic persisting physical signs. Brain imaging, nerve conduction and neuropsychological techniques discussed in this book continue to amplify the physical changes apparent to the careful and learned observer.

Summary

References 1. Gilliam A.G. (1938) Epidemiological study of an epidemic, diagnosed as poliomyelitis, occurring among the personnel of the Los Angeles County General Hospital during the summer of 1934, United States Public Heath Bulletin No. 240, pages 1-90, page 18.

13. Leon-Sotomayor L., idem(12) page 17, see also this text, Clinical Observations.

2. Gilliam A.G. idem (1) page 9.

15. Personal communication with Dr. John Richardson of Ryton, England.

14. Behan P., Behan W. Post viral fatigue syndrome, a review. CRC Reviews. Cleveland, Ohio: CRC Press, pages 12-13,1988.

3. Gilliam A.G. idem (1) page 11.

16. Gilliam A.G. (1938) Epidemiological study of a n epidemic, diagnosed as poliomyelitis, occurring a m o n g the personnel of the Los Angeles County General Hospital during the summer of 1934, United States Public Heath Bulletin No. 240, pages 1-90.

4. Hyde B., Bergmann S. Chronic Aspects of Akureyri Disease, page 214, chapter on Post-viral Fatigue Syndrome, Jenkins and Mowbray, John Wiley & Sons, (1991) page 211. 5. Pellew R.A. (1951) A clinical description of a disease resembling poliomyelitis seen in Adelaide, The Medical Journal of Australia, 1, 944 page 944.

17. Hyde B., Bergmann S. Chronic Aspects of Akureyri Disease, page 214, chapter on Post-viral Fatigue Syndrome, Jenkins and Mowbray, John Wiley & Sons, (1991).

6. Crowley N., Nelson M., Stovin S. Epidemiological aspects of an outbreak of encephalomyelitis at the Royal Free Hospital, London, in the Summer of 1955, Journal of Hygiene[Camb] 1957;55;102-122, page 117-118.

18. Moore M., Morens D. Enteroviruses, including polioviruses, Chapter 17, pages 447-449, Belshe R. Textbook of Human Virology, PSG Publishing Company, Littleton, Massachusetts 1985.

7. Eden, J. Wecalleditthe pestilence, World Medicine, June 15, 1977, page 25.

19. Moore M. idem 11, page 451. 20. Labor-day 1984 Montreal cluster, Sean O'Sullivan M.D, Tilsonburg Ontario. In publication.

8. Yousef G. E., Bell E.J., Mann G.F. and Mowbray J.F. (1988) Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet, i, 146-150.

21. Wallis A.L. An Investigation into a n unusual disease s e e n in epidemic and sporadic form in a general practice in Cumberland in 1955 and subsequent years, Doctoral Thesis, University of Edinburgh pages 16-17(1957).

9. Schnurr D., Schmidt N., Persistent Infections, Chapter 11, pages 181-201, Bendinelli & Friedman, Coxsackieviruses, A General Update, Plenum Press (1988).

22. Parish J. G., personal communications.

10. BendinelliM. Interactions with the Immune System, pg 95, idem (2).

23. The medical staff of the Royal Free Hospital, An Outbreak of Encephalomyelitis in the Royal Free Hospital Group, London, in 1955, Br. Med. J., 1957; 2:896.

11. Holmes, DeFreitis and Martin See this text. 12. Leon-Sotomayor L., Epidemic Diencephalomyelitis, Pageant Press, 1969, pages 13-15.

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The Clinical and Scientific Basis of M.E. / CFS

24. Crowley N., Nelson M., Stovin S. Epidemiological Aspects of an Outbreak of Encephalomyelitis at the Royal Free Hospital, London, in the Summer of 1955. Journal of Hygiene (Cambridge) 1957: 55: 102-122.

45. Leon-Sotomayor L. ,idem(12) Conjuctival injection, page 119. 46. The Medical Staff of the Royal Free idem (23), page 896. 47. John Richardson Cherry Red Fundus, Workshop Newcastle upon Tyne, 1989.

25. Wallis A.L. idem(21) pages 46-48. 26. Biddle R. Lake Tahoe epidemic MRI findings in publication. 27. The medical staff of the Royal Free Hospital, idem(23) pages 896.

48. Hill R., Cheetham R., Wallace H. Epidemic Myalgic Encephalomyelopathy, The Lancet, Saturday 4 April 1959, 689-693.

28. Pellew R.A. (1951) A clinical description of a disease resembling poliomyelitis seen in Adelaide, The Medical Journal of Australia, 1, 944 page 946.

49. P a m p i g l i o n e G., H a r r i s R., Kennedy J . Electroencehpalographic investigations in myalgic encephalomyelitis, Postgraduate Medical Journal November 1978, 54, 752-754.

29. Pellew R.A. idem (28), page 945.

50. Leon-Sotomayor idem (12) abnormal ECG page 20.

30. Montague T., Marrie T., Klassen G., Bewick D., Horacek B.M. Cardiac Function at Rest and with Exercise in the Chronic Fatigue Syndrome,Chest, Vol 95, p779-784, April 1989.

51. The Medical Staff of the Royal Free idem (23), page 898. 52. Gilliam A.G. idem (16) page 21 hypalgesia, hyperesthesia.

31. The Medical Staff of the Royal Free, idem (23) page 899.

53. SigurdssonB. Siguijonsson J. Sigurdsson J.H.J., Thorkelsson J & Gudmundsson K.R. (1950) A disease epidemic in Iceland simulating poliomyelitis, American Journal of Hygiene, 52, 222, page 227.

32. Gilliam A.G. idem (16) page 23. 33. Mildon A. Canada Diseases Weekly Report, Supplement, J a n 1991 Vol 17S1E, page 18.

54. Pellew R.A. idem (28) page 945.

34. Ramsay A. Melvin, Dr. Ramsay used this term, ghastly pallor frequently when speaking at EME meetings in London.

55. The Medical Staff of the Royal Free idem (23), page 897. 56. Sigurdsson B. idem (53) page 231.

35. Leon-Sotomayor L.idem(12) palpebral oedema, page 121.

57. Gilliam A.G. idem (16)page 33.

36. GalpineJ., BradyC.BenignMylagicEncephalomyelitis, 1 The Lancet Aril 13, 1957, pages 757-758, page 758.

58. Leon-Sotomayor, idem (12) page 18.

37. Ryll E. 1975 Mercy San J u a n Hospital Epidemic in Sacramento, California, work in preparation.

59. Richardson J., Workshop Newcastle upon Tyne, 1989. 60. Innes S. Encephalomyelitis resembling benign myalgic encephalomyelitis, The Lancet, May 9,1970 969-971, page 970.

38. Cheney P. San Francisco Conference, SanFrancisco Hilton, 1989.

61. Gilliam A.G. idem (16), page 26.

39. Leon-Sotomayor L. idem(12)vein engorgement page 121.

62. Sigurdsson B. idem (53), page 234.

40. The Medical Staff of the Royal Free idem (23), toe spasm, page 899.

63. The Medical Staff of the Royal Free idem (23), page 897.

41. Leon-Sotomayor L. idem, (12) acrocyanosis, page 119.

64. Hardtke E. Iceland Disease in Indiana, Journal of the Indiana State Medical Association Vol 48, March 1955, number 3, page 248.

42. Fog T. (Danish)Ugeskrift for Laeger, Vol 115, July-Sept 1953, pages 1244-1250.

65. Wilson J, Walker P. Acute Anterior Poliomyelitis, (Aspects of 1934 California Epidemic), Archives of Internal Medicine, (1936), Vol. 57, No.3, March.

43. Harrison T.R. Principals of Internal Medicine, fourth Edition, 1962, Tumulty P., SLE 1892-96. 44. Andrews G., Domonkos A. Disease of the Skin,Fifth Edition, Saunders, 1966, SLE 129-133.

66. RyllE., Chabursky B. Mercy San J u a n Hospital Epidemic, California, in preparation.

78

Section 2

Opening Remarks of the Honorary Chairmen

A.M. Ramsay, MB and E.G. Dowsett, MB

ME, Then and Now

Chapter 7 Symposium Speaker and Honorary Chairman

The late A. Melvin

Ramsay

Myalgic Encephalomyelitis - Then and Now An Epidemiological Introduction A. M. Ramsay, MB, Ch.B Hon. Consultant Physician, Royal Free Hospital, London E. G. Dowsett, MB Hon. Consultant Microbiologist, BasildonXThurrock Health Authority, Essex Dr. Ramsay was born in Preston, Lancashire, in 1901. He was educated at the Mackie Academy, Stonehaven, and proceeded to Aberdeen University where he graduated MA in 1923 and MB, ChB in 1926. From 1926 to 1935 he was in general practice in South Africa and then returned to the United Kingdom to enter hospital practice

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The Clinical and Scientific Basis of M.E. / CFS

at Fulharn Hospital. He was transferred to the North Western Fevers Hospital in 1937 and went on to become Deputy Medical Superintendent. He was involved in the instruction of nurses and undergraduate medical students in the practical principles of the management of infectious diseases. In 1939, he received the degree ofMD (Aberdeen) with a thesis on the Clinical, Epidemiological and Bacteriological Findings in 1205 cases of Puerperal Sepsis. In 1947, the North Western Fevers Hospital was taken over by the Royal Free Hospital and Dr. Ramsay became consultant Physician to the Infectious Diseases Department. He was also consultant in smallpox to the Ministry ofHealth and Lecturer in infectious diseases to the University of London. He later became Lecturer and Examiner in infectious diseases for postgraduates who were training for the Diploma of Public Health. He has written extensively on infectious disease and was co-author of a textbook on the subject. The earliest cases of a new and extremely puzzling type of infection were admitted to the Infectious Diseases Department at Hampstead in the Spring of1955. In July, this outbreak spread to the main body of the Royal Free Hospital and was responsible for around 300 cases before terminating in November. The infection became known as "Royal Free Disease". Dr. Ramsay presented papers on the subject at international conferences in Madrid (1958) and Vienna (1965). Between 1971 and 1974, he was President of the Association for the Study of Infectious Diseases (now the British Society for the Study of Infection). Dr. Ramsay was very active in the organization of a symposium on the subject of "Epidemic Neuromyasthenia" held at the Royal Society ofMedicine in April 1978 and shared the chairmanship. He was a member of the Study Group on the subject of "Myalgic Encephalomyelitis" since its inception in 1978. Dr. Ramsay, much loved by patient or physician and all who had the privilege to meet him, died a few weeks prior to the First World Symposium on M.E. and the production of this paper that he was to present at Cambridge. Dr. Ramsay was instrumental in encouraging the 1990 Cambridge Symposium. (Please see Chapter 28 for Dr. Dowsett's photograph and curriculum

vitae.)

History This survey is based on 35 years experience of Myalgic Encephalomyelitis, beginning with the dramatic epidemic which affected the Royal Free Hospital in July 1955. In May of the same year, sporadic cases of a new and puzzling illness began to be admitted from the local community in North West London to the Infectious Diseases Unit at Hampstead and to other hospitals in the area. On July 13th, a ward sister and a resident doctor at the Royal Free Hospital in Grays Inn Road fell ill with the same infection, and, by July 25th, 70 similar cases had occurred. The hospital was closed until October 29th, by which time 290 cases had been identified in hospital staff of all grades (predominantly nurses) though only 12 patients were affected. This epidemic ceased on November 24th although smaller outbreaks occurred in associated units the following Spring. 1

elitis in many clinical aspects, could clearly be distinguished and was diagnosed as Benign Myalgic Encephalomyelitis. This name gives a clearer clinical description than many of the eponyms used previously. (Iceland Disease, Akureyri's Disease, Epidemic Neuromyasthenia) 2 or invented subsequently (Post viral syndrome, Chronic Fatigue, Immune Dysfunction Syndrome). These share the common disadvantage of obscuring the world-wide incidence or of trivialising the clinical severity of the illness. Diagnosis Three factors have done much to cause the obscurity surrounding the aetiology, pathogenesis and prognosis of myalgic encephalomyelitis. First, there has been an absence of objective evidence of organic disease from laboratory and other studies, often leading to an inappropriate diagnosis of psychiatric or behavioural disturbance. Fortunately, re-

Nomenclature The illness, though similar to non-paralytic poliomy-

82

ME, Then and Now

A.M. Ramsay, MB and E.G. Dowsett, MB

cent advances in molecular biology and in neurophysiological techniques will now enable us to rewrite that history.

Prevalence Myalgic encephalomyelitis is an endemic illness with epidemic periodicity. It is a common disability in the UK, based on evidence from GP referrals to clinics. In the sporadic form, it appears to be at least three times as common as multiple sclerosis in South East England. Epidemic myalgic encephalomyelitis is said to affect between 3 and 7% of the exposed population in the UK and USA4, suggesting an infecting agent not previously encountered in childhood.

Second, the failure to distinguish the characteristic fatigue of myalgic encephalomyelitis from other more short lived post infective debility (e.g. following Influenza or Infectious mononucleosis) or from other causes of fatigue has led to unrealistic estimates of recovery. Third, the failure to agree on firm diagnostic criteria has distorted the data base for epidemiological and other research, thus denying recognition of the unique epidemiological pattern ofmyalgic encephalomyelitis.

Age/Sex The peak age at onset in both sexes lies in the mid thirties, with a smaller peak between 15 and 20 years in females only. Females of all ages suffer more severely than males and the F/M ratio of 3:1 in the acute stage rises to 9:1 after 10 years illness. Myalgic encephalomyelitis is rare under the age of 15 (less than 10% of total) and less common after 45 (20% of the total).

We adopted the following diagnostic criteria: A syndrome initiated by a viral infection commonly described as a respiratory/gastro intestinal illness but a gradual or more dramatic onset following neurological, cardiac or endocrine disability is recognised.

Season/Geography The cardinal features, in a patient who has previously been physically and mentally fit, with a good work record are:

As in poliomyelitis, the seasonal and geographical distribution of myalgic encephalomyelitis reflects the interaction ofhygiene and climate. The prodromal illness is more common in Summer and Autumn in the UK and commonly affects the whole community. It is not invariably followed by myalgic encephalomyelitis but secondary cases arising after days or weeks in family or social contacts are reported by 25% of patients.

1. Generalised or localised muscle fatigue after minimal exertion with prolonged recovery time. 2. Neurological disturbance, especially of cognitive, autonomic and sensory functions, often accompanied by marked emotional lability and sleep reversal. 3. Variable involvement of cardiac and other bodily systems.

Social Groupings

4. An extended relapsing course with a tendency to chronicity. 5. Marked variability of symptoms both within and between episodes.

There is a marked ethnic and sociological divide in this country with professional classes (predominantly teachers and health care workers) most commonly affected.

Epidemiology

Prognosis

We base our epidemiological experience on 700 patients seen in clinic, some 50% of whom have evidence of enteroviral infection,5 and 2,000 postal questionnaires (including 420 from patients ill for more than 10 years).

Myalgic encephalomyelitis is an illness with high morbidity and low mortality (if cardiac complications and suicide can be excepted). Complete recovery, however, appears to be confined to one third of cases, predominantly young people who have been able to rest from onset of the illness. A tendency to relapse

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The Clinical and Scientific Basis of M.E. / CFS

spontaneously or under stress (physical/mental exertion, hormonal disturbance, secondary infection, and other factors commonly noted in poliomyelitis) remains for many years. The remaining two thirds of patients are equally divided between those who pursue a fluctuating course initially and then stabilise at a lowered energy level and those who have a severe and debilitating downhill course. Stabilisation often permits limited work and socialisation.

come. Over 80% of professional and technical workers suffering chronic disease have been obliged to retire early or work part time. The peak incidence of myalgic encephalomyelitis in the third decade has led to serious family disruption in 70% of patients in all occupational groups. The potential financial loss to the community (based on a comparison with multiple sclerosis) suggests £300 million annually in lost earnings, to say nothing of lost skill and lost parental care and education. If we must add to this, the distress caused by misdiagnosis or disbelief, myalgic encephalomyelitis remains an illness with a tragic aftermath which still presents a challenge to the skill of the medical profession.

Economic Outcome A study of our patients who have been ill for more than 10 years indicates a disastrous economic out-

References: 1. Ramsay, A.M. Post viral fatigue syndrome - The saga of the Royal Free Disease. Gower Medical Publishing London (1986)

3. Dowsett,E.G. Human Enteroviral infections J. Hosp: Infect (1988) 11 103-115

2. Acheson, E. D. The syndrome variously called Benign Myalgic Encephalomyelitis, Iceland Disease and Epidemic Neuromyasthenia. Am J. Med (1959) 26 569-595

4. Behan, P. O. Behan, W. M. H. Post viral fatigue syndrome. C. R. C. Critical Reviews in Neurobiology (1988) 4 157-178 5. Dowsett, E. G.; Ramsay, A. M.; Bell, E. J.; McCartney, R. A. Myalgic Encephalomyelitis - a persistent enteroviral infection? Post grad med. J. (in press)

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M.E., The Epidemiological

John Richardson, MB, BS

and Clinical Observations of a Rural

Practitioner

Chapter 8

J.

Richardson

M.E., The Epidemiological and Clinical Observations of a Rural Practitioner Dr. J. Richardson MB BS, Belle Vue, Grange Road, Ryton, Tyne & Wear NE40 3LU England Dr. John Richardson was a founding member of the Department of Family and Community Medicine at the University of Newcastle-upon-Tyne, England. He has had extensive experience in Physical Medicine, Cardiology, Neurology, and Histopathology as well as Obstetrics. He has delivered more than 5 600 babies in his own practice. Dr. Richardson has been examining and treating M.E. patients on a continual basis for the last 37years, longer than any physician alive today. He has carried out four decades of research into the effects of viruses and subsequent organ pathology. Polio a n d M.E. I n t h e d a y s w h e n polio r e g u l a r l y occurred,

Acute bulbar polio

affecting grey matter of poste-

t h e following t e r m s w e r e u s e d :

Posterior polio

rior part of the 4th ventricle.

Polioencephalitis

inflammatory disease of the grey matter of the brain.

Acute anterior polio or paralytic polio

the one we remember and easy to "see".

Polio haemorrhagica superior

a haemorrhagic type of above. (Oxley)

Posterior spinal polio or sensory polio

in the posterior grey horns of the spinal cord.

Polio acuta infantum

encephalitis with fits, fever etc. and paralysis.

Ascending polio

which we now define as Guillain-Barre syndrome.

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The Clinical and Scientific Basis of M.E. / CFS

his VP1 titre has risen from 25% to 375% and his CMV titre to 1/300.

Thus polio itself was a pleomorphic entity. Moreover, 20% of cases had a concomitant myocarditis from which 20% succumbed.

P a t h o l o g i c a l Aetiology The Role of Immunization in M.E. I suggest that it is too complex to define simplistically. The reason?

I suggest that we are dealing with something similar to the posterior polio variety now in some of those with Coxsackie and enteroviral infections. Moreover, this has followed in the wake of the international immunisation for the anterior polio variety. Historically, it can be seen from the literature that the varying national programmes of immunisation for smallpox, polio, rubella and pertussis resulted in a number of cases of encephalitis which was not due to the vaccine used. The evidence is that immunisation in some, could result in activation of a dormant virus of another species; it is well known that a viral illness can activate another dormant virus, e.g. herpes.

1. Some suggest that a persisting viral infection may be the cause. This can be so, as shown by my family studies, but without any illness. Thus, this on its own is too simplistic. 2. Some say autoimmune dysfunction may be the cause. This may be so, but it begs the question of how, and also does not answer precisely the following questions : (A) Is it failure to eradicate the virus before end organ effect?

We must recall also that rarely was there more than one member in a family who succumbed to polio, though it was shown that the virus could be cultured from the stools of other members of the family. I have recently cultured live virus from the mother whose baby was immunised against polio, the mother having developed a transient facial palsy.

(B) Is it failure to prevent cells decoating virus and allowing replication in cells? (C) Is it failure in NK cell mechanisms to eradicate cells already infected? (D) Is it indiscriminate autoimmune reaction attacking all host tissue, irrespective of infection? This may be evidence of molecular mimicry.

This does not make it easy to specify in time when infection actually occurs. The first titre we do may be high but I have shown in many a persisting high titre month after month, for several years. In retrospect, it may have been high before the first blood was taken.

(E) Is it purely cellular pathology, as collagen and CNS white matter is also affected? In the light of this, and from my studies, I submit the following as a guide-line, maybe for future channels of research :

Related Cardiac P a t h o l o g y This raises the question of host reaction and mutation and my family studies confirm that this does take place. "Resistance de passage" makes the virus lethal to the host and innocuous to a foreign or subsequent host. This is seen in family studies such as the W family, where the mother had Coxsackie infection with viral meningitis and was in the last trimester of pregnancy. The baby had endocardial fibroelastosis and died before it was one year of age. I titred the other members of the family and they had significant high titres to the same group. Recently the eldest son of 17 years of age succumbed with viral myocarditis and had to have a heart transplant. That this is not a complete cure is shown by the fact that

Group 1 Comprises those who have a viral illness, most of whom recover without sequelae. Is this purely a blood stream infection? Group 2 Comprises about 20% who have had a second illness with the same virus. Does this suggest that the virus remained hidden and, due to some stimulus or co-factor, was again stimulated? Is it reinfection? Group 3 Comprises those where there is definitive end organ effects - be it CVS, CNS, gland, white matter, collagen etc etc.

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M.E., The Epidemiological and Clinical Observations of a Rural Practitioner

Group 4 Comprises those with multi-organ effect as in diabetes etc.

must be careful. It raises the query, is it myelin, is it cellular, or is it vasonervorum, i.e. vascular?

Group 5

Group 4 Is it inordinate immunological activity, i.e. truly auto-immune? If so, then why?:

Alas this is the death column.

From this I deduce the following :

I might be criticised for presenting alarming material but I have tried to present the truth and this in perspective. The slides which follow will demonstrate the truth as all the patients are well known to me and have been followed up for years, together with the family members. Hence, it is not merely a matter of figures, for the truth is much more dramatic than the slides and statistics.

Group 1: There is evidence for complete recovery and possible immunity. Group 2: There is evidence for reinfection or reactivation of persisting virus. Group 3&4: There is evidence for tissue tropism which accepts the virus may be previously hidden (self-host) or acquired (family mutation).

This bears on the symptomatology, for the symptoms vary. In muscle, it is healthy fatigue which results in the marathon runners holding their arms high in ecstasy, but in the M.E. victim is it gross fatigue even before the exercise commences? In the CNS it is not the tiredness which results in happy deep sleep and awakening refreshment, but in disturbed rest and awakening tiredness. Lastly, it is not "depression" but "oppression".

To return to the previous hypothesis : Cellular access I now believe that it is the host and not the virus which has tropism. Is this because the previous host has mutated the virus? This would explain family sequential illness, where one member "mutated" the virus and made it more acceptable to another family host of similar genetic structure.

Investigations Clinical Examination

Decoating and replication I now accept this as a step following access and again due to family mutation or failure of interferon activity, only more sinister.

Skeletal Muscle: The muscles of the limbs, back and abdomen, should be palpated for softened, tender areas and measured for loss of bulk. Fasiculation at rest is rare but on raising and lowering the legs, peculiar jerking muscle movements are to be found in some cases; this is the visual evidence of the 'jitter' which is found on myographic studies. Raising the arms above the head tends to show flail-like movements in more severe cases and a tendency for the palmar surface to be turned outwards - the so called pronator sign. Some of these I have recorded on video tape.

NK activity Is the lack of this due to the host treating the "sick cell" as an embryonic tissue (coating some with protective CGT) and thus not lysing the cells? In my series in a sinister number this can go on to a state of malignancy. Results c a n be : Group 1 Complete recovery.

Neurology: In the long tracts, overt signs are often not remarkable, save perhaps for cord involvement when temperature and touch sensation are sometimes abnormal.

Group 2 Recrudescence with or without complete recovery. Group 3 Organo-tropism and organ pathology. In the series presented it is useful to break it down to ectoderm, mesoderm or endoderm derived organs. In some, eg muscle, repair can occur and be more or less complete. In some, eg CNS, this may not be so and we

Facial Nerve Involvement: In the face, it is not unusual to find loss of sensation in a 5th nerve segment and audiometry often confirms the tensortympani syndrome, i.e. intolerance of high frequencies, which are often painful. Lack of sensation of 87

The Clinical and Scientific Basis of M.E. / CFS

Modified Romberg Abnormality: This is a common feature and may persist years after all other symptoms disappear. The patient may be able to stand well with eyes closed and feet together, but the patient finds it difficult or impossible to do toe heel walking.

one side of the tongue or mouth was not an uncommon finding if sought for and the patient would admit having had a scald from time to time. Bladder dysfunction: It is routinely seen early in M.E. and may persist for several months, very similar to what used to be seen in poliomyelitis. This tends to be seen more frequently in women, and may consist of nocturia, frequent dribbling, pain and less frequently interstitial cystitis. In men, these same symptoms may present as an apparent or pseudoprostatitis. Frequently, this symptom is misdiagnosed as a bladder or urinary tract infection. The bladder dysfunction may represent a hypothalamic disorder and is referred to in the Purves-Stewart book of Neurology.

Opthamology Nystagmus, does occur, sometimes only in the abducting eye, but this is not common. However, if one observes M.E. patients in the "CNS group", up to 15% of these have nystagmus. This failure to focus completely can be shown by computerised testing to be due to saccadic movements of the eye similar to the 'jitter' shown in the limbs and like the limbs, when it is more marked can be seen as nystagmus.

Akinetic lapses: This can be observed at any time of day, but is more frequently noted during the hypnogogic period, either when waking or falling asleep. The patients are aware of their surroundings and can hear conversation but are unable to respond or to move. This may last from one to ten minutes and then remit.

Fundoscopy was performed in every case and not infrequently hyperaemic fundi were observed that may involve the whole of the posterior fundus, or to appear early, as a "cherry red spot".

Seizure activity: Seizure activity of various types is a common finding in the first year of M.E. but is rarely recognized. Absence spells, noted by family, are an almost universal finding in M.E., though rarely noted by patient or physician. Frank Grand Mai or Jacksonian type seizures do occur but much less frequently and usually remit.

One notable feature in a number of cases was the inability to focus. Trying to read resulted in nausea and giddiness in some and in children can be overlooked and put down to school or lesson avoidance. This was observed significantly in many in the acute stage but can persist rather relentlessly.

Cogwheel-like rigidity: In some 10% of cases, chiefly those who complain of considerable muscle fatigue etc., there is a sign which should be looked for. This is to grasp the leg above the knee whilst the patient sits on the examination couch and raises and lowers the leg slowly. The observer will find in some, an odd jerking somewhat different from cogwheel rigidity in that it occurs with the patients voluntary movement and cannot be mimicked. It may have some origin in the response of the myofibrils themselves as we know there is a change in the relationship of type 1 and type 2 fibres. Reflexes are usually normal in these cases but sometimes can be accentuated and then the difficulty arises as to whether this phenomenon may have its origin in the spinal reflex arc and not in the muscle itself.

ENT Hyperacusis: The tuning fork test is useful for picking up the acute case who finds sounds above the 6.000 range to be very painful. This may be of hyperthalamic origin or be a sign of the tensor tympani syndrome. In the latter there is pain behind the ear apart from sound, but augmented by the tuning fork test. In the hypothalamic disorder the pain only occurs with the TF test and is a spontaneous pain not generated in the end organ. Dermatological Facial pallor can frequently be observed and this is a feature noted by relatives as usually preceding an

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M.E., The Epidemiological and Clinical Observations of a Rural Practitioner

exacerbation of symptoms. Relatives note facial pallor when the patient is experiencing a 'bad patch' which may not be a full blown relapse. Sometimes, however, an erythema occurs almost of the 'butterfly' type. This may also involve the 'necklace area'of the chest - similar to that seen in the acute flushing of embarrassment, only in these cases the patient is not embarrassed. These signs appear to be of autonomic CNS origin.

It is often not easy to define. In the case of some for whom we have performed open heart surgery, interesting things come to light. One male of middle age developed a systolic mitral murmur suddenly and it was obvious to me that he had ruptured one of his chordae tendinae. This was proved at operation which again I recorded on video. He had to have a valve prosthesis and did well afterwards. In another who had a six vessel coronary grafting performed, the histology showed stenosis without atheroma. In my humble opinion, this is similar to the old mitral stenosis in that it is collagen which is involved and occurred in a man who had had a longish history of viral pericarditis with friction rubs appearing and disappearing for months at a time. Two other cases with myocarditis came to transplant surgery and one died. In one youth in whom it was touch and go for a transplant, I gave him gammaglobulin in high doses and he is currently well. It should be emphasised that only a minority developed these serious sequelae.

Head, Foot and Mouth Disease: Other changes occur and may be of acute origin as with the hand, foot and mouth disease, usually of Coxsackie A or ECHO virus origin and these have been photographed also. Liver Palms: Late signs sometimes are the so called liver palms and I have seen two cases where as a late sequel dermatomyositis developed with pulmonary symptoms also. However, one case had diabetes of Coxsackie origin and a liver biopsy showed only a vasculitis of the liver. Thus the liver palm is not definitive of one single syndrome.

Dysrhythmias, however, are not at all uncommon and occur in the acute stage and can remit. It must not be assumed that this is always so, as some tend to relapse as we have seen and in one where the medication was withdrawn by a hospital department a sudden recurrence occurred and he collapsed and died. They should be followed up for long periods of time. However, sadly in some cases, a fatal collapse occurs. This has happened recently in a 31 year old who collapsed suddenly whilst walking to work. It is also a matter of public knowledge that athletes have died thus when they should have been resting. Also in mutant mice, this can be proven, in that mice, which are forced to swim after virus infection developed a cardiomyopathy whereas resting mice do not. It is not surprising that this should be, as it is well known that patients who were incubating polio and exercised were much more severely affected.

The M.E. scoring chart and Hamilton chart should be answered in every case. Typical findings would be about 15 in the former and only 2 in the latter. (The M.E. score chart was formed by the author from symptoms which were annotated as occurring in at least 80% of the hundreds of cases which were carefully recorded). The score chart delineates some of the features mentioned above. MRI of brain was also undertaken in selected cases but it is not proposed to discuss this here. Cardiovascular A routine careful examination is essential, also a pericardial friction rub should be carefully listened for in each case. This is more often elicited at the lower sternal area with the breath held in expiration. Many complain of discomfort in bed when lying in a particular position, no doubt due to a possible mediastinal inflammation, which may be the basis of the pericarditis.

Malignancy Although malignancy is not a common finding in M.E., certain unusual malignant features have stood out over the last 37 years. (A) Retroperitoneal Undifferentiated Carcinoma. This is an extremely rare malignancy and almost never encountered in general practice. However, over the past 37 years, I have documented close

In my 4 decade study, mitral valve disease per se is not occurring as frequently as it did nor is it due to streptococcus infection. The viral disease produces pericarditis, myocarditis and sometimes endocarditis.

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The Clinical and Scientific Basis of M.E. / CFS

to 10 such malignancies. This appears to occur 15 to 25 years after the patient first falls ill with M.E. Some of these malignancies may be of pancreatic origin. (B) Increased Incidence of gliomas, astrocytomas and lymphomas. These number 16 over the years in patients who had evidence of CNS involvement. Sadly another patient, a man in his 40s has developed a similar lesion and will not survive. (C) There appears to be an unusual decrease in the expected finding of breast carcinoma when the M.E. patient group is compared to the non M.E. patient group. In all my years of practice, I have had only one case of carcinoma of the breast in female patients.

Serological S t u d i e s A full viral antibody screen is wise, especially for the enteroviruses, but a note of caution, do not assume that the first titre is the highest and a serial repetition is wise to determine any tendency for rise or fall in titre. Immunoglobulin estimations using the ELISA technique is helpful. This defines the specific IgM and IgG in these cases. IgM was positive in 78% and may signify recent infection. IgG was positive in 21% and may signify prolonged or previous infection. Complement tended to be depleted initially in about 50% with a rise above normal after the acute phase. ESR is not usually raised but can be if auto-immune inflammatory disease is a sequel.

Electrocardiography In 76% of this series where auto-antibodies have developed, a leucopenia has been observed with an aplastic type of anemia in the rare case (one required transfusion and it is of interest that after this she recovered - another, a boy, had a RBC count less than 2,000,000). This is due no doubt to a hypothalamic lack of control of absolute RBC numbers. There is evidence that the hypothalamus does control the RBC population at its fairly steady level of around 5,000,000 per cu mm and whilst not frequent nevertheless an erythropenia has been observed in some cases.

If there is any doubt whatsoever this should be done and repeated if need be for the ECG can vary from day to day in some cases. One feature found over the years was the tendency on exercise tolerance testing, using the Tenturi treadmill, for tachycardia to occur without pain, rising from a resting rate of say 70 to a rate of 160 per minute, but without ischaemic changes occurring. This again is not the M.E. syndrome itself but can occur with it as shown. The usual criteria for myocarditis or pericarditis will apply. I have examined many cases where cardiac involvement has been found, and in fact several died suddenly of dysrythmias. This does not exclude M.E. and in fact, if the cardiac symptoms abate and the patient still complains of feeling very ill, the physician may become very frustrated, not realising that the patient also has M.E. which is the main cause of the distress.

VP1 TEST Recently developed in the Department of Immunology in St. Mary's Hospital, London by Professor James Mowbray. This defines the presence of persisting viral protein of enteroviral origin. It is helpful, providing it is construed correctly, but it is not a test for M.E. per se. It will be equally positive in myocarditis of enteroviral origin as well as negative if adenovirus is the agent. If it is negative it therefore should be taken to indicate either a non-entero viral infection or if enteroviral, that viral protein is not being replicated and released by infected cells. I have found the VP1 highly positive and the ordinary serological antibodies of the Coxsackie only 1.8.

These are the minimal clinical examination requirements. Investigations Muscle biopsy studies have been carried out and viral protein has been isolated in peripheral muscle similar to isolation in a viral myocarditis, but this would not be feasible at the moment for all routine examinations.

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M.E., The Epidemiological and Clinical Observations of a Rural Practitioner

often treating it in isolation, either as a myth or as a separate entity unrelated to other pathology of the same aetiology. This has resulted in a combination of misconceptions as follows :

Interpretation It is important to realise that these tests all point to an assumed aetiological agent but do not define the severity of the ensuing illness. Not only so but it is possible that other co-factors may be responsible for the incompetent immune response and host vulnerability.

1. Any concomitant illness of the same aetiology, e.g. myocardial, glandular, thyroid, pancreatic, renal etc., is assumed to be the reason for the malaise. The reasoning is then, that when this is corrected, the patient should be better. In these patients, it is not so.

However, it should be reiterated that the height of the titre bears little relationship to the severity of the illness. I have titred family contacts in over 400 families and many have had titres as high as the patient but without illness, albeit some succumbed at a later date.

2. The corollary to 1, that if there is no concomitant illness definable by the doctor, then it must all be in the mind. Varying hypotheses have been put forward to explain this. None of these is really convincing to those of us who have worked in the field for many years and, indeed, cause us considerable distress. This must be minimal compared to the distress felt by the patient when the effects of the illness are compounded by a negative approach, sometimes amounting to a denial of the illness itself.

Autosomal Antibody Tests Thyroid antibodies are found in my series in about 50% as well as other mitochondrial antibodies. This links with other immune changes.

This has resulted in suicides in some cases and the very act itself is then seen as verification of the original "all in the mind" diagnosis. There is conclusive evidence of the viral aetiology in myocarditis by Archard et al. and also in pancreatitis and diabetes by Professor J. Banatvala, who is also interested in the genetic HLA typing in these cases. I have also documented these.

LFTs are sometimes abnormal and signify sometimes a vasculitis of the liver. C.P.K. in some is raised at rest and with mild effort can rise to fairly high levels. In my experience this coincides with tender and often palpably softened areas of muscles and, as is found with cardiac tissue, does not correlate with pain per se but rather with muscle fibre necrosis.

There is also abundant evidence showing the effects of a virus in the CNS and I have documented a case of M.E. whose serology was positive and sadly, after suicide, the enterovirus was detected in the brain by hybridisation probe analysis. Moreover, the postmortem isolation in this case is of importance as it supported the previous serological evidence of viral infection.

Discussion Aetiology a n d R e l a t i o n s h i p to S e q u e l a e In differentiating between sequelae and concomitant illness it is well to consider aetiology. It is obvious to me that this is not simple for, as shown, a high titre does not signify illness. This is seen with the Mantoux test. Not only so but a family contact with a high titre may not be ill until some years later and may then succumb with a serious illness which could have been justifiably expected with the first contact.

Historical Finally, it may be well to consider that we do not have poliomyelitis in this part of the world, as least not in the way in which it was remembered. For those who can remember, the diagnosis was obvious and the results long lasting, but that was the anterior variety. Yet, here again, many will not be aware that up to 20% with the virus of anterior poliomyelitis had also a viral myocarditis and the death rate was about

Final R e m a r k s Myalgic encephalomyelitis has been an elusive as well as a provocative subject and much has been written both by antagonists and protagonists alike,

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20%. Many have forgotten posterior poliomyelitis was also a defined entity, "affecting the posterior grey horns of the spinal cord". (Dorland American Illustrated Medical Dictionary). This was not so obvious to the beholder but was just as real to the victim as the anterior variety; the aetiological agent was of the same order. After immunisation the scene changed and it is probable that the word "changed" is the correct definition, for this did not eradicate the virus but changed or modified the host response.

and restless movements occur. Insomnia may be severe. In fatal cases, confusion is marked and progressive to lethargy and death. In focal polioencephalitis, there may be clinical evidence of brain damage, or the lesions may be silent and demonstrable only at necropsy. Visual-verbal agnosia, myoclonic jerks, grand-mal convulsions, which occasionally persist for a long while after recovery, spastic hemiparesis, ataxia of one arm or leg, - all were observed. If the medullary respiratory centre was involved, then the rhythm, rate and depth of breathing was affected and the cold, mottled, clammy skin was seen." (Harrison text book of Medicine.)

In the literature, polioencephalitis is described as seen as well as the spinal and bulbar syndrome. Harrison makes mention of one epidemic where "most patients had this type of disease. The diffuse form is characterised by confusion, agitation, coma, anxiety with a feeling of impending doom, or somnolence. Quivering or jerking of the facial muscles or extremities, flushing of the face, tremor of the hands

This is so reminiscent of the process involved in M.E. that we should perhaps begin to consider and take the matter seriously.

"To suggest that the diagnosis of M.E. is covered by the term "fatigue of mind and muscle" is equivalent to defining diabetes as merely polydipsia and polyuria and ignoring the eye, the renal, the CNS and arterial consequences which may ensue."J. Richardson

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Section 3

Opening Remarks of Some of the Chairmen

The M.E.

John Campbell Murdoch, MD, PhD

Syndrome

Chapter 9

John Campbell

Murdoch

This article is reprinted with the kind permission of The New Zealand Medical

Journal.

The Myalgic Encephalomyelitis Syndrome John Campbell Murdoch, MD, PhD, FRCGP, MRNZCGP General Practitioner, Mornington Health Centre / Elaine Gurr Professor of General Practice Department of General Practice, Otago Medical School, University of Otago P.O. Box 913, Dunedin, New Zealand Dr. Murdoch graduated MBChB from the University of Glasgow and held several positions, mainly in the field of General Practice, in Glasgow, Scotland. While working at the University of Dundee from 1977 to 1983, Dr. Murdoch graduated MD and practised as Senior Lecturer in General Practice, Community and Occupational Medicine and as Principal in General Practice at West Gate Health Centre. Once Dr. Murdoch had completed his PhD at the University of Dundee, he accepted his present appointments in New Zealand. Dr. Murdoch has extensive publications to his credit in M.E. Dr. Murdoch was one of the Chairmen at the First World Symposium at Cambridge University.

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The Clinical and Scientific Basis of M.E. / CFS

Over the past five years in New Zealand, there has been debate concerning the clinical validity of a syndrome, the main features of which have been relapsing fatigue, muscle pain and muscle weakness, particularly on exercise. Other features have included neuropsychological symptoms such as irritability, memory impairment and depression. The illness has affected females more than males and is most common between the ages of 20-40 years. The term "Tapanui flu" has commonly been used in this country, largely due to the fact that the first description ofthe syndrome here was from West Otago1. Since that original description, there have been two further clinical accounts from New Zealand 2,3 and two other studies looking at a possible aetiology for the syndrome 45 . In contrast to this paucity of both clinical description and research, there has been much media coverage of the subject and the correspondence columns of these journals have contained beliefs aplenty from both doctors and sufferers, but there has been little informed debate on the facts of the matter, particularly with regard to recent research.

and the illness seems to have been milder and of shorter duration in these groups 811 . It is possible that the reason for this was that the opportunities for observing and recording were greater in these situations where access to medical observation was easier. In the community based outbreaks, eg. in Iceland12, Adelaide13, Florida14, Cumbria 15 , and recent case descriptions in Scotland 1618 the symptoms appear to have been similar to those described in New Zealand. The most recent descriptions of the syndrome have come from the United States where large numbers of people have been diagnosed as suffering from "chronic mononucleosis syndrome"19 22 and the United Kingdom where the preferred pathogen has been the Coxsackie virus, and where the membership of the Myalgic Encephalomyelitis Society has recently p a s s e d t h e 10,000 m a r k . Even on purely phenomenological grounds it would seem necessary to take this problem seriously. The first essential step seems to be to agree on a definition for the syndrome, whatever we wish to call it. A recent list of the criteria for chronic fatigue syndrome by Holmes and his colleagues seems to provide the basis for consensus on the syndrome.23 A patient is deemed to have the syndrome, if, in addition to two major criteria, eight or more of eleven symptom criteria or six or more of symptom criteria and two or more of physical criteria, are present. A similar list of criteria was suggested by a Working Group of physicians, researchers and patients convened by the Roy McKenzie Foundation in 198724. This suggested that four key features should be present at some time during the course of the illness. These were (a) a relapsing or intermittent course, (b) exhaustion, (c) muscle pain or tenderness and (d) unusual muscle fatigue. There will continue to be dispute over nomenclature. In the view of those who attended the Working Group, the term "M.E. syndrome" seemed to be an acceptable compromise between the doctors who deny any inflammatory process in the nervous system, the patients who have come to accept the term and the long history of the name in the medical literature. The name given to the syndrome is, however, relatively unimportant compared to the need to ensure that a common definition is being used.

The medical literature has contained frequent reports of patients experiencing similar symptoms since 1934 when, during a polio epidemic, members of the medical and nursing staff of the Los Angeles County Hospital became ill with muscle pain and paresis 6 . Since then, there have been numerous reports of outbreaks in various parts of the world, referred to as benign myalgic encephalomyelitis - a term first suggested for this "new clinical entity" in a Lancet editorial in 19567. The history of the published work on this clinical entity seems to fall into three main phases. The early reports coincided usually with poliomyelitis epidemics and the underlying theme was the desire to connect these with a similar virus 8 . The publication of the papers by McEvedy and Beard in 1970910 claimed that mass hysteria was the cause, but recent studies have suggested a viral and immunological aetiology for the syndrome. The clinical features of the syndrome have been remarkably consistent over the years during which it has been described, with the main features being extreme fatigue, myalgia, distressing psychological symptoms and a tendency for the illness to relapse after apparent recovery. Many of the earlier reports were of outbreaks of the illness in closed institutions amongst nursing staff, soldiers, nuns and schoolgirls

Having first agreed what we are describing there seems to be three urgent tasks which will use up all

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the available energy at present being expended in the controversy surrounding this syndrome. The first is to establish the epidemiology of the syndrome. There is undoubtedly a "halo effect" associated with any outbreak of illness, as was found by Holmes and his colleagues when investigating the epidemic in Nevada25. In that case, fifteen out of 134 cases were found to have severe persistent fatigue of undetermined etiology lasting more than two months. However, using the same stringent definition, a study in a Boston general medical practice found that 215 of 500 unselected patients, aged 17 to 50 years, seeking primary care for any reason, were suffering from a chronic fatigue syndrome26. They had been experiencing severe fatigue, usually cyclic, for a median of 16 months (range 6-458 months), associated with sore throat, myalgias, or headache. Using the definitions given above, there is a need to carry out periodic community surveys to establish whether such a prevalence exists in this country and whether this prevalence is growing. Murdoch has estimated that the prevalence of M.E. syndrome in the greater Dunedin area in 1985-6 was 127 per 100, 000, but this figure assumes that he had seen all the cases in the area in those two years and is certainly an underestimate 2 . The second issue concerns the management of the patients presently enduring these symptoms. While it is true that we do not fully understand why patients have such problems, it is important that a scientific assessment of the value ofvarious general approaches to management be undertaken. Vallings3 has demonstrated what can be achieved by a family physician by analysing the response to a whole range of therapies and found that group support was the most effective. The real problem in our dealing with this syndrome is our approach to the patient rather than our differences with regard to aetiology. Werry27, in stating his belief that many of these patients suffer from depression, has made a plea for diagnostic probing which "should be made clear to the patient for what it really is - our acceptance that something is wrong and that this is our fumbling for a diagnosis, not the assignment of one." It is the relief from the burden of illness, or healing, which patients seek in their encounters with physicians and this healing cannot occur where the physician fails to recognise that the patient is ill or fails to give any meaningful explanation for the illness. Doctors schooled in scientific medi-

cine have a problem where the patient's illness cannot yet be described in these terms. Perhaps in these cases we need to develop an understanding of the philosophic discipline of phenomenology which could be used, according to Baron 28 to bridge the gap between the way we think about disease as physicians and the way we experience illnesses as people. Finally we need to apply ourselves to research into the possible etiologies of this most interesting clinical condition. Because of the nature of the illness occurring in outbreaks over the past 50 years, effort has been concentrated on finding a viral cause for the syndrome. In the United Kingdom the favoured virus has been Coxsackie B (CBV) and serological studies have suggested higher titres of neutralising antibodies to CBV in sufferers than controls29. Enterovirus-specific probes have detected the presence of virus-specific RNA in muscle biopsies from 20 of 96 patients with postviral fatigue syndrome30. Positive cultures of enteroviruses were obtained from the faeces of 22% of 76 patients and from 7% of controls in another study31. In the United States, the Epstein Barr Virus (EBV) has been associated with chronic fatigue syndrome in several studies19-20. There is a problem, however, in incriminating EBV in the etiology offatigue states because the virus is a ubiquitous pathogen which infects virtually everyone by early adulthood 21 and because capsid IgG titres may persist at high levels for up to 10 years after infection32. The role of EBV in chronic fatigue states has been reviewed recently by Straus 2133 and his conclusion is that, while there is evidence to suggest a pathogenic role for EBV in some patients, it is by no means the universal cause. Another virus which has been suggested to have a role is the Human Herpesvirus Type 6 (HHV6) which has been recovered from the peripheral blood mononuclear cells of some patients from the Lake Tahoe outbreak 21 . The problem with the interpretation of these studies is that no one virus can be demonstrated to be present in all cases, in the same way that AIDS patients are all HIV positive. A possible hypothesis is that such patients are immunosuppressed by an unknown retrovirus or herpes virus and that they then become infected by other viruses such as CBV or EBV. Behan et al.34 demonstrated in an uncontrolled study that 35 of 50 patients with acute or chronic fatigue had altered lymphocyte function in vitro. The acute

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group showed a reduction in the numbers of suppressor / cytotoxic (T8) lymphocytes and the chronic group showed a highly significant reduction in helper cells (T4) and a reversed T4 / T8 ratio. In fatigue states associated with EBV, the results with respect to lymphocyte function have been mixed with one study showing increased 20 and another decreased helper to suppressor ratios35. Two studies 36,37 have shown decreased natural killer cell activity in patients with chronic fatigue syndrome. Since the publications of McEvedy and Beard in 1970 which suggested that the cause of M. E. syndrome was mass hysteria, there has been debate on the role of psychological factors in its etiology. David et al.38 in an important review of this topic, have drawn attention to the fact that hysteria is an outmoded diagnosis which is, in any case, inappropriate to patients seen sporadically in primary care presenting with unexplained fatigue and emotional upset. "Abnormal illness behaviour39" is their preferred term for the psychological aspects of the problem and they point out that this may co-exist with a physical etiology. This view is reinforced by Straus 21 who reports that a very high proportion of patients with chronic fatigue syndrome have a history of depression, phobias and anxiety, and that over half of his patients score as being depressed on a Beck's Depres-

sion Scale. Taerk et al40 have reported that 67% of a sample of 24 patients with neuromyasthenia met criteria for major depression and that 50% had a major depressive episode prior to the development of neuromyasthenia. They suggest that the syndrome may be the result of an organic illness in psychologically susceptible individuals. It is important, therefore, that psychological factors, particularly depressive illness, be assessed in the groups of patients to be studied. The presence of such findings may not necessarily deny the validity of the immunological research described above, since there is now growing evidence that psychological factors have a profound effect on immune function 4142 . Fatigue, pain and emotional upset are the most common problems affecting humanity, and yet we understand little about their causation. While the physical characteristics of fatigue within skeletal muscle can be expounded43, the distinction between psychological and physiological aspects is so unclear that one reviewer has concluded that experiments could not be done in this field44. It is perhaps not surprising therefore that the study of a phenomenon producing all three of these most common symptoms should generate so much heat and so little light. Much more research needs to be done on this most difficult subject before any of us can have the privilege of being dogmatic.

References 1. Poore M, Snow P, Paul C. An unexplained illness in West Otago. NZ Med J 1984; 97:351-4.

7. Editorial. A new clinical entity? Lancet 1956; 1:789-90. 8. AchesonED. The clinical syndrome variously called benign myalgic encephalomyelitis, Iceland disease and epidemic neuromyasthenia. Amer J Med 1959; 26:569-95.

2. Murdoch JC. Myalgic encephalomyelitis (ME) syndrome an analysis of the clinical findings in 200 cases. NZ Family Physician 1987; 14:51-4.

9. McEvedy CP, Beard AW. Royal Free epidemic of 1955: a reconsideration. Brit Med J 1970; 1:7-11.

3. Vallings R. Myalgic encephalomyelitis - a consideration of treatment. NZ Family Physician 1989; 16:9-13.

10. McEvedy CP, Beard AW. Concept of benign myalgic encephalomyelitis. Brit Med J 1970; 1:11-15.

4. Murdoch JC. Cell-mediated immunity in myalgic encephalomyelitis syndrome. NZ Med J 1988; 101:511-2.

11. Henderson DA, Shekelov A. Epidemic neuromyastheniaclinical syndrome? N Eng J Med 1959; 260:757-64, 814-18.

5. Simpson LO, Shand BI, Olds RJ. Blood rheology and myalgic encephalomyelitis: a pilot study. Pathology 1986; 18:190-2.

12. SigurdssonB.Sigurjonsson J,Sigurdsson J e t a l . A disease epidemic in Iceland simulating poliomyelitis. Amer J Hygiene 1950; 52:222-38.

6. Hart TM, Luck JV. Orthopedic aspect of the Los Angeles County poliomyelitis epidemic. Amer J Public Health 1935; 24:1224-8.

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13. PellewRAA. A clinical description of a disease resembling poliomyelitis in Adelaide 1949-1951. Med J Aust 1951; 1:944-8.

Syndrome

30. Bowles NE, Archard LC, Behan WMH et al. Detection of Coxsackie B virus specific RNA sequences in skeletal muscle biopsies of patients with the postviral fatigue syndrome. Ann Neurol 1987; 22:126.

14. Poskanzer DC, Henderson DA, Kunkle EC et al. Epidemic neuromyasthenia. An outbreak in Punta Gorda, Florida. N Eng J Med 1957; 257:356-64.

31. Yousef GE, Bell EJ, Mann GF et al. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet 1988; 1:146-150.

15. Wallis AL. An unusual epidemic. Lancet 1955; 2:1091. 16. Fegan KG, Behan PO, Bell EJ. Myalgic encephalomyelitis - report of an epidemic. J Roy Coll Gen Practit 1983; 33:339-41.

32. Horwitz CA, Henle W, Henle G et al. Long term serologic follow-up of patients for Epstein Barr virus after recovery from infectious mononucleosis. J Infect Dis 1985; 151:1150-53.

17. Keighly BD, Bell EJ. Sporadic myalgic encephalomyelitis in a rural general practice. J Roy Coll Gen Practit 1983; 33:335-7.

33. Straus SE. EB or not E B - t h a t is the question. JAMA 1987; 257:2335-36.

18. Calder BD, Warnock PJ. Coxsackie B infection in a Scottish general practice. J Roy Coll Gen Practit 1984; 77:1376-81.

34. Behan PO, Behan WMH, Bell EJ. The postviral fatigue syndrome - an enalysis of the findings in 50 cases. J Infection 1985; 10:211-22.

19. Dubois RE, Seeley JK, Brus l e t al. Chronic mononucleosis sydrome. Southern Med J 1984; 77:1376-81.

35. Hamblin TJ, Hussain J, Akbar AN et al. Immunological reason for chronic ill health after infectious mononucleosis. Brit Med J 1983; 287:85-7.

20. Jones JF, Ray CG, Minnich LL et al. Evidence for active Epstein Barr virus infection in patients with persisting unexplained illnesses. Ann Int Med 1985; 102:1-6.

36. Kibler R, Lucas Do, Hicks MJ et al. Immune function in chronic Epstein Barr virus infection. J Clin Immunol 1985; 5:46-54.

21. Straus SE, Tosato G, Armstrong G et al. Persisting illness and fatigue in adults with evidence of Epstein Barr virus infection. Ann Int Med 1985; 102:1-6.

37. Caligiuri M, Murray C, Buchwald D et al. Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome. J Immunol 1987; 139:3306-13.

22. Straus SE. The chronic mononucleosis syndrome. J Infect Dis 1988; 157:405-12.

38. DavidAS,WesselyS,PelosiAJ. Postviral fatigue syndrome: time for a new approach. Brit Med J 1988; 296:696-99.

23. Holmes, GP, Kaplan JE, Gantz NM et al. Chronic fatigue syndrome: a working case definition. Ann Int Med 1988; 108:387-9.

39. Pilowsky I. Abnormal illness behaviour. Psychol 1969; 42:347-51.

24. Murdoch JC. ME Syndrome. Therapeutic Notes No. 205 Dept of Health, Wellington 1988.

Brit J Med

40. Taerk GS, Toner BB, Salit I et al. Depression in patients with neuromyasthenia. Psychosomatic Med 1987; 49:214.

25. Holmes GP, Kaplan JE, Stewart JA et al. A cluster of patients with a chronic mononucleosis syndrome. JAMA 1987; 257:2297-2302.

41. Baker GHB. Psychological factors and immunity. Psychosomat Res 1987;31:1-10.

26. Buchwald D, Sullivan JL, Komaroff AL. Frequency of chronic active Epstein Barr virus infection in a general medical practice. JAMA 1987; 257:2303-7.

42. Locke SE, Kraus L, Leserman J et al. Life change stress, psychiatric symptoms and natural killer cell activity. Psychosomatic Med 1984; 46:441-53.

27. WerryJS. The ME Syndrome. NZ Med J 1988; 101:642.

43. Editorial. Fatigue. Lancet 1988; 2:546-8.

28. Baron RJ. An introduction to medical phenomenology: I can't hear you while I'm listening. AnnlntMed 1985; 103:606-611.

44. Kennedy HG. Fatigue and fatigability. Brit J Psychiat 1988; 153:1-5.

29. Calder BD, Warnock PJ, McCartney RA et al. Coxsackie B virus and the postviral syndrome - a prospective study in general practice. J Roy Coll Gen Practit 1987; 37:11-14.

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Chapter 10

Henri

Rubinstein

"Spasmophilia" and/or "Myalgic Encephalomyelitis" ? Henri Rubinstein, MD Neurology (EMG) Consultant, Hopital St-Joseph, 11, rue Franklin 75116 Paris, France Dr. Rubinstein studied medicine in Paris, France, specializing in Neurology at Salpetriere and Sainte-Anne Hospitals. He currently operates a private practice and also practices in the Neurology Department at the StJoseph Hospital. Dr. Rubinstein has published numerous books and articles, more recently Spasmophilic and L'Equation du Bonheur. Dr. Rubinstein is France's best-known expert in Spasmophilic, or M.E. Dr. Rubinstein was one of the Chairmen at the First World Symposium Cambridge University. This was his address to the delegates. It is now common knowledge that medical practices vary according to countries and cultures; even within the realms of occidental medicine, where therapeutic results are globally equal.

on Myalgic Encephalomyelitis

at

spasmophiliac, a specifically French syndrome; in any case an unrecognized syndrome in Englishspeaking countries, who acknowledge only the "hyperventilation syndrome", considered to be a demonstration of anxiety.

In Germany, a tired individual will be treated for low blood pressure, in the United States, a patient with constrictive chest pain will have six more chances to get a coronary bypass than in Great Britain. In England, a sick person will often leave his doctor's office without any prescribed drug, while, in Italy, he may get a prescription for more than ten different medicines.

What about spasmophilia which has an effect on the health of fifteen to twenty percent of the French population? We understand spasmophilia as a neuro-muscular hyperexcitability that causes chronic fatigue, anxiety, nervous breakdown, loss of intellectual efficiency, headaches, muscular pain, spasmodic colopathy, chest pains, insomnia ...

In France, we suffer from "crises de foie", a rare ailment across the Atlantic. Above all, we are

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"Spasmophilia" and /or "Myalgic Encephalomyelitis"?

The primary causes of this n e u r o - m u s c u l a r hyperexcitability syndrome are believed to be found in metabolic disorders related to the metabolism of calcium, magnesium, potassium, phosphorus and others, involving either intake deficiency or perturbed cellular membrane permeability.

one day, they felt ill, they became anxious and tired. They related how, for sometimes many years, they could not return either to their previous state or to their health. They described the real obstacle course they had to struggle with in the medical world that insisted that they were not sick, or that they had a nervous breakdown, or they had too much stress, or that they needed to relax, or to calm down, or to endure, or to change their way of life, their diet, their habits, to take tranquilizers or anti-depressants, or to go to an analyst...

Spasmophilia syndrome appears to be triggered by physical and/or psychologic stress and occurs, usually, among healthy people, with no known psychiatric background, leading to chronic illness often diagnosed as psychotic depression or anxiety neuroses. In 1981, the publication of my book DoYou Have Spasmophilia ? answered to a real need among laypeople and focused on this little known disease. The book heartened a lot of patients who were frightened by the symptoms related to the neuro-muscular hyperexcitability.

For this large number of patients, the discovery of spasmophilia was a real break-through. At last the physicians took into consideration what the patients had lived through, what they had been told. At last the patients no longer felt guilty, because the real reasons for their illness were said to be outside of themselves. Their illness was induced by exterior facts, a lack of minerals triggered by a special kind of background, "terrain" in french.

To find a clear explanation for their numerous perturbations was a great relief for these people who are often misunderstood by their physicians.

At last they got a glimpse of a way of recovery, and could hope to go back to their previous health, after having corrected and balanced their metabolic disorders.

The now classical description of various, but especially agonizing symptoms, crippling chronic fatigue, muscular pain, loss of intellectual efficiency, headaches, digestive and cardio-vascular spasms, sleep disorders, allowed, above all, the recognition of the reality and the genuineness of the spasmophilia syndrome.

This hope has become reality for a majority of people with spasmophilia, 70 to 80% regain their health, more or less quickly, after an episode of unbalanced spasmophilia. Of course, they still have to be careful, like a diabetic person for example who continues to check his blood sugar level, but their pathological symptoms have vanished, they lead a normal life, they feel well.

This is an authentic disease, radically different from mental pathology. Spasmophilia is neither a kind of hysteria, nor an anxious neurosis or a nervous breakdown, nor an expression of stress. To give a name to this disorder, to take it out of the field of the imaginary diseases, to codify some easy and harmless therapeutic attitudes was a first step. Listening to the patients and believing what they said was, for them, an intense relief. Their newly found well-being was the best evidence of it.

Today, new and exciting facts make it necessary to take a second look at the spasmophilia problem; not for the description of a list of symptoms but for the mechanisms that cause this illness and for its therapeutic consequences.

Most of these patients stated that they did not live in particularly dramatic or distressing situations, either in their jobs or in their families; that they did not feel depressed and had no reason to be depressed. But most of the doctors did not believe them. The patients described simply, sometimes angrily, how

As a matter of fact, Anglo-Saxons, who, for a long time, turned down the concept of spasmophilia, now describe "Myalgic Encephalomyelitis", a disease that looks almost exactly like our spasmophilia. British and Canadian physicians who wrote to me about this matter were astonished by the numerous likenesses

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To say more, if the viral assumption is true, we can better understand some of the classical features of spasmophilia : - acute and chronic fatigue. - high prevalence of the disease. - the metabolic disorders, instead of being the primary causes, could be the result of the infection. - even the very notion of spasmophiliac background, or "terrain" could be a consequence of the large diffusion of the viral infection.

between their subject and mine. And they willingly acknowledge my clinical description. These are extremely important facts, "M.E." is supposed to be caused by a virus, to be contagious and widely disseminated. "M.E." is said today to be the biggest single cause of chronic fatigue, anxiety and depression. Like the 'flu, an acute viral disease, it provokes, for a few days, an intense fatigue, diffuse pains, mind obnubilation. "M.E.", a chronic viral disease, causes these very symptoms for months, even for years. An acute infectious beginning may occur in primary "M.E." but secondary "M.E.", where the signs of an obvious viral infection are missing appear to be more frequent.

I am neither a virologist nor a bacteriologist, and I don't state positively that spasmophilia has a viral origin; this fact has to be substantiated by the current research. This is why we are here, to tell what we know, to make new hypotheses, and to exchange information.

This virus, as yet unidentified, is either close to the group of viruses that cause paralytic poliomyelitis or is a retro-virus involved in the creation of an acquired immune dysfunction syndrome.

But I see disconcerting correspondences that arouse our attention, because they lead us farther from the psychological explanations of these agonizing symptoms. Too many doctors are still using these explanations because they don't know, or forget, what biologists have discovered.

This virus, as contagious as the ones that cause influenza and poliomyelitis is much more prevalent that the AIDS' virus. But, like the AIDS' virus, "M.E.'s" virus provokes an acquired collapse of immunologic defenses. People no longer have any resistance to ordinary infections like colds or sinusitis often associated with mental and physical chronic fatigue.

Maybe there are several kind of spasmophilia syndromes, some of them related to a viral origin, and others to metabolic disorders. Maybe it is the virus that make us weaker when under stress. We all live through numerous stressful situations, why do only some of us fall ill ?

To demonstrate a viral cause of the spasmophilia syndrome it would be useful to explain some of its still mysterious characteristic features :

In a few years, spasmophilia became a well-known syndrome in France. Now the viral hypothesis gives us a new perspective or point of view. That's the way progress works.

Characteristic Features sudden onset of the symptoms, often described by the patients, long duration of the disease. impossibility for the patient, if not healed, to r e t u r n to normal m e n t a l or physical state, importance of sleep disturbances. importance of persistent digestive disorders ( b e c a u s e of the intestinal location of the virus), importance of cerebral dysfunctions and of loss of intellectual efficiency, resistance to healing in 20% of t h e patients, even if they receive a correct medical t r e a t m e n t , absence of significant metabolic disorders seen in some patients. high frequency of infections among the p a t i e n t s (sinusitis, cold, cystitis ...), related to t h e decline of i m m u n e defences. high frequency of allergic symptoms.

From a therapeutic point of view, "Myalgic Encephalomyelitis" is said to be presently incurable. In my opinion, the viral hypothesis is quite encouraging, because we can use minerals, gamma-globulins and other substances together to stimulate immunity. We can search for the virus in the digestive tract. It makes it possible to consider the use of auto-vaccines development of a vaccine. If a viral origin appeared to be true for spasmophilia, stress, anxiety, depression, are we no longer responsible for these ailments? Will we no longer be responsible for our laziness, our bad temper, our aggressivity,

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Henri Rubinstein, MD

our sadness? Are we no longer responsible for going over our problems during our sleepless nights?

factors are the same for all of us. Risks and perils are the same for all of us in life's wheel of fortune.

The guilty party is here, easily perceptible in the electron microscope. It is a new virus that wants to get its freedom in the city, that wants to be known, that wants everybody to realize how important it is in our disinfected brave new world.

People who advocate an everyday prevention want us to live a tasteless, odourless, smooth, eventless life. I doubt this kind of life is less dangerous, but I am sure it would make us die from boredom.

But it is a very nice virus, indeed. He does not kill us!! He makes us only more human, more fragile, more anxious, even more creative!

Unfortunately, any of us, at any moment, may draw an unlucky card and become sick, unintentionally; but we must learn to react, and know how to react in order to be healthy again.

He is also an obliging and civil virus, acting like a scapegoat, the scape-virus assumes our responsibility to evacuate it. We are no longer responsible for our diseases, as the virus has destroyed our immunity processes. But we can decide to react, to fight, to counter-attack, to strengthen our natural defenses to live a fuller life.

Our organism knows how to recognize the real aggressors, our body knows how to start its defence mechanisms in order to maintain or find again its balance. The physician's task is to "put to work the Doctor inside us" as Albert Schweizer said. A physician has to use his technical knowledge to give us the will to heal.

It is a habit of our time, to make the patients feel guilty. If we are sick, it is our fault, we eat too much, we smoke too much, we do not engage in enough sports, we live a dangerous sexual life, we do not know how to relax, we do not fight the stress ...

Guilt destroys the defences. A guilty patient is often unable to find enough energy to defend his body. French spasmophiliacs have already learned to know themselves better, learned how to choose among the medical technologies the ones they trust. They no longer believe theories which contradict the experience they live. A great number of viruses have appeared during history, which have been swept off by medical science.

The truth is different. If unfortunately, we become sick, it is not our responsibility. Viruses can be mild, like the one for the 'flu, severe, like the one for "ME" or deadly, like the one for AIDS, but the viruses are the same for all us.

If the virus of breakdown wants to have its place in the sun and if there is still no vaccine effective against it, we can, at least, do everything we can to defeat it.

Pathogenic agents, toxic or hazardous products are the same for all of us. Losses of minerals, and stress

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Chapter 11

Peter Snow

Tapanui Flu ( A quest for a diagnosis) Peter Snow, MB, ChB, FRNZCSP Medical Officer Otago Tapanui Hospital, Suffolk Street, Tapanui, West Otago, New Zealand Dr. Snow is a solo rural medical practitioner serving a rural community, Tapanui, in the south of the South Island of New Zealand. His research interests include Maori prehistory, Selenium deficiency and Chronic Fatigue Syndrome. Dr. Snow is the describer of the original New Zealand epidemic of Chronic Fatigue Syndrome on "Tapanui Flu". Dr. Snow was one of the evening chairmen at the 1990 First World Symposium on Myalgic at Cambridge University. Tapanui is a small rural town in the far south of the south island of New Zealand which services a productive farming forestry district, much like many small towns in New Zealand.

Encephalomyelitis

This illness was noted to appear during the late Winter, peak about late Spring to subside during the Summer months (equivalent to late summer-fall in the North temperature zone). I also noted that this condition was common amongst my farmer clients who experienced a type of contagious abortion in their sheep, cattle, deer or pigs.

The Condition Some twelve years ago I became aware of a recurring epidemic of a chronic fatiguing illness associated with lymphadenopathy, myalgia, muscle weakness, hepatomegaly, splenomegaly, arthralgia, myopericarditis, personality changes, headache, vertigo and a multitude of odd neurological symptoms such as parasthesias, dysethesias, shooting pains, dead arm, and dead leg, to name a few.

The I n v e s t i g a t i o n During the year of 1983, an investigation of this illness was undertaken which had three aims; to describe the illness, to describe the characteristics of the people affected, and to look for causes. Our conclusions were that a definite disease entity did exist.

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Tapanui Flu

We considered a wide range of viral agents: Hepatitis A and B, Infectious Mononucleosis, Coxsackie A and B, ECHO, CMV, Epstein Barr. All investigations proved negative. Non A, B hepatitis remains a possibility. Associated Animal Illness Zoonoses were and still are considered, because of the common association with contagious abortion in stock. Most of the abortion cases were undiagnosed but as Toxoplasmosis and Campylobacter abortion, these diseases were considered but proved negative amongst the trial group. Leptospirosis is not a problem in the southern part of the South Island and screening for this disease proved negative.

neck, buttocks, and intercostals. Cold hands and feet have been a not uncommon finding mainly in the elderly sufferer but not unknown in the young. These were associated with joint destruction, atrophy and pigmentation of the skin. Other skin reactions have been variable. Approximately 50% cannot recall a rash; most cannot recall insect bites, but four of the patients can recall being bitten by insects unknown whilst overseas, resulting in an expanding red rash. The most common rash in New Zealand is a red Tineaform like rash that can recur and come in crops. These are sterile and contain no fungi. They are similar to but not identical with the northern Hemisphere ECM. I associate this condition with a high incidence of multiple autoimmune diseases such as Thyroiditis, Pernicious Anaemia and Addison's disease.

Selenium Toxic reaction to farm chemicals was considered but found to be not related. This district is in a very low selenium deficient area. Farm stock require selenium supplementation for good health and some farmers self dose with selenium. No causal relationship to the taking of selenium was found.

Finally, the striking long term complications seem to be some degree of neurological involvement. This includes cortical dysfunction such as personality changes, memory loss, impairment of concentration, bizarre visual hallucinations (particularly prior to sleep) vertigo, diploplia, visual loss and impairment, cranial nerve involvement such as Bell's palsy, Homers and Supratrochlear palsy's, paraesthesia's, dysethesia's, loss of power in limb or muscle group, incoordination, ataxia, shooting or lightning pains, sometimes severe, neuritis (intercostal, brachial, sciatic, facial etc.) nerve entrapment syndromes and enthesiopathies, severe headaches often associated with stiff necks and photophobia. All or some of the above can be present in the one patient. Some of the symptomatology is vague and fleeting.

The age and sex distribution suggested that it wasn't a disease of psychogenic origin. The results were published in the N.Z.M.J. The response to the results by the public was intense; they appeared to be aware of the presence of such a disorder throughout New Zealand. The disease was dubbed "Tapanui Flu", much to the displeasure to the residents of our small community! The Years that F o l l o w e d

Characteristically, these patients are considered for diseases such as Rheumatoid Arthritis, Multiple Sclerosis, Amytrophic Lateral Sclerosis, Alzheimers, Sciatica, Nerve entrapment syndromes, Myelitis, Cardiopathies of various sorts, and psychiatric disorders. I have been convinced however that the disease process is a multisystem disorder of one aetiology, a view not unreasonably considered with skepticism.

The disease over the years has demonstrated its chronic remitting and relapsing nature. Approximately 15% of sufferers have had a permanent recovery. The rest have demonstrated some degree of impaired health. The most common complaint has been fatigue of varying degrees exacerbated by effort, recurring lymphadenopathy, hepatomegaly, sore throats, cardiac irregularities resulting in distressing palpitations, arthralgia and arthritis of any joint, but commonly the knees, elbows, temporomandibular joint and shoulders, fibromuscular rheumatism of the

L y m e Borrelosis Whilst we were describing Tapanui Flu, Steere et al were publishing their works on Lyme Disease, which, in the American model, appeared to be identical to

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our condition. The Spirochaetal aetiology raised some exciting possibilities, particularly if this Borrelia resembled the Treponemes in its clinical presentation. It is true that the presentation of the original Tapanui Flu was dominated by fatigue but the syndrome as it progressed seemed the same. It is also true that New Zealand does not have the Ixodes tick daminni or ricinus of North America and Europe. We do have an Ixodes in some of our sea birds, one of which is a transequatorial migrator, spending a lot of its time feeding off the coast of North America coming to the New Zealand Southern Island groups to breed. This tick is currently under investigation. We do however have a sundry of blood suckers that may be capable of being vectors such as fleas, mosquito's, sandflies and a variety of other non ixodes blood sucking ticks. The similarities impressed sufficiently for a further trial to be done.

(2) We may have a strain variation, but according to Dr Klaus Hansen this was unlikely. (3) Because of the suggestive clinical picture a new spirochaete or Borrelia is feasible. (4) The result would also question what is happening in the States with regard to Lyme Borrelosis where there is some criticism about the validity of the interpretation of the results. This criticism is centered around the lack of specificity of the test used and the selection of cut off points to indicate a positive result. The other point of interest is that, world wide, it seems as if only about 10% of those tested with the syndrome are positive. Datwyler has suggested an abrogated immune response because of antibiotic suppression of the immune system. (5) It could also suggest that the European results should be questioned, which are apparently at variance with the American finding.

The Borrelia trial Initial serological investigations on tests performed at C.D.C. Atlanta and then Colorado indicate a positive response to a number of sufferers and some skin specialists indicated they had seen ECM type lesions so a trial was organised by the N.I.H. where Dr. Nick Wilson epidemiologist, Dr. Nigel Dickson, Paediatrician, and members of the Department of Health carried out a sex matched control trial using the flagellar antigen ELIZA test of Dr. Klaus Hansen of the Statenserum Institutes Copenhagen. This test was used because of its greater specificity and a greater claimed accuracy. Results of this survey indicated only one of the sufferers had a positive titre of 400 OD. All of the others, both sufferers and controls, proved negative to the Hansen test which, incidentally, showed negative results to the positive controls from the United States. The conclusions were (1) We do not have Borrelosis in New Zealand.

106

(6) The sceptics could be right that the large numbers of so called positives are false, which still leaves the world with what is now a well defined three stage fatiguing syndrome! Where to F r o m H e r e In New Zealand and, indeed, world wide, the condition seems to be occuring at the same rate which, because of its chronicity, means that a large number of sufferers are accumulating. I believe that the effect that the disease has on people's lives is devastating and, coupled with the implied complications using the spirochaetal model, the disease should be viewed with some gravity. I consider that insufficient effort has been put into researching this disorder, particularly in my own country. Finally, I believe the concepts arising out of the Borrelia research in the United States and Europe will have a profound impact on our understanding ofthe chronic fatigue syndromes beingreported from around the world.

J.E. Banatvala, MA, MD, MRCP,

Symposium

FRCPath

Chairman

Chairman

J. E.

Banatvala

J.E. Banatvala, MA, MD, MRCP, FRCPath Professor of Clinical Virology, United Medical and Dental Schools of Guy's and St. Thomas' Hospitals, St. Thomas' Campus, Lambeth Palace Road, London SE1 7EH England Professor Banatvala has held his present position as Professor of Clinical Virology at St. Thomas'Hospital since 1975 and was previously Reader and Senior Lecturer at the same institution. He is also a past Vice President of The Royal College of Pathologists and a past President of the European Society Against Virus Diseases. Professor Banatvala's interests include intrauterine infections and persistent infections, with particular emphasis on enteroviruses. Dr. Banatvala was one of the Symposium chairmen.

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Chairman

Alan

Smith

Alan Smith, MD Senior Specialist Virologist, Southern Transvaal Health Region Senior Lecturer, University of the Witwatersrand Senior Specialist Virologist, National Institute for Virology Pte Bag X4, Sandringham 2131 Johannesburg, South Africa Dr. Smith has held his present position as Senior Specialist Virologist at the National Institute for Virology for seven years with a special emphasis on the mechanisms of viral pathogenesis. Previously, he has practised as a Medical Toxicologist (AECI), a Factory Medical Officer (AECI), a General Practitioner in Johannesburg, SAIMR Registrar Haematology, and has also worked at Baragwanath Hospital in both the Medicine and Surgery Departments. Dr. Smith has a particular interest in computers, whether it be the application ofdirect interfacing to laboratory equipment, the application of databases for quality control in laboratories, utilizing databases in laboratories for epidemiology research, or LANs (Local Area Networks). Dr. Smith was one of the Symposium

chairmen.

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Section 4

An Historical Review of M.E. / CFS Like Disease

Byron Hyde, MD

Myalgic Encephalomyelitis

(Chronic Fatigue Syndrome): An Historical Perspective

Chapter 12 Myalgic Encephalomyelitis (Chronic Fatigue Syndrome): An Historical Perspective Byron Hyde, MD, Chairman, The Nightingale Research Foundation, 383 Danforth Ave., Ottawa, ONT K2A 0E1 This article is reprinted with the kind permission of Health and Welfare Canada, Proceedings of a Workshop, January 1991, Vol 17S1E, pages 5-8. (Please see Chapter 5 for Dr. Hyde's photograph and curriculum

vitae.)

Introduction It is the third theory that the Nightingale Research Foundation uses as its working premise. Subjective evidence suggests that there is a lack of significant viral studies funded for M.E. and that this is part of the reason why current information in this area is ambiguous.

There have been several viral theories of the cause for myalgic encephalomyelitis (M.E.) postulated over the past 45 years. The principle theories are as follows: 1. Single Enterovirus Theory: one of the following viruses can cause M.E.: poliovirus 1 , coxsackie virus 2 , and echo group of viruses 3 .

This article will discuss the history of M.E.-like disease and the enterovirus or polio-like viruses and their probable role in the cause of M.E. Let us first look at the history.

2. Multiple Enterovirus Theory: any or all of the above viruses are capable of causing M.E. 4 . 3. Precursor + Multiple Enterovirus Theory 5 : an initial immune injury occurs which may be of a temporary or chronic nature and is followed by the causal infection with any of the enteroviruses. This initial immune injury can be due to infection of a different or the same group of viruses or can be due to non-viral immune system injury.

History The origins of M.E. are ancient. A disease complex that may have been M.E. was described in 1900 B.C. and is partially preserved in a papyrus fragment from that date. It is obvious that the origins of this text were considerably older. A complete copy of that information exists in the papyrus Ebers and is dated circa 1400 B.C. 11 Much of the mythology of M.E. was incorporated into western medicine at the time of Hippocrates in the fourth century B.C. and later taken up by Galen in the second century A.D. Galen, in fact, was one of the first to suggest that the disease complex known today as M.E. was related to physical disease and not hysteria. His view was not heeded.

4. Single Herpesvirus Theory: one of the following herpesviruses causes M.E. 6 ' 7 ' 8 : Epstein-Barr virus (EBV) Cytomegalic virus Human herpesvirus 6 or roseola virus 1 (HHV6) Inoue-Melnick virus Varicella-zoster (chicken-pox) virus. 5. Multiple Herpesvirus Theory: any or all of the herpesviruses (above) are capable of causing M.E.

For most of the next 2,000 years there were very few physicians who believed that M.E. or any disease had an infectious cause. The theory of infection, though hinted at by the atomists, was never seriously entertained. The early Egyptian mythology that any unexplained illness is simply due to the gods or hysteria has never died but has simply been clothed in the modern pseudoscientific terminology of the day and has persisted with few critics for most of the last 2,000 years.

6. Retrovirus Theory 9 - 10 : a retrovirus, similar in action but different from the acquired immunodeficiency syndrome (AIDS) and HTLV viruses, can cause M.E. 7. Common Precursor Retrovirus Theory: a common precursor to AIDS and M.E. exists. This may be associated with HHV6 or some other yet unknown virus or viral-like body. Ill

The Clinical and Scientific Basis of M.E. / CFS

for that matter, any other disease. She would take a short, halting walk in the garden in front of her house but was unable to walk any distance and frequently had to be carried. She was unable to concentrate when more than one person spoke to her and so received only private audiences of one or two persons. Yet, isolated physically from the world in her bed and chambers, she reorganized the British hospital and health services, developed and pushed through the architectural concepts for British hospital construction, started a nursing school, and organized the field services for the Prussian army and the sewer system of Calcutta. We name our Foundation after Nightingale since it is highly likely that she suffered either from M.E. or a disease indistinguishable from it 14 .

The first epidemic of what appears to have been M.E. to strike an English-speaking country arrived in England from Holland at the time of Henry VIII 12 . In fact one of his several wives, Anne Boleyn, fell ill during this epidemic, then called "The English Sweats" 13 . But medical language was rarely written in such a manner that we can be absolutely sure of what they were talking about. This lack of adequate description changed in the 1650s when M.E. was first described by "the English Hippocrates", Thomas Sydenham. Even then, M.E. had several names. It was described by physicians in various ways including "muscular rheumatism", while the common public name at the time was simply "The English Disease" 13 . One of Sydenham's remedies for the many muscle aches of M.E. was Balm of Gilead. It probably was the first symptomatic M.E. medication that actually worked. Let me describe how to compound this first English prescription for M.E.:

In 1856, Finsen 15 observed an epidemic of muscle rheumatism and chest pains in Iceland. This was probably the first recorded coxsackie epidemic, later to be called Bornholm disease, and one of the several precursors of M.E. The same epidemic repeated itself in a more serious fashion in Iceland in the district of Oflord in 1865 15 .

Balm of Gilead, The First Treatment

'Mi^one poundof the best Sees wa^ over a moderate fire in a tike quantity of canary udne. Add of the best oCive oi[ and Venice turpentine washed to whiteness in rose water, add half a pound. "Evaporate the wine by boiling at a gentle heat. Remove the mixture from the fire, and add two ounces of redsandal wood, finely powdered. Stir until coo fl*.

The First Therapeutic Regime In the American Civil War, M.E. surfaced as "Soldiers' Disease" and the neurologist-in-chief for the Union Forces, Silas Weir Mitchell, published a book on this disease. The book was largely concerned with treatment, proposing total bed rest and hypernutrition for a period of several months 16 .

From this preparation one learns why the British were obliged to become a seafaring nation. This exotic balm was applied externally. Not only did this balm assist the muscle aches, it undoubtedly improved many a patient's perfume.

The Paralytic Years, 1881-1955 Despite the work of Jenner of smallpox fame and other important scientific workers, until approximately 1880 very few physicians thought in terms of or even believed in infectious diseases or the concept of microbes causing disease. In 1881 this all changed with the first recorded epidemic of paralytic poliomyelitis. This epidemic 17 of 18 cases occurred in northern Sweden. Almost simultaneously another small epidemic of 5 cases appeared in Norway. In 1885 an epidemic of 13 cases occurred in southern France. By 189018, when an epidemic of 44 cases of poliomyelitis struck Stockholm, paralytic poliomyelitis was at epidemic proportions as far away as California. In Sweden in 1905, Wickman 19 described the first of the colossal epidemics that were to occur.

Florence Nightingale In 1854, the very active Florence Nightingale, while organizing the field services for the British Army, succumbed to an infectious disease in the Crimea. She recovered briefly only to fall ill again. At 35 she had been an extraordinary worker and had worked for years with a diligence that would have exhausted the most hardened general. She became chronically ill with chest pain, headaches, and a rapid muscle fatigue that lasted until she was 60 years of age. She had persistent upper back pain. Numerous heart specialists failed to find any fault with her heart or,

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Byron Hyde, MD

Myalgic Encephalomyelitis

In this first macro-epidemic, 1,031 cases were recorded in Stockholm, while a simultaneous and similar epidemic took place in Norway.

(Chronic Fatigue Syndrome): An Historical Perspective

is known about what happened to the 198 doctors and nurses concerned and, although 54 years later I have been able to track down some of the surviving doctors, I have yet to contact any of the nurses, a few of whom must still be alive. Part of the reason for the lack of published follow-up is the fact that the 198 staff members sued the hospital and eventually settled for $6 million in 1939. Such an amount in 1939, divided among the group, would have purchased 3 houses in the best section of Los Angeles. Contingent on receiving the payment was non-publicity of the epidemic.

Blind to the increasing information indicating that poliomyelitis was due to an infectious process, as late as 1901 Dejerine 20 in France insisted that paralytic poliomyelitis was the result of a psychological predisposition. It is a view proposed by some physicians today when discussing M.E. The 1934 Epidemic It was not until the full-blown poliomyelitis epidemic that swept California in the summer of 1934 1 that M.E. was actually recognized as a separate epidemic disease. During that poliomyelitis epidemic another and different type of epidemic occurred among the personnel ofthe Los Angeles County General Hospital. There were no deaths and 198 or more cases occurred among the nurses, physicians, ambulance drivers, and other medical support staff.

Immunization as a Cause

It is important to note that the 1934 epidemic followed as part of a larger California epidemic in which 1,301 cases of paralytic poliomyelitis were hospitalized in the Los Angeles General Hospital alone. Another 1,198 that presented were diagnosed as not having poliomyelitis. What did they have? It is quite probable that many had M.E., but when there were 1,301 paralyzed and dying cases of poliomyelitis, M.E. patients would have been rightly dismissed as unimportant. It is perhaps for this reason that recorded epidemics of M.E. were largely reported among doctors and nurses, individuals who, due to their proximity, could not be ignored.

The symptoms of this epidemic were those of M.E. The patients developed relapsing muscle weakness, unusual pain syndromes, personality changes, memory loss, aphasias — all typical M.E. symptoms. Many of the staff doctors never returned to full employment although they were all very young at the time. The nurses in particular were all treated as having hysteria and as late as 1968 Marinacci writes, tongue in cheek, that several of the nurses affected in the 1934 epidemic had been hysterectomized as a technique to treat their hysteria, and that the surgery had not helped 21 . This first, carefully recorded, epidemic disease came to be called atypical poliomyelitis.

It is apparent from the work of Gilliam 1 that the large majority of the medical staff fell ill with M.E. after being injected with immune prophylactic globulin prepared from the serum of those who had fallen ill during this epidemic. Was this the first recorded clinical transfer of M.E.? The majority of these health-care workers have never fully recovered.

The investigation of this 1934 epidemic by the Past Assistant Surgeon of the United States Public Health Services, Dr. A. G. Gilliam, was not published until 4 years after the event, in 1938. Dr. Leake, Medical Director, United States Public Health Services, makes a point in the foreword of Public Health Bulletin, No. 240 of stating that "none of these cases is definite poliomyelitis." The report was, nevertheless, published by Gilliam as An epidemic, diagnosed as poliomyelitis.

The Poliomyelitis Association Up until 1955, when general poliomyelitis immunization was introduced, many, if not most, of the M.E. epidemics occurred concurrently with or followed epidemics of paralytic poliomyelitis. After the introduction of poliomyelitis immunization, paralytic poliomyelitis stopped but M.E. persisted. Paralysis

The First Legal Action But the nature of M.E. itself also changed. When you

Though a lot is known about the epidemic itself, little

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The Clinical and Scientific Basis of M.E. / CFS

doned and forgotten in the midst of the epidemic turmoil. There was no time for them. The medical and nursing staff were usually exhausted from caring for the enormous n u m b e r s of dying and paralyzed patients.

investigate any large numbers of these pre-1955 M.E. patients, as I have done, it is not hard to observe that many are paralyzed and in wheelchairs. When post-1955 M.E. patients are examined, severe muscle failure is common, but paralysis is for all purposes totally lacking. This paralytic facet of M.E. is last described in the M.E. literature by Acheson 22 . This large review of epidemic M.E. is well-worth reading. It describes an epidemic disease process that is identical to endemic M.E. now with one exception: today, in the western world, there are no associated cases of paralysis. Clearly the introduction of poliomyelitis immunization has had an effect on preventing paralysis in M.E. patients. Since 1955 there have been few records of death or paralysis in M.E. epidemics. Clearly this suggests a viral connection between M.E. and poliomyelitis. The 1936 Wisconsin epidemic of M.E. occurred when a student nun returned to her cloistered school from Brooklyn 22 . Her friend in Brooklyn developed poliomyelitis at the same time as the student nun fell ill with M.E. It appears that the novice from Brooklyn was the source of the epidemic that followed in her dormitory. Up to 1942, 3 epidemics of M.E. in Switzerland were called abortive poliomyelitis 23 . The 1948 epidemic in Iceland started as a poliomyelitis epidemic 24 - 25 and finished as a major M.E. epidemic involving 1,116 patients. The non-stop 1949-51 M.E. epidemic in Adelaide, South Australia 2 6 ' 2 7 - 2 8 ' 2 9 , was associated with an epidemic of paralytic poliomyelitis. The 1951 M.E. epidemic in upper New York State, described by Dr. White of Queen's University, Kingston 30 , was associated with a poliomyelitis epidemic. In 1953, the M.E. epidemics in both Copenhagen, Denmark 3 1 ' 3 2 , and Coventry, England 33 , were associated with poliomyelitis, as was the Royal Free epidemic 34 . Another name for M.E. was Coventry Disease and it was this name that was used by the M.E. patients in Pittsfield, Massachusetts 35 . The 1956 Pittsfield outbreak combined an M.E. and poliomyelitis epidemic. This reputedly started when an American airman was brought home from Iceland with paralytic poliomyelitis. His arrival in Pittsfield started a mixed polio-M.E. epidemic. This poliomyelitis-M.E. association is so constant that it becomes boring to even recount the events. Patients with M.E. symptoms were generally aban-

The Poliovirus Theory of ME is Also Abandoned After 1955 and the general introduction of polio immunization, people stopped falling ill with both paralytic poliomyelitis and paralytic M.E. but nonparalytic M.E. continued. Since poliomyelitis no longer existed as a major public health problem in the temperate climatic zones, it was only normal to conclude that the continuation of M.E. must have been due to another virus or group of viruses. This conception, of course, was based upon theories of poliovirus immunization. These theories frame our entire understanding of poliomyelitis and were responsible for M.E. researchers abandoning the polio theory as a cause. For 35 years researchers have looked for another cause. To date, they have met with considerable failure. Before proceeding to discuss other agents, let us make a few final comments on poliomyelitis. Poliomyelitis is caused by death or injury to the anterior horn cells. These anterior horn cells exist in the anterior part of the spinal cord. Other cells in the lower part of the brain were also attacked in some cases of poliomyelitis. These "motor" cells were responsible for the normal muscle stimulation and function. With the death of these anterior horn cells, innervation to the muscles was interrupted and the muscle "died". But why were these anterior horn cells or other motor cells selectively destroyed or injured in poliomyelitis? Anterior horn cells have specific receptors for paralytic poliomyelitis viruses. The virus is capable of paralyzing only because it has a specific reciprocal receptor on the motor nerve cell. Simply stated, polio immunization may work not just by an increase in the antibody response to polioviruses that are capable of causing paralytic poliomyelitis but by a selective blockade by non-virulent poliovirus vaccine strains of the receptors in the anterior horn and other motor cells.

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Byron Hyde, MD

Myalgic Encephalomyelitis

In August of 1989 we received a call at the Nightingale Research Foundation from the Provincial Viral Laboratories. One of our patients had a dangerous rising titre to polio 3 virus. "Is she in the hospital? Is she paralyzed?" "No," I said, "she has simply got M.E." She happened to be one of the few M.E. patients for whom we could tell exactly what virus had caused her illness.

(Chronic Fatigue Syndrome):

An Historical

Perspective

Up to 1955, recognized M.E. was clearly previously associated with poliomyelitis. Many of the symptom complexes associated with poliomyelitis epidemics we call M.E. today. In the past we attributed these findings to abortive polio, atypical polio, or posterior polio. The viruses that cause paralytic poliomyelitis are some of the same viruses that cause M.E. But these enteroviruses that are capable of causing paralysis attach to more than one set of tissue receptors. These other receptors are found on different cells in the brain and spine as well as in other body areas. The symptoms described by M.E. sufferers are due to injury to these other cells.

The Immunization Link At the Nightingale Research Foundation we believe, like Albert Sabin, that many of the enteroviruses cause paralytic "poliomyelitis". We also believe that many of the enteroviruses cause M.E. It is a fact that the majority of M.E. patients today, as well as in the post-1955 period, are not in high-stress occupations as the popular press frequently suggests, but are teachers, nurses, physicians, and other health-care workers. This group represents those most closely related to infectious illness, frequent immunizations, and those most frequently immunized.

In North America, subjective observations would indicate that very little of the global viral research budget is dedicated to investigation of enteroviruses. Without heed, we are sitting on the edge of a cliff, waiting for disaster. For many sufferers of M.E. that disaster is already here, and few are listening.

References 8. Straus SE, Tosato G, Armstrong G, et al. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med 1985; 102: 7-16.

1. Gilliam AG. Epidemiological study of an epidemic, diagnosed as poliomyelitis occurring among the personnel of the Los Angeles County General Hospital during the summer of1934. United States Public Health Bulletin No. 240, April 1938:1-90.

9. Young AJ. A profile of mononuclear lymphoid cells in patients with chronic fatigue syndrome. University of Otago Medical School, NZ, 1989.

2. Calder BD, Warnock PJ. Coxsackie B infection in a Scottish general practice. J R Coll Gen Pract 1984; 34: 15-19.

10. Ablashi D. Reverse transcriptase recovered in two children with chronic fatigue syndrome. Presented at the Great Lakes Midwest CFS Conference, October 21-22, 1989

3. Lyle WH. An outbreak ofdisease believed to have been caused by Echo 9 virus. Ann Intern Med 1959; 51: 248-69. 4. Behan PO, Behan WMH. Post viral fatigue syndrome, a review. CRC Reviews. Cleveland, Ohio: CRC Press, 1988.

11. The Papyrus Elbers: the greatest Egyptian medical document. Translated by B. Ebbell. Copenhagen: Levin & Munksgaard 1937: 108-13.

5. Hyde B. The Nightingale Research Foundation Journal 1989; 1: 16-17.

12. Sylvest E. History of epidemics, 6. Jones JF, Ray CG, Minnich LL, Hicks MJ, Kibler R, Lucas DO. Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated antiearly antigen antibodies. Ann Intern Med 1985; 102: 1-7.

1933.

13. Sydenham/Greenhill T. The works of Thomas Greenhill translation, bk 1, 1948.

Sydemham.

14. CookET. Life of Florence Nightingale. Volsl&2. MacMillan 1913.

7. Tosato G, Straus S, Henle W, Pike SE, Blaese RM. Characteristic T cell dysfunction in patients with chronic active Epstein-Barr virus infection (chronic infectious mononucleosis). J Immunol 1985; 134: 3082-88.

15. FinsenJ. Uagttagekserangaaende i Island. Copenhagen 1874: 145.

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Sygdomsforholdene

The Clinical and Scientific Basis of M.E. / CFS

16. Mitchell SW. Fat and Blood. J. B. Lippincott, 1877. 17. Wickmanl. Acute poliomyelitis. 18. Medin 0 . Kinderlahmung. 1890.

J N e r v M e n t D i s 1913:3.

26. Pellew RAA. A clinical description of a disease resembling poliomyelitis seen in Adelaide, 1949-1951. Med J Aust 1951; 1: 944-46. 27. Jackson JF. Monthly incidence of cases. 14th Annual General Report, South Australia Institute for Medical and Veterinary Science, July 1951-June 1952; 17.

Uber eine Epidermie von spinaler Verhandl. d. x. Internat. Kongr. Berlin

19. Wickmanl. Studien uber poliomyelitis acuta. Path. Inst. d. Universitat Helsingfors. 1, 1905.

Arb.a.d.

28. Pellew RAA, Miles JAR. Virus and animal studies. investigation on a disease resembling poliomyelitis Adelaide. Med J Aust 1955; 42: 480-2.

20. Dejerine J J . Seminologie du systeme nerveux. Dans: Traitedela paihologie generate. Paris: Bouchard, 1901.

29. Pappenheimer AM, Bailey OT, Cheever FS, Daniels JB. Experimental polyradiculitis in monkeys. J Neuropath Clin Neurol 1951; 1: 49-62.

21. Marinacci A. Applied electromyography. Philadelphia: Lea & Febige, 1968:91.

30. White DN, Burtch RB. Iceland disease - a new infection stimulating acute anterior poliomyelitis. Neurology 1954; 4: 506-16.

22. AchesonED. The clinical syndrome variously called benign myalgic encephalomyelitis, Iceland disease, and epidemic neuromyasthenia. Am J Med 1959; 26: 569-95. 23. Gsell O. Abortive poliomyelitis. 1938: 20-1.

Further seen in

31. Fog AT. Neuritis 1953; 115: 1244-51.

vegitiva

epidemica.

Ugeskr Laeger

Leipzig: Verlag Thieme, 32. KrarupNB. Ophobet optraeden of myositer (epidemic of myositis: poliomyelitis). Ugeskr Laeger 1952; 114:1534.

24. Siguijonsson J. Poliomyelitis and the Akureyri disease, mixed epidemics of poliomyelitis and a disease resembling poliomyelitis with the character of the Akureyi disease. Nord Med 1959; 61: 174-82. 25. Sigurdsson B, et al. A disease epidemic simulating myelitis. Am J Hyg 1950; 52: 222-38.

polio-

33. Macrae AD, Galpine JF. An illness resembling elitis observed in nurses. Lancet 1954; 2: 350-2. 34. RamsayAM,0'SullivanE. Encephalomyelitis poliomyelitis. Lancet 1956; 1: 761-64.

poliomy-

simulating

35. Henderson DA, Shelokov A. Epidemic neuromyasthenia clinical syndrome? N Engl J Med 1959; 260: 757-64, 814-8.

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Section 5

The Twentieth Century History of M.E. / CFS

The 1934 Los Angeles County Hospital

B. Hyde, MD

Epidemic

Chapter 13

Alexander G. Gilliam

The 1934 Los Angeles County Hospital Epidemic Review Chapter written by Byron Hyde, M.D., Review of Publication of A.G. Gilliam, M.D. Taken from: Epidemiological Study of an Epidemic, Diagnosed as Poliomyelitis, Occurring Among the Personnel of the Los Angeles County General Hospital, During the Summer of 1934 Public Health Bulletin No. 240 Curriculum vitae and photograph courtesy of The Archives of Environmental Health, Vol. 8, Issue 3, pp 7612, 1964. Reprinted with permission of the Helen Dwight Reid Educational Foundation. Published by Heldref Publications, 1319 13th Street, N.W., Washington, D.C. 20036-1802. Copyright 1992. Dr. Gilliam was born in Petersburg, Va, and graduated from the University ofVirginia and its medical school, after which he took the Doctor of Public Health degree in 1934 at Johns Hopkins University in Epidemiology under Dr. Wade Hampton Frost, whose teaching deeply affected his subsequent career. He was an officer of the United States Public Health Service for 25 years. This period really embraced two careers in epidemiology: first, in the field of infectious diseases, and later in cancer epidemiology. He was the first epidemiologist assigned to the National Cancer Institute, where he worked from 1948 until his retirement from the service in 1960 to become Associate Professor, then Professor of Epidemiology at his alma mater, Johns Hopkins. It was early in this third career that his life was tragically cut off by malignant disease which he bore with great fortitude to the end. His infectious disease investigations touched upon many problems, of which poliomyelitis was the one to which he devoted most time. He served during World War II with the United States of America typhus commission and while on an over-seas assignment acquired a near-fatal attack of scrub typhus. After the war, he served for two years as the Chief of Epidemiology in the Office of Malaria Control in War Areas, which later became the Communicable Disease Center. His subsequent interest in cancer was broad, but centered upon leukemia, cervical carcinoma, and breast and lung cancer. He was author or co-author of some 45 publications.

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The Clinical and Scientific Basis of M.E. / CFS

While these studies were of uniformly high excellence, an equally important contribution was his introduction of sound epidemiologic methods into new field and his constant insistence of the avoidance of errors of interpretation based on what he so frequently referred to as "jokers" in the data and their methods of analysis. In a kindly way, he was intolerant of shoddy work. His influence as a teacher on his colleagues and students, while difficult to measure, was undoubtedly large. Those who knew Dr. Gilliam will best remember him for his personal warmth and kindliness. He leaves a very large number of affectionate friends, and a place in epidemiology that will be impossible to fill.

Abstract: Gilliam describes a disease process, with an acute fulminant onset, related to an infectious disease process that, over a course of six months, generally improves to a level of stability and even one where some of the patients can return to work. For many individuals, the pattern is one oflong standing, chronic illness. There is considerable variety in the severity of the disease. It would appear that most individuals described never returned to their original state of health. Since no thorough follow-up examination of these patients was ever conducted, one can only speculate as to the percentages that remained chronically ill. Gilliam also describes the recurrent nature of this disease process. Nevertheless, from the work of Marinacci in the 1950's, one can state that a great many of the women patients who fell ill in the 1934 epidemic never returned to normal work levels or normal health. Although others may have described features of this disease process at earlier dates, this is the first truly excellent scientific examination of an Epidemic of M.E. /CFS. Despite the excellent material organized by Dr. Gilliam, it is rarely inspected for the wealth of information it contains. This review also relates Gilliam's work to subsequent findings. U.S. Government Resistance to Publication In April 1938, having overcome the serious obstruction by senior officials in the United States' health bureaucracy 1 , Dr. A. G. Gilliam published the first scientific review of an epidemic of what is known today as M. E. or CFS2. This small 90 page book should be required reading for any researcher or student of M.E./CFS, for it outlines, for the first time, in clear medical language, many of the largely unresolved problems facing investigators even today.

If the first part of the question is true, it would suggest that the viruses causing paralytic poliomyelitis, having sustained one or more passages through a human intestine, a perfect immune modifying system, produced a changed or altered virus capable of acting on different CNS receptors and causing the significantly different disease that Gilliam describes. If the second part of the question was a factor, it is just possible that a new and then unidentified virus, such as the foamy cell retrovirus, was being transmitted into some of these patients with the prophylactic injections. Whatever the process, the second wave of illness appears to have been caused iatrogenically by the injecting of prophylatic serum. Gilliam told Dr. Shelokov that he has been "stymied by his superiors from telling the whole story." For all of these reasons and more, it is worthwhile to go back into source material and take another look at the 1934 Los Angeles Epidemic.

Was illness provoked by prophylactis? Not only did Gilliam give the first clear description of the acute and subacute characteristics of M.E./CFS and its epidemiological features, but his book also implicitly posed a question that has been both avoided and unanswered to this day. "(A) Did the 198 health care workers fall ill, or remain ill, solely as a result of the poliomyelitis epidemic of 1934 or (B) did some of the 198 fall ill, or remain ill, as a result of the "prophylactic serum" that Gilliam persistently documents as having been given, often prior to any symptom, to the majority of patients in this epidemic?"

If the question concerning the pooled adult serum and convalescent prophylactic serum as a potential cause of some of the pathology is not clearly stated in the text of his book, there is ample reason for this. We

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The 1934 Los Angeles County Hospital Epidemic

know of the battle that Gilliam fought to even have the epidemic findings published. It was obvious that he was not going to rock any more boats if he was to see the document in print. Today, few know that many of the 198 disabled by the epidemic brought a legal action for compensation against the state and the hospital. The action has never been published but we do know the result. The disabled health care workers were finally compensated in 1938-39, with several millions of dollars3.

As far as I am aware, no follow-up study of the chronic features was ever produced. In fact, other than the work of Marinacci, the later literature then forsakes these patients. I assume, correctly or otherwise, that the legal settlement obtained by these patients required total suppression of further medical reporting by the press. Yet it is obvious from the work of Marinacci as late as 1955, that the number of women afflicted in this epidemic was apparently large, many of whom were still ill in 19557, 21 years later. This question will be addressed at the end of this document.

What were the grounds of their victory? Why did the hospital and the state settle? I would be surprised if the role of the pooled human serum given to the majority of these victims was not critical in the final judgement.

In 1989,1 was able to speak to two male physicians, one female physician, and to the relatives of one male physician who had recently committed suicide after a long history of unspecified psychiatric illness. All had fallen ill in the 1934 epidemic. The female physician had returned to work shortly after and had worked until retirement in her late 60's. One of the male physicians had never returned to work and another had reputedly had a spotty work history due to chronic illness. There had also been great difficulty in maintaining any long-term marital relationship. However, I was not able to ascertain whether this was due to the illness or other factors. I have no way of knowing if these four cases are representative of the 198 persons who first fell ill. To date, I have totally failed to find any of the women who fell ill. Undoubtedly some are still alive at the time of writing in 1991.

Gilliam describes observations lasting from onset to six months after the beginning of the epidemic. Very rarely is the symptom picture described as persisting beyond six months simply because the study did not last longer than that period. This 1934 description is consistent with that found today in early M.E. / CFS patients. Also, as Gilliam points out in his case histories 4 , the symptom picture is more pronounced in the first six months and particularly early on in the illness.

This observation is the same today: the symptom picture is both more intense and more varied during the first 6 months of illness in the majority ofpost-infectious M.E./CFS patients.

The 1934 Document It is worthwhile quoting Dr. Gilliam's first paragraph in his report:

Persistence of Illness "Coincidental with an epidemic of poliomyelitis in the city and county of Los Angeles, CA., in the summer of 1934, there occurred among the employees of the Los Angeles County General Hospital an epidemic of illness diagnosed at the time as poliomyelitis. If this diagnosis may be accepted in any large proportion of the cases, the epidemic is unique in the history of poliomyelitis because of the altogether unusual symptomatology, and the extraordinarily high attack rate in an adult population. If the disease were not poliomyelitis, the epidemic is equally extraordinary in presenting a clinical and epidemiological picture, which, so far as known, is without parallel8."

The epidemic was studied and graphed from the apparent beginning on the 5th of May until approximately the 16th of November, a period of 28 weeks. Clinical histories were recorded from the beginning of the epidemic in May until mid-December 19345. The longest period of follow-up appears to be 30 weeks6. Accordingly, it would be unsubstantiated to assume that those that fell ill in the epidemic were, for the main part, back to work and in reasonably good health, as one would assume from reading some of the case histories.

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The Clinical and Scientific Basis of M.E. / CFS

In this epidemic, 198 employees of the Los Angeles County General Hospital fell ill. There were no deaths and the personnel most severely attacked were nurses, technicians and physicians, with an attack rate of 10.7 and 5.4 respectively9.

(a) High attack rate: 73.3 per 100,000 (b) Low case fatality rate: 1.39% (c) High adult age distribution: 29% of all cases were 29 and over but this does not document those 1,198 turned away. (d) Paralytic cases: Leake and others estimated that the paralytic rate in the Los Angeles area was 50%, but this included any cases that showed slight and often transient localized muscular weakness, only discovered by a careful test of muscle function. (e) Low residual paralysis rate: Hart and Luck estimated this to be less than 2% of all reported cases.

It is generally considered today, as it was then, that the major epidemic, starting in May 1934 in the San Francisco9 area and rapidly engulfing all of southern California, was an epidemic of paralytic poliomyelitis. Yet, by the then considered norms, it was an unusual epidemic. Gilliam states that, within the hospital epidemic, the 198 adults: "rarely exhibited the disability that is classically associated with poliomyelitis, namely, paralysis of a kind that might be expected to result from destruction of anterior horn cells."10

Experimental Studies 13 :

Gilliam discusses the epidemic figures in Los Angeles City and County. The epidemic was documented for 7 months, from May 6 until December 1, 1934. However the peak period was typical of a poliomyelitis epidemic and lasted 2 months, from May 19 until July 14. He does not give the figures for the state of California or even for the many hospitals in the Los Angeles area, but he does note that 2,499 cases suspected of being poliomyelitis were treated in the General Hospital. Of these, 1,301 cases were reported as poliomyelitis and 1,198 were not commented upon. The median onset of the L.A. epidemic was June 23 and the median onset of the 198 hospital cases was within the following week.11

When this virus was injected into monkeys, it demonstrated a 96.3% complete paralytic rate with only 4.7% recovery.

Rockefeller Institute reference poliomyelitis virus

Los Angeles strains When this virus was injected into monkeys, it demonstrated a complete paralysis rate of only 22% with 84% recovering. Monkeys infected and recovered from the L.A. virus demonstrated both immunity and higher neutralizing titre when challenged by the Rockefeller strain of virus. This suggested a virus with similar characteristics but a remarkable difference in the severity of the clinical outcome. In other words, the L.A. virus that caused pain, headache, muscle tenderness, muscle weakness, sensory disturbance, cognitive disturbance, irritability, drowsiness, emotional upsets, insomnia, menstrual difficulties, urinary retention and provoked a remitting course with symptoms identical to what we see today in M.E. / CFS, protected the monkeys used in the experiment from more virulent poliomyelitis virus strains.

Was the 1934 California epidemic, poliomyelitis or M.E. / CFS? Are they both simply different facets of the same infectious agents? It was a very large epidemic, but the question arises: was it a bona fide poliomyelitis epidemic or was it an enormous M.E. / CFS epidemic? Were the 1,301 cases that demonstrated primarily muscle weakness, poliomyelitis, and the remaining 1,198 cases part of a giant M.E. / CFS epidemic?

This experimental model was acted out in real life in Iceland some 20 years later when a poliomyelitis epidemic devastated the population in Iceland, but not where the epidemic of Akureyri Disease had struck in 1947 and 194814.

Some of the figures uncharacteristic of a typical poliomyelitis epidemic12 noted by Gilliam are as follows:

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The 1934 Los Angeles County Hospital Epidemic

Pathology

Type two: The patient recalls a transient illness, often having occurred several months earlier, (not specified by Gilliam) which resembled systemic poliomyelitis (presumably muscle weakness or fatigue?) or meningeal symptoms.

In the few human cases coming to autopsy, the lesions were consistent with those regularly found in poliomyelitis. However, "neurophagia was not marked and diffuse and perivascular round cell infiltration was very prominent". Likewise, the monkeys showed "a lesser degree of cell destruction with a comparatively greater amount of diffuse and perivascular infiltration" than seen in monkeys injected with the Rockefeller strain 15 . Acute and Insidious Onset Type Disease Gilliam is the first to note that the disease process starts in two distinct fashions 6 . He subdivided the 191 cases for which he had good records into the following groupings: Onset

Category

Percentage

(A) Immediately after an apparent acute infection (B) Insidiously or with a gradual onset

poliomyelitis

125/191(65%)

missed poliomyelitis

66/191(35%)

The significance of these two names is that he considered both forms as polio variations, but he considers the gradual onset group to be cases of polio in which the initial diagnosis had been missed. Gilliam goes further than any modern clinician in breaking this Type B, insidious onset group, into three sub-classifications. I have not seen this type of breakdown anywhere else but it is quite informative.

Comment: To my knowledge this meningeal type precursor is described nowhere in the subsequent literature but should be. All of us who have seen more than 100 M.E. I CFS patients are well aware that many have had a previous unusual illness, either resembling and perhaps erroneously diagnosed as infectious mononucleosis (glandular fever) that may linger for months, following a period ofapparent total recovery - or - as a meningeal type illness. The meningeal symptoms as a distant precursor are, to my knowledge, mentioned nowhere in the literature except in the London Free epidemic. At Nightingale, we frequently note in both acute and gradual onset patients, a severe meningeal symptom history, usually in the previous 2 year period. The patient will describe an isolated incident in which he I she experienced a severe disabling meningeal type headache "the worst I ever had", "I thought my head was going to explode", "I never get headaches but I remember that one" lasting anywhere from 3-10 days, associated with complete prostration and frequently severe hyperpyrexia. This meningeal episode is usually unique and followed by a complete recovery with no sequellae until 1-2 years later when they fall ill with M.E. / CFS. Approximately 20% of all of our acute or gradual onset M.E. / CFS patients will give such a history if questioned. It is my opinion that a similar percentage of non M.E. / CFS patients, whether well or with other illness, can rarely recall a similar meningeal episode or do so with such precision. Type three: No earlier symptom history but a gradual development of illness occurred.

Type one: The patient has earlier hospital admission with another diagnosis, namely bladder infection or enterocolitis. The patient is apparently then discharged and returns at a later unspecified time with what we would recognize today as classical M.E. / CFS symptomology.

Comment: This insidious onset with no obvious acute infection stage is regularly described in the literature. Temperature: 16

Comment: Type one suggests an initial apparent incitory illness followed with a lacunar period of apparent recovery prior to the onset of M.E. / CFS symptomology that many clinicians note.

Gilliam notes the following regarding temperature: "...fever above 100 F was not a particularly prominent symptom...instability of temperature, with a

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The Clinical and Scientific Basis of M.E. / CFS

frequent daily range from 97-99 °F, was much more characteristic of this illness than a real elevation of temperature..."

most heavily attacked...earlier and in...higher (numbers) in the communicable disease wards and in the main admitting office..."

In fact, of the hospitalized patients, only 32% of the acute onset group and 16% of the insidious onset group had temperatures confirmed at over 100°F.

The employees of the hospital comprised both residents who lived in the hospital and non-residents. Residents were seven times more likely to fall ill than non-residents.

Their charts demonstrated major temperature fluctuation as the primary finding and the elevation in temperature was the exception.

The epidemic developed in residents working on the communicable diseases wards or in the main admitting office and somewhat later in non-residents at the stations of duty.

Comment: Curiously, the CDC criteria for CFS note elevated temperature as a diagnostic criterion of CFS17. In the several thousands of patients we have seen, we have rarely encountered significantly elevated temperature, although patients routinely cite the subjective sensation of feeling hot. When we find an abnormal temperature, we usually register a subnormal temperature. Since we rarely have M.E./CFS patients in hospital, we have never been able to document a fluctuating temperature, although it is reasonable to assume a fluctuation beyond the normal diurnal range. We believe that the CDC criteria may be based upon subjective statements of the patient rather than the nurse taking the temperature. Age, Occupation and Sex Ratios Associated with Illness 18 The attack rate is associated with age, sex and occupation. Occupation

Cases

Nurses Social Service Workers Laboratory Technicians Physicians Maids Orderlies Attendants

138 5 3 20 6 6 5

Attack Rate 11.4 9.6 6.4 6.2 2.6 2.3 1.8

"...females suffered a greater incidence than males and that among females there was a quite definite selection of the younger age groups below 30..." "...the epidemic developed more rapidly in the groups

124

Gilliam is not precise in subgrouping the lab technicians as the group with the third highest attack rate. Lab technicians have many different functions. In our experience, the only lab technicians that we have seen who have fallen ill with M.E./CFS are those who draw blood. It is possible that they fall ill due to the fact of constant exposure to a wide variety of patient's blood. However, a more likely explanation is that every coughing patient sent for a blood or urine sample, coughs all over these technicians. If the disease is spread primarily by cough or close contact as Gilliam suggests, then these lab technicians at the front line of drawing blood are the ideal candidates to fall ill with M.E./CFS. Incubation Period Gilliam notes that the minimum incubation period was 4 days18. This was inferred from workers who came to work at the hospital for the first time and either started to work on the contagious ward or started to work on non-contagious wards. None of the new workers who went to work on the noncontagious stations fell ill, however 6 workers who went to work on the contagious wards fell ill starting on the 4th day. Noting nurses who moved from a noncontagious to a contagious nursing station, it was again on the 4th day that these nurses started to fall ill. Gilliam's tabulations bring to six, the number of persons in whom the apparent incubation period was 4 days. There is a second peak on their graph at 7 days. It therefore appears possible that the incubation period in this illness is as short as 4 days. But Gilliam, in noting the high attack rates on the

The 1934 Los Angeles County Hospital

B. Hyde, MD

Epidemic

Signs and Symptoms Noted by 1934 Patients (extrapolated from throughout the 90 pages)

General difficulty with fine muscle coordination respiratory difficulties weakness out of proportion to the muscle atrophy wandering muscle weakness legs became n u m b with little control over t h e m a f t e r m u c h s t a n d i n g or walking foot drop from driving car a n d p u s h i n g on gas or brake pedal t e n d e r n e s s of specific a n d general m u s c u l a t u r e weakness cramps respiratory distress

easy fatigue on slight exertion malaise lethargy, drowsiness loss of appetite, sometimes to t h e point of anorexia diarrhea constipation inflamed and/or infected t h r o a t n a u s e a was common and vomiting r a r e mild oedema of extremities negatively affected by cold weather restlessness relapses without any obvious precipitating causes recurrences in some cases were more disabling t h a n the original attack pain in the epigastrium aggravated by eating

Pain and Neurosensory Disturbances neurosensory disturbances were frequently more pronounced t h a n motor disturbance a n d were t h e most disabling f e a t u r e of the illness mild to severe headaches frontal headaches occipital headaches fronto-occipital headaches sore extremities tingling in extremities n u m b n e s s or cutaneous a n a e s t h e s i a hyperesthesia paresthesias

Dermatological one handed failure of nails to grow r a r e intense itching both hypertrichosis and hair loss

Bladder and Uterine Dysfunction difficulty in voiding, rarely with obstruction painful burning urination dismenorrhea m e n s t r u a l disturbance in a t least 14 patients who h a d previously h a d no difficulty with increase, decreases in flow and change of cycle.

pain a n d aching in feet a n d toes neuritis shooting pains, causalgia tendon pains, specifically archilles tendon terrific pain along t h e spine

Neurological

Neuropsychiatric

photophobia sometimes associated with severe ocular pain diplopia loss of or disturbance of position sense in h a n d s a n d feet ataxia

insomnia extreme irritability difficulty in concentration difficulty with memory

Hypothalamic Psychiatric u n u s u a l sweating chills

nervousness apprehension feeling of depression emotional instability depression followed by euphoria spells of weeping for no a p p a r e n t cause emotional u p s e t s varying from slight displays of irritability a n d impatience to violent manifestations of dislike to for people a n d things formerly liked.

Neuromuscular stiffness of the neck, back unsteady gait fibrillary twitching and spasms easy fatigue in specific muscle groups persistent paralysis was quite r a r e b u t difficulty in lifting against gravity common

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The Clinical and Scientific Basis of M.E. / CFS

communicable disease wards, states that it would be improbable that cases developing over a month after exposure to working on these wards could have escaped opportunities for infection during this time. He also stated that it would appear likely that the incubation period in some individuals might be prolonged, or that repeated exposures to infection were necessary to produce illness in these persons. Gilliam does not comment on the possibility of "well carriers" infecting these patients at a later date. It is of interest to compare these results to those of the Akureyri epidemic in 194819, those of the London Free Hospital epidemic in 195520 and that of the wife of Dr. R.K. Davis in the Massachusetts epidemic of 195321. In the Akureyri epidemic, the incubation period was calculated at 5 days19 and a maximum of 10 days. In the London Free epidemic an incubation period of 56 days20 was given. In the case of Mrs. Davis, she fell ill with typical M.E./CFS 4-5 days after starting to nurse a seriously ill patient with acute paralytic poliomyelitis. Like many of these epidemics, this was a mixed M.E./CFS epidemic. She remained ill with M.E. symptoms for over 20 years. Much later, her husband developed Parkinson's disease.

Infectivity Gilliam notes that, of the 198 cases, 185 were interviewed and, of these 185,170 (92%) were able to recall a direct contact with a case of poliomyelitis. He writes that this is contrary to the usual experience in careful case investigations during epidemics of poliomyelitis where it is more common to find only about 20% of patients giving a history of direct contact with a case (of poliomyelitis)23. The distribution of food stuffs, milk products, water supply and laundry were each independently investigated as a possible source of infection transmission. None was found to be a likely candidate for infection transmission 24 . It was assumed that none of these potential vectors played a role in transmission of the epidemic. Lumbar Puncture 2 8 Nearly all cases in which pressure was recorded showed the spinal fluid to be under increased pressure. Only 3% showed pleocytosis an 16% increased globuline and 28% changes in the colloidal benzoin reaction. It should be remembered that these samples were taken early in the disease process. Gilliam's Summary 25

It would appear that the incubation period is as short as 4 days and that some people who fall ill at approximately 7-10 days may have contracted their illness either from a well carrier or simply through slower development of the illness. It is interesting that these figures are so consistent. Incubation Period of Epidemic M.E. / CFS Epidemic

Incubation Period

Los Angeles

4 -7 days

Akureyri

5 - 10 days

London Free

5-6 days

Pittsfield, Mass

4-5 days

Non-epidemic or sporadic incubation period: Marinacci, who in 1948 was seeing two non-epidemic cases per month, gives an incubation period of 7-10 days in these cases of what he refers to as Iceland Disease or benign Myalgic Encephalomyelitis 22 .

126

"The observed distribution of the disease is therefore what might have been expected had it been an epidemic of a disease, such as scarlet fever, spread by direct personal contact with cases and carriers. It is quite different from what one would have expected in an epidemic such as typhoid fever, spread by contamination of the hospital water, milk, or food supply. The facts appear to be consistent with an hypothesis of spread by direct personal contact with cases and carriers, with the former playing the most important role. From an epidemiological point of view, the disease was distributed as an infectious disease would be expected to be distributed. Despite the peculiar clinical character of any of these cases, there appear to be good grounds for assuming that the majority of them resulted from infection with the virus of poliomyelitis. Whatever may have been the actual origin and mechanism ofspread of this infection, the distribution of the disease was such, both in intensity of risk of attack and in time-sequence, as might be expected had it spread through direct personal contact from the communicable diseases ward and main admitting office."

B. Hyde, MD

The 1934 Los Angeles County Hospital

Family Contacts

Epidemic

Marinacci describes the chronic features of the 1934 epidemic. I repeat his comments since so rarely in the medical literature do we find mention of the chronic features of M.E./CFS.

Gilliam makes an extremely important observation when he examined the family contacts of employee cases who lived outside of the hospital. He notes that family members of those hospital employees who fell ill during this epidemic, particularly those under the age of 15, developed a secondary attack rate of about twice that of reported cases, and that, when the study was confined to children 15 years of age and younger, the attack rate was three times the expected rate 26 . There is ample evidence of this family spread from both our experience at Nightingale and that of most clinicians who have a large M.E. / CFS practice. However, the only publication that acknowledges such a finding is that of the Mercy San Juan Hospital epidemic that occurred in Sacramento, California in 1975, in which the authors of the epidemic study note that the infection propagated itself through secondary and tertiary contacts27.

"In 1937, while I was an intern at the Los Angeles County General Hospital I came in contact with many of the epidemic cases, some of whom were (still) hospitalized (three years after the epidemic) and others who were readmitted because ofa recurrence of the symptoms. The chief complaints were fatigue, insomnia, impaired memory, emotional instability and hysterical episodes. As these symptoms were often misinterpreted by the attending physicians, many of these cases were labelled as'malingerer' or 'compensationitis.' This attitude often produced a conflict between the patient and the attending medical staff, and the patients were transferred from clinic to clinic and from department to department." The first electromyographic evaluation on any of these patients was done during the period 19481952, (14 -18 years after the epidemic). Twenty-one patients in all were examined; all were females, the majority being nurses. The main complaints were recurring fatigue, pains and some muscle spasms in the distribution of the cervical and lumbosacral segments. In these cases there was also impaired memory. It was obvious that the chronicity of the 1934 epidemic persisted until at least 1952.

It would appear possible, then, that the patients that developed the M.E. / CFS form of the disease, did so either from contact with infectious poliomyelitis patients, well carriers, or from the pooled adult serum or convalescent serum that was used as prophylactic. Long Term Chronicity In his book Applied Electromyography 7 Alberto

References 5. Idem, pages 7 & 8.

1. Private communication between Dr. A. G. Gilliam and Dr. Alexis Shelokov at a Symposium on Epidemic Neuromyasthenia in the mid 1950's, in which Dr. Gilliam related that Dr. James P. Leake, Medical Director, United States Public Health Service and others at NIH attempted to block publication of the report (2).

6. Idem, page 32. 7. Chapter 9, Applied Electromyography, Alberto Marinacci M.D., Lea & Febiger, Philadelphia, 1968.

2. Public Health Bulletin No. 240, April 1938, Epidemiological Study of an Epidemic, Diagnosed as Poliomyelitis, Occurring Among the Personnel of the Los Angeles County General Hospital During the Summer of 1934, by A. G. Gilliam, Past Assistant Surgeon, U.S. Public Health Service, Division of Infectious Diseases, National Institute of Health, United States Government Printing Office, Washington: 1938.

8. Idem page 1. 9. Idem, page 1. 10. Idem, page 2. 11. Idem, pages 4 & 5, also 9-11.

3. Private communication between Dr. Marinacci and Dr. Hyde in 1989.

12. Idem, pages 2 & 3, also 48-52.

4. Idem, (all idems refer to (2)), see case histories pages 70-80.

13. Idem, pages 3 & 4.

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The Clinical and Scientific Basis of M.E. / CFS

14. Bjorn Sigurdsson, Margaret Gudnadottir, Gudmundur Peterson, R e s p o n s e to Poliomelitis Vaccination, The Lancet, 15 Febuary, 1958, page 370-371 also

21. Personal communication between the wife of DrR.K. Davis and Dr Hyde in 1988 concerning the Pittsfield, Mass. epidemic described by Roy H. Hart, Correspondence, New England Journal of Medicine, 1969, vol 281, no 14, page797.

15. Idem, pages 3 & 4. 22. Idem, Applied Electromyography, page 93. 16. Idem, pages 22 & 23. 23. Idem, page 81. 17. Holmes, G.P., Kaplan, J.E., Gantz, N.M. et al(1988) Chronic Fatigue Syndrome; A Working Case Definition, Annals of Internal Medicine, 108, 387-389.

24. Idem, pages 82-84. 25. Idem, pages 68-69.

18. Idem, pages 88-89.

26. Idem, page 85. 19. Bjorn Sigurdsson, Julius Siguijonsson, Jon H.J. Sigurdsson, Johann Thorkelsson and Kjartan R. Gudmundsson, A Dise a s e Epidemic in Iceland Simulating Poliomyelitis, American Journal of Hygiene, Vol 52, page 222-238. 20. The Medical Staff of the Royal Free Hospital, An Outbreak of Encephalomyelitis in the Royal Free Hospital Group, London, in 1955, The British Medical Journal, 19 October, 1957, pages 895- 904.

128

27. In preparation, Ryll E., Chabursky B., Hyde B. Mercy San J u a n Hospital Epidemic. 28. Idem, page 66.

E.D. Acheson,

DM,

MRCP

The Clinical

Syndrome

Variously

Called...

Chapter 14

Sir Photograph April

courtesy

1959, pages

of The Times.

569 to 595.

(Ernest)

This classic article

For c.v. please

Donald

is reprinted

see end of this

Acheson,

KBE

with the kind permission

of The American

Journal

of

Medicine,

chapter.

The Clinical Syndrome Variously Called Benign Myalgic Encephalomyelitis, Iceland Disease and Epidemic Neuromyasthenia* E.D. Acheson, D.M., M.R.C.P.f Washington, D.C. "Disease is very old and nothing about it has changed, It is we who change as we learn to recognize what was J.M. Charcot formerly imperceptible." Kingdom1. There is also suggestive but incomplete evidence that Coxsackie B, Echo2 and other viruses 3 may occasionally cause acute flaccid paralysis. The position of "non-paralytic" poliomyelitis is even less secure4 and the diagnosis can no longer be established on clinical grounds alone.

Recent technical advances have added greatly to the ease with which virological methods may be applied to the study of poliomyelitis and allied infection of the central nervous system. These technics have already borne abundant fruit in the development of a vaccine against poliomyelitis. The accurate appraisal of the preventive value of such a vaccine will depend on our ability to diagnose poliomyelitis accurately. It had long been believed that the clinical features of acute paralytic poliomyelitis were sufficiently characteristic for a confident diagnosis to be made on clinical grounds alone. This confidence has recently been shaken by the finding that the virus of louping-ill (Russian spring-summer encephalomyelitis) may produce a similar clinical picture, even in the United

The purpose of this article is to review a number of obscure outbreaks of paralytic illness, the majority of which were at first confused with poliomyelitis but which were later differentiated on clinical and epidemiologic grounds. Although investigations have been restricted by the fact that no deaths have occurred, the most careful virologic studies have failed to incriminate the polio virus, the Coxsackie or

* From the Department of Medicine, State Univeristy of New York, College of Medicine of New York, and the Department of Medical Services, Maimonides Hospital, Brooklyn, New York. The expenses of the study have been defrayed in part by a grant from the Wallace Laboratories, New Brunswick, New Jersey. t Radcliffe Traveling Fellow of Oxford University in the United States. Present address: Department of Medicine Central Office, Veterans Administration, Washington, D.C. 129

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Figure 1

Geographical Distribution of Outbreaks Echo groups of organisms, or any other known neurotrophic agent. The outbreaks will be compared, and the basis for the view that they constitute a clinical entity will be discussed. Such information as is available about the etiology, prognosis and treatment will be reviewed.

from typical poliomyelitis lay in the cerebrospinal fluid, which was normal in fifty-three of fifty-nine cases studied. After an interval of fourteen years, an epidemic with many features in common was reported in Iceland 6 , and later other similar outbreaks occurred in Australia 7 , Europe 813 , the United States 1416 , Alaska17, and South Africa18 20. The names "Iceland disease" (White and Burtch 195414), "Akureyri disease" (Sigurdsson and Gudmundsson 195621), "benign myalgic encephalomyelitis" (Lancet 195622), and "epidemic neuromyasthenia" (Shelokovetal. 19571616) amongst others have been given to this syndrome. Of the fourteen outbreaks which form the basis of this study, no less than seven have occurred in the staff of hospitals. More than 1,000 persons are known to have been affected up to the present time. The geographical distribution of the outbreaks is shown in Figure 1.

Historical In the summer of 1934 an epidemic of poliomyelitis struck Los Angeles5, and many of the sick patients were treated in the Los Angeles County Hospital. Within a few weeks an alarming number of cases of a similar illness had appeared among the hospital staff, particularly in the nurses. As the hospital outbreak developed, certain clinical and epidemiologic features appeared which made the diagnosis of poliomyelitis difficult to sustain. Thus disturbances of sensation and mental symptoms were unduly prominent, and although muscular pain and paresis were the rule, muscular atrophy was a rare sequel. In spite of the fact that no less than 198 cases developed (an attack rate of 4.4 per cent) there were no deaths, and the general trend of the disease was towards complete recovery. A further distinction

Criteria and Definition The difficulties in defining a disorder from which no

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deaths have occurred, and for which no causative infective or toxic agent has been discovered, are obvious. Recognition has to depend on the clinical and epidemiologic pattern. These features must be sufficiently characteristic to separate the disorder from other conditions. A parallel may be helpful. Von Economo23 first described encephalitis lethargica on the basis of the clinical triad of fever, stupor and ophthalmoplegia. Although autopsy material was abundant, the pathologic picture was not in itself distinctive and the findings were often insignificant. No etiologic agent or specific diagnostic test was ever found. It was the clinical pattern and the characteristic sequelae which set the seal on the condition as a nosological entity. Epidemic myalgia (epidemic pleurodynia; Bornholm disease) affords a closer analogy. Here the disease became established as a clinical entity 2426 in spite of the absence of mortality or any specific laboratory test long before the discovery of the Coxsackie group of viruses. In the instance under discussion, the problem has been attacked by making a clinical and epidemiologic analysis of a number of similar outbreaks in which it has been difficult to sustain a diagnosis of poliomyelitis or any other known infection of the nervous system. All the outbreaks shared the following characteristics: (1) headache; (2) myalgia; (3) paresis; (4) symptoms or signs other than paresis suggestive of damage to the brain, spinal cord or peripheral nerves; (5) mental symptoms; (6) low or absent fever in most cases; (7) no mortality. In addition, (1) a higher frequency in women; (2) a predominantly normal cerebrospinal fluid, and (3)

relapses have occurred in almost all outbreaks. In eleven of the fourteen epidemics symptoms which suggest activity of the disease have persisted for months or years in a few cases, and in eight instances there was an apparent predilection for the nursing or medical professions. Lymphadenopathy was a feature in four outbreaks. The case for an entity will depend on the distinctiveness of these findings. Epidemiologic Features Of the fourteen outbreaks considered in this paper, seven occurred amongst the staff of hospitals; one in an army barracks; two in small towns; two in semirural communities, and two in the populations of large cities. The attack rate was measured in eight outbreaks. It varied from 2 per cent* in the Middlesex Hospital Nurses' Home8 to approximately 20 per cent* in the Nurses Homes at Durban 18 and Coventry10. At the Los Angeles County Hospital 5 the attack rate was 19.0 per cent among nurses, and 4.4 per cent for all employees, resident or living out. At the Royal Free Hospital in London27 the figures were 18.3 per cent for nurses and 8.3 per cent for the whole population at risk. In the small communities at Akureyri in Iceland 6 , Seward in Alaska 17 and Punta Gorda in Florida16, the attack rates were approximately 6 per cent. These attack rates were much higher than usually seen in poliomyelitis. Ten of the twelve outbreaks in the Northern Hemisphere commenced between April and September. * The denominator is the total number of nurses employed.

Table 1 Attack R a t e s b y S e x Females

Males Outbreak Los Angeles 1934 Iceland 1948-49 Royal Free Hospital 1955 Punta Gorda 1956

Population at Risk 1,779 3,339 950 497

No. of Cases 28 171 27 20

Attack Rate per 100 1.6 5.1 2.8 4.0

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Population at Risk

No. of Cases

2,536 3,548 2,550 513

168 294 265 42

Attack Rate per 100 6.4 8.3 10.4 8.4

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The exceptions were the epidemic in Punta Gorda16 which commenced in February and the small outbreak in Berlin11 which began in November. In the Southern Hemisphere the outbreaks began in February (Durban) 19 and August (Adelaide)7.

rates in these two outbreaks cannot be calculated as the population by sexes is not given. Sporadic cases28" 32 are also reported more frequently in women than in men. The single outbreak with a predominance of affected males was that described in a military barracks in Berlin11. The patients were all men.

On the basis of case to case contact, attempts have been made to fix the incubation period of the disorder. In the Iceland6, Bethesda 15 , Royal Free Hospital 27 and Punta Gorda16 outbreaks the evidence indicated an incubation period of less than one week, probably five to six days. In Los Angeles5 the information on this point is incomplete, but a few patients became ill four days after their first exposure, indicating the minimum incubation period. On the other hand, the Middlesex Hospital 8 and Durban 18 reports suggested a longer period of two to three weeks. An incubation period of fourteen days was present in the single case in which isolated contact occurred in the small second outbreak in the Royal Free Hospital in 195613.

All age groups have been affected from late childhood 6141617 to the eighth decade16. However, many reports stress the high frequency amongyoung adults. In the Los Angeles outbreak 5 the figures show a strikingly selectivity of the disorder for women between the ages of twenty and twenty-nine. In men the relationship to age was irregular. In the Middlesex Hospital 8 , Coventry10, Durban 18 , Bethesda 15 and Berlin 11 outbreaks most of the cases occurred in the third decade, but this may be due, in part at least to the composition of the population at risk. Figures from which attack rates may be calculated by age are not given. In the Royal Free Hospital outbreaks 1213 the incidence was higher in the nineteen to thirtyfive age group (11 per cent)* than in older people (4 per cent).* In Iceland 6 the highest incidence was in adolescents aged fifteen to nineteen. Cases in small children have been rare.

The general consensus is that the disorder occurs more frequently in women. (Table 1) This is certainly true of the outbreaks in hospital staffs. In the Middlesex8, Coventry10 and Durban Hospitals 18 no men were affected, and only one man became ill at Bethesda 15 . In the Los Angeles5 and Royal Free Hospital27 outbreaks the attack rates for women were 6.4 per cent and 10.4 per cent respectively, and for men 1.6 per cent and 2.8 per cent. The higher attack rate in women on the staff of a hospital might indicate an occupational hazard rather than a true sex susceptibility. However, outbreaks in the general population confirm the higher incidence in women noted in the hospital cases. White and Burtch 14 regarded the ratio of 15:1 in favor of women in their small series as due to chance. Poskanzer and his colleagues16 believed that in Punta Gorda, women were affected both more commonly and more severely than men. If the figures for white people and Negroes derived from their house to house survey are combined, the attack rate for women is 8.2 per cent, and for men 4.0 per cent. This female predominance is largely due to a high incidence in Negro women. Sigurdsson 6 found that at Akureyri females were affected more commonly than males in the ratio of 8:5. All patients studied by Fog9 in Copenhagen were female. In the Alaska17 outbreak, the syndrome developed in 122 females and 53 males. The attack

A prevalence of poliomyelitis in the area of the outbreak has been noted on several occasions and has made differential diagnosis difficult. The most striking example is the Los Angeles outbreak 5 of 1934. There the cases among the staff occurred after the admission of large numbers of patients with poliomyelitis from the city and the rise and fall of the epidemic in the city corresponded closely with that of the hospital outbreak. Virus studies and autopsy material proved that the city epidemic was poliomyelitis, although there were certain atypical features5. However, the clinical characteristics in the cases among the staff differed in important particulars. Coincident outbreaks of poliomyelitis also occurred in Copenhagen 9 , New York State 14 and Alaska17. In Adelaide7 and Durban 18 , epidemics of poliomyelitis preceded the outbreaks of illness and in Iceland 6 there were a few cases of typical poliomyelitis at the beginning of the outbreak. At Coventry the outbreak occurred amongst the staff of an infectious diseases hospital which was commonly concerned with the treatment of poliomyelitis. In the Middlesex 8 , Bethesda 15 , Royal Free Hospital12, Berlin11 and Punta * Approximate figures.

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Gorda16 outbreaks there was no known association with poliomyelitis.

food- or water-borne. The distribution of cases did not correspond with any source of water or food. In the Iceland outbreak spread occurred along the main traffic route from Akureyri. Instances of spread by personal contact have been recorded8,13,27 and most authors agree that this is the probable means of dissemination. The best authenticated example is cited by Crowley27. A nurse who had attended the first and fourth girls to fall sick in the Royal Free Hospital epidemic became ill six days later. During the incubation period "she had accompanied a surgical case from ward to operating theatre, remained in attendance during the operation, and escorted the case to bed in a different ward. The patient, the ward sister, the theatre sister, a medical officer, a medical student working in the theatre, and the second ward sister all became ill within eight days." In the Bethesda outbreak 15 the discovery of a paracolon organism in the stools of a large proportion of the affected nurses and in a kitchen attendant focussed attention on the possibility of food-borne infection. However, only one doubtful case developed among the patients who were also supplied with food from the same source. The world-wide distribution of the outbreaks (Fig. 1) together with the marked differences in the types of community affected are points against either an insect vector or a toxic agent, both of which have been sought without success.

Most curious of all the epidemiologic features is the apparent susceptibility of the nursing, medical and ancillary professions. Seven of the fourteen outbreaks have occurred in the staffs of hospitals. In one other16 a high attack rate among nurses, doctors and their helpers was noted. Thus the attack rate among medical personnel was 40 per cent (sixteen of thirtyeight) as opposed to 6.1 per cent (62 of 1,010) in the community as a whole. In the Los Angeles5 and Royal Free Hospital12 outbreaks the attack rates were higher in nurses than in the other hospital staff. In the Middlesex8, Coventry10, Bethesda 15 and Durban 18 epidemics the disorder was virtually confined to nurses. It is recognized that nurses through contact with patients have an increased risk of contracting certain infections. As far as this syndrome is concerned, however, there has been evidence that the nurses might have been infected by patients in only two outbreaks 510 . Thus, in Los Angeles6, cases occurred both earlier and more commonly in those members of the hospital staff who were in close contact with patients with poliomyelitis who had been admitted from the city. On the other hand, the clinical evidence suggests that the illness among the staff was different. In the Coventry Hospital10, the disorder may have reached the staff by way of the patients. Galpine and Brady12 were of the opinion that some of the cases admitted immediately prior to the outbreak in the staff in Coventry were not poliomyelitis but an illness identical with that which affected the staff. In the remaining five institutional outbreaks there is no evidence that nurses were infected by patients. Spread in the reverse direction (nurses to patients) has either been extremely uncommon 1215 or absent.

Clinical Features An exact numerical comparison of the symptoms and signs reported in the various outbreaks is not possible. Thus in some instances only cases selected on the basis of severity or convenience were examined in detail 6,9,14,16 while in others 5,8,12 in over-all picture of the outbreak was provided. Reports of the Durban epidemic are fragmentary, and it has been necessary to refer to unpublished data 18 . The description of the Adelaide epidemic7 differs from the rest of the material in that it refers only to cases which were admitted to an isolation hospital from an urban community. Presumably, this would bias the material in favor of severe cases.

This apparent predilection for medical personnel, particularly nurses, remains one of the most difficult and interesting features of these outbreaks. It should be recalled, however, that a high standard of diagnostic skill is usually available to nurses, and that similar outbreaks in other types of residential institutions may have been unrecorded.

Broadly speaking, the epidemic cases have fallen into two groups: patients with definite localized muscular paresis, and those without. Only the former will be described in detail, as it is doubtful whether the latter could be distinguished from many other

Observations concerning the possible mode of spread are available in nine outbreaks. In eight there is good reason to suppose that the agent responsible was not

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to be admitted to an isolation hospital from a city were dealt with in this report, a striking contrast to the selection of the New York cases.

illnesses in the absence of an epidemic. The frequency of paretic cases in the various outbreaks has varied from about 10 per cent in the Punta Gorda outbreak to 80 per cent in Los Angeles. An approximate over-all figure is 40 per cent.

In the Middlesex Hospital outbreak 8 , like the other epidemics involving hospital staffs, the whole population at risk was under close medical supervision throughout. In most cases symptoms appeared abruptly. Headache, malaise and backache were almost invariable, and pain in the limbs occurred early in ten of fourteen cases. Mild pyrexia was present at the onset in nine cases. Vomiting and diarrhea occurred infrequently. In one case there was a definite biphasic illness similar to that which is seen in poliomyelitis.

Mode of Onset. The onset of the illness has usually been abrupt. According to Gilliam's detailed report 5 the onset in the Los Angeles cases was sudden, the most prominent early symptoms being headache and muscular pain, both of which occurred in over twothirds of all cases during the first three days of the illness. Next in frequency were nausea, which occurred in about half the cases, and sensory disturbances, stiffness of the neck and back in about onethird. Fever, with a temperature in excess of 100°F., was found in only a quarter of all cases and in almost all of these it appeared on the first day of the illness. Muscular tenderness and localized pareses were uncommon initial symptoms, but by the end of the first week they had developed in about half the cases.

According to Fog9 headache associated with low fever was an invariable initial symptom in the Copenhagen patients. In a few it was accompanied by stiffness of the neck or back, nausea, vomiting, dizziness and pain in the limbs.

In the Akureyri outbreak 6 pains in the neck and back were almost universal in the first few days of the disease. Low fever was also common. Within a few days pains accompanied by paresthesias appeared in the limbs. In the more severe cases fibrillary twitchings of muscles were also noted. In the paralytic cases paresis usually appeared three to seven days after the onset.

In the Coventry epidemic10 the preparetic symptoms were usually insidious and insufficiently severe to make the patients report sick before the onset of paralysis. The premonitory symptoms included sore throat, headache, backache, nausea, chills and lethargy. Paresis developed from two to thirteen days after the onset of these symptoms, usually on the sixth day. In only six of the thirteen patients was fever noted after reporting sick, and in none of these did it exceed 100°F.

According to White and Burtch 14 the onset of illness in the Thousand Islands district of New York State was acute in four and insidious in fifteen of the cases selected for detailed study. The average duration of symptoms prior to the initial examination was twentyone days. In retrospect, the commonest presenting symptoms were found to have been muscle pain and headache associated with low fever. Coryza, sore throat, cough, nausea and diarrhea were also noted during the first few days. An exact account of the time of onset of paresis was not given, but it seemed likely from the two "representative case reports" that it did not occur before the end of the first week.

In their description of the Bethesda outbreak, which occurred in the staff of a psychiatric hospital, Shelokov and his colleagues15 confined their detailed description to the twenty-six confirmed paretic cases. Twenty-one of these patients presented with premonitory symptoms before the onset of paralysis. The prodomal illness was characterized by malaise, headache, aches and low grade fever, which lasted from four to six days. Sometimes there was an interval of apparent well-being between the prodomal illness and the paretic manifestations. Occasionally, the prodomal illness was prolonged by the appearance either of acute respiratory or gastrointestinal symptoms, namely, cough, diarrhea, nausea and vomiting.

In the Adelaide epidemic7 the onset was abrupt with stiff neck and backache. Headache, pain on moving the eyes, malaise, aching in the limbs and hyperpathia were other common early symptoms. It should be recalled, however, that only patients sufficiently ill

In the small outbreak in an army barracks in Berlin11 the patients presented with abrupt onset of head-

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ache and low fever. Three days later muscular pains, backache and photophobia appeared.

illness in the literature. The postwar European, Icelandic, Adelaide and Durban epidemics were recorded without knowledge of Gilliam's findings and are unbiased by his interpretation of them. The Los Angeles outbreak therefore affords an ideal basis for comparison with later epidemics.

According to Adnams 18 most of the patients amongst the staff of the Durban Hospital became ill with severe occipital headache, stiffness of the neck, backache and weakness of the muscles of the back and abdomen. Heaviness, weakness and paresthesias in a limb or limbs followed within twenty-four hours. Prodromal symptoms of lassitude, sore throat, vomiting and diarrhea in the preceding ten to fourteen days were sometimes volunteered by the patient, but more frequently were ascertained only by direct questioning. It would appear, therefore, that the prodomal illness in this outbreak was mild in most cases. According to Hill19 coryza and sore eyes were also occasional prodomal features.

Severe generalized headache was almost invariable (94 per cent) and was accompanied by some stiffness of the neck or back in two-thirds of the patients. Pain in muscles was also an almost constant feature. The common sites were the neck, shoulders and limbs. It varied in intensity, both from case to case and from day to day, and was usually aggravated by exertion. In severe cases it was agonizing and unresponsive even to opiates. When severe, it was accompanied by exquisite muscular tenderness, tender nerve trunks and by skin sensitivity so that the affected limb required cradles to prevent contact with bed clothes. Muscular twitching, sometimes sufficient to move a whole extremity, was noted and cramps were frequent. Definite paresthesias occurred in 42 per cent of the cases. Low fever, with temperatures which uncommonly rose above 100°F., accompanied these symptoms during the first few days.

Both in size and in the wealth of clinical detail reported, the Royal Free Hospital epidemic12 compares with the Los Angeles outbreak of 1934. The following presenting symptoms occurred in at least a third of the 200 patients in whom records were complete. In order of frequency they were headache, sore throat, malaise, lassitude, vertigo, pain in the limbs and nausea. A striking feature was the intensity of the malaise, which was out of proportion to the slight pyrexia. In only nine cases (4.5 per cent) was a temperature over 100°F recorded. On examination the superficial lymph nodes of the neck were enlarged in almost every case, particularly in the posterior triangle. Paralysis and other neurological signs developed toward the end of the first week in many cases. The small second outbreak affecting the Preliminary Training School of the same hospital a year later 13 had a similar pattern of onset.

Localized muscular weakness developed in 80 per cent of the cases. It was notably variable both in site and in intensity from day to day. Of a total of 152 paretic cases, the weakness was noted within the first fourteen days in 119. In about half it had cleared within four weeks, and in a further 25 per cent within eight weeks. In 12 per cent demonstrable paresis was present three months after the onset. There is a notable absence of information about the changes in tone, sensation and deep reflexes associated with the paresis. Gilliam admits that full neurological examinations were rarely performed; this was doubtless due partly to the pressure of the epidemic. More important perhaps is the fact that orthopedic surgeons rather than internists had much of the clinical responsibility. As it was, patchy anaesthesia was noted in a few cases, diplopia in thirty-one, facial paresis in three and difficulty in swallowing in six. Other cranial nerve symptoms or signs were found in eleven patients. True vertigo was rare and hyperacusis and deafness were not recorded. Two patients required treatment in a respirator for a short time.

According to Poskanzer and his colleagues16 the onset of the Punta Gorda outbreak was insidious, and was marked by fatigue, headache, pains in the back and limbs, depression and instability. The average period between onset and confinement to bed was nineteen days with a range of one to sixty-five days. In half the patients there was a sudden exacerbation of symptoms one to four weeks after the onset. The Fully Developed Acute Illness. Gilliam's5 account of the Los Angeles outbreak is of particular interest, not only because of the richness of the clinical detail but because it is the first definitive description of the

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Emotional lability, irritability, depression and lack of concentration appeared in convalescence and were extremely troublesome. The duration of the illness in the milder cases was from two to four weeks and in the more severe cases from two to three months.

Urinary retention requiring catheterization was a complicating feature in 12 per cent. It was frequently accompanied by constipation. Although these symptoms developed only in the paralytic cases following total immobilization in Bradford frames, Gilliam was satisfied that the time relationships showed that they were a real part of the illness and not an artifact introduced by the mode of treatment.

In the New York State cases14, muscular aching often accompanied by head or neck ache was the most consistent symptom. It affected the muscles of the shoulder girdle in seventeen of nineteen cases at some state of the illness, but other muscles were usually involved and pleuritic chest pain was also reported. The aching was invariably accompanied by muscular tenderness and usually by hyperpathia and paresthesias. Muscular weakness, which was common, never coincided with the distribution of the tenderness. The deep tendon reflexes were usually reduced in the weak limb, but atrophy did not develop. Sensory loss was noted in three cases. Marked mental depression occurred in eleven of the nineteen subjects studied.

Gilliam observed the mental symptoms which have been an almost constant feature of more recent outbreaks. Later writers have also shared his perplexity in assessing their significance. In the Los Angeles outbreak they occurred in 30 per cent of the patients. His original description of them deserves direct quotation. "The emotional upsets reported are difficult to interpret. They varied in degree from relatively slight displays of irritability and impatience to violent manifestations of dislike for people and things formerly liked. A common type of upset consisted of crying spells resulting from no known provocation. The emotional upsets of a few individuals were undoubtedly hysterical in nature, but it would be manifestly erroneous to consider as hysteria the emotional instability associated with this illness in all of the cases in which it was present. Other disturbances chiefly consisted of loss of memory and difficulty in concentration. Transient personality changes of varying degrees of severity were relatively common." Coma and reversal of sleep rhythm did not occur. After running a course of four to eight weeks, the illness abated and paresis disappeared in most cases. However, in some cases one or more well defined relapses occurred. The average period of hospitalization was eight weeks.

In the Adelaide outbreak 7 the acute illness was short. Following the development of severe headache and mild generalized muscular aching, widespread paresis occurred. It cleared rapidly after a few days. Cranial nerve palsies, paresthesias and hyperpathia were rare. Retention of urine occurred in a number of cases. A recrudescence of the disease, characterized by hyperacusis, depression and fatigue, often occurred four to eight weeks after the original illness. It was protracted and resistant to treatment. In the Middlesex Hospital outbreak 8 the characteristic features were "the association of severe muscular pain affecting the back, limbs, abdomen and chest with evidence of mild involvement of the central nervous system in which the weight of the damage appeared to fall on the pyramidal tracts, the posterior columns, and the cranial nerves rather than on the anterior horn cells". Following the prodromal symptoms already described, nine of the fourteen patients experienced sudden onset of pain, tenderness spasm and paresis in the muscles of a limb or limbs associated with paresthesias and hyperpathia. The discomfort was always sufficiently severe to require full doses of analgesics for relief. Any handling of the limb at the bedside was resented and the patient could not bear the weight of the bed clothes upon it. The paresis was usually most marked in the distal

In the Iceland outbreak 6 paresis was usually confined to a single muscle group, the abductors of the shoulders and the abductors and rotators of the hip being the most commonly affected. Paresis was accompanied by an exacerbation of pain and tenderness in the muscles concerned, together with paresthesias. In severe cases, hyperpathia or anesthesia developed in the affected limb. Coarse m u s c u l a r t w i t c h i n g was common, b u t t r u e fasciculation was absent. The paralysed limb was always hypotonic, although reflex changes were reported as variable. Extensor plantar responses were not noted. Cranial nerve palsies were rare and urinary retention was reported in two cases only.

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muscles and was accompanied by variable reflex changes. The plantar response was frequently extensor on the paralysed side and loss of vibration sense was common in affected limbs. Pleuritic chest pain and urinary retention and incontinence were also prominent features. In the cranial nerves nystagmus was almost invariable, and vertigo, deafness and paresis of the soft palate were also reported. One patient was nursed in a respirator for a short time. In most cases the muscular pain and paresis had disappeared by the end of the third week. Relapses in the second and third weeks occurred in a few cases. Emotional disturbances were common in the acute stage, but did not persist into convalescence8®.

noted. Paresthesias were common and were sometimes accompanied by changes on formal sensory testing. Nervousness, unprovoked crying spells, difficulty in concentration, undue irritability and anxiety occurred in nineteen of twenty-six patients studied in detail. Nausea, diarrhea, somnolence and insomnia were unusual manifestations of this outbreak. Cranial nerve palsies were not mentioned. In the Alaska outbreak 17 muscular pain was accompanied by photophobia, hyperacusis, disturbances of taste and extreme anxiety. Paresthesias were common. Use of the affected muscles exacerbated the pain, but marked muscular tenderness did not occur. Tremors in the acute stage were a bad prognostic sign as far as the subsequent development of paralysis was concerned. Muscular weakness was widespread and commonly affected one or the other side of the body exclusively. Incoordination and myoclonic jerks were also seen, and constipation and transient urinary retention were common.

In Copenhagen9 the fully developed syndrome was characterized by severe pain and unpleasant paresthesias in the extremities. Definite paresis associated with increased deep reflexes was present in one patient and weakness and clumsiness in several others. Hyperhidrosis and muscular tenderness also occurred in the affected limbs. Nystagmus, diplopia, ptosis and extensor responses were each noted on one occasion. Depression and mental lability were prominent.

The clinical account of the small Berlin outbreak 11 is incomplete. Severe pains in the limbs with muscular tenderness were invariable. Paresthesias and other sensory changes are not mentioned. Slight muscular weakness unaccompanied by reflex changes developed in three of the seven cases and hyperacusis in two. Depression was a feature in three patients and persisted into convalescence. Conjunctival injection occurred in five patients and an erythematous rash in two.

In the Coventry cases10 the onset of paresis was coupled with an exacerbation of headache and pain in the neck and usually first manifested itself by clumsiness and heaviness of a limb. Muscular pain occurred but does not appear to have been severe. Chest and abdominal pain are not described. Tenderness, unsteadiness in response to effort and hyperpathia were often noted. Temporary loss of position sense was found in four patients. The deep reflexes in the affected limb were usually diminished and the plantar responses were flexor. Difficulty in micturition was noted in four cases. Recovery took place in some instances within a month, and in all cases was substantially complete within two months. Lack of concentration and ability to memorize was described as a characteristic symptom in convalescence.

In the extensive outbreak among the nurses at the Addington Hospital, Durban 1820 the onset of paresis, backache, shoulder girdle and subcostal pain followed an ill-defined period of prodromal symptoms. Headache, if pre-existing, became very severe at this stage. Weakness of the abdomen and back were so common that the inability to sit up from the supine posture became an important early diagnostic sign. Paresis in a limb was usually accompanied by paresthesias and patchy sensory loss. Posterior column signs were also noted. The deep reflexes were usually altered in a paralysed limb. Although the plantar responses were equivocal on a number of occasions, they were never frankly extensor. Retention of urine occurred in ten cases. Affection of the cranial nerves was rare 19 and was limited to a few instances of facial paresis and perceptive deafness. Mental symptoms

Shelokov's15 description of the Bethesda outbreak resembles the Coventry epidemic in many ways. The onset of paresis was heralded by an exacerbation of the headache and stiffness of the neck, together with heaviness and numbness in one or more limbs. Myalgia and muscular tenderness were invariable in the paralysed limbs and pleuritic chest pain was also

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exaggerated later in the disease. They were never abolished. Frank extensor plantar responses occurred in two cases only, but equivocal or absent responses were common. Muscular wasting occurred in two cases. Bladder dysfunction, including retention of urine, developed in one-fourth of the patients. In the phase of recovery, jerkiness of the paretic limbs in response to voluntary movement was noted and considered to be characteristic. (A similar phenomenon was also noted in the Coventry and Durban outbreaks.)

were prominent, particularly in the severer cases and included defective concentration and memory, drowsiness, emotional instability and nightmares. In the majority, full recovery occurred within two months. Muscular atrophy was never observed. In the epidemic at the Royal Free Hospital 12 no clear division of symptoms into those appearing early and late was possible. Neurological manifestations appeared most commonly in the second and subsequent weeks of the disease, but occasionally in the first. The fully developed clinical picture consisted of pain in the neck, back, subcostal region or limbs, out of all proportion to the degree of pyrexia, and general constitutional disturbance, and dizziness. The intensity of the symptoms fluctuated widely from day to day but on occasion the pain required the strongest analgesics for relief. Pyrexia rarely reached 100°F., and there was little tachycardia. Tender enlargement of the cervical lymph nodes was almost invariable. The liver was palpable in 8.5 per cent of cases.

The clinical picture of the Punta Gorda outbreak 16 was described on the basis of the findings in twentyone of thirty patients interviewed between May 24 and June 6,1956, "who presented similar histories of illness, and had no major intercurrent medical problems." It will be recalled that these patients had been ill with vague symptoms for periods ranging from one to sixty-five days. The most prominent general symptom was fatigue coupled with headache, pain in the neck, nausea and vomiting. Depression and impaired memory was present in nineteen, and was associated with terrifying dreams and episodes of crying without provocation. Symptoms suggesting involvement of the central nervous system consisted of paresthesias, unsteadiness, vertigo, blurring of vision and diplopia. The account of paresis is confusing and is recorded as present in eight cases in the text, and in only two cases in the accompanying table. In any case, it appears to have been mild and localized, and other neurological signs were absent. It seems that the illness in Punta Gorda ran a subacute rather than an acute course, and that objective evidence of disease was minimal.

The neurological symptoms and signs which developed in 148 (74 per cent) were believed to form "a characteristic picture that distinguishes this disease from other infections of the nervous system." Hypersomnia, nightmares, panic states, uncontrollable weeping and amnesia were frequent symptoms in the acute state. In six patients severe mental illness developed in which the dominant feature was depression. Two of these had to be committed and subsequently were treated with convulsive therapy; a third took her own life. Cranial nerve lesions occurred in sixty-nine of the 200 fully documented cases, the ocular, facial and acoustic nerves being most commonly affected. Bulbar palsy appeared in eleven cases.

Status of Patients on Discharge from Hospital. In addition to formal follow-up studies, some information is available about the state of health of the patients on discharge from the hospital, and in the case of nurses, about the total time lost from work.

In the limbs, motor weakness occurred in 102 patients and sensory disturbances in eighty-two. The paresis was almost invariably accompanied by pain and marked muscular tenderness and the slightest attempt at active or passive movement was resented. Cutaneous hyperpathia, paresthesias and loss of position and vibration sense were common accompaniments. Spasm, fasciculation and myoclonic jerks occurred less frequently. The paresis was usually most marked in the peripheral muscles and was commonly of hemiplegic distribution. The deep tendon reflexes were sluggish in the early stages and

According to Gilliam5, the average period which elapsed from the onset of illness to return to duty in Los Angeles was 13.6 weeks, but this figure is based on less than half the cases, as 55 per cent of the patients were still on the sick list at the time of his report. When he last observed them, forty-three patients (22 per cent) still had definite localized paresis, and in eighteen this was moderate or severe.

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Muscular atrophy was a rare sequel and in the ten cases in which it was noted it was slight. He stated that the irregularities in the course of the disease and the peculiarities of the paresis forbade an accurate estimate of the recovery rate.

The Aftermath. Relapses: The majority of patients afflicted in these outbreaks have been discharged from the hospital within two months and have returned to work after a period of convalescence prolonged by fatigue, aches and pains, depression and lack of concentration. However, in a proportion which has varied from outbreak to outbreak, relapses or a chronic state of ill health have developed.

Adnams18 gives an account of the disability rate in the Durban Hospital outbreak six months after the appearance of the last case. Of ninety-eight nurses, fifty had returned to full duty with no apparent sequelae, and a further thirty-two were on duty with "mild or more serious residua." Seven were on sick leave with serious sequelae, seven were on vacation or had resigned, and two had been readmitted to the hospital in relapse. In mild cases full recovery of muscular power occurred within a few days and convalescence, which was punctuated by headache, aching and fatigue, was complete within a month. In moderate cases the return to normal took three to four months. In the severe cases, which fortunately were few, relapses were continuing up to seven months after the onset.

Relapses have been a feature of all outbreaks except one (Coventry10). They have usually occurred within a week or two of the initial illness, while the patient was still in the hospital, but in some instances they have necessitated a second admission to the hospital. In the New York State cases14 the timing of the relapses was not described, but they are mentioned indirectly as a feature in common with the Iceland outbreak. In the Punta Gorda outbreak the course was subacute from the onset and exacerbations, rather than relapses, occurred. In five outbreaks 5 9, is. is, 17 r e i a p s e s o r exacerbations of symptoms in women have coincided with menstrual periods. Physical exertion and cold weather have also been incriminated. Most reports indicate that the chance of relapse diminished with the interval after recovery from the initial illness and that recurrences are rare after the end of the third month. However, Deisher 17 described cyclical recurrences in many of his patients up to two and a half years after the first illness, but it is not clear whether these were relapses in a p p a r e n t l y h e a l t h y people or r e p e a t e d exacerbations of chronic symptoms. Galpine and Brady32 have described a second attack three years after a previous similar illness. There had been complete recovery in the interim with perfect health.

In the Royal Free Hospital outbreak 12 , the duration of hospital in-patient treatment was less than one month in 57 per cent; from one to two months in 28.5 per cent; from two to three months in 7.5 per cent and more than three months in the remaining 7 per cent. Convalescence was very prolonged, "and extreme fatigue and general aches and pains made the rehabilitation period extremely tedious and long." A period of six weeks convalescence was found necessary for patients who had been in bed for more than a month. Even when this was completed many patients could work only four hours a day. Four patients still had marked disability at the time of the report, two years after the epidemic. In one patient choreoathetoid movements had developed in her paralysed right hand; two required leg callipers and a fourth crutches.

The relapses have consisted either of a return of paresis to areas previously affected, or to fresh areas, accompanied in some cases by fresh neurological signs, or simply of fresh muscular pains or mental symptoms. Fever is a frequent but not invariable accompaniment. Little has been added to Gilliam's original description, "Following a recrudescence of constitutional symptoms there was frequently an extension of pain or weakness into muscle groups not previously involved. In many cases the constitutional symptoms during the recurrences were considerably more severe than at onset...The milder "relapses" were sufficiently annoying that all convalescents were constantly "keyed up" in fear they would

In the Middlesex Hospital outbreak 8 , seven of the fourteen patients showed no physical signs of disease on discharge from the hospital on an average of one month after the onset. Of the remainder, four showed mild pyramidal tract involvement, one had absent position and vibration sense in the right foot, another had mild bilateral deafness of the inner ear, and a third had patchy anesthesia involving the left thigh with marked tenderness of the underlying muscle.

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Seven to ten months after the Akureyri outbreak, Sigurdsson and his colleagues6 found that most of the fifty-seven patients whom they examined had returned to work. However, only six were free of symptoms. Among the remainder, nervousness, fatigue and persistent muscular pains were common, and eleven complained of mild paresis. On examination, nineteen of the patients were found to be free of all objective evidence of disease but in the rest there was a confusing mixture of signs, some of which were thought to represent organic disease and others to indicate hysteria. Localized muscular tenderness was found in nineteen, Paresis in sixteen, muscular atrophy in fourteen and sensory changes in twelve.

develop one. There appeared to be no predisposing cause for them, though in many, they were associated with untimely overexertion or with some phase, usually the onset, of menstruation. Cold damp weather frequently increased pain and a sense of illbeing in patients in whom a definite recrudescence was not precipitated. A few of the "relapses" were unquestionably hysterical in nature." It is interesting to compare the description of relapses in the Royal Free Hospital outbreak, which was written without knowledge of Gilliam's account. "There might be periods of two weeks in which the symptoms were mild and fever had disappeared. Such periods were often followed by marked recrudescence of old symptoms and sometimes by the appearance of fresh neurological manifestations. In such relapses further fever and tender enlargement of glands occurred. Relapses occurred in some cases after patients had been fit enough to return to their homes...Functional manifestations in a few cases overlaid the organic picture, particularly in those cases longest in hospital."

Six years later, thirty-nine of these patients were examined again21. All had returned to their previous occupations (except one who was suffering from a gastric ulcer), but only five considered themselves completely recovered. Of the remainder, twentyeight complained of nervousness and tiredness, twenty-four of muscle pains, and eight of loss of memory. Sleeplessness and paresthesias occurred less frequently. Muscular tenderness was found in ten, paresis in nine, and atrophy in six. Unfortunately, both these follow-up studies are lacking in any description of changes in tone, coordination or reflexes.

The subacute and chronic stages: In seven of the recorded outbreaks, a proportion of the patients has been followed for periods of months or years. Once again the methods of selection have varied and prevent an accurate assessment of the comparative incidence of sequelae and chronic cases. In the Iceland epidemic, fifty-seven (12 per cent) of the 465 patients originally affected at Akureyri were examined seven to ten months after the onset6. These patients were not representative of the epidemic as a whole, as 74 per cent of them had been paralyzed whereas the paralysis rate for the whole outbreak was only 28 per cent. Six years after the outbreak Sigurdsson21 examined thirty-nine ofthese fifty-seven patients again (thirty-three women and six men) and reported his findings. There is no information as to what had happened to the remaining eighteen. It seems reasonable to suspect that a bias was operating in favor of patients with continued symptoms. The grounds for the selection of eight of nineteen patients for re-examination fifteen months after the New York State outbreak 14 and twelve of fifty patients six months after the Bethesda epidemic15 are uncertain. The follow-up studies in the Alaska 17 and Punta Gorda16 outbreaks are important because all patients originally examined were traced and studied after the elapse of two years in the former, and of five months in the latter.

Two to three years after the acute illness, Pellew33 interviewed the five Adelaide patients who had originally been chosen for virological studies. In all, there had been emotional instability or lack of concentration for eighteen months to two years, and in four, muscular pains had also been a feature. All five had improved and were well at the time of interview. Fog9 describes the enormous fluctuations in symptomatology in his Copenhagen patients during the first two to three months of the illness. Six months after the outbreak, three of the ten patients had returned to their occupations, three were working part time, two were convalescent and two were still in the hospital. None were free of symptoms, but all had improved. In the Bethesda outbreak 15 , none of the twelve patients selected for re-examination three to five months after the onset felt well, although they considered that they were improving slowly. They complained of recrudescences of low grade fever, myalgia, chest pains and localized weakness.

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Interrogation of the Punta Gorda patients 16 five months after the original study demonstrated a paucity of signs as compared with symptoms, an over-all tendency towards slow improvement and a fluctuating course. Only one patient was completely well. In the remainder there had been periods of improvement interrupted by exacerbations of symptoms with a definite trend towards recovery. Thus, whereas in the second month of the disease more than half of the patients were confined to bed, only three were thus confined in the sixth month. Symptoms remained common; nervous tensions in eighteen, fatigue in fifteen, and depression in twelve. On the other hand, objective evidence of mental tension (the criteria are not described) was found in only one case. Diminution in sensation was found in ten patients, muscular tenderness in seven and paresis in one.

in all outbreaks and pain in the neck, back and limbs are also common early symptoms. These complaints and the malaise which accompanies them have been out of proportion to the fever, which is usually slight even at the onset and sometimes absent 812 ' 1516 . Symptoms of an upper respiratory or gastrointestinal disturbance (sore throat, coryza, nausea, vomiting, diarrhea) may also develop at this stage. A definite intermission between the prodromal symptoms and the paretic illness is rare, and has been reported as a constant feature in only one outbreak 15 . Muscular pain, headache or pain in the neck, and paresis have been features of the fully developed syndrome in all outbreaks. In the worst Los Angeles, Middlesex and Royal Free Hospital cases, the myalgia has been agonizing, requiring administration of narcotics for its relief. Its variability both in site and in intensity from day to day has been remarked on a number of occasions. Pain in the limbs has occurred at some stage in most cases, but pain in the shoulders, chest and abdomen is also a prominent feature, and has raised the question of a Coxsackie infection. In the New York State and Coventiy cases the discomfort in the limbs scarcely amounted to pain.

Deisher17 appears to have had the unusual opportunity of re-examining all his 175 patients two years after the onset of the illness. Unfortunately, the information derived was incomplete; there are no data available about the number who were free of symptoms or the number who had been unable to resume work, and no description is given of reflex and sensory changes. Of the 175 patients, 110 complained of tiring easily, eighty-one of pain and stiffness, and fifty-seven of muscle weakness (as distinct from "paralysis," which was present in sixteen cases). Emotional instability, tension, poor concentration and memory defects were extremely common. Tremor, incoordination and muscular jerking were also seen.

With the exception of the New York cases the distribution of the paresis has followed that of the muscle pain and tenderness. Numbness, tingling and in some cases deficiencies of sensation on formal testing have been a feature of all outbreaks except one11, and usually occurred in limbs affected by paralysis. Hyperpathia, muscular spasm, cramps, tremors and involuntary movements were noted in severely affected patients in about half the outbreaks. The deep reflexes in the paretic limbs may be hyperactive or depressed, but are rarely if ever abolished. Frank extensor plantar responses have been unusual, but equivocal or absent responses are relatively common. Retention of urine requiring catheterization or incontinence has occurred in eight outbreaks, and urinary frequency was a feature of one other.

Summary of the Clinical Features. In all outbreaks prodromal symptoms preceded the development of paresis or other neurological signs, but their severity and duration varied. In eight, the prodromal illness was well defined, and lasted about a week. In the Coventry and Durban cases it was mild and most of the patients presented for treatment in the paretic phase. In the Berlin outbreak the prodrome was sharp but abbreviated, lasting three days. The Punta Gorda outbreak differs in the length and vagueness of the premonitory phase. Most of the patients were not confined to bed until the end of the third week. Information about the length of the prodomal illness in the New York and Alaska cases is incomplete.

Symptoms or signs indicating damage to the cranial nerves or their central connections have occurred in nine outbreaks. In six they were uncommon, but in the Royal Free Hospital Middlesex and Los Angeles cases they were relatively frequent. Diplopia, facial paresis, tinnitus, vertigo, inner ear deafness and bulbar involvement have all been reported. Hypera-

Headache has been reported as a presenting feature

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cusis was a feature of no less than five epidemics7'8' 11,12,17 Nystagmus was almost invariable in the Middlesex Hospital and Berlin patients, common in the Royal Free Hospital cases, and an unusual finding in four other outbreaks. Mental disturbances, of which depression, emotional lability and lack of concentration are commonest, have occurred in all reported outbreaks. In most instances they appeared during the acute illness5,8,12,14"18 but in others they first became manifest during convalescence6,7,10.

was absolute immobility. She was admitted to the hospital as a poliomyelitis suspect and on examination was found to have questionable weakness of the lower left side of the face and exaggerated unequal reflexes. The cerebrospinal fluid was normal, and in the absence of any flaccid paralysis, a diagnosis of poliomyelitis could not be sustained. A relapse occurred in February 1954, and when examined in July she was found to be depressed, with loss of memory and absent gag reflex on the right, diminished sensation on the left side of the body and persistence of the reflex abnormalities already described. Coxsackie infection was not excluded in this instance, although the combination of neurologic signs with a normal cerebrospinal fluid and a chronic course make this diagnosis unlikely.

Lymphadenopathy was first reported by White and Burtch 14 in four of the New York State cases. It also occurred as a rare feature in the Durban and Middlesex Hospital cases. In the Royal Free Hospital outbreaks it was such a constant feature that the illness was at first diagnosed as infectious mononucleosis. Hepatic enlargement was also noted in a few of these cases.

In 1956 Ramsay and O'Sullivan29 reported on eight patients admitted to the Infectious Diseases Department of the Royal Free Hospital from the population ofnorthwest London between April and October 1955, before, during and after the extensive epidemic in the staff of the main hospital. None of these patients, of whom seven were female, had been in contact with the sick nurses.

In most patients recovery has been complete within one to two months. However, in a proportion, which has varied from outbreak to outbreak, the course has been punctuated by relapses. These have involved simply a return of pain and fever in some instances, in others, fresh paresis and other neurological signs, or mental disturbances. In general, even in these patients there has been a trend towards improvement but in some instances a characteristic syndrome of chronic ill health has developed, with cyclical recrudescences of pain, fatigue, weakness and depression, often coincident with menstruation, cold weather and exertion. Objective neurological sequelae, such as muscular atrophy, involuntary movements, sensory loss, deafness and incoordination have occurred in a small minority.

The onset was generally gradual with headache, pain in the limbs, giddiness and upper respiratory or gastric symptoms. Fever rarely exceeded 100°F. Earache, tinnitus, cramps, muscular twitching, tremors and paresthesias were also noted. On examination, lymphadenopathy occurred in seven; stiffness of the neck, paresis and exaggerated deep reflexes in six; sensory impairment and muscle tenderness in five; and cranial nerve involvement in four. Extensor plantar responses were noted in three cases. Convalescence was protracted. In four cases it was complicated by emotional disturbances. Full virological studies, including the use of tissue culture methods, were carried out in all eight cases and were negative.

Sporadic Cases In addition to epidemics, sporadic cases with the familiar clinical features have occurred. The first endemic case in which a diagnosis of "Iceland disease" was made was reported by Hardtke 28 . He described the illness of a forty-one year old female physiotherapist in Indiana in October 1953. She presented with headache, stiff neck, pain in the shoulders and limbs, and incoordination. Within a few days she found that attempted movements or the slightest jolting precipitated agonizing cramp-like muscular spasms against which her only defense

Jellinek 30 described two patients on the staff of hospital in Hampshire who suffered from a similar illness in the summer of 1955. Both were females, one a doctor and the other a nurse. Both had headache, stiffness of the neck, fever, myalgia and a variety of neurological signs, including nystagmus (two), facial weakness (one), exaggerated reflexes (two), clonus (one) and sensory changes (one). There

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were two well defined relapses in each case in which retention of urine, requiring tidal drainage, was a distressing feature. Lymphadenopathy occurred in one case. In both, emotional lability was noted. Repeated examination of the cerebrospinal fluid revealed no abnormality. Virological studies were incomplete.

mus and extensor plantar responses were found in about one-fifth. Cranial nerve lesions, tremors and myoclonus occurred in four patients. Low pyrexia was the rule. Results of serological tests for lymphocytic choriomeningitis, mumps, leptospirosis and poliomyelitis were negative in each case. Throat washings and feces were also examined.

Galpine and Brady32 reported seven cases which arose sporadically in the Coventry area in the late summer and fall of 1956, three years after the outbreak in their nursing staff. Four patients were female and three male. The early symptoms (sore throat, lassitude, drowsiness, vomiting, nuchal pain, backache, giddiness and headache) were similar to those reported elsewhere. Paresis was found in all cases and tended to fluctuate and shift. It was usually accompanied by aching, paresthesias and tenderness. Alterations in tone were rare, but twitching, cramps, involuntary movements and tremors occurred. The reflexes were brisk and the plantar responses difficult to obtain. The sensory changes noted included hyperpathia, hypoasthesia, anesthesia and astereognosis. Difficulty in starting micturition occurred in three cases and incontinence in one other. Shotty lymph nodes were found in the posterior triangle of the neck in three. Of six patients who were examined three months after their discharge from the hospital, two had recovered completely. The remainder complained of myalgia, weakness, paresthesias and diminished metal grasp. Examination of the feces in three cases failed to show any evidence of a cytopathogenic agent, and serological tests for poliomyelitis were negative.

Other Unexplained Outbreaks. Other problematic outbreaks have been described which share some of the characteristics already outlined. Bond34 mentions briefly an outbreak of 463 cases in Tallahassee, Florida, in the fall of 1954. The disease, which was selective for married white women, was characterized by disturbances of mood, t r a n s i e n t paresis, parasthesias and relapses. This outbreak, and that reported by Wallis35"37 from Cumberland, England, are probably similar to those already described but sufficient data have not been published on which to base a definite opinion. Rose38 and Wright and Morley39 have reported epidemics of obscure encephalitis in West Africa, and have referred in their discussions to the outbreaks already described. In the former, which occurred in Sierra Leone, the onset resembled cholera with high pyrexia and prostrating diarrhea and vomiting, and the course was fulminating with terror, severe myalgia and vertigo. Pains around the costal margin similar to those of Bornholm disease were a common feature. A little less than one-third of the patients died. The cerebrospinal fluid was normal. The outbreak in Nigeria, described by Wright and Morley39, was characterized by low fever, tremor, aphasia, a normal cerebrospinal fluid and a favorable outcome in all cases. Certain of the epidemiologic features suggested an intoxication.

In a second paper, Ramsay 31 reviewed his experience with thirty-four patients admitted from northwest London between April 1955 and December 1957. Headache was an almost universal symptom, and pain in the limbs, giddiness and pain in the neck occurred in about half of the patients. Lassitude, subj ective sensory phenomena and back pain occurred in about a third, and sore throat, earache and cramps were less frequent. On general examination conjunctivitis and evidence of an upper respiratory infection were noted in one-third, and enlarged lymph nodes in one-fourth of the patients. In the nervous system, definite evidence of paralysis occurred in 50 per cent. Exaggerated deep reflexes, sensory disturbances and muscular tenderness were also prominent. Nystag-

Other than an unknown etiology, the predilection of the agents for the nervous system, and a normal cerebrospinal fluid, neither of these outbreaks resemble those described in this paper. McConnell40 reported sixteen cases of illness among the student nurses of the University Hospital of Pennsylvania in 1945. Severe headache was invariable, hyperesthesia occurred in thirteen, meningism in twelve, and pleurodynia in ten. A diagnosis of epidemic pleurodynia (Borholm disease) was made,

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in fact, poliomyelitis is not dispelled by the failure to isolate polio virus from the stools in the fifth week. An unconvincing twofold rise in antibody titre against type 2 polio virus was demonstrated between the seventh and twenty-first day. The Coxsackie virus was not found. The third and fourth patients described by Hook suffered indefinite illnesses characterized by fatigue and paresthesias but exhibited no physical signs.

although the clinical picture was considered to be atypical. A low grade fever accompanied by "disproportionate severe generalized headache and myalgia" persisted for several weeks in five cases, and in two there were four and five relapses, respectively. Stupor and episodes of loss of consciousness occurred in one patient and sensory loss in another. The sequelae were headache, myalgia and pleuritic pain. Of five patients examined a mild pleocytosis was found in the cerebrospinal fluid in two. The similarities which this outbreak shares with the fourteen already described are obvious. However, in view of the absence of paresis, and the fact that the outbreak preceded the isolation of the Coxsackie viruses which could thus not be excluded in this instance, it has been classified separately.

Hook's outbreak is difficult to classify. The localization of four cases to a small segment of a community suggests a common etiology. However, although the second case is clinically consistent with a diagnosis of poliomyelitis, the first with its slowly progressive paraplegia and sensory loss is not. The flaccidity of the paralysis, the failure to improve, and the electromyographic picture of denervation (Case I) are features quite unlike the cases reported from Los Angeles, the Royal Free Hospital and elsewhere. Cases III and IV resemble the milder cases reported from these outbreaks. In our present state of ignorance it may be well to suspend judgment on this outbreak.

Hook's41 report from Hygiea, Sweden, underlines the nosological difficulties in this field in the absence of pathological support. Under the title "Iceland disease" he described four cases in the staff of a hospital in the summer of 1956. The affected persons, of whom two were physicians, worked in a "single room". (It is not clear whether this was a laboratory or a clinic.) The first patient's illness developed gradually with mild muscular aches, paresthesias and weakness in the hands and feet. The paresis progressed over a period of several weeks and was accompanied by flaccidity and diminished reflexes. Mental depression was a feature in the later stages. Lumbar puncture in the second month of his illness revealed a protein of 60 mg. per cent, with a normal cell count. Electromyography showed the typical picture of denervation and a provisional diagnosis of infective polyneuritis was made. Polio and Coxsackie viruses were searched for without success. Vague illnesses characterized by headache and paresthesias subsequently developed in the patient's family.

Laboratory Investigations The Peripheral Blood. Examination of the cells of the peripheral blood has been, on the whole, unrewarding. Anemia has not been reported. In eight outbreaks5,6'8'10'14-1618 the total and differential white counts have been normal in most cases. A special study of the leukocytes was made in the first Royal Free Hospital epidemic12, a total of 750 specimens being examined from more than 400 confirmed or suspected cases. In addition, smears from 138 selected patients were examined by three independent observers. No specific changes were found. In about half the cases, relative lymphocytosis was seen during the early course of the illness. Occasional abnormal lymphocytes (Turk and plasma celllike forms) were noted in some patients, but the changes characteristic of infectious mononucleosis did not occur. Similar findings have been reported in the endemic cases in the neighborhood of the Royal Free Hospital 29 31. The authors stress the point that the changes are not specific, and are identical to those seen in virus infections, such as poliomyelitis and the common cold. A relative lymphocytosis was

The second patient's illness, which developed four weeks later, was acute. Three days after the onset of myalgia and paresthesias she had fever, indefinite stiffness of the neck and weakness of the legs. Within a further four days flaccid paralysis of the lower limbs WE.3 virtually complete. It had not regressed eight weeks later, and no fresh signs had developed. Lumbar puncture shortly after the onset showed 44 polymorphonuclear leukocytes, 52 lymphocytes and 90 r of protein. The suspicion that this case was,

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aJso observed in one-third of the Bethesda cases. The small Berlin o u t b r e a k differed in t h a t a polymorphonuclear leukocytosis occurred in all seven patients (range 9,700 to 15,300 cells per cu. mm.).

concentrations ranged between 50 to 80 mg. per cent in 4 cases; in the remainder the protein concentrations were less than 40 mg. per cent. Apart from an occasional weakly positive Pandy test, no other abnormalities have been reported in the cerebrospinal fluid.

Information about the erythrocyte sedimentation rate is incomplete. In the Royal Free and Middlesex Hospital outbreaks it was normal. In the Alaska outbreak it was raised in the few patients in whom it was performed.

Creatinuria. White and Burtch 14 studied the excretion of creatine in thirteen patients. In twelve the urinary output was more than 100 mg. daily and in eight of these it exceeded 200 mg. It was considered that the findings could not be explained on the basis of physiological creatinuria as there were no athletes with exceptional muscular development in the group, and only one child. Creatine studies have not been reported by other workers.

A positive agglutination reaction to washed sheep erythrocytes (Paul Bunnell test) is extremely uncommon14 and when present further studies have suggested a remote infection. The Cerebrospinal Fluid. The cerebrospinal fluid is known to have been examined in 199 cases in eleven outbreaks in which exact figures are available. The number of additional cases examined in the Durban and Alaska outbreaks is not recorded; lumbar punctures were not performed in the second Royal Free Hospital outbreak.

Electromyography. Electromyographic studies were performing in two patients in the Copenhagen outbreak in 1952. Unfortunately, no description of the tracings is given. They were interpreted as showing "neurogenic weakness of peripheral or radicular origin." Macrae and Galpine10 were the authors who first drew attention to a consistent electromyographic pattern in affected muscles on voluntary movement, which h a s s u b s e q u e n t l y been confirmed by Richardson 42 and Ramsay 31 .

The cells: Normal cell counts (less than 5 cells per cu. mm.) have been the rule in all outbreaks except those in Iceland6 and Alaska17. At Akureyri, two of five patients studied showed mild lymphocytosis, as did three others examined at Reykavik. In Alaska the total number of examinations is not stated but it appears that in two-thirds of those studied counts of 10 to 30 cells were found. In the remaining ten outbreaks in which exact figures are available, lumbar punctures were performed in 194 cases and less than 5 cells were observed in 180 of these (92.8 per cent). In the other fourteen cases (7.2 per cent) the cell counts ranged from 6 to 66 lymphocytes. In sporadic cases the results have been similar. Of twenty-seven cases studied, normal cell counts were found in twenty-five, a mild lymphocytosis in two.

According to Richardson, who studied twenty-eight patients with marked motor involvement from the Royal Free Hospital outbreak, the strength-duration curves of the involved muscles were normal in all cases except one. Nerve conduction measurements were within normal limits. Evidence of lower motor neurone degeneration was therefore exceptional. Similar results were reported by Alexander 43 who performed nerve conduction studies on twenty patients from Durban. Electromyography early in the disease revealed fasciculation potentials. With the onset of paresis an abnormality of recruitment occurred similar to that which has been described in involvement of the motor units at the level of the cord by Bauwens 44 . On volition, the number of motor unit potentials was severely reduced and in some instances the movement was initiated by prolonged polyphasic potentials. However, the accompanying evidence of nerve fibre degeneration which might be expected in a protracted lesion of the motor neurone was not obtained.

Protein: Protein estimations were made in 194 cases in ten epidemics. In 182 cases (94.6 per cent) concentrations of 40 mg. per cent or less were found, and in the remaining eleven (5.4 per cent) the readings varied from 48 to 85 mg. per cent. In addition, we have the observation that in the Durban outbreak, abnormal concentrations of protein were "very rare." There is no information about the Alaska outbreak. Of twenty-seven sporadic cases examined, protein

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F i g u r e 2A

Recording from severely involved tibialis anterior muscle on maximal sustained electrode and maximal sustained volition.

volition.

Recordings with concentric needle

F i g u r e 2B

Recordings with concentric needle electrode and maximal sustained volition. A, from weak tibialis anterior muscle. B, from normal contralateral tibialis anterior muscle. Calibration 50 cycles. 300 microvolts. (From Brit. M.J., 2:895, 1957.)

Figure 3

L

w ^

A —

V

^

h

t

-

R

Electromyograms: upper register, from left (affected) tibialis anterior muscle on maximal volition, showing grouping of large polyphasic motor-unit potentials; lower register, from right (unaffected) tibialis anterior muscle on maximal volition, whowing complete interference pattern of normal motor-unit potentials. Calibration 500 and 1001xVat 50 cycles per second. (From Ramsay, A.M. Lancet, 2:1196, 1957.)

During recovery, Richardson found changes similar to those described by Macrae and Galpine10. On volition the motor unit potentials were grouped in sequences lasting from 50 to 80 milliseconds, with regular intervals of complete inactivity giving rise to a tremulous contraction at a frequency of 5 to 10 per second. Ramsay and O'Sullivan29 studied eight sporadic cases and reported similar findings. On electromyographic exploration of affected muscles,

voluntary movement produced action potentials in groups of the same duration and frequency as those reported by Richardson. The similarity of the findings in the Royal Free Hospital cases and Ramsay's material is strikingly demonstrated in Figures 2 and 3. In his later review of thirty-four cases, Ramsay 31 reported that twenty-one of twenty-six patients examined electromyographically (including the eight originally described) had shown the changes de-

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The Clinical Syndrome Variously Called...

scribed. Galpine and Brady32, reporting seven sporadic cases from Coventry, found a reduction in the number of motor unit potentials and grouping in all five patients examined. Polyphasic and abnormally large potentials were also found.

Etiological Studies

Electroencephalography. Electroencephalograms have been studied by Fog9, Ramsey and O'Sullivan29, Galpine and Brady32 and Poskanzer et al. 16. Some non-specific abnormalities were reported in patients

Virology. In view of the dissimilarity of the clinical picture to any known bacterial infection, attention has naturally been focused on isolating a virus as the responsible agent. (Table 2). In nine of the fourteen

with behavior disorders by Ramsay and O'Sullivan. In all other cases the electroencephalogram has been normal.

Table 2 A t t e m p t s to Isolate Virus Location

Los Angeles Iceland

No. of Cases Examined 0 12

Nil Blood, C.S.F., feces

Middlesex Hospital

3

Blood, C.S.F., throat washings, feces Feces, throat washings Feces

Copenhagen Coventry Hospital

0 5

Nil Feces

Bethesda Hospital

?

Blood, C.S.F., throat washings, feces

Seward, Alaska Berlin

0 4

Nil Feces

Durban Hospital Royal Free Hospital(l)

?

5

Adelaide

New York State

Punta Gorda

Royal Free Hospital(2)

17

Animal species

Pathological Material Studied

Nil Nil Guinea pigs, hamsters, mice, suckling mice, monkeys Monkeys, suckling mice, Embryonated hen eggs weaned mice Monkeys (2), suckling mice (15) Monkeys, suckling mice

Monkey kidney, monkey testicle Nil Nil Human embryonic muscle Guinea pigs (2), adult and skiri; monkey kidney, mice, suckling mice, monkey testis monkeys (2), rabbit (1) Human HeLa(28), chorion Suckling hamsters (9), (20), fibroblasts (10),monkey adult mice (26), kidney (28), monkey testicle suckling mice (40) (31) Nil Nil Inoculated into mice and tissue cultures were set up for Coxsackie and polio virus Extensive virologic studies negative

?

Blood clots, throat washings feces

Ferrets, guinea pigs, suckling hamsters, adult mice, suckling mice, monkeys

19

Blood clots, throat washings, feces

Suckling mice

Nil

Nil

Tissue Culture Material

Fertile hen eggs, HeLa cells (9); human embryo brain (2), liver (1), spleen (1), kidney (6), human infant kidney (3), monkey kidney (10) HeLa, human liver, monkey kidney

Nil

Note: Number of experiments, where given, indicated in parentheses. C.S.F. = cerebral spinal fluid.

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The Clinical and Scientific Basis of M.E. / CFS

Table 3 Los Angeles A.P.C. virus Brucellosis Coxsackie Encephalitis Eastern Equine Encephalitis Japanese B Encephalitis Western Equine Encephalitis St. Louis Encephalomyocarditis Herpes Simplex Influenza A Influenza B Influenza C Leptospirosis Louping 111 Lymphocytic Choriomeningitis Mumps Paracolon (Bethesda-Ballerup) Polio Virus Psittacosis Q. Fever Rabies Rickettsia Burneti Toxoplasmosis

Iceland

Adelaide

New York State

Middlesex Hospital

Copenhagen

Coventry Hospital

0(17) Nil

0(12)

Nil

Nil

0(12)

Nil

0(12) 0(12) 0(10)

0(5) 0(12)

0(12)

0(5)

0(8)

0(10)

0(5) 0(5)

0(8) * (8)

0(10) * (10)

31" (10)

0(10)

0(5)

0(17)

0(12) 0(12)

Bethesda Hospital A.P.C. virus 0(7) Brucellosis t (13) Coxsackie 0(5) Encephalitis Eastern Equine Encephalitis Japanese B Encephalitis Western Equine Encephalitis St. Louis Encephalomyocarditis Herpes Simplex Influenza A Influenza B Influenza C Leptospirosis Louping 111 Lymphocytic Choriomeningitis Mumps Paracolon See text (Bethesda-Ballerup) Polio Virus Psittacosis Q. Fever Rabies Rickettsia Burneti Toxoplasmosis

Seward, Alaska

Durban Hospital

Berlin

Royal Free Punta Hospital (1) Gorda

Royal Free Hospital (2)

0(?) 0(7)

0(12) No

0(12)

details

Nil

known

0(12) 0(12) 0(6) 0(?) 0(?) 0(?) 0 (?) 0(?) 0(?)

0(7) 0(7)

0(12) 0(12) * (12)

0(?) 0 (12)

t (19)

0(?) 0(?) 0(?)

Note: Figures indicate number of positive tests; in parentheses, number of cases studied. * Immune bodies in titres suggesting remote infection found in some cases, f The findings were of doubtful significance and are discussed in the text. 148

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outbreaks unsuccessful attempts were made to isolate the poliomyelitis and Coxsackie viruses. In the Middlesex Hospital outbreak 8 polio virus Type 3 was isolated from the feces of one case. However, in view of the failure to isolate any detectable antibody from serial specimens of this patient's serum, the extremely unusual clinical picture (bilateral perceptive deafness developed), and a normal cerebrospinal fluid, it was concluded that this virus was probably not responsible for her illness. Table 2 shows that unsuccessful attempts have also been made to isolate other viruses in a number of outbreaks. Particularly extensive investigations were carried out in the Bethesda and Royal Free Hospital epidemics.

nurses and in three of twenty-seven control subjects. In eleven affected nurses a rise and fall in titre was demonstrated during the period of observation. A kitchen girl who had started work one week before the onset of the epidemic was the only person in the entire study who showed both serological strains of organism in her stools. Examination of sixty asymptomatic nurses three to seven months after the end of the epidemic revealed antibody titres in two cases, but no positive cultures. There is thus strong circumstantial evidence to suggest that the Bethesda-Ballerup paracolon organisms were related to the epidemic of clinical illness among the nursing staff. However, in the absence of other evidence (1) that a disease can be transmitted by these organisms either in man or in animals, (2) or that they produce a neurotoxin, it is premature to conclude that they caused the epidemic. As Shelokov and his colleagues have themselves suggested, the findings may indicate simply that fecal contamination of food was occurring in the hospital kitchen at the time of the epidemic. It is possible that an unknown causative organism was being spread in addition to the Bethesda-Ballerup organism.

In four outbreaks no attempts to isolate a virus were made; one of these was the small second Royal Free Hospital outbreak 13 , which was regarded as clinically identical with the large epidemic which had been the subject of extremely extensive virologic studies the previous year. In the Seward outbreak 17 the only investigation performed consisted in random serological studies in nineteen patients who were experiencing subacute symptoms, revealing that the "neutralization titres against the three types of poliomyelitis virus were generally low and showed no consistent pattern." In the Los Angeles5 and Copenhagen9 outbreaks no virological studies were made.

It is important to note that attempts to isolate paracolon organisms from patients during the Punta Gorda outbreak were unsuccessful 16 .

Serological studies (Table 3) have also been widely performed. Immune bodies to the mumps virus in titres suggesting remote infection were found in a few cases. In the Bethesda outbreak 15 thirteen serum pairs were examined for antibodies against polio virus. A questionable fourfold rise in the titre occurred in three cases, one against each of the three types of virus. Otherwise, serological tests have been uniformly negative.

Poisons. In view of the apparent predilection for hospital staffs, the question has arisen whether or not the disorder may be due to an occupational toxic hazard. This possibility received particular attention in the Royal Free Hospital outbreak 27 . Insecticides, paints and detergents received scrutiny, with negative results. Similar studies were negative in the Durban outbreak 18 and at Bethesda 15 . The Case for a Clinical Entity

Bacterial Studies. In the Bethesda outbreak the prominence of diarrhea as an early symptom directed attention to the possibility of an enteric infection. Organisms of two strains of the BethesdaBallerup paracolon group were isolated from feces from twelve of thirty-eight nurses examined and from only one of fifty-four persons who were on the hospital staff at the time of the epidemic and remained well. H and O serum agglutinins against the Bethesda-Ballerup group (at a titre of 1:40 or more) were found in twenty-two of forty-seven affected

It is significant that the first review of the syndrome under discussion was entitled, "Not poliomyelitis"45; the second, "A new clinical entity?"22. In later articles entitled, "Epidemic myalgic encephalomyelitis" 46 , "Benign myalgic encephalomyelitis" 468 and "Epidemic neuromyasthenia" 15,16 , the authors considered themselves on sufficiently strong ground to describe and name the syndrome. This sequence indicates that the first and minimum requirement in the

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The Clinical and Scientific Basis of M.E. / CFS

definition of an entity is the essentially negative one of showing that the syndrome is not an unusual manifestation of a disease already recognized. Later, as evidence accumulates, it may be possible to define the disorder in positive terms.

The final evidence lies in the laboratory findings. In spite of careful search in ten of fourteen outbreaks, poliomyelitis virus was found in only one case8 and in this patient no detectable antibodies appeared in the blood.

Poliomyelitis. In nine outbreaks an initial diagnosis of poliomyelitis was made. In favor of this diagnosis were the mode of onset in many cases (headache, pain in the neck and myalgia), the development of paresis and the season of the year. The low or absent fever, so unusual in poliomyelitis at the beginning of the paretic phase, and the rarity of a biphasic illness were at first discounted. However, other atypical features made their appearance in the later stages of the illness in such frequency that the diagnosis of poliomyelitis was withdrawn. In the second and third weeks the distinguishing features were (1) a longer active course with the development of fresh neurological symptoms and signs later than occurs in poliomyelitis, (2) the prominence and persistence of sensory phenomena, (3) the retention or exaggeration of deep reflexes in the paralyzed limbs, and (4) the normal cerebrospinal fluid in most cases.

Other Enteric Viruses. There is now good evidence that enteric viruses of the Coxsackie group49 cause epidemic pleurodynia 50 and encephalomyocarditis in babies51. Viruses of the Coxsackie and Echo groups have also been recovered from cases of aseptic meningitis 52 and lower motor neurone type paralysis. Scrutiny of reports claiming that they have been concerned in outbreaks of encephalitis in adults shows that objective evidence of damage to the central nervous system has, in fact, been the exception rather than the rule53,54. In the outbreaks reported here certain clinical similarities with epidemic pleurodynia, notably the occurrence of pleuritic chest pain in six outbreaks, of abdominal pain in six, and pain in the shoulders in twelve, stimulated a search for these viruses. In nine outbreaks material was injected into suckling mice with negative results (Table 2); and in five instances 8, IO, I2, is, I6 T I S S U E cultures of kidney cells from monkeys failed to grow ECHO viruses. In other respects, notably the mental symptoms and the chronicity of some cases, the outbreaks reported here are unlike any that have been found to be associated with Coxsackie or Echo viruses.

In some outbreaks the persistence of muscular pain after the development of paresis 47 , the occurrence of tremors and involuntary movements, and the high incidence of retention of urine in the absence of severe paralysis 48 were further points against the diagnosis of poliomyelitis at this stage. The subsequent subacute and chronic course of the disorder, with its mental symptoms and partial or complete remissions and exacerbations, is quite distinct from poliomyelitis which runs its active course within a week of the onset of the major illness. With the exception of the Iceland epidemic, muscular wasting in patients with persistent paralysis has been extremely rare and in such patients no electromyographic evidence of denervation has been found. The over-all mortality in more than 1,000 cases has been nil. From the clinical point of view, the differences from poliomyelitis become progressively clearer as the illness develops.

Encephalitis Lethargica. The occurrence of tremors, myoclonus or other involuntary movements in a few cases in seven outbreaks raised the question of the reappearance of encephalitis lethargica in epidemic form. Although this disease was notably pleomorphic56, it has certain distinct clinical and epidemiologic features, which are not shared by any of the outbreaks reported here. According to Von Economo55 it occurred chiefly in the first three months of the year, was of low infectivity, with no sex predominance and a high mortality. Postencephalitic Parkinsonism occurred in about 30 per cent of all recognized cases. This complication has not been recorded in the illness described here, although one Royal Free Hospital patient had choreoathetoid movements of the right arm with cog-wheel rigidity some months after the acute illness. Involuntary

Epidemiologically, the high attack rates (Table 1) and the predilection of the disorder for small semiclosed communities are also against the diagnosis of poliomyelitis.

150

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The Clinical Syndrome Variously Called...

movements have also been reported in the chronic stage in a few of the Alaskan cases17. Delinquent behavior, such as occurred after encephalitis lethargica epidemics, has not been described.

Other Infections. Searches for a wide variety of other agents have been carried out (Tables 2 and 3) without success. The Question of Hysteria. The question of hysteria has been raised in five outbreaks6'6,912'20 and by Galpine and Brady 32 and Ramsay 31 in the discussion of their endemic cases. Most authors agree that hysterical manifestations have occurred in a few patients 6 ' 9 31, particularly in the later stages,12, but none has felt that it has contributed significantly to the pattern of the disease.

The Arthropod-Borne Encephalitides. The various arthropod-borne encephalitides have common epidemiological and clinical features which distinguish them from the syndrome reported here. As might be expected, these diseases occur most frequently in field and forest workers who are exposed to the bites of mosquitoes, ticks, and bird and animal parasites 66 , and evidence of spread by personal contact is uncommon. The various types of insect-borne encephalitis share an acute onset with high fever and headache, followed in severe cases by delirium, convulsions, tremors and spastic paralyses. Death occurs within ten days in a variable proportion. A pleocytosis of 100 to 500 cells in the cerebrospinal fluid and a polymorphonuclear leukosytosis in the peripheral blood are characteristic.

In an illness in which there has been a selectivity for young women, no mortality, and few positive laboratory findings, it is important to examine the possibility that hysteria may have accounted for part or all of the clinical picture more closely. Epidemic hysteria has been recognized for many centuries as a particular hazard in institutions containing women68. It has presented in many bizarre ways from the mass compulsive dancing (St. Vitus Dance) of the middle ages, to the "quaking" of the early Quakers, the fits of Wesley's converts and the effort syndrome of soldiers in the 1914-1918 World War. The form and content of the manifestations depend upon the ideas and fears of the age69.

The syndrome described in this paper, with its institutional outbreaks, evidence of spread by personal contact6,612, absence of delirium or convulsions, predominantly normal cerebrospinal fluid and absent mortality, is in striking contrast. From the virological point of view, the agents of the insect-borne encephalitides are best recovered from nervous tissue which was not obtained from this material. However, a search for antibodies against some of the known types of encephalitis virus was made in the Iceland6 and Punta Gorda16 outbreaks and against louping ill (Russian spring-summer encephalomyelitis) in the Royal Free Hospital cases12 without success.

No one can seriously contend that every patient in all the outbreaks described in this paper has been hysterical. The presence of definite ocular, facial and palatal pareses, or nystagmus, and of extensor plantar responses in rare instances, and a definite pleocytosis in the cerebrospinal fluid in a few cases indicate organic disease of the nervous system in a minority at least, unless we are to doubt the competence of a number of different observers.

Infectious Mononucleosis. A diagnosis of infectious mononucleosis was seriously entertained at the onset of the Royal Free Hospital outbreak 67 . In favor were the known predilection of this disease for hospital staffs, the lymphadenopathy, and the presence of a few atypical lymphoctyes in the peripheral blood in some cases. A wide variety of neurological manifestations have been described in infectious mononucleosis, but these are rare. As the epidemic developed, the overwhelming frequency of neurological symptoms and signs made this diagnosis unlikely, and the failure to demonstrate typical Downey cells or significant titres of heterophile antibodies finally excluded it.

A more reasonable viewpoint would be that the majority of the cases constitute a hysterical reaction to a small number of cases of infection of the nervous system, for example, poliomyelitis. Thus it will be readily admitted that an epidemic of poliomyelitis, such as occurred in Los Angeles in 1934, would produce overwork and emotional strain in the nursing staff of the hospital concerned. Many of the nurses would naturally feel apprehensive about becoming ill with the disease, and might be inclined to misinterpret the minor aches and pains of every day life. With the development of a few genuine cases of poliomyeli-

151

The Clinical and Scientific Basis of M.E. / CFS

Thus we would be forced to the conclusion, on this hypothesis, that even the patients with objective findings were also suffering from hysteria. This seems unlikely.

tis among the staff and the resulting increasing tension, it is possible to envisage an epidemic of hysterical paralysis. An attractive case could be made for such a hypotheses. The high attack rates in the most suggestible groups of the community, the predilection for hospital staffs, and the association with preceding or concurrent outbreaks of poliomyelitis might thus be explained. Clinically, the absent or insignificant fever, the prominence of sensory phenomena, which are admittedly often of bizarre distribution and content13,15, the fluctuation of symptoms and signs from day to day, and the high incidence of negative cerebrospinal fluid findings would also fit in with this hypothesis. Further support might be obtained from the peculiar nature of the paresis. Paralysis without the disappearance of tone and deep reflexes and subsequent atrophy on the one hand, or true spasticity and extensor plantor responses on the other, is suspicious of hysteria. As Brain 60 has pointed out, inability of the patient to relax the affected limb in such cases may cause the deep reflexes to appear exaggerated. Tremors on volition and involuntary movements may also be present in such patients. A jerky contraction against resistance is often prominent 60 . If we add muscle pain and tenderness, which are admittedly uncommon in hysterical paralysis, such a description resembles closely the features of the paralysis in the Royal Free Hospital cases12 which were attributed to a deep subcortical lesion, and is similar to those described in many less detailed reports.

In the second place, the relationship to poliomyelitis is not constant. At the Royal Free Hospital no patient with poliomyelitis had been admitted to the hospital prior to the outbreak, nor was the diagnosis entertained in the initial cases. There was no undue apprehension about poliomyelitis among this hospital staff, but rather about infectious mononucleosis which was the early diagnosis. In spite of this the course of the disease and the type of neurological involvement was similar to that found in Los Angeles. In the Coventry outbreak six of the twelve patients had been nursing poliomyelitis cases for several years, and it is difficult to imagine why such experienced persons should suddenly manifest a hysterical reaction to the fear of this disease. In the Middlesex Hospital, Berlin and Bethesda cases there was no known contact with poliomyelitis and, in the early cases at least, no reason for anxiety about it in the communities concerned. The mental symptoms which are a constant feature of all the outbreaks are not typical of hysteria. Disorders of consciousness and convulsions such as may be seen in hysteria have been extremely rare. A single grand mal seizure was reported in a small child in Alaska. Shallowness of affect and "belle indifference" have not been seen. On the contrary, depression and undue emotional lability have been the rule. In the acute stage, terrifying dreams, panic states, uncontrollable weeping and hypersomnia occur. In the convalescent stage the prominent features are impairment of memory, difficulty in concentration and depression. These symptoms are more consistent with cerebral damage than with hysteria. Many years ago Von Economo55 stressed the ease with which the mental symptoms of encephalitis may be confused with those of psychoneurosis. The slight lymphocytosis in the cerebrospinal fluid in two outbreaks 6,17 which shared many other features with the remainder, and the presence of a characteristic electromyogram in cases from three separate localities, are further strong arguments in favor of an organic etiology.

There are also strong arguments against the idea that the syndrome constitutes a mass hysterical reaction to a few cases of poliomyelitis. In the first place, in the minority who had undoubted objective physical signs, the clinical picture was quite unlike poliomyelitis. In this minority, nystagmus7,8,9,12,18,19, ophthalmoplegia 8,12 , facial palsy5,7,9,12,18,19, palatal paresis5,8,12 and extensor plantor responses8,9,12 were recorded, but true flaccid paralysis with absent reflexes did not occur, and subsequent atrophy was recorded with any frequency in only one outbreak 6 and in exceptional instances in two others5,12. In addition, these patients shared the other characteristic features, namely myalgia, sensory changes, low pyrexia, mental symptoms, and a chronic or relapsing course, which were experienced by the majority of patients who had no truly objective physical signs.

Final points against mass hysteria as a major factor

152

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The Clinical Syndrome Variously Called...

in the syndrome are the consistency of the course of the illness, and the similarities in the symptoms described, in spite of a wide variation in the types of community affected, from hospital staffs on the one hand to semi-rural and urban populations on the other. The fact remains that in sporadic cases the illness may be extremely difficult to differentiate from hysteria and other types of psychoneurosis31. The diagnosis should therefore be reserved, in isolated instances, for patients with evidence of acute damage to the brain or cord, including the characteristic paresis. If not, the syndrome will become a convenient dumping ground for non-specific illnesses characterized by fluctuating aches and pains, fatigue and depression.

Angeles cases. The Los Angeles, Middlesex, Durban and Royal Free Hospital epidemics differ quantitatively from the remainder in regard to the frequency of neurological signs (other than paresis), notably cranial nerve lesions, hyperpathia, and retention of urine. They share with the Copenhagen cases a high incidence of paresthesias. On the other hand the Royal Free Hospital epidemics stand apart from the remainder because of the very high incidence of lymphadenopathy, which was otherwise limited to a few cases in the New York State, Middlesex8'0' and Durban outbreaks. The Iceland and Alaska epidemics differ from the rest in that a slight lymphocytosis in the cerebrospinal fluid was the rule rather than the exception. The length of the illness and the incidence of subacute and chronic cases have also varied.

The Homogeneity of the Material. The clinical and epidemiologic evidence suggests that the fourteen outbreaks described in this review have not been due to any known neurotropic infection. The virologic evidence supports this contention so far as it goes, but it is incomplete. Thus poliomyelitis and Coxsackie virus were not formally ruled out in four outbreaks, and Echo viruses were not excluded in nine. It might be argued that at least some of the apparent clinical similarities are due to unconscious bias or undue emphasis on the part of observers familiar with the features of previous epidemics. Such bias cannot have contributed towards the striking reported similarities between the Los Angeles and Royal Free Hospital outbreaks 5,12 because Gilliam's paper was unknown to the British authors. These similarities are even more impressive when it is appreciated that bias was probably operating in opposite directions. In the Los Angeles outbreak the initial diagnosis was poliomyelitis, and the patients were cared for by orthopedists; in the Royal Free Hospital cases the initial diagnosis was infectious mononucleosis, and patients were treated by internists and neurologists. Further independent evidence is supplied by the Copenhagen cases. Fog's paper 9 was not known to the authors of the later Middlesex, Durban, and Royal Free Hospital reports, although once again they share many common features. It seems therefore that the syndrome is not a self-perpetuating medical artefact.

Two outbreaks in particular stand apart in several important respects from the rest and it is debatable whether or not they should be classified with them. In the small Berlin outbreak 16 the illness was brief, sensory symptoms and signs were absent, and there were no sequelae or chronic cases. A leukocytosis in the peripheral blood was another distinguishing feature. The onset was November, later than in any other outbreak in the Northern Hemisphere. The outbreak at Punta Gorda16 also began at an unusual time of the year (February). The onset of symptoms was insidious in all cases. Most of the cases were diagnosed on the basis of a house to house survey, presumably by retrospective questioning. Paresis was exceptional, and other objective evidence of disease of the nervous system was extremely uncommon. In mild cases, when paresis and other signs of neurological involvement are absent, the illness has few differences in its early stages from many short-lived infections characterized by headache and generalized aches. Even in these patients, however, the degree of malaise and the severity of the pains are disproportionate to the disturbance of temperature and pulse. In the convalescent stage in such cases the easy fatiguability, the aches and pains, and the emotional disturbances without definite physical signs lead to difficulty in differentiation from psychoneurosis. Indeed, in the absence of an epidemic such a differentiation may be impossible.

There are also important differences between the outbreaks. The paralysis rate varies from 10 per cent in the Punta Gorda outbreak to 80 per cent in the Los

In its epidemic form the illness is distinctive and therefore has a rightful place in medical literature as a clinical entity. Its epidemiological features suggest 153

The Clinical and Scientific Basis of M.E. / CFS

casionally catheterization or even tidal drainage will become necessary 8 30. In rare instances of bulbar palsy, tube feeding has been necessary 12 . An artificial respirator has been required for a short time in three cases5 8. Shock treatment for severe depression was required in three of the Royal Free Hospital patients 12 .

that it may be an infection. However, in the absence of any pathological evidence it remains uncertain whether it is due to a single agent or to a group of related agents. As far as sporadic cases are concerned the diagnosis can be made with a degree of certainty only in cases which show all, or nearly all, the characteristics herein described, including paresis and some other objective evidence of neurological involvement which cannot be simulated. Negative virologic studies are also desirable. The diagnosis of less severe sporadic cases must await further knowledge of the pathology and the development of an objective laboratory test. Although further work is required before the electromyographic changes can be regarded as diagnostic, they may provide objective evidence of disease when this is otherwise lacking.

In the subacute and chronic stages constant encouragement and support is essential. The patient may be reassured that the trend is toward improvement and final recovery. Rehabilitation should be conservative, and return to work gradual. Nomenclature The wisdom of naming a disorder, the nature of which cannot at present be proved, and which may be due to more than one agent, is debatable. That there are successful precedents is shown by the history of epidemic pleurodynia 24,25,50 and herpangina 4,61 , both of which have subsequently proved to be virologic entities. In view of the widespread agreement that the illness described here is clinically recognizable in its own right, at least in severe cases15'17,22,31,46, various authors have been of the opinion that a name is necessary for reference purposes. Unfortunately there has been no agreement as to what this name should be. White and Burtch 14 suggested "Iceland disease." This has the disadvantage of all eponyms that it gives no inkling to the uninformed of the nature of the disorder. It is also incorrect on historical grounds as the Los Angeles outbreak described by Gilliam is the original account in the literature. The same disadvantages (with the added difficulty of pronunciation) apply to "Akureyri disease" which is preferred by Sigurdsson and Gudmundsson 21 .

Treatment. No specific treatment is known to affect the course of the disease. Antibiotics were tried in the early stages of the Bethesda outbreak, when the diagnosis was uncertain, and in those patients in the Royal F r e e Hospital who h a d complicating intercurrent bacterial infections. No beneficial effect on the basic disease was observed. Steroid therapy has not been tried. The importance of rest, as early in the disease as possible, and as absolute as practicable, is stressed by many authors 51215 ' 1819 . Paretic limbs should be immobilized in the correct posture. Local heat may be used to abate pain and spasm. The association of premature rehabilitation with relapse is well described 5121819 and it is probable that bedrest should be maintained for some time after the disappearance of symptoms. Symptomatic treatment is important in this painful and protracted disorder. Muscle relaxants such as meprobamate* have been tried12,1517 and have relieved muscle pain and tenderness in some cases. The sedative action may also be of value 17 .

The first attempt at a descriptive name was made by Fog9 who suggested "neuritis vegetativa" in the belief that the autonomic nervous system bore the brunt of the damage. A further suggestion was made in an editorial in the Lancet in 195622. It was hoped that the term "benign myalgic encephalomyelitis" would emphasize the absent mortality, the severe muscular pains, the evidence of parenchymal damage to the nervous system, and the presumed inflammatory nature of the disorder. This term has been adopted by Galpine and Brady32 and Deisher 17 in subsequent articles. It has also been criticized by Sigurdsson62

In a few cases full doses of narcotics may be necessary to control pain 5 8,12. Complications should be treated as they arise. Retention of urine can usually be controlled by parasympathomimetic drugs such as carbachol12 but oc* Miltown (Wallace Laboratories, New Brunswick, New Jersey). 154

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The Clinical Syndrome Variously Called...

and the staff ofthe Royal Free Hospital1227. Sigurdsson objects that the disease is not always benign, not invariably myalgic, and possibly never encephalomyelitis Benignity is relative; it seems that "benign" is justified by the fact that there is no other recorded infective disease of the central nervous system without mortality. As various authors have stressed5,8,12, the pain in this disease, although not invariably present, may be devastating, and is perhaps the feature which impresses itself most forcefully on the observer. As far as the final term is concerned, the clinical impression that the lesion is central rather than peripheral is supported by the electromyogram. In our present state of ignorance "encephalomyelitis" seems preferable to "encephalopathy" because it conveys the suggestion that the disease is infective in origin, which is almost certainly the case.

The epidemiologic features are a high attack rate as compared with poliomyelitis, a predilection for residential communities, a higher attack rate in women than in men, a tendency to occur more commonly in young adults, and the commencement of most outbreaks in the summer months. The evidence is consistent with the hypothesis that the disorder is an infection which is spread by personal contact. The fact that hospital staffs, particularly nurses, have borne the brunt of seven outbreaks suggests an occupational hazard. An alternative explanation is that the unusual nature of the illness has been noted in such persons because of a higher standard of diagnostic skill at their disposal than is available to the members of other residential communities. Severely affected patients show a characteristic clinical picture. After an acute or subacute onset with headache, symptoms of a gastro-intestinal or upper respiratory upset, muscular pains and low or absent fever, an unusual type of paresis develops which is rarely associated with the classic signs of lower motor neurone or pyramidal tract involvement. This is often accompanied by paresthesias, sometimes by sensory loss, and occasionally by painful muscular spasms, myoclonus or other types of involuntary movement. As the paresis recovers a curious jerky muscular contraction on volition has been noted in some instances. Involvement of the cranial nerves and the bladder may occur.

In the Royal Free Hospital report it is pointed out that the name fails to describe the involvement of the lymph nodes and liver. As the author has indicated elsewhere63, a fully descriptive name such as "benign ameningitic myalgic lymphoreticular encephalomyelopathy" is impracticable. Shelokov et al.15 and Poskanzer et al.16 have coined the phrase "epidemic neuromyasthenia." The first term is misleading because it suggests that the disorder is confined to epidemics; the second (translated nerve-muscleweakness) is either meaningless or, if it means anything, suggests a disorder of the muscle end-plate, which is contrary to the electromyographic evidence. The verbal similarity with "neurasthenia" (i.e., psychoneurosis) is particularly unfortunate.

Convalescence has been prolonged by fatigue and recurring myalgia but recovery has usually been complete within three months. In a proportion which varies from outbreak to outbreak a well defined state of chronic ill health has developed, characterized by fluctuating myalgia and paresis, partial remissions and exacerbations, and depression, emotional lability and lack of concentration. The major differences within the group of outbreaks lie in the incidence of lymphadenopathy, paresis, and mild lymphocytosis in the cerebrospinal fluid.

It is unlikely that an adequate term will be found until fresh evidence is available. In the meantime "benign myalgic encephalomyelitis" may act provisionally as a rallying point in the current list of medical literature for patients with the clinical features already described. Summary and Conclusions

Clinical laboratory studies have on the whole proved unhelpful. With the exception of two outbreaks in which a mild lymphocytosis was found, the cerebrospinal fluid has been normal in 95 per cent of cases

Fourteen outbreaks of a paralytic illness of worldwide distribution are described. Twelve of these have so many epidemiologic and clinical features in common that there is a prima facie case for a single or related group of causative agents.

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The Clinical and Scientific Basis of M.E. / CFS

It is concluded that the disease is recognizable in its epidemic form on clinical and epidemiologic grounds and therefore may properly be considered a clinical entity. In its sporadic form, which is now well documented, the diagnosis should be reserved at present for severe cases with definite neurological signs including paresis and the characteristic fluctuating course. The disease is probably due to infection by an unknown agent or group of related agents.

investigated. An unusual electromyogram has been found in two outbreaks and in some sporadic cases. No deaths directly attributable to the disease have occurred and the pathology remains unknown. In spite of the widest investigations, no known bacterial or viral pathogen has been incriminated. In particular, there is no evidence that the poliomyelitis, Coxsackie or Echo groups of viruses have been responsible.

The problems of nomenclature and treatment are also discussed.

Evidence is adduced to show that the outbreaks can be distinguished on clinical grounds from poliomyelitis, encephalitis lethargica, the arthropod-borne encephalitides, epidemic myalgia and infectious mononucleosis. The disorder is not a manifestation of mass hysteria.

Acknowledgment: It is a pleasure to acknowledge the help and encouragement provided by Professor Max Michael, Jr., during the preparation of this paper.

References 1. Likar, M. and Dane, D.S. An illness resembling acute poliomyelitis caused by the virus of the Russian spring/summer encephalitis louping ill group in Northern Ireland. Lancet, 1: 456, 1958.

(b) Acheson, E.D. Unpublished data; (c) Acheson, E.D. Letter. Lancet, 2: 395, 1955. 9. Fog, T. Neuritis vegetativaepidemica. Ugesk. f. laeger, 115: 1244, 1953.

2. Hammon, W.M., Yohn, D.S., Ludwig, E.H., Pavia, R.A. and Sather, G.E. A study of certain non-poliomyelitis and poliomyelitis enterovirus infections. J.A.M.A., 167: 727, 1958.

10. Macrae, A.D. and Galpine, J.F. Illness resembling poliomyelitis in nurses. Lancet, 2: 350, 1954.

3. Rhodes, A.J. Recent advances in study of virus diseases with particular reference to neurotrophic infections. Report of annual meeting and proceedings of Royal College of Physicians and Surgeons of Canada, p. 40. 1954.

11. Sumner, D.W. Further outbreak of disease resembling poliomyelitis. Lancet, 1: 764, 1956. 12. The medical staff of the Royal Free Hospital. An outbreak of encephalomyelitis in the Royal Free Hospital group, London, 1955. Brit. M. J., 2: 895, 1957

4. Kumm, H.W. Relationship of Echo and Coxsackie viruses to paralytic and non-paralytic poliomyelitis. Journal-Lancet, 77: 469, 1957.

13. Geffen, D. and Tracy, S.M. Outbreak of acute infective encepahlomyelitis in a residential home for nurses in 1956. Brit. M. J., 2: 904, 1957.

5. Gilliam, A.G. Epidemiological study of an epidemic diagnosed as poliomyelitis occurring among the personnel of the Los Angeles County General Hospital during the summer of 1934. Public Health Bulletin, U.S. Treasury Dept. No. 240, 1938.

14. White, D.N. and Burtch R.B. Iceland disease, a new infection simulating acute anterior poliomyelitis. Neurology, 4: 506, 1954.

6. Sigurdsson,B., Sigurjonsson, J., Sigurdsson, J.,Thorbelsson, J. and Gudmundsson, K.R. Disease epidemic in Iceland simulating poliomyelitis. Am. J. Hyg., 52: 222, 1950.

15. Shelokov,A.,Habel,K.,Verder,E.andWelsh,W. Epidemic neuromyasthenia. An outbreak of poliomyelitis-like illness in student nurses. New England J. Med., 257: 345, 1957.

7. Pellew, R.A.A. Clinical description of disease resembling poliomyelitis. M.J. Australia, 1: 944, 1951.

16. Poskanzer, D.C., Henderson, D.A., Kunkle, E.C., Kalter, S.S., Clement, W.B. and Bond J.O. Epidemic neuromyasthenia. An outbreak in Punta Gorda, Florida. New England J. Med., 257: 356, 1957.

8. (a) Acheson, E.D. Encephalomyelitis associated with poliomyelitis virus: an outbreak in a nurses'home. Lancet, 2: 1044, 1954; 156

E.D. Acheson, DM, MRCP

The Clinical Syndrome Variously Called...

17. Deisher, J.B. Benign myalgic encephalomyelitis (Iceland disease) in Alaska. Northwest Med., 56: 1451, 1957.

34. Bond, J.O. Letter. Lancet, 2: 257, 1956. 35. Wallis, A. L. An unusual epidemic. Lancet, 2: 291,1955.

18. Adnams, J.N. Observations on the epidemic of encephalomyelitis affecting the nursing staff of the Addington Hospital, 1955. Unpublished.

36. Wallis, A.L. Letter. Lancet, 2: 1091, 1955. 37. Wallis, A.L. Letter. Lancet, 2: 146, 1956.

19. Hill, R.C.J. Memorandum on the outbreak amongst the nurses at Addington, Durban. South African M.J., 29: 344, 1955.

38. Rose, J.R. An outbreak of encephalomyelitis in Sierra Leone. Lancet, 2: 914, 1957.

20. Clinical meeting of the Natal Coastal Branch. The Durban mystery disease. South African M.J., 29: 997, 1955.

39. Wright, J. andMorley, D.C. Encephalitis tremens. Lancet, 1: 870, 1958.

21. Sigurdsson, B. and Gudmundsson, K.R. Clinical findings six years after outbreak of Akureyri disease. Lancet, 1: 766, 1956.

40. McConnell, J. An epidemic of pleurodynia with prominent neurologic symptoms and no demonstrable cause. Am. J.M.Sc., 209: 41, 1945.

22. Leading Article. A new clinical entity? Lancet, 1: 789, 1956.

41. Hook, O. Islandssjuka, Nord.med., 7: 373, 1956. 42. Richardson, A.T. Some aspects of the Royal Free Hospital epidemic. Ann.Phys.Med., 3: 81, 1956.

23. Von Economo,C. Encephalitis lethargica. Jahrb.f.Psychiat. u. Neurol., 39: 202, 1917.

43. Alexander, J.S. Observations on neuromuscular dysfunc tion in the Addington outbreak. South African M.J., 30: 88, 1956.

24. Daae, A. Epidemi i Drangeldal AfAkut Muskelreumatisme UdbredtUedsmitte. Norsk.mag.f.laegevidensk., 3: 409,1872.

44. Bauwens, P. Variations of the motor unit. Proc. Roy. Soc. Med., 49: 110,1955.

25. Homann, C. Om En I Kragero Laegedistikt Herskende Snitsam Febersygdom. Norsk.mag.f.laegevidensk., 3: 542, 1872.

45. Leading article. Not poliomyelitis. Lancet, 2: 1060,1954. 26. Sylvest, E. Epidemic Myalgia. London, 1934. Oxford University Press.

46a. Leading article. Epidemic myalgic encephalomyelitis. Brit. M.J., 2: 927, 1957.

27. Crowley, N., Nelson, M. and Stovin, S. Epidemiolgical aspects of an outbreak of encephalomyelitis at the Royal Free Hospital, London, in the summer of 1955. J.Hyg., 55: 102, 1957.

46b. Galpine, J.F. Benign myalgic encephalomyelitis. Brit.J.Clin. Practice, 12: 186, 1958. 47. Russell, W.R. Poliomyelitis, London, 1952. Oxford University Press.

28. Hardtke, J. Iceland disease in Indiana. J. Indiana M.A., 48: 245, 1955.

48. Weatherley, C.H. and Steigman, A.J. Influence of age and sex on the urinary bladder retention associated with acute poliomyelitis. Am.J.M.Sc., 226: 38, 1953.

29. Ramsay, A.M. and O'Sullivan, E. Encephalomyelitis simulating poliomyelitis. Lancet, 1: 761, 1956. 30. Jellinek, J.E. Benign encephalomyelitis. Lancet, 2: 494, 1956.

49. Dalldorf, G. and Sickles, G.M. An unidentified filtrable agent isolate from the faeces of children with paralysis. Science, 108: 61, 1948.

31. Ramsay, A. M. Encephalomyelitis in Northwest London. An endemic infection simulating poliomyelitis and hysteria. Lancet, 2: 1196, 1957.

50. Melnick, J.L. Coxsackie group of viruses. Ann. New York Acad.Sc., 56: 587, 1953.

32. Galpine, J.F. and Brady, C. Benign myalgic encephalomyelitis. Lancet, 1:757, 1957.

51. Van Creveld, S. and DeJager, H. Myocarditis in new borns caused by coxsackie virus. Ann.Paediat., 187: 100,1956.

33. Pellew, R.A.A. Further investigations on a disease resembling poliomyelitis seen in Adelaide. M.J.Australia, 2: 480, 1955.

52. Johnsson, T. Poliomyelitis epidemic in Stockholm in 1953. IV. Acta med. Scandinav., (supp. 316) 154: 33, 1956.

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53. G a l p i n e , J . F . a n d M a c r a e , A.D. O u t b r e a k of meningoencephalitis; isolation of coxsackie virus. Lancet, 1: 372, 1953.

58. White, A.D. A History of the Warfare of Science with Theology in Christendom, vol. 2, p. 135. New York, 1896. Appleton.

54. Stanley, N.F. Coxsackie virus infections in Australia with special reference ot their epidemiology. M.J. Australia, 2: 216, 1953.

59. Sargent, W. The Battle for the Mind. London, 1957. Heinemann. 60. Brain, R. Diseases of the Nervous System. Oxford, 1955.

55. Von Economo, C. Encephalitis Lethargica; Its Sequelae and Treatment. Translated by Newman, K.O. London, 1931. Oxford University Press.

61. Zahorsky, J. Herpangina. South. M.J., 13: 87, 1920. 62. Sigurdsson, B. Letter. Lancet, 2: 98, 1956.

56. Schlesinger, R.W. The Seasonal and Arthropod-Borne Virus Encephalitides, p. 380. Baltimore, 1952. Monographs in Medicine. Williams & Wilkins.

63. Acheson, E.D. Letter. Lancet, 1: 834, 1957.

57. Annotation. Outbreak at the Royal Free Hospital. Lancet, 2: 351, 1955.

Sir (Ernest) Donald Acheson, KBE 1986 Sir (Ernest) Donald Acheson, KBE 1986, has just retired after holding the post of Chief Medical Officer, Departments of Health and Social Security for Great Britain. It is of notable interest that this principal early M.E. / CFS researcher had risen to become the chief Medical Officer for Great Britain. Dr. Donald Henderson, one of the early American M.E. / CFS pioneers whose work is also in this book, went on to become Dean of Medicine of Johns Hopkins and is presently the White House Chief of Science for the U.S.A. After Sir Donald Acheson graduated from Oxford in 1946 he held numerous senior positions, including Professor of Clinical Epidemiology, University of Southampton, Chairman of Slow Virus Group, Visiting Professor, McMaster University, Canada 1977. He has also held numerous important posts in many universities in the United Kingdom and New Zealand. The information about Sir Acheson was obtained from the British Who's Who 1992, Collier Macmillian Press, Cambridge, Ontario.

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- Clinical

Syndrome?

Chapter 15

D. Henderson This article is reprinted with the kind permission of The New England Journal of Medicine, Apr. 9,1959, Vol. 26, Number 15, pages 757 to 764.

Epidemic Neuromyasthenia - Clinical Syndrome?* Donald A. Henderson, M.D. f and Alexis Shelokov, MD. f t Atlanta, Georgia, and Bethesda, Maryland Dr. Henderson is presently the Associate Director for Life Sciences, Office of Science and Technology Policy in the Executive Office of the President in Washington, D.C. He received his M.D. at the University of Rochester School of Medicine and his M.P.H. at the John Hopkins University School of Hygiene and Public Health. He has also been the recipient of many honorary degrees including Sc.D.s from Yale University, Albany Medical College, University ofMaryland and L.H.D. from the State University ofNew York. In the past, Dr. Henderson has held various positions including Chief, Epidemic Intelligence Service and Assistant to Chief, CDC, and Chief Medical Officer, Smallpox Eradication, World Health Organization, Geneva, Switzerland. He has played an integral part in many societies such as the American Board ofPreventive Medicine, American Public Health Association, Royal College of Physicians (Edinburgh), Fellow and the Royal Society of Tropical Medicine and Hygiene, Fellow. Dr. Henderson has been involved in many professional committees which include Institute of Medicine, Board on International Health, Foundation for Development of International Health (Japan), Scientific Consultant and Rotary Foundation of Rotary International, Polio Plus Advisory Committee. Dr. Henderson has been involved in more than one hundred scientific publications dealing primarily with smallpox eradication, epidemiology and immunization.

* From the Communicable Disease Center and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Public Health Service, United States Department of Health, Education, and Welfare, t Epidemiologist, Epidemiology Branch, Communicable Disease Center, assigned to the Mary Imogene Bassett Hospital, Cooperstown, New York, t t Chief, Laboratory of Tropical Virology, National Institute of Allergy and Infectious Diseases; director, Middle America Research Unit, Canal Zone.

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A. Shelokov

(No recent photograph was available.)

Dr. Alexis Shelokov was born in Harbin, China and was educated in Gymnasium, China and Stanford University where he obtained his A.B. and M.D. Dr. Shelokov has held many affiliations with institutions, including, Massachusetts Memorial Hospitals, National Institutes of Health, University of Texas, Health Science Center at San Antonio, John Hopkins University School of Hygiene and Public Health and The Salk Institute, where he is presently the Director of Vaccine Research in the Government Services Division. He also holds outside appointments including Adjunct Professor of Epidemiology, School of Hygiene and Public Health, The John Hopkins University and a Member of the Core Group of the Expert Working Group on Biological Toxin Weapons Verification, Federation of American Scientists. Dr. Shelokov's research interests include infectious diseases, tropical medicine, preventive medicine, virology, epidemiology and vaccinology. Dr. Shelokov's photgraph is courtesy of Industrial

Medicine and Science, Vol. 33, Issue #10, pg 716, 1964.

During the past ten years an impressive number of outbreaks of bizarre, clinically similar illnesses have been reported from several areas of the world. The cases have shared the features of a protean symptomatology, including fatigue, headache, alterations in emotional status, aching muscular pain, paresis and paresthesias. Regarding the severity of the illnesses, few significant and consistent physical findings and abnormal laboratory determinations have been noted. The courses of the patients have been unaccountably prolonged and debilitating and marked by frequent exacerbations. Cases have been confined principally to young and middle-aged adults; females have been more frequently and severely afflicted. Although most of the outbreaks have involved the general community, the most notably susceptible have been nurses and physicians. Intensive efforts to characterize these illnesses, etiologically and pathologically, have met with little success.

The illnesses have been termed, variously, "Iceland disease," 1 "benign myalgic encephalomyelitis," 2 "Akureyri disease,"3 4 epidemic vegetative neuritis," 5 "acute infective encephalomyelitis," 6 "encephalomyelitis"7,8 "persistent myalgia following sore throat," 9 "a disease resembling or simulating poliomyelitis,"10,11 "atypical poliomyeltis"12 "encephalomyelitis resembling poliomyelitis,"13 and, more recently, "epidemic neuromasthenia." 14,15 Careful appraisal reveals differences among the various epidemics, but most of these concern minor details. The apparent similarity in the courses of illness, the common nature of most symptoms and signs, the remarkable paucity of abnormal laboratory determinations and the similar epidemiologic characteristics suggest a nosologic, if not etiologic, association among the various outbreaks. Reviewed are the epidemics that to us appear to share these

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basic associations. Included are data from epidemics presently recorded in the literature, reports of several of significance previously overlooked by others and a number of unpublished reports of epidemics obtained from sources as gratefully acknowledged.

- Clinical Syndrome?

a low paralytic and case fatality rate and a relative age selection for adults, particularly females. 17 Gilliam believed that the symptomatology among the hospital personnel was not characteristic and that the very high attack rate among the hospital personnel was without parallel in the history of poliomyelitis. He concluded, however, that since classic poliomyelitis prevailed among a large number of the patients with communicable disease in the hospital, the simpler explanation of the facts was that the atypical disease seen among the hospital staff was the same.

History Attention was focused on this group of illnesses in 1950 by Sigurdsson and his associates,10 who reported from Iceland an epidemic of over 1000 cases of an illness, superficially simulating poliomyelitis but presenting a number of inconsistent features. Among these were the following: a clinical course marked by easy fatigability, disturbances in sensibility and emotional instability persisting for several years 3 ; an inordinately high community attack rate of 6.7 per cent; a morbidity rate twenty times higher among those fifteen to nineteen than those zero to four years of age; and an absence of deaths. Fecal specimens from patients with acute cases injected intracerebrally into rhesus monkeys and by various routes into other laboratory animals, including suckling mice, proved negative. Serums were found negative by complement-fixation t e s t s for the arthropod-borne encephalitides, choriomeningitis, rabies and Q fever, and by hema glutination-inhibition tests for influenza viruses.

Two years later, after studying an outbreak of 32 similar cases among 63 novitiates and candidates at a convent in Fond du Lac, Wisconsin, Armstrong 25 concluded that the disease "is not explainable on the basis of any infection or intoxication with which I am familiar." Described by Houghton and Jones 9 were 7 cases occurring over a four-week period in the fall of 1939 among young nurses at Harefield Sanatorium in England. The illnesses began with an apparent streptococcal pharyngitis, but after seven to fourteen days, a multiplicity of debilitating symptoms developed, evolving into the clinical picture and course similar to that described elsewhere. The authors were unable to identify the illness and suggested tentatively that an unidentified virus might be the cause.

Reports of outbreaks of clinically similar but previously unrecognized illnesses followed in succeeding years from England, Australia, South Africa, Denmark, Germany, Greece and in the United States, from Florida, New York, Maryland, Alaska, Connecticut and Massachusetts (Table 1).

Epidemics of similar illnesses occurring between 1939 andl948 are unknown to us. Since almost two thirds of the recorded outbreaks have occurred during or at the end of the usual poliomyelitis season, and since they present a number of clinical features in common with poliomyelitis, misidentification may have occurred. It would be surprising indeed if no outbreaks had occurred in view of the relative frequency of reports since 1948.

Preceding the report of the outbreak in Iceland were 2 epidemics in the United States and 1 in England, all of which, in retrospect, bear it a striking resemblance. Gilliam12 documents in detail an outbreak in 1934 of 198 cases among personnel at the Los Angeles County General Hospital during which 10 per cent of the 1531 physicians and nurses were afflicted. Occurring concomitantly in Los Angeles and in other areas of California were many cases that were considered typical of paralytic poliomyelitis and a great many others that were not.24 In addition to a number of hitherto unknown clinical manifestations particularly among adults, epidemiologic appraisal of reported cases revealed an unusually high attack rate,

Clinical Characteristics Features in common among cases in these outbreaks are headache and aching pains in the extremities and usually the neck and back, associated with symptoms of paresis in one or more muscle groups. Initial appraisal has suggested to most observers the diagnosis of poliomyelitis. Subsequently the protean

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The Clinical and Scientific Basis of M.E. / CFS

Table 1 APPARENT OUTBREAKS OF EPIDEMIC NEUROMYASTHENIA Location

Year

No. of Cases Reported

United States - Los Angeles, California* United States - Fond du Lac, Wisconsin

193412,16-24

198f 35

England - Harefield Iceland Australia - Adelaide United States - Louisville, Kentucky United States - Northern New York Denmark United States - Lakeland, Florida England - London (Middlesex Hospital) England - Coventry United States - Rockville, Maryland

19399 1948-493'4-10 1949-5111,26 195027 19501 1952 528 195929 195230 195331 195314

7 1090 800 37 19t

United States - Tallahassee, Florida United States - Seward, Alaska Germany - Berlin England - London (Royal Free Hospital) South Africa - Durban United States - Ridgefield, Connecticut United States - Punta Gorda, Florida United States - Pittsfield Williamstown, Massachusetts England - London (Royal Free Hospital) England - Coventry Greece - Athens

195432 195433 195534

450 175 7 300 140t 70 124

193625

10tJ

27t 14 13t 50

19557,8,13,35,36

195537'38 1955-5639 195615'40 195641 19566 195642 195843

7 7 7 27

Nature of Outbreak

Hospital staff; community.* Convent candidates & novitiates Hospital staff Community Community Student nurses Community Community Community Student nurses Hospital staff; community. Student nurses predominantly; community. § Community Community Barracks group Hospital staff; community./ Hospital staff, community. Community Community Community Student nurses Community Hospital staff

* 198 cases at Los Angeles County Hospital documented in detail by Gilliam.12 From other reports16,24 large numbers of similar cases seen elsewhere in California. t Number noted indicates only cases studied. Additional cases known or thought to have occurred. J10 cases reported in detail by Fog.5 An additional 70 cases were reported but only sketchily described by Heidemann.28 § Community cases suspected. / Community cases described by Ramsay and O'Sullivan.12

symptomatology, accompanied by emotional instability and depression, a relative paucity of physical findings (and these often of a bizarre nature) and the lack of significant laboratory findings has led to the consideration of psychoneurosis or mass hysteria as the underlying problem. Increasing numbers of remarkably similar cases sharing also the features of protracted debility and recrudescences over months to years have indicated to each investigator an illness foreign to his previous experience.

are differences in the over-all severity of cases from one outbreak to another and well defined differences in presence or absence of some symptoms and physical findings. For a number of reasons, the differences may be more apparent than real; protean symptomatology makes complete recording of all findings difficult; physical findings are frequently on the borderline of abnormality and may be recorded or disregarded depending on the observer; patients were seen almost at the onset in some outbreaks whereas in others the evaluation was not begun until several weeks of illness had elapsed; and in some cases it is probable that an effort to make the clinical picture

Although the clinical and epidemiologic descriptions indicate a close relation between epidemics, there

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Epidemic Neuromyasthenia

conform to some conventional neurologic process unwittingly biased observations. Because of these factors, construction of a comprehensive table that quantitatively compares the symptoms and physical findings among outbreaks is impossible. For purposes of orientation, however, a summary of the more prominent clinical features is presented in Figure 1. These, with other notable aspects of the illnesses, are discussed below in a narrative synthesis that seeks to embody the impressions of other writers and our own about the natural history of these illnesses.

- Clinical Syndrome?

Malaise and fatigability are particularly pronounced and persist long into convalescence. Headache and extremity, neck and back pain are usually present in about that order of frequency. The headache is commonly suboccipital or generalized although other variants are described. It is moderate to very severe in intensity, and usually nonthrobbing in character. The extremity pain is aching, diffuse, poorly localized, and, in general, more frequent in the lower limbs, although in some outbreaks it appears to be more common around the shoulder girdle. Pain is usually present in more than one limb, not uncommonly is asymmetrical and may shift in location. The neck and back pain is of the same general character as that in the extremities. Nuchal pain and a sense of tightness in the nape of the neck or back on extreme forward flexion of the head are usual; nuchal rigidity is not common. Abdominal pain, initially mistaken for peritoneal irritation, has been found, on careful examination, to be related to the abdominal musculature. Pleuritic-type chest pain, occasionally associated with a friction rub, has been related by some observers not to pleural irritation but to lesions in the intercostal or diaphragmatic musculature.

Within each outbreak, there is a spectrum in the severity of illness. Apparently milder cases present some combination of the prodromal symptoms of fatigue, headache, diffuse, aching muscular pain, upper respiratory infection, diarrhea, tension or lowgrade fever, most of the symptoms subsiding within a few days or weeks. Because of the uncertainties of diagnosis of such cases, authors, when compiling clinical and epidemiologic statistics, have commonly disregarded these illnesses. The clinical picture discussed relates then principally to the moderate or severe cases.

Uniformly present in all outbreaks, although not in all cases, is paresis, which usually begins with the acute illness but may be delayed for a period of days to several weeks. Manifestations of paresis seem to be of two general types. Most common initially is a diffuse weakness of one or more limbs usually accompanied by aching pain and a sense of heaviness in the affected part. Some have commented on this form of paresis as appearing to be more a disinclination than an inability on the part of the patient to contract the muscles. Deep tendon reflexes in the affected extremity range from being moderately hyperactive to depressed but are rarely absent or unilaterally unequal. Weakness of a similar type in the shoulder or hip girdle, back, neck, and abdominal musculature has been observed.

The onset of illness ranges from a fairly abrupt to a more usual, insidious evolvement of the prodromal symptoms already noted. This phase extends over a period of a few days to several weeks and may be difficult to date precisely. The symptoms may be intermittently or constantly present. A respiratory infection, often reported at the outset, may be accompanied by mild cough or coryza, t e n d e r lymphadenopathy most evident in the posterior cervical chain and, rarely, conjunctival injection or pneumonitis. Diarrhea, usually mild and of fairly brief duration, is frequently alluded to, particularly in the early course of the illness. After a period of days to three or four weeks, there is often an abrupt exacerbation of symptoms accompanied by paresis, paresthesias, changes in emotional status and mentation, and dizziness, nausea or blurring of vision, with, in some patients, even vertigo, projectile vomiting and diplopia. This acute phase persists for one to several weeks and is accompanied by numerous symptoms, many of which are difficult to evaluate in the presence of tension, depression, anxiety and alterations in mentation.

The second form of paresis involves single muscles or muscle groups, more commonly in the hand, arm, lower leg, hip or shoulder girdle, the facial muscles or the external rectus of the eye. Foot drop in a few patients has been mentioned in several epidemics. Although sometimes evident during the early acute phase, weakness in these muscles usually becomes manifest with resolution of the more extensive pare-

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The Clinical and Scientific Basis of M.E. / CFS

sis noted above and appears, in a few cases, to constitute permanent residual damage. Contraction of paretic muscles is often jerky and associated with a coarse tremor. Fibrillary twitching and painful myoclonic spasms of involved large-muscle groups are frequently described. Fasciculations are rarely present. Atrophy of the involved muscles is exceptional despite persistence of measurable paresis. Involved muscles are commonly tender, either diffusely or in focal, discrete areas. Focal areas of tenderness are stable in location, and relieved sometimes by procaine injection but without evident improvement in strength of contraction of the involved muscle. More diffuse tenderness has been associated with muscles described as edematous, doughy, or rubbery in consistence. Present from early in the acute phase and often corresponding in distribution to the involved musculature are paresthesias, including numbness and tingling, hypesthesia or hyperesthesia, and, occasionally, anesthesia. Severe hyperesthesia requiring the use of bed cradles has been observed. Characteristically, the paresthesias are shifting in distribution over a period of hours or days and do not usually correspond to a peripheral nerve or root distribution. Cutaneous sensory examination discloses a similar bizarre shifting pattern of areas of marked impairment of touch, pain and temperature or hyperesthesia to touch. Less commonly, cutaneous sensory changes correspond to peripheral nerve or root zones and may be associated with tenderness over nerve trunks, especially the ulnar or sciatic. Anesthesia is rarely observed. Loss of position and vibration sense usually in the lower extremities and corresponding to the distribution of muscular pain and paresis has been seen in a number of outbreaks. The Babinski sign was demonstrated in a very few patients in two of the outbreaks. Depression, tension and emotional instability have been impressive and among the most incapacitating and persistent symptoms. Repeated episodes ofcrying without provocation, insomnia, terrifying dreams and difficulty in concentration are probably secondary phenomena. Persons tending to be emotionally labile before illness have appeared to be most severely afflicted.

Mild confusion, impaired memory for recent events, alterations in personality structure, euphoric behavior and tendencies to transpose and "stumble over" words have frequently been observed during the more severe acute phase and during recrudescences, although sometimes persisting into convalescence. Common also as an initial symptom in the acute phase is "dizziness", which varies in severity from a commonly observed postural giddiness to actual vertigo among fewer cases. Nystagmus on lateral or upward gaze is found accompanying some of the severe illnesses, b u t , as with numerous other signs, seems to appear and disappear over the course of hours to several days. Persistent vomiting, sometimes projectile in character, commonly accompanies the vertigo. Vertigo rarely persists for more than a few days, but a postural "dizziness" may persist for many weeks or months. Other symptoms much less common but probably related to eighth-cranial-nerve involvement include tinnitus, hyperacusis, and, uncommonly, transient hearing impairment. Possible involvement of other cranial nerves is suggested by occasional transient facial pareses and the more regularly noted symptoms of blurring of vision or diplopia. These visual symptoms have often been associated with eye pain aggravated by movement, less commonly with photophobia. Most observers have been unable to demonstrate associated ocularmuscle weakness, although paresis of the external rectus with evident strabismus has been seen in some outbreaks. Symptoms of functional impairment of swallowing are not uncommon, but are only occasionally associated with palatal paralysis or regurgitation. Whether this symptom is related to cranial-nerve involvement, some lesion in the deglutitional muscles or emotional factors is not clear. During several outbreaks a few patients were placed in respirators, never for more than a few days. Clear documentation of respiratory embarrassment because of diaphragmatic or bulbar involvement, however, is not reported. Gastrointestinal disturbances, particularly nausea, are common in the acute phase. These may or may not be related to vertigo. Diarrhea is usual early in the course, and constipation later.

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D. Henderson, MD, MPH, A. Shelokov, MD

Epidemic Neuromyasthenia

- Clinical Syndrome?

Figure 1 S e l e c t e d S y m p t o m s a n d S i g n s in 23 Outbreaks of E p i d e m i c N e u r o m y a s t h e n i a

BACK PAIN A B D O M I N A L PAIN CHEST PAIN

MUSCLE CRAMPS or SPASM PARESTHESIAS

DEPRESSION,TENSION IMPAIRED MENTATION

DIZZINESS or VERTIGO FACIAL PARESIS DIPLOPIA or BLURRING OF VISION OCULAR PAIN PHOTOPHOBIA

NAUSEA, VOMITING DIARRHEA CONSTIPATION

URINARY RETENTION MENSTRUAL IRREGULARITIES

NUCHAL RIGIDITY - M I L D

CUTANEOUS SENSORY CHANGES MUSCLE TENDERNESS

PROTRACTED D E B I L I T Y RECRUDESCENCES H I OVER 5 0 % OF C A S E S 2 5 % IC 5 0 % OF C A S E S UNDER 2 5 % OF CASES [ § ] FREQUENCY NOT STATED

165

The Clinical and Scientific Basis of M.E. / CFS

A mild hepatomegaly without splenomegaly in somewhat less than a tenth of the patients was found in the Royal Free Hospital outbreak, but only 1 patient had evidence of jaundice.

Menstrual disturbances, including amenorrhea, menorrhagia and disturbances of cycle, have been repeatedly noted. Throughout most of the illness, the temperature does not exceed 100°F. Early in the course a temperature of 100 to 103°F. occurs in a fourth to a half of the patients, but rarely persists for more than two or three days. Among three groups of carefully studied patients, an instability of body temperature was noted consisting of a variation of two or three degrees over the course of a day but within the normal range. As symptoms subsided, a more normal diurnal temperature fluctuation was assumed.

Present inconstantly and in small numbers from epidemic to epidemic were symptoms of urinary retention without dysuria but of sufficient severity to require catheterization and occasional tidal drainage. These symptoms subsided within five to six days. Symptoms suggesting angiospasm have been particularly prominent in several outbreaks and rare or unremarkable in others. Hyperhidrosis, marked pallor and flushing or occasionally cyanosis of the hands or feet, accompanied by numbness and tingling over the affected area and sometimes edema, has been noted in several epidemics. These were so impressive in the Danish outbreak as to suggest primary involvement of the autonomic nervous system. 5

Course of Illness After an acute phase lasting a few days to several weeks, there is a slow resolution of symptoms punc-

Table 2

R e s u l t s of Cerebrospinal-Fluid E x a m i n a t i o n - 17 Outbreaks Location of Outbreak

No. of Persons Examined

No. of No. of Persons Cells with Pleocytosis* per cu. mm.

Day of Illness

California12 Wisconsin25 England9 Iceland3410

59 2 1 8

3 0 0 5

12,50,66

0,2,4

18

50,59,75,80

59 3 11 5 6 9 25 101 7 18 5 7 4

5 0 2 0 0 0 0 7 0 0 0 0 0

3,6,4 3,10 7

4

Australia11 Kentucky27 New York1 Denmark5 London, England30 Coventry, England31 Maryland14 Tallahassee, Florida32 Germany34 London, England8 Punta Gorda, Florida15 Coventry, England42 Greece43

10,18,35 50,80 44-88

2

45,60

27,44

4,12

?

3

48,58,61

"Up to 15"

1

85

3 1

50,60,80 66

*>6 cells/cu.mm.

tTrace of globulin

§+test for globulin.

166

No. of Protein Patients Concentration with Elevated Protein mg./100ml. (I2t;6.§)

D. Henderson, MD, MPH, A. Shelokov, MD

Epidemic Neuromyasthenia

tuated by exacerbations during which all the symptoms initially present may recur in their original, severe form and persist for days to weeks. Exacerbations commonly coincide with increased exertion, with cold or damp weather, in the premenstrual period, with trauma or with upper respiratory infection. The most persistent and incapacitating symptoms are fatigability and malaise, headache, neck, back and extremity pain, paresis, depression, irrit a b i l i t y , i m p a i r m e n t of c o n c e n t r a t i o n a n d paresthesias.

- Clinical Syndrome?

patients had returned to work, but only 13 per cent considered themselves free of symptoms. 3 Laboratory

The protracted debility engendered by the illness is illustrated by studies from several epidemics. Among 198 cases in the Los Angeles County Hospital outbreak, the average time lost from work was fourteen weeks: 24 per cent of the personnel lost more than twenty weeks.12 Inpatient hospital care among 300 cases from the Royal Free Hospital outbreak extended for periods in excess of a month in 43 per cent. 8

White-cell counts have been reported as normal in most outbreaks, although ranging in a few patients as high as 14,000. In one series an absolute neutropenia was noted, 4 of 7 patients having total counts below 3000.42 A relative lymphocytosis (counts of 50 to 60 per cent) during the acute illness was observed in the Maryland outbreak 14 ; a low normal neutrophil count and a high normal lymphocyte count were found among half of 138 studied at the Royal Free Hospital.8 In this outbreak abnormal adult lymphocytes, with cytoplasmic vacuolation, and plasma-cell-like forms, with coarsely reticulated nuclei and deeply basophilic cytoplasm, were frequently noted. The cells were not, however, considered to be those seen in infectious mononucleosis.

In the sixth month after onset, studies of 21 patients from the Punta Gorda, Florida epidemic revealed that 5 of the group were confined to bed for one or more days, and definite restriction of activity because of residual symptoms represented 43 per cent of patient days in that month.16

Erythrocyte sedimentation rates, when recorded, were rarely elevated. The exceptions were among patients from the Alaska outbreak, two thirds of whom were said to have had higher than normal values 33 and among nurses in thel939 English outbreak, in which slight elevations were recorded.9

A few long-term follow-up studies have been carried out that suggest definite gradual improvement extending over several years' time. Exacerbations or relapses of varying severity, although mimicking the original acute phase of illness, became increasingly milder and of shorter duration.

With few exceptions, cerebrospinal-fluid examinations have shown slight or no abnormality. In Table 2 are the compiled results from the reports in which the number of lumbar punctures performed is stated. A few cases in each of five outbreaks have shown pleocytosis between the time of onset and the twelfth day. Increased cerebrospinal-fluid protein was found in about the same number although not always in the same patients. Glucose and chloride determinations were normal. Colloidal-benzoin and colloidal-gold determinations in the Los Angeles outbreak showed a mid-zonal elevation in 18 of 59 cases.12 Since these epidemics have tended to occur during or at the end of the enterovirus season and have sometimes been coincident with epidemics of poliomyelitis, it is conceivable that those with cerebrospinal fluid abnormalities in fact represent cases of poliomyelitis, Coxsackie virus or ECHO meningitis. Conversely, because it is uncommon to see patients early in the course of the illness, transient cerebrospinal fluid changes could be missed in the majority of cases. Interpretation of these data is thus difficult.

Re-examination of 8 patients in New York State fifteen months after onset showed none to be completely without symptoms although the symptoms were mild.1 Muscle pain, easy fatigability and more labile emotional habitus were the principal complaints. An eighteen-month re-examination of patients from the Punta Gorda outbreak revealed all to be much improved or essentially well.40 Residual symptoms similar to those reported by the New York State patients were noted by some but were so equivocal as to be difficult to ascribe to the original illness. A six-year follow-up study of 39 cases from the Icelandic epidemic, one of apparently greater initial severity than that in Punta Gorda, revealed that all

167

The Clinical and Scientific Basis of M.E. / CFS

Liver-function studies performed in significant numbers in the Maryland 14 and Royal Free Hospital 8 outbreaks revealed but 1 to be notably abnormal in a patient from the latter outbreak who became clinically jaundiced. Serial twenty-four urinary creatine determinations performed on 10 adult patients from the New York State outbreak revealed initial levels in excess of 100 mg. daily among 9 of the 10, 6 of these returning to normal levels within four to seven weeks. Three patients showed little change during this period; 1 showed an increase from about 230 mg. to 300 mg. perlOOml. at four weeks and to 400mg. per 100ml. at seven weeks.1 Estimations of the serum cholinesterase in 7 patients and cerebrospinal-fluid cholinesterase in 1 patient were normal. Electrophoretic patterns showed no abnormality in these serums. 8 Heterophil-antibody determinations in several outbreaks revealed no significant elevation except for 1 of 7 patients in the Coventry outbreak 42 and 4 of 121 in the Royal Free Hospital outbreak. 8 Repeat determinations in the latter outbreak revealed, however no change in titers - findings interpreted as indicative only of probable past infection.

normalities of a nonspecific nature were seen in some, but all except 1 were interpreted as being within normal limits. One severely afflicted patient from the epidemic in Greece had a tracing showing paroxysmal or continuous slow-wave activity at high potentials predominating over the frontal leads and sometimes extending simultaneously to all leads.43 Electrocardiograms obtained on patients in the Maryland 14 and Punta Gorda, Florida,15 outbreaks were interpreted as normal. Three of 42 in the Royal Free Hospital epidemic showed abnormalities consisting of abnormal T waves in two or more leads and a prolongation of the QT interval in one. Two reverted to normal records. One patient with extensive neurologic abnormalities initially showed isoelectric T waves in Lead 1 and inverted T waves in Lead V3 that, although improved over an eighteen-month period, were still abnormal at that time. 8 Electromyographic studies have given conflicting results. Two Danish cases studied four months after onset showed neurogenic paresis of radicular or peripheral origin in isolated, involved muscle groups. 5 Observations in 20 cases from the Durban, South Africa outbreak showed no abnormalities. 38 Among the 1953 Coventry cases, 3 during the fourth to eighth week of illness gave inconclusive evidence of partial denervation of muscle groups.31 The most consistent evidence of dysfunction was reported among 28 cases studied from the Royal Free Hospital epidemic. Examinations carried out one or two months after onset showed largely unremarkable nervemuscle excitability and nerve-conduction measurements, but electromyography, in the early stages, indicated some irregularly occurring fasciculation potentials of nor- mal motor-unit potential form. With the onset of paresis, a severe reduction in the number of motor-unit potentials on volitional movement of the affected muscles was apparent, of long duration and polyphasic in some cases. In the less severely involved and, particularly during recovery, the motor- unit potentials were grouped resulting in a tremulous contraction of 5-10 per second that rapidly fatigued. This combination of findings was thought to suggest a myelopathic lesion indicating involvement of the motor unit at the level of the spinal cord. The absence of lower-motor-neuron degeneration in the face of persistence of these lesions could not be explained. 8 Similar myographic findings were reported among 7 patients in the 1956 Coventry outbreak, 42 and 4 of 6 in the 1958 outbreak in Greece.43

Complement-fixation, neutralization and agglutination studies have been wholly unrevealing. Tests for antibodies for the following were reported negative in the various outbreaks: poliomyelitis11415'26'29,31" 33 ; lymphocytic choriomeningitis 10,15,26,29-32 ; 8,26,31 encephalomyocarditis ; Eastern equine encephaio,is,29,32. Western equine encephalitis10,15,29,32 St. litis 10,15,29,32 Louis encephalitis ; Japanese B encephalitis 10 ; Port Augusta encephalitis 26 ; influenza8,10,29'33; Q fever8,10,29;leptospirosis8'9,15'26,29"31'34; trichinosis 9,14 ; toxoplasmosis8,15; adenovirus 8 ; herpes simplex 8 ; psittacosis lymphogranuloma venerem8,32; brucellosis8,9,25; tularemia 25 ; rabies 10 ; typhoid 9,25 ; paratyphoid25; louping ill8; Coxsackie A and B viruses 14 ; ECHO virus, Type 6 14 ; and Salmonella u typhimurium. A very few serums with elevated complement-fixation titers for mumps have been observed, but the majority have been negative.815'26'29" 32 Tests for cold agglutinins 34 and Wassermann reactions have been negative. 8914 Toxicologic studies carried out in three outbreaks were unrevealing.1415,38 Electroencephalography was performed on 19 patients from five outbreaks.5,13,15,42,43 Borderline ab168

D. Henderson, MD, MPH, A. Shelokov, MD

Epidemic Neuromyasthenia

- Clinical

Syndrome?

This article is reprinted with the kind permission of The New England Journal of Medicine, Apr. 16, 1959, Vol. 260, No. 16, pages 814-818.

Epidemic Neuromyasthenia - Clinical Syndrome? (Concluded)* Donald A. Henderson, M.D.,t and Alexis Shelokov, M.D.tt, Atlanta, Georgia

Viral and Bacteriological Studies sive days. The monkeys inoculated with material from 2 of the 5 gave evidence of illness. One of the 4 had a lowered temperature (95°F.) on the eighth day, and was sluggish. No definite abnormalities were found at post-mortem examination. The remaining monkeys showed sluggishness and abnormal temperatures between the sixteenth and eighteenth days.

The nature of these illnesses has suggested to most a viral etiology, but, despite intensive efforts to implicate such an agent, results have been meagre. Cerebrospinal fluid, feces, throat washings, acutephase serums and blood clots have been inoculated by a variety of routes into many different laboratory animals and various tissue-culture systems. Despite the frequent use of blind passages, attempts to infect the following animals have thus far proved futile: sucklingiAio.14,15,26,29-31,34 and adult mices, 14,26,29,31; guinea pigs with» and without cortisone10,26,31; ham2 31 sters8,io,i4,26; rabbits ^ ; rats with and without corti1 sone ®; ferrets^; and cynomologus and rhesus monkeys withs.27 and without cortisone.1,8,10,14,27,30,31

One showed wasting, particularly of the hind limbs and tremulousness and was killed on the eighteenth day. Of the remaining 2, 1 died on the twentyseventh day, and the other recovered by the twentysixth day and remained well. At post-mortem examination, the only gross abnormality was the occurrence of minute red spots along the course of the sciatic nerve in the last 2 monkeys. Microscopical sections showed localized infiltrations of inflammatory cells and exudation of red cells in the sciatic nerves. In the nerve roots close to their point of exit from the spinal canal there was pronounced infiltration with lymphocytes and mononuclear cells. In some of the nerve fibers axon swelling and vacuoles in the myelin sheaths were found. No abnormalities in the brain or spinal cord were detected. The heart muscle of the monkey that died showed severe myocarditis, with widespread infiltration of lymphocytes and mononuclear cells. Passage of a pool of brain, spinal cord, nerve, skeletal and heart muscle from these animals led to no illness in the monkeys inoculated. Repeat inoculation with the original material caused similar symptoms in 2 of 4 monkeys, but passage was again unsuccessful.26

Embryonated hens' eggs of various ages injected into the chorioallantoic membrane, allantoic sack, yolk sack a n d a m n i o n h a v e yielded n e g a t i v e results.8,14,26,27,29 Tissue-culture systems employed with similarly negative results include the following: monkey testicleit.30,31; monkey kidneys,14,15,30,31; HeLa cells8.i4.i5; human-embryo skinsi, brains, livers,15 and spleens; human-infant kidneys; human fibroblast"; and human chorioamnion.s.w Positive findings of possible significance are reported by Pellew and M i l e s 2 6 from specimens obtained from Australian patients. In their studies throat washings, feces and cerebrospinal fluid from each of 5 patients with acute cases were inoculated in combinations into paired young r h e s u s monkeys intranasally, and subcutaneously on three succes-

* From the Communicable Disease Center and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Public Health Service, United States Department of Health, Education, and Welfare. fEpidemiologist, Epidemiology Branch, Communicable Disease Center, assigned to the Mary Imogene Bassett Hospital, Cooperstown, New York. ffChief, Laboratory of Tropical Virology, National Institute ofAllergy and Infectious Diseases; director, Middle America Unit, Canal Zone.

169

Research

The Clinical and Scientific Basis of M.E. / CFS

Confirmation of these observations has not been forthcoming from other outbreaks.

Isolates of the Bethesda-Ballerup bacilli were obtained only from 12 nurses with the illness and an asymptomatic kitchen helper. One type (antigenic formula, la, lb, lc: 8, 9) was found in the stools of 7 nurses; the second type (formula, 2a, lb: [21] 25,26) was detected in the stools of 5 nurses; both types were isolated from a kitchen helper. Neither of the strains appeared in large numbers in the stools, and neither was isolated from more than two stools of the series obtained from any person.

Because of at least superficial resemblance of these illnesses to poliomyelitis, efforts to isolate a possible etiologic agent have been focused on viral studies. Thorough bacteriologic studies have been reported from the Maryland outbreak only.w Results obtained suggest at least a coincidental relation between cases of the disease, isolation from the stool of organisms of the Bethesda-Ballerup paracolon group and rises in serologic titer.

H and O agglutinins for the freshly isolated strains were found in titers of 1:40 or greater in the serums of 15 of the 26 paretic patients, in 7 of the 24 with "minor illness," in 3 of 27 nurses without illness and in the kitchen helper. Among 11 of the 22 ill nurses showing the presence of agglutinins, there was a rise and fall of antibody titers; in 5, there was a demonstrable rise, and in 3, a fall in the antibody levels (in the remaining 3, single specimens only were available).

Table 3 Age-Specific Attack Rates in Two Community-Wide Outbreaks.

Rate in Akureyri, Iceland Male Female Patients Patients Age yr-

%

%

Rate in Punta Gorda, Florida Male Female Patients Patients (White) (White) %

%

0-9

1.4

2.0

10-19

11.7

13.2

10.9

10.7

20-49

4.8

11.1

9.1

11.5

50 & over Average

2.1 5.1

2.9 8.3

2.0 4.7

8.3 8.3

-

Serial serum specimens from 9 patients from the Punta Gorda, Florida, epidemic tested against the two Bethesda-Ballerup strains from the Maryland outbreak showed 1 with falling 0 agglutinins and a 1:160 H agglutination titer that was preceded and succeeded by negative titers in other specimens, is Epidemiology

-

The epidemiologic features of these illnesses have been uniquely distinctive, and because of the absence of specific pathognomonic findings in the individual case, these features must be regarded as integral to the diagnosis. They include, particularly, the concentration of cases among young and middle-aged adults, the increased frequency and severity of cases among females, the virtual absence of illness among preadolescents and the marked susceptibility of nursing personnel and physicians.

A total of 218 fresh fecal specimens from 113 persons, both ill and well, were painstakingly examined. Specimens were placed in enrichment mediums and then grown aerobically and anaerobically on a variety of selective and nonselective mediums. Obtained were 13 isolates of 2 strains of Bethesda-Ballerup paracolon organisms and 2 isolates ofS. typhimurium. Serial serum samples from persons from whom the latter organisms were isolated showed no antigen agglutination with these organisms, thus discounting their pathogenic significance.

Two epidemics in communities of similar size (Table 3) in which detailed data regarding age-specific attack rates were obtained include the outbreaks in Akureyri, Iceland") (population, 6887) and Punta Gorda, Floridais (population, 2020). The similarity in attack rates between these two outbreaks is notable. Most heavily afflicted were those between ten and forty-nine years of age. In the Akureyri epi-

170

D. Henderson, MD, MPH, A. Shelokov, MD

Epidemic Neuromyasthenia

demic, those aged fifteen to nineteen seemed particularly susceptible; in Punta Gorda, it was the group aged thirty to thirty-five. Although the rates indicate a predominance of female to male cases in the ratio of more than 1.5:1, the severity of cases among females in both epidemics was considerably greater. An absence or virtual absence of cases in persons under the age of ten is surprising, and despite intensive search for some minor illness variant among this group in Punta Gorda, none was found. Equally interesting is the decrease in frequency of cases beyond the age of fifty. In the Tallahassee outbreak, a similar age distribution of cases was noted, those age twenty-five to forty-four being most susceptible.sz All the other outbreaks have involved primarily young and middle-aged adults, principally females.

- Clinical Syndrome?

The differences noted between the larger and smaller community outbreaks suggest, and other studies support, the necessity of close contact for spread of the disease. With the exception of the outbreaks in Iceland 10 adjacent communities have not become involved, and a spread of illness to surrounding rural areas has been quite uncommon for all outbreaks, including those in Iceland. Outbreaks among groups in intimate contact (Table 5), particularly those living together in dormitories, have produced attack rates considerably in excess of those seen among comparable age groups in community epidemics. A tendency for aggregation of cases by households has been observed in several outbreaks. 10,15,18,32

Table 5 Suggestive that the disease may be one with which communities have had no previous experience or, at least, to which they have built up no immunity is the remarkable similarity in attack rates in different community epidemics (Table 4). The rates in the Seward, Akureyri and Punta Gorda outbreaks are essentially identical. That in Tallahassee is lower but may be the result of a less homogeneous spread of illness throughout this much larger community. In Table 4, the rates noted for Punta Gorda and Tallahassee are for the white population since Negro rates were somewhat lower in the former and over sixtyfold lower in the latter epidemic despite intensive search in both for cases among Negroes.

Attack Rates among Groups in Close Association. Group

Los Angeles student nursesis

Table 4

Population

Outbreak 10

Number

Percentage

111

111

Akureyri, Iceland

6,887

465

6.7

Seward, Alaska^

3,000

175

5.8

Punta Gorda, Florida^

1,604*

104*

6.5

Tallahassee, Florida32

23,708*

346*

1.5

Number Percentage 111 111

401

65

16

Wisconsin convent

65

32

49

Akureyri high-school residents")

70

34

49

Kentucky student nurses27

161

37

22

Maryland student nurses14:

Attack Rates in Community Epidemics. Location of

Population

* White population only.

171

Paretic cases

66

19

29

All cases

66

36

55

Royal Free Nurses Preliminary Training School7 - 1955 40

8

20

Royal Free Nurses Preliminary Training School6 - 1956 27

5

19

The Clinical and Scientific Basis of M.E. / CFS

contact is obtained by a comparison of rates between personnel resident at the hospital contrasted to personnel not living on the hospital grounds. Among those resident at the Royal Free Hospital,? males experienced an attack rate of 20 per cent, and females one of 19 per cent; among nonresidents, males had a rate of 2.5 per cent, and females one of 6.1 per cent. Among residents at the Los Angeles County Hospital,12 9.4 per cent of physicians and 19 per cent of the nurses were afflicted whereas among nonresidents, only 3.1 per cent of physicians and 5.8 per cent of nurses were ill.

Disproportionate among the total of outbreaks is the number among hospital groups. Tens,7,9,12,14,27,30,31,38,43 of twenty-three epidemics studied dealt principally with cases among hospital personnel, although it is known or believed that cases in the surrounding community were occurring concomitantly in six of these.?,9,12,14,si,38 Two outbreaks in which studies were principally of community cases, disclosed rates four or five times greater among medical and allied p e r s o n n e l ^ , 3 2 than among similar age groups in the general community. Among 275 employees at the Tallahassee Memorial Hospital, 16 cases were reported — an attack rate of 5.8 per cent as contrasted to 1.5 per cent for the white population of Tallahassee fifteen years of age or older. In Punta Gorda, medical and allied personnel had an attack rate of 42 per cent as compared to one of 8.6 per cent for white persons in the community aged ten to sixty-nine. That degree of exposure was probably the principal cause of these differences is further suggested by the virtual absence of cases at the university in Tallahassee, where a large student population of a presumably highly susceptible age resided.

Although transmission of the disease to hospital inpatients has been noted,7,12 the frequency with which this occurs is not known. The relative restriction of outbreaks by communities or groups in close association has suggested possible common-source exposure to water, foods, or some toxic agent in the environment. Efforts to identify such exposure have been made in several studies, but without success.10,14,15,32 Additional evidence weighing against a common exposure, at least in community outbreaks, is the very high attack rate accompanied by the uniformly consistent selection of cases by age and sex and the noted predominance of cases among medical and allied personnel. It is difficult to postulate a chemical agent that would produce such an epidemiologic pattern.

Among those afflicted in major hospital epidemics, the nursing staff and physicians have shown particular susceptibility as contrasted with other hospital personnel. In the Los Angeles County Hospital epidemici2 three groups within the hospital were delineated: occupations having intimate patient contact; occupations having less regular patient contact; and occupations rarely involving patient contact. Rates for these groups were, respectively, 8.2 per cent (169 cases among 2072 employees), 1.7 per cent (16 cases among 951) and 0.8 per cent (11 cases among 1291). These differences could not be accounted for by age differences between groups. In the Royal Free Hospital? outbreak, the rates among nurses, resident domestics, doctors and inpatients and ancillary medical, technical and social workers ranged from 13 to 18.6 per cent whereas among 2060 other employees, the rate was 2.2 per cent.

The incubation time has been found to be between five and eight days when precise single dates of exposure could be determined.7,i°,12,i4,3i Indirect determinations based on patterns of spread of illness and cases with continuing exposure suggest that the incubation period may be longer in some cases, but definite evidence of this is lacking. Geography and Season The epidemics are scattered in both latitude and longitude although concentrations are to be noted in the London-Coventry area of England and in Florida. This may reflect better recognition and reporting in these areas or may indicate a tendency for illness to recur in areas in which it is once established. With four exceptions, reported epidemics have been located on or very near salt water. Specific inquiry, however, during two epidemics regarding possibly related factors has been unrevealing. 15,32

Analysis of cases among nurses by place of work in the Los Angeles epidemici2 demonstrated that cases occurred considerably earlier and four times more frequently among those working on the communicable-disease wards and in the main admitting office than among those working elsewhere in the hospital. Further demonstration of the importance of intimate

172

Epidemic Neuromyasthenia

D. Henderson, MD, MPH, A. Shelokov, MD

Over half the epidemics have occurred during the summer and particularly during the fall months, often succeeding or overlapping the latter portion of the poliomyelitis season in the particular area. This seasonal predilection accounts in part for the initial confusion in diagnosis between cases of these illnesses and poliomyelitis. The seasonal occurrence is not constant, however. Other epidemics are described that began in the fall and extended through the winter,17 or appeared in late winter and continued through the spring,^ in addition to other variants.

- Clinical Syndrome?

Etiologically, the Australian studies 26 indicate the possibility of a viral agent, and the Maryland studiesi4 implicate a bacterial agent of the BethesdaBallerup paracolon group possibly as a toxin-producing pathogen, or perhaps as a fellow traveller with an unknown virus. These represent, as yet, but interesting leads. In summary, despite intensive study by competent investigators in a number of different areas, the etiology and pathophysiology of these illnesses remains almost a total mystery.

The Process, the Name and the Future Crucial to a definitive classification and understanding of the group of diseases reviewed is a knowledge of the pathophysiology involved. Of this, essentially nothing is known. Deaths that occurred among definite cases during the acute phase or could be directly attributable to the illness have nowhere been reported. Two fatal cases occurring within a year of onset of illness have been noted, both of which occurred months after the initial episode and from unrelated causes. Post-mortem findings were wholly unrevealing.s Material for histologic study has almost been nil. The only positive finding reported is a nonspecific reactive hyperplasia found in a biopsied lymph node two weeks after the onset of illness in 1 case. 8 The symptoms indicate a multiorgan system involvement, but which systems are primarily and which secondarily involved is not clear. There is agreement among investigators that altered functions in either the central or the peripheral nervous system or both must be present to account for many of the symptoms and findings, but confirmation through histologic study is lacking. To define the anatomic sites of lesions on the basis of symptomatology and physical findings is not as yet possible. A multifocal, changing process is postulated. If it involves the central nervous system, it does so in such a way that it rarely, or but briefly, alters the cerebrospinal fluid. Postulates based on these criteria have little precedent from other communicable diseases. A primary myalgic process has been considered likely by most investigators, but no histologic material to confirm this is available and electromyography to date has been confusing.

As a group, however, the illnesses share a great number of common features and, both clinically and epidemiologically, present a unique and distinctive appearance. A nosologic relation is strongly suggested. For convenience of reference and identification a single descriptive name would be useful. Originally proposed by White and Burtch,i the name "Iceland disease" has been most commonly used in this country. Since this designation, however, has not been used in other countries, and since Sigurdsson, who originally focused attention on these illnesses through his studies in Iceland, objects to it, it seems wise to discard it. Sigurdsson in a counterproposal has suggested "Akureyri disease'^ named for the medical district in which the studies of his group were concentrated. To date, this has been ignored. In 1956 an editorial in the Lancet introduced the term "benign myalgic encephalomyelitis." 2 To those who have observed cases, the illnesses are anything but benign, except in terms of mortality. Encephalomyelitis, additionally, implies knowledge of a centralnervous-system inflammatory process of which there is presently no proof. English studies published since this proposal, with one exception,*2 have ignored this name. In reporting the Danish outbreak, Fog,5 unaware of similar outbreaks, designated the illness seen in Denmark as "epidemic vegetative neuritis" because of what appeared to him to be major, although not exclusive, involvement of the autonomic nervous system. Objection must be registered to use of this term as well as to that in a recent English report, "acute infective encephalomyelitis,'^ since both again imply knowledge of an inflammatory process that has not as yet been demonstrated. The latter term, in addition, properly includes essentially all the infectious encephalomyelitides, the etiology of many of which is well established.

173

The Clinical and Scientific Basis of M.E. / CFS

study of biopsy material, particularly involved muscle, and by autopsy of patients dying early in the disease. Indicated also are intensive bacteriologic, virologic and serologic studies of specimens obtained early in the prodromal phase, especially among those complaining of respiratory illness in whom the fullblown picture of the disease subsequently develops. Previous studies have too often been obliged to deal with specimens obtained many days to weeks after the insidious onset of the prodromal phase. In a community outbreak intensive study of hospital personnel, particularly nurses and student nurses, should be especially fruitful in yielding cases in greater proportionate numbers than among other groups in the population.

To date, there is no agreement on a name, almost every epidemic receiving a different designation. For purposes of referencing and indexing, this presents a chaotic problem. Until an etiologic agent or agents are identified or until the underlying pathophysiologic processes are defined, we recommend use of the name, "epidemic neuromyasthenia."",^ This, we believe, meets previous objections and is specifically distinctive within the limits of current knowledge. Use of the word "epidemic" emphasizes the need for epidemiologic as well as clinical appraisal of cases. Diagnosis of a single, sporadic case of illness marked by a protean symptomatology within pathognomonic physical or laboratory findings and presenting many of the features of psychoneurotic illness is fraught with difficulty. Adequately characterizing the most prominent symptoms of the illnesses without reference to the underlying pathologic processes are the terms "neurasthenia" and "myasthenia" or, when linked, "neuromyasthenia."

Although, from current reports, these illnesses do not appear numerically important on a national scale, the long-term morbidity among those who are ill and the very large percentage involved in a single out break indicate a need for intensive, comprehensive investigation and surveillance of outbreaks as they occur.

In the light of the frequency of reports in the past few years, it is probable that further epidemics will occur. In the study of these, particular emphasis must be placed on elucidating the pathophysiologic processes involved, indirectly by electroencephalography, psychometric t e s t i n g , p e r s o n a l i t y e v a l u a t i o n , electromyography and careful serial physical examination, and more directly through the histologic

We are indebted to Dr. E. Charles Kunkle, professor of neurology, Duke University School of Medicine, for many helpful suggestions in the appraisal and synthesis of material.

References 1. White, D.N., and Burtch, R.B. Iceland disease: new infection simulating acute anterior poliomyelitis. Neurology 4:506-516, 1954.

7. Crowley, N., Nelson, M., and Stovin, S. Epidemiological aspects of outbreak of encephalomyelitis at Royal Free Hospital, London, in summer of 1955. J. Hyg. 55:102-122, 1957.

2. Leading article. New clinical entity? Lancet 1:789,1956.

8. Outbreak of encephalomyelitis in Royal Free Hospital Group, London, in 1955. Brit M.J. 2:895-904, 1957.

3. Sigurdsson, B., and Gudmundsson, K.R. Clinical findings six years after outbreak ofAkureyri disease. Lancet 1:766,1956.

9. Houghton, L.E., and Jones, E.I. Persistent myalgia following sore throat. Lancet 1:196-198,1942.

4. Sigurdsson, B. New clinical entity? Lancet 2:98, 1956. 10. Sigurdsson, B., Sigurjonsson, J., Sigurdsson, J.H., Thorkelsson, J.V., and Gudmundsson, K.R. Disease epidemic in Iceland simulating poliomyelitis. Am. J. Hyg. 52:222-238, 1950.

5. Fog, T. Vegetative (epidemic?) neuritis. Ugesk, f . laeger. 115:1244-1250,1953. 6. Geffen, D., and Tracy, S.M. Outbreak of acute infective encephalomyelitis in residential home for nurses in 1956. Brit. M. J. 2:904-906, 1957.

11. Pellew, R.A.A. Clinical description of disease resembling poliomyelitis, seen in Adelaide, 1949-51. M.J. Australia 1:944946, 1951.

174

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Epidemic Neuromyasthenia

12. United States Public Health Service, Division of Infectious Diseases, Institute of Health. Gilliam, A.G. Epidemiological Study of Epidemic, Diagnosed as Poliomyelitis, Occurring among Personnel of Los Angeles County General Hospital During the Summer of1934. 90pp. (Public Health Bulletin No. 240.) Washington, D.C.: Government Printing Office, 1938.

- Clinical

Syndrome?

26. Pellew, R. A. A. and Miles, J. A.R. Further investigations on disease resembling poliomyelitis seen in Adelaide. M.J. Australia 2: 480-482, 1955. 27. Steigman, A.J. Personal communication. 28. Heidemann, H. Increasing occurrence of myositis. Ugesk. f. laeger. 114:1504,1952.

13. Ramsay, A.M., and O'Sullivan, E. Encephalomyelitis simulating poliomyelitis. Lancet 1:761-764, 1956.

29. United States Public Health Service, Communicable Disease Center. Unpublished data.

14. Shelokov, A., Habel, K., Verder, E., and Welsh, W. Epidemic neuromyasthenia: outbreak of poliomyelitis-like illness in student nurses. New Eng. J. Med. 257:345-355,1957.

30. Acheson, E.D. Encephalomyelitis associated with poliomyelitis virus: outbreak innurses'home. Lancet 2:1044-1048,1954.

15. Poskanzer, D.C., et al. Epidemic neuromyasthenia, outbreak in Punta Gorda, Florida. New Eng. J. Med. 257:356-364, 1957.

31. Macrae, A.D., and Galpine, J.F. Illness resembling poliomyelitis observed in nurses. Lancet 2:350-352, 1954 32. Bond, J.O., Wolff, H.G., and Bistowish, J.M. communication.

16. Dunshee, J.D., and Stevens, I.M. Previous history of poliomyelitis in California. Am. J. Pub. Health 24:1197-1200, 1934.

Personal

33. Deisher, J.B. Iceland disease in Alaska. Paper presented at clinical meeting of American Medical Association, Seattle, Washington, November 27-30, 1956.

17. Leake, J.P., Cedar, E.T., Dearing W.P., Gilliam, A.G., and Chope,H.D. Epidemiology of poliomyelitis in California, 1934. Am. J. Pub. Health 24: 1204-1206, 1934.

34. Sumner, D.W. Further outbreak of disease resembling poliomyelitis. Lancet 1:764-766, 1956.

18. Van Wart, R., Courville, C., and Hall, E.M. 1934 epidemic of poliomyelitis in Los Angeles: preliminary report on pathological changes in nervous system. Am. J.Pub.Health 24:12071209, 1934.

35. Public health. Outbreak at Royal Free.

Lancet2:351,1955.

36. Jelinek, J.E. Benign encephalomyelitis. Lancef 2:494, 1956. 19. Bower, A.G., Meals, R.W., Bigler, M., Ewing, J., and Hauser, V. Clinical features of poliomyelitis in Los Angeles. Am. J. Pub. Health 24:1210-1212, 1934.

37. Hill, R.C.J. Memorandum on outbreak amongst nurses at AddingtonHospital, Durban. SouthAfricanM.J. 29:344,1955.

20. Stevens, G.M. 1934 epidemic of poliomyelitis in Southern California. Am. J. Pub. Health 24:1213, 1934.

38. Alexander, J.S. Observations on neuromuscular dysfunctioninAddingtonoutbreak. SouthAfricanM.J. 30:88-90,1956.

21. Kessel, J.F., Hoyt, A.S., and Fisk, R.T. Use of serum and routine and experimental laboratory findings in 1934 poliomyelitis epidemic. Am. J. Pub. Health 24:1215-1223, 1934.

39. Henderson, D.A., Shelokov, A., Heller, J.H., andSafford,T. Unpublished data. 40. Henderson, D.A.,Kunkle,E.C., and Clement, W.B. Unpublished data.

22. Hart, T.M., and Luck, J.V. Orthopedic aspect of Los Angeles County 1934 poliomyelitis epidemic. Am. J. Pub. Health 24:1224-1228, 1934.

41. Deutaman,W., and Davis, R.K. Personal communications.

23. Shaw, E.B., and Thelander, H.E. Poliomyelitis in San Francisco. Am. J. Pub. Health 24:1229-1233, 1934.

42. Galpine, J.F., and Brady, C. Benign myalgic encephalomyelitis. Lancet 1:757, 1957.

24. Wilson, J.C., and Walker, P.J. Acute anterior poliomyelitis: orthopedic aspects of California epidemic of 1934. Arch. Int. Med. 57:477-492, 1936

43. Daikos, G.K., Garzonis, S., Palaiologos, A-, Papadojianakis, N., and Bousraros, G. Personal communication.

25. Armstrong, C.A. Personal communication.

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The Clinical and Scientific Basis of M.E. / CFS

Chapter 16

J. Gordon Parish with A. Melvin

Ramsay

A Bibliography of M.E./CFS Epidemics This list was largely based on bibliographies first published by Sir Donald Acheson (see Chapter 14) and also by Drs Henderson and Shelokov (see Chapter 15). They were collected, improvedupon and circulated by the British physician, Dr. J. Gordon Parish. I have added some of the more recent epidemics to this list. The numbering of epidemics up to 1975 is that of Dr. Gordon Parish. Although Dr. Parish may not be in agreement with the additions and deletions to his original compilation, I wish to acknowledge my gratitude for his considerable assistance, the use of his library and the extensive time he shared with me, without which this chapter and much of this book could not have been written. His photograph, shown here, was one of the last photographs taken of Dr. Ramsay. Byron Hyde, M.D.

1934

Epidemic 1 Los Angeles City and California State, U.S.A. Gilliam AG, Epidemiological study of an epidemic diagnosed as poliomyelitis occurring among the personnel of the Los Angeles County General Hospital during the Summer of 1934. Public Health Bulletin No. 240 - April 1938. United States Public Health Service, Washington, D.C., Government Printing Office.

Archives of Internal Medicine 1936; 54:477-91. (Statistics for California State, description of atypical features including arthopathy.) The following references appeared in the American Journal of Public Health, 1934:24, describing the unusual features of the 1934 poliomyelitis epidemic in California, U.S.A.

Wilson JC, Walker PJ, Acute anterior poliomyelitis: Orthopaedic aspects of California epidemic of 1934.

Dunshee JD, Stephens IM. Previous history of poliomyelitis in California, pp 1197-1200.

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A Bibliography of M.E. / CFS Epidemics

Public Domain

Leake JD, Cedar ET, Palmer W, Dearing WP, Gilliam AG, Chope HD. Epidemiology of poliomyelitis in California, 1934 (describes cases in Ruth Protection Home), pp 1204-6. Van Wart R, Courville C, Hall EM. 1934 epidemic of poliomyelitis in Los Angeles. Preliminary report on the pathological changes in the nervous system, pp 1207-9. Bower, AG, Meals RW, Bigler M, Ewing J, Hauser V. Clinical features of poliomyelitis in Los Angeles, pp

Epidemic 4 Frohburg Hospital, St. Gallen, Switzerland Gsell O. Abortive Poliomyelitis. Leipzig 1938,13-18. The three Swiss epidemics 3,4 and 6 are summarised in review articles by Gsell O (1958) and Parish JG (1978).

1939 Epidemic 5

1210-2.

Harefield Sanatorium,Middlesex, England

Stephens GM. 1934 Epidemic of poliomyelitis in Southern California, pp 1213-4.

Houghton LE, Jones EI. Persistent myalgia following sore throat. Lancet 1942; 1:196-8.

Kessel JF, Hoyt AS, Fisk RT. Use of serum and routine and experimental laboratory findings in 1934 poliomyelitis epidemic, pp 1215-23.

Epidemic 6

Hart TM, Luck JV. Orthopaedic aspects of Los Angeles County 1934 poliomyelitis epidemic, pp 1224-8.

Gsell O. Abortive Poliomyelitis. Helv Medica Acta 1949; 16:169-83.

Shaw EB, Thelander HE. Poliomyelitis in San Francisco, pp 1229-33.

1945 Epidemic 7

Pathology: Kessel JF, Van Wart R, Fisk RT, Stimpert FD. Observations on the Virus recovered from 193435 poliomyelitis epidemic in Los Angeles. Proc Soc. Exp Biol Med. 1936; 35:326-9.

University Hospital of Pennsylvania, U.S.A.

Electromyography: Marinacci AA, Von Hagen KO. The value of the electromyogram in the diagnosis of Iceland Disease. Electromyogram 1965; 5:241-51.

1936 Epidemic 2

Degersheim, St. Gallen, Switzerland

McConnell J. An epidemic of pleurodynia with prominent neurologic symptoms and no demonstrable cause. Am J Med Sci, 1945; 209: 41-8.

1946-47 Epidemic 8 Iceland Sigurjonsson J. Poliomyelitis and the Akureyri Disease. Mixed epidemics of poliomyelitis and a disease resembling poliomyelitis with the character of the Akureyri Disease. Nord Med 1959; 61:174-82. (The 1948 epidemic appears to have started in 1947.)

Fond-du-Lac, Wisconsin, U.S.A. Armstrong G. Report to the Surgeon General, U.S. Public Health Service of the investigation of an outbreak of "Encephalitis" in the St. Agnes Convent, Fond-du-Lac, Wisconsin.

1948-49 Epidemic 9

1937 Epidemic 3

North Coast Towns, Iceland; Akureyri Nov-Dec 1948, Saudakrokur Dec 1948- Feb 1949, Isafordur Jan-April 1949

Erstfeld, Switzerland Stahel H. Die Poliomyelitis - Epidemic bei Stab Geb. I.R. 37 and Geb Sch Bat #11, Erstfeld 18-30 Juli 1937. Die Abortiv -Poliomyelitis. Schweiz Med Wochenschr 1938; 68: 86-91. Gsell O. Abortive Poliomyelitis. Leipzig 1938, 20-1.

Sigurdsson B, Sigurjonsson J, Sigurdsson JHJ, Thorkelsson J, Gudmundsson KR. A disease epidemic in Iceland simulating Poliomyelitis. Am J Hyg 1950; 52:222-38.

Verlag Thieme,

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The Clinical and Scientific Basis of M.E. / CFS

1952 Epidemic 13

Sigurdsson B, Gudmundsson ICR. Clinical findings six years after outbreak of Akureyri Disease. Lancet 1956; 1:766-7.

Middlesex Hospital Nurses' Home, London, England

Effect of previous experience of Akureyri Disease on subsequent poliomyelitis epidemic and poliomyelitis vaccination (see Sigurdsson B), Gudnadottir M, Petursson G. Response to poliomyelitis vaccination. Lancet 1958; 1:370-1.

Main Article: Acheson ED. Encephalomyelitis associated with Poliomyelitis Virus. Lancet 1954; 2:1044-8. Acheson ED. Outbreak at the Royal Free. Lancet 1955; 2:395 (letter giving further details of 1952 Middlesex Hospital epidemic).

Hyde B, Bergmann S, Chronic Aspects of Akureyri Disease, p 205-215, Post-Viral Fatigue Syndrome. Jenkins & Mowbray, John Wiley and Sons, (1991)

Epidemic 14 1949-51 Epidemic 10

Copenhagen, Denmark Main Article/Electromyography: Fog AT. Neuritis VegitivaEpidemica? UgeskrLaeger 1953; 115:1244-51.

Adelaide, South Australia Main Article: Pellew RAA. A clinical description of a disease resembling poliomyelitis seen in Adelaide, 1949-51. Med J Aust 1951; 1:944-6.

Heidemann H. Ophobet optraeden af myositer (epidemic myositis). Ugeskr Laeger 1952; 114:1504.

Monthly incidence of cases: Jackson JF. 14th Annual General Report South Australia Institute of Medical and Veterinary Science, July 1951 - June 1952;17.

Krarup NB. Ophobet optraeden af myositer: poliomyelitis? (Epidemic of myositis: poliomyelitis?). Ugeskr Laeger 1952; 114:1534.

Virus and Animal Studies: Pellew RAA, Miles JAR. Further investigations on a disease resembling poliomyelitis seen in Adelaide. Med J Aust 1955; 42:480-2.

Epidemic 15

Pappenneimer AM, Bailey OT, Cheever FS, Daniels JB. Experimental polyradiculitis in monkeys. J Neuropath Clin. Neurol 1951; 1:48-62.

Henderson DA, Shelokov A. Epidemic Neuromyasthenia-clinicalsyndrome? NEJM 1959;260:757-64.

Lakeland, Florida, U.S.A.

1953 Epidemic 16

1950 Epidemic 11

Whitley Hospital, Coventry and Coventry District, England

St. Joseph Infirmary, Louisville Kentucky, U.S.A. SteigmanAJ. An outbreak of an unidentified illness in the Nurses' Training School of St. Joseph Infirmary, Louisville, in Kentucky in October 1950. Report to the National Foundation of Infantile Paralysis, 1951. Data summarised by Henderson DA, Shelokov A, (note review article 2,1959). Steigman AJ. epidemic neuromyasthenia. NEJM 1969;281:797.

Main Article and Electromyography: Macrae AD, Galpine JF. An illness resembling Poliomyelitis observed in nurses. Lancet 1954; 2:350-2.

Epidemic 17 Chestnut Lodge Hospital, Rockville, Maryland, U.S.A.

Epidemic 12 Main Article, bacteriological and serological studies: Shelokov A, Habel K, Verder E, Welsh W. Epidemic Neuromyasthenia. An outbreak of poliomyelitis-like illness in Student Nurses. NEJ M 1957; 257:345-55. Case Report, Indiana University, Bloomington, Indiana, U.S.A.

Upper New York State White DN, Burtch RB. Iceland Disease - a new infection simulating Acute Anterior Poliomyelitis. Neurology 1954; 4:506-16.

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Public Domain

Hardtke EF. Iceland Disease in Indiana. J Indiana State Med Assoc 1955; 48:245-50. Case also described by Acheson ED, see Review article (1), 1959.

Epidemic 18 Jutland, Denmark Pedersen EP. Epidemic Encephalitis in Jutland. A clinical survey for the years 1952-54. Dan Med Bull 1956; 3:65-75. (Encephalitis with vertigo, Autumn 1953).

2:290. Further details in letters, Lancet 1955; 2:1091 and Lancet 1956; 2:146. Main account: Wallis AL. An investigation into an unusual disease seen in epidemic and sporadic form in a general practice in Cumberland in 1955 and subsequent years. MD Thesis. University of Edinburgh 1957. Spread to County Durham: Parish JG. Epidemic malaise. Br Med J 1970; 3:47-8.

Epidemic 24 Royal Free Hospital, London, England

1954 Epidemic 19 Tallahassee, Florida, U.S.A. Bond JO. A new clinical entity? Lancet 1956; 2:256.

Epidemic 20

Leading Article: Infectious mononucleosis. Br Med J 1955; 2:309-10. (July 30th, refers to what was first believed to be infectious mononucleosis - glandular fever at the Royal Free Hospital, an error that later was magnified in the USA into the theory that M.E/ CFS was Chronic Epstein Barr disease). Public Health report. Outbreak at the Royal Free. Lancet 1955; 2:351.

Seward, Alaska Deisher JB. Benign Myalgic Encephalomyelitis (Iceland Disease) in Alaska. Northwest Med 1957; 56:1451-6.

Epidemic 21

Vital Statistics. Outbreak at the Royal Free Hospital. Obscure nature of infection. Br Med J 1955; 2:442-3. Compston ND. Epidemic at the Royal Free Hospital. Br Med J 1956; 2:157. (Brief report to the BMA meeting at Brighton).

British Army, Berlin, Germany Sumner DW. Further outbreak of a disease resembling poliomyelitis. Lancet 1956; 1:764-6. Review of epidemics Leading Article Akureyri 1948 (9) Not Poliomyelitis. Lancet 1954; Adelaide 1949 (10) 2:1060-1. New York State 1950 (12) Middlesex Hospital 1952 (13) Coventry 1953 (16)

Official Public Health report and Comparative Epidemiology Report of the Ministry of Health for the year ended 31/12/55. Part II on the state of the Public Health: Being the Annual Report of the Chief Medical Officer for the year 1955. Her Majesty's Stationery Office; 71-4. Epidemics 13,16,22,24,27. Main articles: The medical staff of the Royal Free Hospital. An outbreak of encephalomyelitis in the Royal Free Hospital Group, London, in 1955. Br Med J 1957; 2:895-904.

Epidemic 22 Liverpool, England Outbreak involving medical and nursing staff in a Liverpool Hospital.

Compston ND. An outbreak of encephalomyelitis in the Royal Free Hospital Group, London, in 1955. Postgrad Med J 1978; 54:722-4. (precis of the previous report).

Comparative Epidemiology: see Official Public Health report for Epidemic 24 (1955).

1955 Epidemic 23 Dalston, Cumbria,England Wallis AL. An unusual epidemic.

Geffen D. An outbreak of encephalomyelitis in the Royal Free Hospital Group, 1955. Public Health, 1957; 71;13-24. Lancet 1955;

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The Clinical and Scientific Basis of M.E. / CFS

Durban outbreak Lancet 1959; 1:689-93. (Non-nitrogenous acidity toxic metabolite noted in urine of some patients).

Crowley N, Nelson M, Stovin S. Epidemiological aspects of an outbreak of encephalomyelitis at the Royal Free Hospital in the summer of 1955. J Hyg (Camb) 1957; 55;102-22. (Bacteriological and viral studies, serological tests, heterophile antibody types, lymphocyte changes and biochemical tests).

Sporadic cases Johannesburg, South Africa July 1954 - March 1955

Electromyography: Richardson AT. Some aspects of the Royal Free Hospital epidemic. Ann Phys Medl956; 3:81-9

Jackson AL, Jacobson S, Cooper B. A disease resembling poliomyelitis. Report of an outbreak in Johannesburg. S. Afr Med J 1957; 31:514-7.

Review article: Benign mylagic encephalomyelitis. Lancet 1957; 1:1342.

1955-6 Epidemic 28

Epidemic 25

Segbwema, Sierra Leone Oct 1955 - Oct 1956

Perth, Western Australia,

Preliminary report: Rose JR. A new clinical entity? Lancet 1956; 2:197.

Steen AS. Virus epidemic in recurrent waves. BR Med J 1956; 1:235.

Main Article: Rose JR. An outbreak of encephalomyelitis in Sierra Leone. Lancet 1957; 2:914-6.

Epidemic 26

Epidemic 29

Gilfach Goch, Wales

Patreksfordur and Thorshofn,Iceland Oct 1955 - April 1956

Jones TD. Virus epidemic in recurrent waves. BR Med J 1956; 1:348. Sporadic Cases Boscombe, Hants, England JelinekJE. Benign encephalomyelitis. Lancet 1956; 2:494-5.

Sigurdsson B, Gudnadottir M, Petursson G. Response to poliomyelitis vaccination. Lancet 1958; 1:370-1 (outline of 1955-6 epidemic and unusual response to subsequent poliomyelitis vaccination.)

East Ham, London England

Epidemic 30

Bonomini V, Montuschi E. Benign encephalomyelitis. Lancet 1956; 2:629-30.

N.W. London, England April 1955 -September 1957

Epidemic 27

Main article-electromyography- electroencephalography: Ramsay AM, O'Sullivan E. Encephalomyelitis simulating poliomyelitis. Lancet 1956; 1:761-6.

Addington Hospital, Durban and Durban City, South Africa

Royal Free Hospital, Nurses Preliminary Training School May - June 1956

Hill RCJ. Memorandum on the outbreak amongst the nurses at Addington Hospital, Durban. S. Afr Med J 1955; 29:344-5.

Ramsay AM. Encephalomyelitis simulating poliomyelitis and hysteria. Lancet 1957; 2:1196-1200.

Association News. Report of the clinical meeting of the Natal Coastal Branch held on 17th May 1955 at the Addington Hospital, Durban. The Durban 'Mystery Disease'. S. Afr Med J 1955; 29:997-8.

Geffen D, Tracy SM. An outbreak of acute infective encephalomyelitis in a residential home for nurses in 1956. Br Med J 1957; 2:904-6.

Alexander JS. Observations on Neuromuscular dysfunction in the Addington Outbreak. S. Afr Med J 1956; 30:88-90.

1956 Epidemic 31

Main Article: Hill RCJ, Cheetham RWS, Wallace HL. Epidemic myalgic encephalomyelopathy - the

Ridgefield, Connecticut, U.S.A. Henderson, DA Shelokov A, Heller JH, Safford T. 180

A Bibliography of M.E. / CFS Epidemics

Public Domain

Unpublished data, quoted by Henderson DA, Shelokov A. Epidemic neuromyasthenia NEJM 1959; 260:757-64.

Epidemic 32 Punta Gorda, Florida, U.S.A. Poskanzer DC, Henderson DA, Kunkle EC, Kalter SS, Clement WB, Bond JO. Epidemic neuromyasthenia. An outbreak in Punta Gorda, Florida. NEJM 1957; 257:356-64.

Epidemic 33 Newton-le-Willows, Lancashire, England Lyle WH. Lymphocytic meningo-encephalitis with myalgia and rash. Lancet 1956; 2:1042-3.

Correspondence: Sigurdsson B. Lancet 1956; 2:98. Review article - 2 Annotation. Encephalitis, meningitis or poliomyelitis. Lancet 1956; 2:1091. (Coxsackie B and Echo Virus infections)

1956-57 Epidemic 35 Coventry, England Galpine JF, Brady C. Benign myalgic encephalomyelitis. Lancet 1957; 1:757-8. Br Med J 1957; 2:645. Galpine JF. Benign myalgic encephalomyelitis. Br J Clin Pract 1958; 12:186-90. Galpine JF. Epidemic malaise. Br Med J 1970; 1:501.

1957 Tyrrell DAJ, Snell B. Recovery of a virus from cases of an epidemic exanthem associated with meningitis. Lancet 1956; 2:1028-9.

Epidemic 36

Lyle WH. An unfamiliar infectious disease: An account of an outbreak. MD Thesis. University of Manchester.

Hicks DA. Anew clinical entity. Lancet 1957; 1:686.

Main article/virology: Lyle WH. An outbreak of disease believed to have been caused by Echo 9 virus. Ann Int Med 1959; 51:248-69.

Epidemic 34 Pittsfield, Williamstown, Massachusetts, U.S A

Brighton, South Australia

Review article - 1 Leading article. Virus meningitis and encephalomyelitis. Br Med J 1957; 1:811-3. (Coxsackie, Echo Virus meningitis and myalgic encephalomyelitis). Review article - 2 Leading article. Epidemic myalgic encephalomyelitis. Br Med J 1957; 2:927-8. Review article - 3 Annotation. Benign myalgic encephalomyelitis. Lancet 1957; 2:1208-9.

Deutaman W, Davis RK. (Unpublished). Data included in survey by Henderson DA, Shelokov A. Epidemic Neuromyasthenia - clinical syndrome? N Engl J Med 1959; 260:757-64 and 814-8.

Nomenclature Acheson ED. Benign myalgic encephalomyelitis. Lancet 1957; 1:834-5.

1958 Hyde, BM Myalgic Encephalomyelitis (Chronic Fatigue Syndrome): An Historic Perspective, Canada Weekly Report, Health and Welfare Canada, January 1991 Vol. 17S1E, pg 5-8, based upon conversation with Dr Davis, whose wife was a patient in that epidemic.

Epidemic 37 Athens, Greece Daikos G, Paleologue A, Garzonis S, Bousvaros GA. Papadoyannakis N. Arch Med Sci, Athens 1958; 14:617.

Sporadic cases, Hygiea, Sweden Main Article: Daikos GK, Garzonis S, Paleologue A, Bousvaros GA, Papadoyannakis N. Benign Myalgic Encephalomyelitis. An outbreak in a Nurses' School in Athens. Lancet 1959; 1:693-6. (No reticuloendothelial involvement but periostitis and arthropathy noted; EMG and EEG studies). Review article - 1

Hook O. Data summarised by Acheson ED, see Review article (1) 1959. Review article - 1 Nomenclature, Leading article. A new clinical entity. Lancet 1956; 1:789-90. (Name "benign mylagic encephalomyelitis" suggested).

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Henderson and Shelokov introduced the term epidemic neuromyasthenia.

Switzerland Gsell O. Encephalomyelitis myalgic epidemic eine poliomyelitisahnliche Krankheit. Schweiz Med Wochenschr 1958; 88:488-91. (German - summarises epidemics in Switzerland 1937-39).

Sporadic cases, England Kendall RE. The psychiatric sequelae of Benign Myalgic Encephalomyelitis. Br J Psychiat 1967; 113:833-40.

Review article - 2 Galpine JF. Benign myalgic encephalomyelitis. British Journal of Clinical Practice 1958; 12:186-90.

1961

1958-9

Sporadic case Basel, Switzerland

Sporadic cases, S.W. London, England

Gsell O. Encephalomyelitis Basel myalgica benigna, epidemische Pseudoneurasthenie. Schweiz Med Wochenschr 1963; 93:197-200.

Price JL. Myalgic encephalomyelitis. Lancet 1961; 1:737-8. (Abnormal ECG, EEG and EGM findings).

1961-2

1959 Epidemic 38

Epidemic 39

Newcastle upon Tyne, England

New York State Albrecht RM, Oliver VL, Poskanzer DC. Epidemic Neuromyasthenia. Outbreak in a convent in New York State. JAMA 1964; 187:904-7.

Pool JH, Walton JN, Brewis EG, Uldall PR, Wright AE, Gardner PS. Benign myalgic encephalomyelitis in Newcastle upon Tyne. Lancet 1961; 1:733-7. (EMG studies).

1964-1966 Epidemic 40

Sporadic cases N.W. London England

N.W. London

Goldwater S. Influenza-like illness. Br Med J 1960; 1:962-3 (arthropathy with effusions prominent).

Scott BD. Epidemic malaise. Br Med J 1970; 1:170. Ramsay AM. Hysteria and Royal Free Disease BR Med J 1965; 2:1062.

Review article- IMajorreviewofliterature: Acheson ED. The clinical syndrome variously called Benign Myalgic Encephalmyelitis, Iceland Disease and Epidemic Neuromyasthenia. Am J Med 1959; 26:56995. Comparative epidemiology: epidemics 1 California, 7 Pennsylvania, 9 Iceland, 10 Adelaide, 12 New York State, 13 Middlesex Hospital (London), 14 Denmark, 16 Coventry (England), 17 Maryland, 20 Alaska, 21 Berlin, 24 Royal Free Hospital (London), 27 Durban (S. Africa), 28 Sierra Leone, 30 N.W. London, 32 Punta Gorda (Florida), 35 Coventry (England).

Ramsay AM. Epidemic neuromyasthenia 1955-1978. Postgrad Med J 1978; 54:718-21.

Epidemic 41 Franklin, Kentucky, U.S.A. Miller G. Chamberlin R., McCormack WM. An outbreak of neuromyasthenia in a Kentucky Factory the possible role of a brief exposure to organic mercury. Am J Epidemiol 1967; 86:756-64.

Review article - 2 Major review of l i t e r a t u r e : Henderson DA, Shelokov A. Epidemic Neuromyasthenia - clinical syndrome? N Engl J Med 1959; 260:757-64 and 814-8. Comparative epidemiology: 1 California, 2 Wisconsin (U.S.A.), 5 Harefield (England), 9 Iceland, 10 Adelaide, 11 Louisville (Kentucky), 12 New York State, 13 Middlesex Hospital (London), 14 Copenhagen, 15 Lakeland (Florida), 16 Coventry (England), 17 Maryland, 19 Tallahassee (Florida), 20 Alaska, 21 Berlin, 24 Royal Free Hospital (London), 27 Durban (South Africa), 30 N.W. London, 31 Ridgefield (U.S.A.), 32 Punta Gorda (Florida), 34 Pittsfield (Massachusetts), 35 Coventry (England), 37 Athens.

1934-1965 Review of Electromyographic Findings, California

1965-6 Epidemic 42 Galveston County, Texas Johnson JM, Micks DW. Epidemic Neuromyasthenia Variant? Texas Reports on Biology and Medicine

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1967; 25:484.

Dillon MJ. 'Epidemic neuromyasthenia' at the Hospital for Sick Children, Great Ormond Street, London. Postgrad Med J 1978; 54: 725-30.

Leon-Sotomayor L. Epidemic Diencephalomyelitis. A possible cause of neuropsychiatric, cardiovascular and endocrine disorders. New York, Pageant Press, 1969.

1974 Review article Parish JG. Epidemic neuromyasthenia: a reappraisal. IRCS J International Research Communications, Medical Science 1974; 2:22-6 (survey of literature to 1974).

1967-70 Sporadic cases Edinburgh, Scotland Innes SGB. Encephalomyelitis resembling benign myalgic encephalomyelitis. Lancet 1970; 1:969-71

1975 Epidemic 47

1968 Mercy San J u a n Hospital Sacramento, California

Epidemic 43 Fraidek, Lebanon

Ryll, E . ; Chabursky, B. (In preparation.) 200 hospital staff in the Sacramento, California hospital fell ill in August September 1975. The epidemic appears to have spread to the children of the hospital staff and from there to the children's teachers. 43 have been seriously disabled with chronic illness from 1975-1992.

Mourad S, Chidiac J. Benign Myalgic encephalomyelitis in Lebanon. Leb Med J 1969; 22:735-40.

1969 Epidemic 44

1976

Medical Centre, State University of New York U.S.A.

Epidemic 48

Damadian R. Unidentified symptom complex. NE JM. 1969; 280:1131. Correspondence: Trimble GX. Epidemic Neuromyasthenia. NEJ M 1969; 281:105; Fisher CM. On Damadian's Ache, 281:106, Epidemic Neuromyasthenia, 281:797-8 Steigman AJ, Hart RH, Adamson JR (criteria for diagnosis).

Southwest Ireland Preliminary report: Corridan JP, Myalgic Encephalomyelitis. J Irish Med Ass 1976; 69:414. Main article: Corridan JP. Epidemic neuromyasthenia in Southwest Ireland. Postgrad Med J 1978; 54:731-6.

1970 Epidemic 45

Review article Ramsay AM. Benign Myalgic Encephalomyelitis or Epidemic neoromyasthenia. GP Update 1976; 12:539-42.

Lackland Air Force Base, Texas, USA.

1977 Graybill JR, Silva J. O'Brien MS, Reinarz JA. Epidemic Neuromyasthenia. A Syndrome or disease? JAMA 1972; 219:1440-3

Definition Anonymous. Reply to question: "What is Icelandic Disease?" Br Med J 1977; 1:965.

1970-71 Epidemic 46

Correspondence: Ramsay AM, Dowsett EG, Dadswell JV, Lyle WH, Parish JG. Icelandic disease (benign myalgic encephalomyelitis or Royal Free Disease) Br Med J 1977; 1:1350.

Hospital for Sick Children Great Ormond Street, London, England

Epidemic 49 Dillon, MJ, Marshall WC, Dudgeon JA, Steigman AJ. Epidemic Neuromyasthenia: outbreak among nurses at a children's hospital. BR Med J 1974; 1:301-5. Correspondence: Epidemic neuromyasthenia. Br Med J 1974; 1:574-5 Wallis GG; Perry FS: 2:276 Parish JG; 2:559 Dillon MJ (Marshall WC, Dudgeon JA: Steigman AJ).

Dallas - Fort Worth, Texas, USA Shelokov A, Currie DM, Nelson M. 'Epidemic Neuromyasthenia' Texas 1977. Postgrade Med J 1978; 54:741 (Abstract).

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Behan PO. Post-infectious encephalomyelitis: some aetiological mechanisms: 755-9 (Similarity of features of acute disseminated encephalomyelitis to those of epidemic myalgic encephalomyelitis - epidemic neuromyasthenia).

Currie DM, Shelokov A. Repetitive stimulation abnormalities in 'epidemic neuromyasthenia': identification and implications. PostgradMed J1978; 54:746 (Abstract).

1978 Cooke WT. The neurological manifestations of malabsorption: 760-2.

First major M.E./CFS Symposium, Royal Society of Medicine London

CrowTJ. Viral causes of psychiatric disease: 763-7. Lyle WH, Chamberlain RN (eds). 'Epidemic neuromyasthenia 1934-1977; Current Approaches Postgrade Med J 1978; 54:705-74.

Thomas M. Epidemiological approaches to 'epidemic neuromyasthenia': syndromes of unknown aetiology (epidemic myalgic encephalopathies): 768-70.

Papers: Parish JG. Early outbreaks of 'epidemic neuromyasthenia': 711-7 (comparative epidemiology: 1 California, 3 Erstfeld (Switzerland), 4 Frohburg (Switzerland), 6 Degersheim (Switzerland), 9 Iceland, 10 Adelaide, 12 New York State, 23 Dalston (England). Ramsay AM. 'Epidemic neuromyasthenia' 1955-78: 718-21 (epidemics 30 and 40 NW London, England).

General discussion: biochemical data. Rundle A (raised lactic dehydrogenase and glutamic oxaloacetic transaminase levels and normal creatinine phosphokinase): Wilkie D (low oxygen uptake of lymphocytes, which are intolerant of chlorimipramine): 771; nomenclature Compson N, Behan PO, Wookey C, Lyle H, Ramsay AM, Richardson AT, Parish JG, Shelokov A: 772-4.

Compston ND. An outbreak of encephalomyelitis in the Royal Free Hospital Group, London in 1955:7224. (epidemic 24).

Review article Editorial Epidemic myalgic encephalomyelitis. Br Med J 1978: 1:1436-7. Correspondence 1969 Easton HG; 2:202 Wookey C.

Dillon MJ. 'Epidemic neuromyasthenia' at the Hospital for Sick Children, Great Ormond Street, London: 725-30 (epidemic 46).

Case Report, Church AJ. Myalgic encephalomyelitis "An obscene cosmic joke" Med J Aust 1980; 1:307-8. Correspondence: 613 Davies GRW: 613-4 Webb J.

Corridon JP. 'Epidemic neuromyasthenia' in Southwest Ireland: 731-6 (epidemic 47).

1979 Epidemic 50

Ball AP. Disease due to echovirus type 19 in Birmingham, England, 1975: relationship to 'epidemic neuromyasthenia: 737-40.

Southampton, England May PGR, Donnan SPB, Ashton JR, Ogilvie MM, Rolles CJ. Personality and Medical Perception in Benign Myalgic Encephalomyelitis. Lancet 1980; 2:1122-4. (Outbreak in a girls' school).

Shelokov A, Currie DM, Nelson M. 'Epidemic neuromyasthenia', Texas 1977 (abstract): 741. Richardson, AT. Electromyographic studies of patients with 'epidemic neuromyasthenia' at the Royal Free Hospital (abstract):745.

Correspondence: Was it "Benign Myalgic Encephalomyelitis"? Lancet 1980; 2:1310 Ramsay AM; 1981; 1:37-8 Goodwin GS, May PGR (Donnan SPB, Ashton JR, Ogilvie MM, Rolles CJ): 221-2 Gosling PJH: 325 Ramsay AM. Myoglobinaemia in Benign Myalgic Encephalomyelitis. Lancet 1981; 1:670 Layzer RB. Myalgic encephalomyelitis: 950-1 Parish JG.

Currie DM, Shelokov A. Repetitive stimulation abnormalities in 'epidemic neuromyasthenia' (abstract)^. Sutton RNP. Ill defined neurological diseases of possible viral origin. 747-51.

Biochemistry Ramsay AM, Rundle A. Clinical and biochemical findings in ten patients with benign myalgic encephalomyelitis. Postgrad MedJ 1979; 55:856-7. (Raised levels of serum myoglobin and GOT, and reduced level of fasting whole blood pyruvate).

Pampiglione G, H a r r i s R, Kennedy J. Electroencephalographic investigations in myalgic encephalomyelitis: 752-4.

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1980

Correspondence: West Otago illness. N Z Med J 1984; 97:502. Snow P. Myalgic encephalomyelitis: 620 Gow PJ:654 Hardman MJ: 698-9 Snow P, Simpson LO (Shard BI, Olds, RJ), Poore M. (Paul C), Gow PJ: 782Matthew C, Brook-Church AJ (Brook-Church JV): 868 Gow PJ: 1985;98:20-1 Simpson LO (Shard BI, Olds RJ), Gow PJ, Murdoch JC, Simpson FO: 201-2 Murdoch J.C.

Review articles: Bishop J. Epidemic myalgic encephalomyelitis. Med J Austl980; 1:585-6 and 609. Behan PO. Epidemic myalgic encephalomyelitis. Practitioner 1980; 224:805-07. Kale SA, Jones JV, Poskanzer DC. Icelandic Disease or Epidemic neuromyasthenia. (Questions and Answers). JAMA 1980; 244:2666.

Dunedin and Hamilton N e w Zealand Clements CJ. Myalgic encephalomyelitis N Z Med J 1984; 97:458.

Behan PO, Behan WMH. Epidemic myalgic encephalomy- elitis. In: Rose FC, ed. Clinical neuroepidemiology. Tunbridge Wells: Pitman Medical 1980; 374-83.

1984 From 1984 until 1992 an endemic period ocurred in which an unusually large number of clusters and epidemics ofM.E. / CFS have been recognized in North America. After an apparent initial increase in morbidity in 1983 there seemed to have appeared in late summer of 1984 an unprecedented increase of sporadic and epidemic cases across North America. Although certain geographical hot spots seem to have taken up much of the medical interest, this endemic situation probably represents an unusual and unremitting morbidity in all areas of the United States and Canada. Some of the clusters and epidemics are listed.

1980-81 Epidemic 51 West Kilbridge, Ayrshire, Scotland Fegan KG, Bell EJ. Myalgic encephalomyelitis in a rural practice in Ayrshire. Communicable Diseases in Scotland 81/2, vii Fegan KG, Behan PO, Bell EJ. Myalgic Encephalomyelitis - report of an epidemic. J R Coll Gen Pract 1983; 33:335-7.

1980-83 Epidemic 52

Epidemic 54 Incline Village, Lake Tahoe Nevada Epidemic August - September

Helensburgh, Scotland

Buchwald D, Cheney P, Peterson D, et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders and active human herpesvirus type 6 infection (1992) 15 Jan, Annals of Internal Medicine, Vol. 116, No. 2, 103-113.

Calder BD, Warnock PJ. Coxsackie B infection in a Scottish general practice. J R Coll Gen Pract 1984;34:15-19.

1981-82

This community epidemic, apparently started in a girls' basketball team, then involved primarily teachers in at least three high schools,and then large numbers of the community. A large number of lay and medical publications have been generated.

Sporadic cases Stirlingshire, Scotland Keighley Bd, Bell EJ. Sporadic myalgic encephalomyelitis in a rural practice. JR Coll Gen Pract 1983; 33:339-41

1982-84 Epidemic 53

Epidemic 55 Chapel Hill, North Carolina

West Otago, New Zealand This epidemic started in February 1983, at the end of the New Zealand Summer

Epidemic amongst members of The North Carolina Symphony Orchestra. Work Prepared by Grufferman, S.; Herberman, R.; Eby, N. Low NKC associated with high yield of lymphoma, astrocytoma, glioma (see this text)

Poore M, Snow P, Paul C. An unexplained illness in West Otago. N Z Med J 1984; 97:351-4.

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The Clinical and Scientific Basis of M.E. / CFS

Epidemic 56

SMON Epidemic in Japan Zhi Fang Epidemic in China

Montreal, Quebec-Ontario,Canada See pages 333, 334 for discussion. The status of these two epidemics in relation to M.E. / CFS can only be speculation at this point.

Labour Day epidemic, Montreal, S O'Sullivan, in preparation

Epidemic 59

Over 500 cases ofM.E./CFS documented in Ontario during the August-November 1984 period. Although these cases were recorded from all over Ontario, there seems to be a curious prevalence along the seaway valley from the area of Kingston to Cornwall, Ontario. This endemic was active in all parts of Canada during this period and appears have maintained its activity until the time of writing in 1991.

Yerington, Nevada Outbreak See Paul Levine's chapter, pages 201, 202. In the same area an M.E./CFS-like epidemic reputedly occurred in a reservation of American Native People. Information is incomplete on this epidemic.

1986

Review Gray JA. Some long-term sequelae of Coxsackie B virus infection. J R Coll Gen Pract 1984; 24:3-5.

Epidemic 60 Placerville Outbreak

Nuclear MagneticResonance Study Arnold DL, Bore PJ, Radda GK,Styles P, Taylor DJ. Excessive intracellular acidosis of skeletal muscle on exercise in a patient with a post-viral exhaustion/ fatigue syndrome. Lancet 1984; 1:1367-9.

See Paul Levine's chapter, page 201.

1988 Epidemic 61

Correspondence: Muscle acidosis in post-viral fatigue. Lancet 1984; 2:293 Fulop M, Arnold DL (Bore PJ, Radda GK, Styles P, Taylor DJ), Gow P J

Sonora, California This epidemic started in August 1988. More than 35 children and adults were diagnosed with M.E. in the mountain country 100 miles from Lake Tahoe. Many of these patients were associated in some way with Columbia Community College. This epidemic involved teachers and students and persisted until 1991. (No medical publication to date)

Review Murdoch JC. Myalgic encephalomyelitis and the general practitioner. N Z Family Physician 1984; 11:127-8.

1989

1884-1985 Epidemic 57

Epidemic 62 ?

Truckee, California

Roseville, California

Involoving teachers and students, see Paul Levine's chapter, page 201.

This epidemic was reported by H. Kallis and J. Fever. It started in 1989 at the Rosedale Hospital, Roseville California where 11 or more cases ofM.E./CFS were diagnosed among the staff of the 3rd floor of the hospital. Roseville is a town adjacent to Sacramento. Reported in the local newspaper. (No medical report to date).

1985 Epidemic 58 Lyndonville Epidemic New York This was an epidemic involving children and adults and was described by Dr David S. Bell in his book "The Disease With a Thousand Names", Pollard Publications, Box 180, Lyndonville NY 14098,1991.

1990 Epidemic 63

Sporadic cases Mac William K, Dadswell JV, Tillet H. Antiviral titres, lymphocytic reactions and low IgA levels in patients with recurrent or persistent symptoms. Lancet 1985; 1:764-5.

This epidemic occurred among teachers and students at the Elgrove High School, starting in AprilMay 1990 (in preparation) Chabursky, B. This epidemic was still active in 1991.

Elkgrove High School, Elkgrove, California

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The Epidemiology and Methodology of M.E. / CFS

Seymour Grufferman, MD, Dr. PH

Epidemiologic and Immunologic

Findings in Clusters of Chronic Fatigue

Syndrome

Chapter 17 «ii;i!SB

Seymour

Grufferman

Epidemiologic and Immunologic Findings in Clusters of Chronic Fatigue Syndrome Seymour Grufferman, MD, Dr. PH Chairman, Department of Clinical Epidemiology and Preventive Medicine, University of Pittsburgh School of Medicine M-200 Scaife Hall, Pittsburgh, Pennsylvania 15261 USA Dr. Grufferman is Professor and Chairman of the Department of Clinical Epidemiology and Preventive Medicine at the University of Pittsburgh School of Medicine, as well as a pediatrician and epidemiologist. He has a long-standing research interest in cancer epidemiology, particularly whether viruses play an etiologic role in human cancer. He has done extensive epidemiologic research on the lymphoreticular malignancies and childhood cancer. Recently, he has become interested in the chronic fatigue and immune dysfunction syndrome (CFIDS) and directs the CFIDS Clinic at the University of Pittsburgh. Abstract natural killer cell activity in cases than in non-cases. Additionally, subjects in the two outbreaks were found to have variable patterns of elevation of Epstein-Barr virus antibodies, elevations of antibodies against human herpes virus Type 6 and elevated T4/ T8 ratios. Surprisingly, similar abnormalities were found in non-cases who were closely exposed to cases. This would be compatible with a model of inapparent infections in close contacts of cases.

Two discrete outbreaks of chronic fatigue syndrome were studied - one in a symphony orchestra and the other in an elementary school. By studying total defined populations, interesting new information on the epidemiology of the syndrome emerged. Laboratory investigations of subjects in the two populations revealed significantly lower levels of

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Study of the closeness of contacts between cases and other cases and between non-cases and other noncases revealed that case-case pairs had significantly closer contacts with one another than did non-casenon-case pairs. This was particularly true for the sharing of eating utensils and bedrooms. Additionally, in the symphony there appeared to be a remarkably increased risk of cancer in cases and their close contacts. However, no such increased occurrence was observed in the school outbreak. In summary, our investigations show that there are objective laboratory abnormalities consistent with a broad spectrum of immune dysfunction in both cases and in healthy people closely exposed to cases. Furthermore, cases appear to have had significantly closer contact with one another than did non-cases, supporting a model of transmissibility. Additionally, it is possible, but not proven, that there may be an increased risk of cancer in subjects with chronic fatigue syndrome and in their close contacts. Findings in these investigations suggest that the name "chronic fatigue and immune dysfunction syndrome" might be more appropriate for the disease than "chronic fatigue syndrome." I am going to be talking today about my research group's investigation of two discrete outbreaks or clusters of chronic fatigue syndrome. By studying two very well-defined groups, albeit small groups, including both cases and non-cases, I think we can add another piece of useful information regarding knowledge of the epidemiology of chronic fatigue syndrome. What we have done in essence is to do a total community study in microcosm. Transmission of Lymphomas

One of the surviving patients moved to an area not far from the Lake Tahoe epidemic and sent me a clipping from a local newspaper entitled: "How Mystery Disease Hits Three Teachers". I ignored it. She sent me another clipping. This was about the Yerrington, Nevada, epidemic and was titled: "Mysterious Illness Strikes Another Town". At about that time, Dr. Paul Cheney called me to ask if I would come out and meet with him and with Dr. Dan Peterson regarding the outbreaks and I went out to visit them. Dr. Cheney thought there might be similarities between the events I reported and the outbreak he was involved with in Nevada. Thus, I thought it was intriguing. I didn't think that our epidemic in the family and his epidemic had much in common at that point, but it did make me very receptive to what happened next. Epidemic in Symphony Orchestra In the fall of 1986,1 was contacted by a member of a symphony orchestra about an outbreak of chronic fatigue syndrome in his group. Fortunately, I had been primed and thought that this would be an interesting outbreak to investigate. This person had read about our investigation of a group of nonHodgkin's lymphoma patients in the family with a common-source exposure to a relative from Africa who was ill during her visit to the U.S. When one of the symphony members with chronic fatigue syndrome developed a non-Hodgkin's lymphoma, he thought we might be interested in investigating the outbreak. Subsequently, we found eight members of the orchestra who had symptoms of chronic fatigue syndrome. The first symptoms began in August of 1984; seven affected persons were diagnosed by a local physician as having had acute infectious mononucleosis. Their ages ranged from 31 to 42 years. The eighth case was initially diagnosed as viral meningitis. Her age was 32.

I might begin by telling you how I got involved with chronic fatigue syndrome. I am a cancer epidemiologist by training and by research interest, and in 1985 I reported the story of a family that was very interesting. A woman from South Africa came to visit her family in the U.S. A few days before leaving Africa she became ill with an infectious mononucleosis-like illness. During her stay in the U.S., she visited family members in four different parts of the country and, within six to eleven months, four of the eleven persons exposed to her developed unusual B-cell lymphomas, one of which was a Burkitt's lymphoma in an adult. 1

In doing investigations of clusters, one has to be very, very cautious. For example, I make it a point never to talk to any of the patients in a cluster initially because I might lead them with questions to provide answers that I want to get to support my hypothesis. We have a space in the questionnaire which we administered to the orchestra asking "Is there any other information in particular you think we ought to

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Epidemiologic and Immunologic Findings in Clusters of Chronic Fatigue Syndrome

know about?" Through this we obtained the story that one of the members of the orchestra had become ill with a chronic fatigue syndrome-like illness after visiting a relative in South Africa, but before the outbreak in the orchestra. I think that this is probably just a chance finding. Also, he had read the story about our interesting family that was written up in TIME magazine, so probably what we got was just selective recall of events. Nevertheless, it raises the possibility that the outbreak in the symphony could have originated from an exposure in South Africa.

done by W. Carl Saxinger, Ph.D. at NIH, and EBV studies were done by Ciro V. Sumaya, M.D. at the University of Texas. All diagnoses were verified by reviewing medical records and past specimens. Dr. Robert Herfkens at Duke University did MRI scans on all eight cases; we found one case with questionable borderline frontal lobe atrophy. I am skeptical about the meaning of this abnormal finding. Working with me at the time was a very bright thirdyear medical student, Mary Huang, and a postdoctoral fellow, Dr. Nancy L. Eby, and we came up with what we thought might be a very clever design. I believe we backed into the right approach without realizing what we were doing. We wanted to study the cases, but we thought it would be very nice to have some controls; so Mary Huang said "Why don't we study the non-cases? They would be a perfect match for the cases". That led us to what I believe is our most important set of findings.

Study Design Let me describe our study design. When you do an investigation of a cluster it is so easy to lead people to give you the information that you want, that you must collect your data in a structured way. Thus, we used questionnaires rather than interviews of people for initial data collection. This is a very important point; you can structure results any way you want by asking leading questions. Use of a questionnaire also forces you to develop a priori hypotheses. In addition to the questionnaire, we did psychological testing using a self-administered scale to rule out depression. We administered a test of fatigability, the "two's and seven's test", which was developed by the U.S. Air Force.

The cases were predominantly female and all white (but all of the non-cases are white). One interesting finding that may or may not mean anything is that most of our cases were non-smokers as compared to half of the non-cases. Cigarette smoking is related to natural killer cell activity. Of interest is the observation that most of our patients met the CDC criteria, although I must say it is very difficult to use those criteria when you cannot personally examine the patients and must rely only on medical records; so this was a real problem. However, they do meet the criteria by and large.

We did immune function assays in Dr. Ronald B. Herberman and Theresa Whiteside's laboratory at the Pittsburgh Cancer Institute. Dr. Herberman is the person who discovered the natural killer cell. (The way this came about is interesting.) I was being recruited from Duke University to the University of Pittsburgh and in a meeting with Dr. Herberman, I told him about this fascinating disease. He pointed out the similarity of chronic fatigue syndrome to a syndrome one of his colleagues, Dr. Aoki in Japan, had reported and called "low natural killer cell syndrome"2. The primary symptom ofthe latter syndrome is severe protracted fatigue. Based on that, we proceeded to do immunologic studies on members of the orchestra.

We looked at EBV antibody titres in this group and we found, surprisingly, little difference between cases and controls. There are no statistically significant differences between cases and controls with regard to any of the subcategories of EBV antibodies. We also looked at HHV-6 antibodies using Dr. Saxinger's assay, where his ELISA score of 1.0 is the population norm, many of our non-cases were above the population norm but, in general, our cases were somewhat higher. Abnormal Natural Killer Cell Activity

The human herpes virus Type 6 was reputed to be a possible etiologic agent, so we looked at antibodies to that virus and, of course, we did Epstein-Barr virus (EBV) antibody studies. These were all done in leading research laboratories. HHV-6 studies were

Of great interest to us were striking abnormalities in natural killer cell activity. Amongst our eight cases we found a mean value of 51 lytic units with a range

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chronic fatigue syndrome, many have the same pattern of abnormalities as do cases in measures of their immune function.

of 13-114; the mean value concurrently measured in normal controls was 235. But surprisingly, many of our non-cases were low as well. With regard to all of the virological and immunological studies we had done, this was the only marker of disease that was statistically significantly different between cases and non-cases.

This underscores my statement about the value of studying a total community, because what we are looking at here are the findings in a group of nonaffected, but close, contacts of cases. I was skeptical about these very puzzling findings, so we searched for and found another epidemic, this time in a school.

We also looked at T4/T8 ratios and found, much to our surprise, high T4/T8 ratios in cases and in controls as well. This was not statistically significantly different between cases and controls, but this was very striking. For example, one of the highest values was a T4/T8 ratio of 11. (The upper bound of normal is usually 2.5 to 3).

I should point out that we did testing for depression; there were some slight differences between cases and non-cases which were not statistically significant. They were primarily related to the two questions on the SCL 90R: "Do you feel low in energy or slowed down?" and "Do you feel everything is an effort?". Those are symptoms of fatigue which are also symptoms of depression. Similarly, we found no differences in fatiguability between cases and non-cases using the "2s and 7s" test.

Up until now we have heard lots of reports of people presenting data on viral antibodies or measures of immune function. However, few people have put all of the data together to look at the array of laboratory studies on individual subjects. For example, for case number 44, there is very low natural killer cell activity, a very high HHV-6 ELISA score, no antibodies whatsoever against the Epstein Barr virus and a T4/T8 ratio of 11. On the other hand, case 46 has a normal level of NK activity, probably a normal ELISA score for HHV-6, but an elevated EBV IgG VCA and a normal T4/T8 ratio. And as you review our results, what you see is no consistent pattern across these variables.

Our second investigation was of an elementary school in Ohio. We had identified three clusters. Since we had no grant support, we chose the one closest to home. We didn't know what we might find, but again we found findings similar to those in the orchestra. In several cases, NK activity levels were very low, but we found the same findings in several non-cases. There was no significant difference between NK activity in cases and non-cases. T4/T8 ratios were on average a little bit above normal, but we uncovered some persons with very high values. For example, one person, had a T4/T8 ratio of 66; six months later it came down to 7, still quite high.

We can say that NK activity is significantly lower in cases than it is in non-cases, but you can't say the same about abnormal EBV studies, or the T4/T8 ratios, or for the other variables we studied. I think this is the pattern of such findings in the disease and it needs further investigation. I believe Dr. Komaroff has observed this non-pattern in his series as well. The cases of ours that went on to develop cancer were really not much different from our other cases with CFS.

When we arrayed the data in the same way as we had done for symphony subjects, we found the same patterns of inconsistent abnormalities in both cases and non-cases that we observed in the symphony. For example, here is a case with low NK activity, a normal T4/T8 ratio, and normal EBV antibody titers. An other person with high EBV antibody titers, had low NK activity, but a normal T4/T8 ratio. Again there was no consistent pattern of abnormalities in cases or in non-cases.

But things became very puzzling to us when we looked at the same array of data for non-cases. I have here some data on selected non-cases (of course, I picked the most interesting ones). As an example of our findings in this group, non-case number 26 has remarkably low natural killer cell activity, a high HHV-6 ELISA score, high IgG VCA, and a borderline-high EBV early antigen titer but a normal T4/T8 ratio. Even though these people have no evidence of

In the school group, we found perhaps even more striking findings in the non-cases than we did in the cases. We attribute this, as a guess, to the fact that

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Epidemiologic and Immunologic Findings in Clusters of Chronic Fatigue Syndrome

these studies were done about a year after diagnosis in the school study whereas the studies were done two to three years after diagnosis in the orchestra outbreak. Again we found close contacts of cases with remarkable laboratory abnormalities, yet no evidence of fatigue. One of the cases in the school was a non-white (half Black, half American Indian) so CFS does occur in non-white people.

parotid gland, an acinic cell carcinoma. It is one of the least frequent histologic types of parotid tumours and it occurred in a 41 year-old man with no overt symptoms of chronic fatigue syndrome. His wife was also an orchestra member and had chronic fatigue syndrome. Incidentally, the MRI scan of her head was the only one of those done that was read as abnormal with borderline frontal lobe atrophy. The fourth was a glioblastoma multiforme, in a 46 yearold woman with no overt symptoms of chronic fatigue syndrome. She had the highest EBV antibody titers of anybody in our study, but she never had any symptoms which could be construed as chronic fatigue syndrome.

To summarize our laboratory findings, we found inconsistent depression of NK cell activity, elevation of T4/T8 cell ratios and what appear to be secondary reactivation antibody responses to the EBV and HHV-6. Similar observations were made in cases and in close work contacts who were asymptomatic. In both cases and contacts, there was no consistent pattern of abnormalities. There is no simple unifying hypothesis which might explain this pattern of laboratory abnormalities. This led me to coin the name "chronic fatigue and immune dysfunction syndrome" in 1987 at a meeting of the (then) National CEBV Syndrome Association in Portland, Oregon. I chose the vague term "dysfunction" because it best fits the diverse and non-specific set of abnormalities observed.

Does this amount to an increased occurrence of cancer? We had complete information available for 58 members of the orchestra. We followed them from the time period 8/1/84 when the first CFS symptoms developed until the end of last year (12/31/89) and within this time window there were four observed cancers. We did an exact computation of the number of cancers we would expect to find in a group of this age/sex/race composition using U.S. national cancer incidence rates and we came up with an expectation of .37 cases. This means that there is almost eleven times more cancer in the group than one would expect. The excess is highly statistically significant. But, would I "hang my hat on it?" My answer is "No." The reason being that we found no such occurrence in the elementary school study. What this suggests is the possibility that there might be an increased frequency of malignancy with chronic fatigue syndrome. It is still an hypothesis - which is a fancy word for a somewhat educated guess. I think that it is urgently necessary to confirm or refute this hypothesis. In the meantime I wouldn't advise anybody to be concerned about an increased risk of cancer based on our findings. There are so many biases that led to my getting involved in this investigation that we have to be extremely cautious in interpreting this preliminary finding.

Now, let me address an important question. Is there an increased risk of cancer in persons with the chronic fatigue and immune dysfunction syndrome? One caveat to remember is that my area of research interest is the clustering and possible transmissibility of cancer. I was contacted by the orchestra because they had read in TIME magazine that I reported an unusual cluster of Burkitt's and other Bcell lymphomas in a family exposed to a visitor from Africa. Many of the members of this group had very high EBV antibody titers. So there could be a selection bias built into our study in that I was contacted because there was an occurrence of cancer in the orchestra and there was an outbreak of CFS which was at that time thought to be related to the EBV. When I spoke to the person who contacted me, he was only aware of one B-cell non-Hodgkin's lymphoma; we subsequently uncovered three other cancers. The first case had B-cell lymphoma. She was a 44 year-old woman with the onset of fatigue in 1984. She had an initial diagnosis of acute infectious mononucleosis. The second cancer was a breast cancer in a 38 year-old woman who was a case. This could very well be a chance occurrence. The third tumour was an extremely unusual carcinoma of the

We can also break down this analysis in terms of the occurrence of cancer in CFIDS cases and in noncases. There were two cancers in CFIDS cases. We computed the expected value and there are 48 times as many tumours in this group as would have been expected. Again this is statistically significant. For the non-cases the risk was lower; a six-fold increased

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bedroom and found that 28% of the case-case pairs had shared a bedroom, but only 5% of the non-casenon-case pairs had shared a bedroom, another statistically significant difference. We didn't have enough numbers of subjects to evaluate intimate sexual contact; they're a friendly group, but apparently not all that friendly. Basically what these figures show is that perhaps cases have had closer contact with one another than non-cases have had with one another. There's an alternative explanation of this; that is, if you look to the literature on alcoholism, alcoholics tend to befriend other alcoholics. Perhaps people with chronic fatigue syndrome tend to befriend other people with chronic fatigue syndrome to commiserate or provide moral support. So, these data must be interpreted with caution. The "flip-side" of these findings is that if we had found no such associations, that would be fairly good evidence against the notion of transmissibility of an etiologic agent. Our findings are compatible with an infectious model, but they are also compatible with an assortative friendship model as well. Nevertheless, these are the first data to suggest that there might be person-to-person transmission of an etiologic agent for this disease. This again illustrates the value of doing total community studies where you can look at people with a disease and those around them without disease.

risk. It was not statistically significant, but we're splitting small numbers here. I'm not sure this means anything except to say that if there is an increased risk of cancer with this syndrome, persons closely exposed to cases probably have an increased risk as well. However, this needs to be confirmed in other studies. Next my colleagues and I tried to develop a statistical approach to evaluate whether cases had had closer contacts with one another than non-cases had had with other non-cases. This approach is an attempt to assess possible person-to-person transmissibility of CFIDS. So we created a large grid, listing everyone's name in the orchestra. Next to each name we asked a series of questions such as: Did you know the person? Did you ever perform in a small chamber group together? Did you ever spend time together outside work? Did you travel together in a car or a bus? This is a travelling symphony, which, if CFIDS is an infectious disease, creates an interesting model. It is a low-budget travelling orchestra in which members share rooms, share cars and eat together. They have a smoker's bus and a non-smoker's bus, (remember our earlier finding on cigarette smoking - this could be related to the buses).

Conclusions We looked at the proportions of subjects answering yes to these questions. Of course everyone knew everyone else, whether they were cases or non-cases. We asked if they played together in a small chamber group and we found that 60% of the case-case pairs had played together in a small group but only 1/3 of the non-case-non-case pairs. This difference was not statistically significant. We asked whether they spent time together outside of work and came up with fairly similar results. We also asked whether they rode together in the same car, and the difference between case-case and non-case-non-case pairs turned out to be statistically significant. When we asked whether people ate together, 90% of case-case pairs did, but so did 76% of non-case pairs.

I believe the chronic fatigue and immune dysfunction syndrome is a real disease with objective laboratory abnormalities. One caveat I must state at this point is that these findings are perhaps not generalizable to all chronic fatigue syndrome cases. What I have been talking about here is the form of the disease that occurs in epidemic fashion. In clusters of cases where there is clearly a point epidemic pattern of transmission, I think our conclusions apply. Depression of natural killer cell activity appears to be the most consistent laboratory abnormality in the syndrome. It was the only one that was statistically significantly different between cases and controls even though the controls (non-cases) had low levels as well.

However, we found that almost 40% of cases had shared an eating utensil with one another case as compared to 16% of the non-case-non-case pairs. This is an intriguing difference which is highly statistically significant. We also looked at sharing of a

EBV antibody responses seen in the syndrome probably represent secondary reactivation responses. I think we all know this; I don't have to preach to the true believers. Probably, the same is true of HHV-6.

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Seymour Grufferman, MD, Dr. PH

Epidemiologic and Immunologic Findings in Clusters of Chronic Fatigue

We have observed subjects over time and have done repeat laboratory tests. The values fluctuate greatly, but these people maintain their laboratory abnormalities over time and they persist for at least two to three years. Dr. Komaroff has longer follow-up data and in his experience these abnormalities persist even longer than they do in our study. We have found that many persons with no fatigue or other symptoms of the syndrome can show the characteristic laboratory abnormalities.

Syndrome

where there are many more inapparent infections than there are apparent infections. If CFIDS does turn out to have a viral etiology, my guess is that you will find that there are many people who have had inapparent infections. Lastly, there seems to be a markedly increased risk of cancer in persons with the syndrome or in persons closely exposed to others with the syndrome. I don't think that I would say this is definitely a causal association, but I think that there is urgent need to confirm or refute this finding and I won't believe it myself until it is confirmed.

I interpret this to mean that if this is a viral disease, we're talking about a pattern of transmission analogous to that seen with herpes viruses and the EBV,

References 2. Aoki T, Usuda Y, Miyakoshi H, et al.: Low natural killer syndrome: Clinical and immunologic features. Nat Immun Cell GrowthRegul 6:116-128, 1987.

1. Grufferman S, Raab-Traub N, Marvin K, Borowitz MJ, Pagano JS: Burkitt's and other non-Hodgkin's lymphomas in adults exposed to a visitor from Africa. N Engl J Med 313:15251529, 1985.

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Chapter 18

Paul H. Levine

Epidemiologic Aspects of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis Paul H. Levine, MD From the Viral Epidemiology Section, Environmental Epidemiology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 Reprint requests to the Environmental Epidemiology Branch, Division of Cancer Etiology, National Cancer Institute, NIH, Executive Plaza North, Room 434, Bethesda, MD 20892 Dr. Levine has been with the National Cancer Institute since 1964, his past positions including Chairmanship of the Immunology-Epidemiology Segment of the Virus Cancer Program, Head of the Clinical Studies Section, Viral Leukemia and Lymphoma Branch, and Chairman of the Viral Oncology Clinical Advisory Group. He has worked for more than 15 years on studies of the Epstein-Barr virus and his current research also includes the epidemiology of human herpesvirus-6 and HTLV-I. Abstract There are at least four areas in the study of chronic fatigue syndrome (CFS) where the epidemiologist can make a contribution: (a) disease classification, (b) disease surveillance, (c) identification of risk

factors, and (d) evaluation of clinical trials. Disease classification is most critical; the process has been initiated with the working guidelines recently published by Holmes et al, in 1988.1 One useful aspect of

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international working groups could be the development of improved guidelines to subclassify CFS using subgroups such as those with or without documented immune dysfunction, etc. Disease surveillance, including the detailed description of individual clusters, is important since this can lead to clues as to specific etiologic agents. A review of published reports suggests that different patterns are associated with various clusters, indicating that different etiologic agents are producing similar but distinguishable syndromes. The identification of risk factors can best be pursued through the development of case-control studies which require a rigid case definition for each study. Our experience indicates that some of the reported risk factors, such as socioeconomic status, may reflect bias in case ascertainment and may be incorrect. Finally, the evaluation of clinical trials is particularly important because of the tendency for the patient population to utilize unproven remedies for the disease based on inadequate data. Several specific projects are suggested whereby clinical as well as laboratory investigators can resolve conflicting data on this disabling enigmatic illness.

D i s e a s e Classification Disease classification and case definition are extremely critical since little sense can be made of etiologic, diagnostic or therapeutic studies unless we have an agreed upon case definition or, at least with this multifaceted group of illnesses, an agreed upon case categorization. Table 1 lists seven commonly used terms as well as published working definitions and/or descriptions that could serve as a common starting point for investigators in different countries. Table 1 Currently Used Terms for CFS/ME with Suggested Working Definitions and/or Descriptions Chronic Epstein-Barr virus (CEBV)—See Refs. 2-7 Chronic fatigue syndrome (CFS)—See Ref. 1 Post-infectious chronic fatigue syndrome (PICFS)—See Ref. 10 Chronic fatigue/immune dysfunction syndrome (CFIDS)— See Ref. 10 Myalgic encephalomyelitis (ME)—See Ramsay, this symposium and Ref. 11

Introduction

Epidemic neuromyasthenia—See Refs. 12-23 Low natural killer syndrome (LNKS)- See Ref. 23a

An attempt to control any disease as complex as the topic of this symposium requires interdisciplinary efforts of clinicians, basic scientists, statisticians, and many others, including the patients who are affected. In this report, I would like to review the role of the epidemiologist, pointing out several areas where either epidemiology has played an important role in our understanding of the chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) or where the epidemiologist could be of value in future studies.

The first term, chronic Epstein-Barr virus (EBV) infection (CEBV), sometimes referred to as chronic infectious mononucleosis or chronic active EBV infection, has been considered as being applicable to those patients with chronic fatigue syndrome (CFS), usually post-infectious CFS (see below and Fig 1), with high antibody titers to EBV who also fulfill the criteria for CFS described in the Annals of Internal Medicine.i This well-documented disease^-" is characterized by elevated IgG antibodies to EBV capsid antigens and early antigen (EA) and may be associated with persistent IgM antibody to EBV VCA. At the National Institutes of Health, Dr. Stephen Straus and his colleagues attempt to document EBV activity by demonstrating increased quantities of EBV in affected tissues by anticomplementary immunofluorosecence or nucleic acid hybridization^ but these findings cannot be documented in most clinical settings. An abnormally low antibody titer to an EBV induced nuclear antigen (EBNA-1) has been suggested as being a manifestation of CEBV«,s but this

First, as documented in this symposium whereby several investigators described their preference for the term chronic fatigue syndrome or myalgic encephalomyelitis based on their views of pathogenesis, it is quite likely that we are discussing a multiplicity of entities. One extremely important outcome of a meeting such as this could be to clarify and categorize as many of these entities as possible since it is quite clear that the triggering infectious agents vary, as discussed below, and therefore it is quite possible that the pathogenesis and approach to therapy also could vary.

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Figure 1

One of the most important steps toward a case definition for the second widely used term, CFS, was made by Dr. Gary Holmes and his associates in 1988 when they developed a working definition for research purposes.i The terms working definition and research purposes need to be emphasized. The authors fully understood the limitations of their definition and developed it with the understanding that it would require modification with the appearance of new information similar to the evolving Jones criteria for rheumatoid arthritis.

PROPOSED INTER-RELATIONSHIP OF CHRONIC FATIGUE SYNDROMES

The definition probably continues to be too all encompassing and still allows the inclusion of a multiplicity of diseases; it also does not take into consideration the co-existence of any of the exclusionary diagnoses with CFS. However, since it was specifically developed as a tool for investigators, it provides guidelines for research efforts and it is very encouraging to see so many reports in this symposium referring to these guidelines. Two relevant points to be emphasized are (a) these criteria are not adequate for clinical diagnosis in an office setting, and (b) all of the criteria are either symptoms reported by the patient or findings observed by the physician. There are no laboratory tests that are included in these criteria and as you have heard from others in this symposium (see Gupta, Chapter 58, this symposium), there are no laboratory tests at the present time that are diagnostic of CFS.

Schematic diagram of inter-relationship among clinical syndromes related to myalgic encephalomyelitis I chronic fatigue syndrome. In this concept, chronic fatigue syndrome and myalgic encephalomyelitis (CFS I ME) are considered to be interchangeable terms for a loosely defined constellation of signs and symptoms. Within the CFS I ME spectrum are two distinct and overlapping groups: a) Chronic fatigue / immune dysfunction syndrome (CFIDS), which is associated with well documented abnormalities of the immune system, and b) Postinfectious CFS I ME which has an acute onset associated with signs and symptoms of an infection. In some cases, the precipitating agent can be identified, as exemplified in this diagram by Lyme disease, brucellosis, and chronic EBV infection. Not all patients with these illnesses have the signs and symptoms of CFS I ME and therefore are not incorporated in the CFS I ME patient population. Similarly, many reports of "epidemic neuromyasthenia" do not fulfill current criteria for CFS I ME and "epidemic neuromyasthenia" also appears to include a heterogeneous group of illnesses. Low natural killer syndrome, which is primarily defined in the laboratory, currently appears to be a subset of CFIDS.

The third term, post-infectious chronic fatigue syndrome (PICFS), describes a subset of CFS patients whose illness began abruptly after an acute infection. Acute onset is only a minor criterion for CFS1 and there is some rationale for specifying those patients whose illness began abruptly after an infectious illness. We have offered a definition for PICFS in our recent review of this syndrome,io emphasizing our preference for post-infectious rather than post-viral CFS because there are no clear distinctions between the syndrome following a documented viral illness, as with EBV, cytomegalovirus (CMV), or human herpesvirus-6 (HHV-6), as compared with the illness following Brucella or Borrelia burgdorferi (Lyme disease).

has not been a consistent finding (Pearson, personal communication). Persistent elevated EBV titers alone may not be diagnostic of CEBV, however, since patients with immunological disorders may have elevated antibody titers to a number of viruses.

Continuing the separation of CFS into subgroups, one major subgroup has been termed chronic fatigue/ immune dysfunction syndrome (CFIDS). It is not appropriate to use CFIDS interchangeably with CFS

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because there are people with classic CFS who do not have any evidence of immunologic dysfunction. Furthermore, there is considerable uncertainty as to the specific immunologic abnormalities found in this illness. An informative review by Dr. Dedra Buchwald, who summarized the results of 45 papers in a review of PICFS,"> documented the varying results in laboratory oriented studies and, as also noted by others in the symposium, some of the reasons for these discrepancies are obvious; heterogeneity of case definition and absence oflongitudinal studies with clinical/ laboratory correlation are two of the most important.

of epidemic neuromyasthenia in nurses, the total duration of symptoms lasted 6-12 weeks, far less than the six months required for the diagnosis of CFS. Future investigations of apparent outbreaks should carefully document the clinical features in the context of the working definition so that outbreaks of epidemic neuromyasthenia can be documented as either being associated with CFS or representing another illness. In general, the distinction of epidemic CFS from the sporadic cases is very important since the etiologic agents are likely to be different.10 Herpes viruses such as CMV, HHV-6, and EBV have been documented as causing mononucleosis which can persist as classical CFS. These are ubiquitous herpes viruses to which virtually everyone has been exposed by the age of 10 and therefore it is highly unlikely that the herpes viruses that are associated with the sporadic cases of CFS are in any way related to clusters of disease.

Regarding myalgic encephalomyelitis (ME), since this is a term that is not often used in the United States, it is more appropriate for those evaluating ME patients to provide the current working diagnosis. The definition utilized by Professor Ramsay, presented at the beginning of this conference (see Ramsay, Chapter 7, this symposium), is very appealing since it coincides so closely with the definition of PICFS and, in particular, the case definition we have developed for the Lake Tahoe cluster (see below). 10 As Dr. Peter Snow pointed out in his presentation (see Snow, Chapter 11, this symposium), however, many consider the classic case to be that of Tony Jeffreys, who described her illness in detail in The Mile High Staircase.u This case report is of great interest because the onset contrasts markedly with that proposed by Dr. Ramsay. Instead of an infectious disease precipitating her illness, Mrs. Jeffreys describes an onset with periodic attacks of abdominal pain not accompanied by evidence of infection. Since Dr. Bell, in his presentation (see Bell,Chapter 19, this symposium), noted a different pattern between his CFS patients with acute and gradual onset, it could be of value if ME investigators maintained separate analyses of patients with acute and gradual onset since they may be distinct entities.

Finally, low natural killer syndrome (LNKS) is an illness described primarily in Japanese patients with prolonged fatigue and low grade fever, often accompanied by upper respiratory signs and symptoms (including pharyngitis and/or tonsillitis) as well as nervous system abnormalities (headaches, dizziness and/or depression)23® The common feature characterizing this illness is low natural killer (NK) cell activity. Thus far, it appears that the laboratory abnormalities appear similar to those described for a large number of patients with CFIDS and therefore LNKS may prove to be a sub-group of CFIDS. Disease Surveillance One of the most common questions that epidemiologists are asked regarding CFS is, "How common is this illness?" Because of the variability in defining this syndrome, variations in incidence and prevalence data are likely to occur in different studies. Lloyd et al 24 attempted to determine the prevalence of CFS in an Australian population but used a definition of the syndrome quite different from the CDC definition;! only unexplained fatigue lasting greater than six months and neuropsychiatric dysfunction were required for the diagnosis. Of the 28 patients appearing for an interview, 21 (25%) gave no history of an acute onset or evidence of infection, therefore emphasizing the heterogeneity of the study population. The prevalence rate of 37.1 cases / 100,000

The sixth common term that appears to have merit currently is epidemic neuromyasthenia, which often (but with important exceptions) is a cluster of PICFS cases occurring as an outbreak with a defined onset and a defined conclusion. A careful review of the reports of epidemic neuromyasthenia and related clusters 12-23 reveals that some have the clinical features of CFS as defined by Holmes et al and could therefore be called epidemic CFS but others do not. Dillon et al 21, for example, note that in their outbreak

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The Clinical and Scientific Basis of M.E. / CFS

estimated in this study, therefore, must be viewed with caution.

A somewhat easier surveillance task is the evaluation of clusters, since the symptom complex is likely to be more uniform. Epidemic neuromyasthenia is not a new problem, having been reported as far back as 1934 in Los Angelesi2 and in a number of subsequent publications. 13-23 The careful evaluation of a cluster is most likely to give clues to the etiology of an individual outbreak of CFS because it should allow a better case definition of a relatively defined group of patients. It is quite likely that various outbreaks of CFS have distinct etiologies and, in fact, both the literature and our own experience indicate that multiple agents are likely to trigger epidemic neuromyasthenia. The importance of developing a systematic approach to the evaluation of clusters cannot be overemphasized. There are certain features of the clusters we observed in Nevada and California, described in part elsewhere, 26-29 which illustrate approaches to the evaluation of other clusters, should they be identified. Briefly, as shown in Table 2 and Fig 2, outbreaks of chronic fatigue following an acute

A study being conducted by CDC 25 which is still in progress is utilizing the 1988 case definition published by CDC and collaborators!. This project, initiated September 1,1989 in four surveillance sites (Atlanta, GA; Grand Rapids, MI; Reno, NV; and Wichita, KS), has a detailed clinical, psychological and laboratory evaluation which results in four discrete groups of cases based on the features compatible with or inconsistent with the 1988 case definition. Thus far, incidence and prevalence data are not available but of the 250 patients classified by the surveillance system, 42% "suffer from debilitating chronic fatigue without either a likely physical cause or any prior diagnosable psychological condition" and most of these (26% of the total group) meet the 1988 CFS case definition. Since referrals continue from these four areas at a rate of 15-20 per month, useful information from this well defined group is expected.

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Epidemiologic Aspects of CFS / ME

Paul H. Levine, MD

identified by Drs. Peterson and Cheney were in the area of their internal medicine practice in Incline Village, NV, an outbreak which appeared almost the same time as another one in Truckee, CA. A separate outbreak was subsequently noted in Yerington, NV, a working class community where farming is the major occupation, and was reported to Dr. Cheney by Dr. Judy Hilbish, a local physician who had noted a high frequency of atypical lymphocytosis in the community hospital laboratory with the concomitant, apparent increase in CFS. The fourth community, Placerville, CA, which is on the other side of the Sierra Nevada Mountains, was brought to Dr. Cheney's attention by one of his patients, and was associated with a giardiasis outbreak documented in local newspapers.si The case definition we developed for the Lake Tahoe c l u s t e r ' 0 consisted primarily of an acute onset following signs or symptoms of infection, severe pain (headache and/or myalgia), prolonged fatigue and cognitive dysfunction. This is very similar to the case definition for ME reported by Dr. Ramsay as well as for certain outbreaks of epidemic n e u r o m y a s t h e n i a , 18,32 but it is quite different from those reported by other investigators (see below).i3-is, 19, 21 Evidence of concurrent familial infection was one feature of epidemic CFS we observed occasionally in Nevada and California, such as the following:

Table 2 Chronology of Events in the Nevada/California Cluster Late 1984 -

Incline Village, NV - first cases of chronic fatigue syndrome reported by Drs. Cheney and Peterson.

Fall 1984 -

Truckee, Calif - Two students noted to have unusually persistent symptoms during an outbreak of infectious mononucleosis.

February 1985 -

Truckee, Calif - First two faculty members affected with chronic fatigue syndrome.

Spring and Summer 1985 -

October/ November 1985 Late Fall 1985 -

February/ March 1986 -

Incline Village, NV - In March/April, rising case production first noted and Drs. Chenev and Peterson suspect an epidemic of chronic fatigue syndrome. In June, the number of cases peaked. Incline Village, NV - Number of new cases notably declined. Yerington, NV - "Outbreak" initially flulike in type, with atypical lymphocytosis and positive mono-spot tests observed in record numbers. Placerville, Calif - Outbreak of chronic fatigue syndrome "coincident with a heavy contamination of the local, unfiltered water supply."

Family 1 (Truckee, Calif)

infectious episode occurred in four communities within 90 miles of Lake Tahoe between late 1984 and early 1986, the first cluster being identified in the Incline Village, Nevada community by Drs. Daniel Peterson and Paul C h e n e y . 2 6 , 2 7

This 44-year-old white female school teacher first became ill in June 1985 with fatigue, headache, lymphadenopathy, sore throat, earache and night sweats. Associated symptoms included loss of memory and coordination, sleeplessness, depression, and tingling and numbness in her arms and legs. Evidence of a cognitive disorder included frequent word reversal and loss of ability to type or proofread. Her illness occurred coincidentally with a similar disease in other faculty members. She had previous symptoms diagnosed as mononucleosis in 1963 but had recovered without apparent residual signs or symptoms. Improvement was noted in the spring of 1986 and the patient was able to return to work in September. She has remained fairly well since then, but continues to complain of fatigue and occasional insomnia. Her 12 year-old daughter became ill in May 1985 with fatigue associated with sore throat, lymphadenopathy, headache, myalgia, and an outbreak of oral herpes. However, her illness was severe

The first epidemiologic investigation of the Lake Tahoe cluster occurred in September 1985 when Dr. Gary Holmes and his colleagues interviewed by telephone 134 patients who had Epstein-Barr virus serology testing between January 1 and September 5, 1985, which was very early in the outbreak. In their report,28 they concluded that, indeed, there appeared to be an epidemic or an outbreak of CFS and that this outbreak was associated with an elevation of antibodies to Epstein-Barr virus and other viruses as well. In 1986, shortly after the discovery of HHV-6,30 my colleague Robert Biggar and I went to Incline Village to attempt to develop a case definition for future laboratory studies. The particular goal of this trip was to interview a series of patients from the four sites noted on Fig 2. The original outbreak

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The Clinical and Scientific Basis of M.E. / CFS

for only two weeks and recovery was complete within seven months.

both were infected from a common source. Furthermore, while it is readily apparent that sporadic CFS is not contagious, these family studies also indicate that host factors play a significant role in determining the clinical outcome.

Family 2 (Yerington, NV) This 22-year-old white female, mother of three children and employed in several part-time jobs, suddenly became ill November 25,1985 noting that "My head felt like it was going to explode." She complained of tightness of her neck, nausea, anorexia and disorientation. There was transient improvement but one month later she relapsed with a sore throat, fatigue and depression. Her symptoms again improved until July 1986 when she had a recurrence of aches, weakness, loss of strength, sore throat and lymphadenopathy. She was treated with Acyclovir with little effect. On July 9 symptoms increased and she became tired, depressed and almost suicidal. In August the headache was still present. When she was interviewed in October 1986 she continued to be depressed and had the feeling of "Not being all here, spacey." In the subsequent ten months she gradually improved and at last follow-up, 2 1/2 years after disease onset, she had recovered almost completely with persistent fatigue her principal remaining symptom. The patient's brother, a 25-year-old power plant worker, became ill at the same time (November 1985) with fever and aching joints, but his symptoms lasted only two days. Their mother, a 46-year-old bookkeeper, subsequently became ill in December 1985 with a sore throat and a positive mono-spot test. Approximately one week after the onset of symptoms, the mother became anorexic and extremely depressed with crying episodes. She tried to return to work butwasunabletoconcentrateonher accounting. She also noted myalgia and tiredness in her arms, being unable even to lift a laundry basket. Normal activities and concentration on numbers, part of her work as a bookkeeper, were impossible during the course of her illness. Her symptoms gradually diminished over the next year, although at last follow-up she still complained of proximal muscle weakness and loss of concentration.

Just as one must have a case definition for the description of a disease, one also needs a case definition for the description of a typical case in a cluster. Table 3 contrasts our case definition with the definition that we find from reading descriptions of some of the other clusters reported in the literature. 12-16,19,21 As noted in Table 3, for example, in one of the classic cases of epidemic neuromyasthenia, designated Iceland disease, a more gradual onset was observed and no cognitive disorder was noted. The groups studied by Shelokov19 and by Dillon et al2' reported as epidemic neuromyasthenia also were notable for an absence of changes in cognitive functions, a major feature in Incline Village, Truckee, Yerington, and also in Punta Gorda, FL. 18,32 Table 3 Comparative F e a t u r e s of E p i d e m i c N e u r o m y a s t h e n i a Reports Acute Onset Akureyri, Iceland (1948-9) Sigurdsson et al

Although these family studies suggest that a single agent produced CFS in one or two family members and a less severe illness in other family members, it is not possible to determine whether the agent was passed from one family member to another or whether

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Epidemiologic Aspects of CFS / ME

Paul H. Levine, MD

Psychologic Predisposition.—The possible importance of psychologic predisposition, which is quite controversial, seems to be well documented in the literature. The series of r e p o r t s 3 5 - 3 8 on brucellosis and influenza that suggest a psychological role in postinfectious CFS are very informative. Imboden et al, 2i,38 stimulated by the finding of a psychological profile suggesting greater depression in patients with more severe brucellosis in the Frederick community 35-37, developed a prospective study evaluating psychologic profiles in a series of 600 subjects prior to the arrival of the Asian influenza outbreak in 1957-58. Their observation that a psychologic profile "characteristic of depression-prone patients" was associated with a more severe course of influenza is frequently cited as evidence for a psychologic predisposition to CFS. As with other aspects of CFS, more standardized psychological and neurological evaluation of patients with this syndrome is needed.

Identification of Risk Factors As with disease surveillance, the problems of case definition have caused major difficulties in defining risk factors for CFS/ME. There are, however, some recent data that confirm certain reported risk factors and cast doubts on others. Age/Race/Sex.—In terms of age, race, and sex, the disease apparently has been diagnosed more often in young white females than any other group. It has a wide age spectrum, being increasingly documented in the pediatric population (Bell, Chapter 19,this Symposium24,33,34) and in patients above age 50 (10% ofthe patients studied thus far by Gunn et al 25X Racial predisposition is currently uncertain. DuBois reported in 19843 that CFS was rarely seen in black patients in his internal medicine practice, which has an almost equal proportion of black and white patients. More recently, in reviewing his case material, Dr. DuBois reported that of approximately 200 patients with CFS that he has seen since 1982, fewer than five were black (DuBois, personal communication). There continues to be the possibility of a referral bias, however, and therefore racial/ethnic predisposition is currently under active investigation.

Endocrine Pattern.—Recent data'w suggest that patients with CFS have impaired activation of the hypothalamic-pituitary-adrenal axis. A study of 30 p a t i e n t s and 72 controls demonstrated mild glucocorticoid deficiency and enhanced adrenocortical sensitivity to exogenous ACTH, among other findings. The authors were unable to define the precise nature of the defect or its etiology, noting that such abnormalities could be compatible with a viral infection.

Socioeconomic Status.— Most articles, particularly in the lay press, will say that CFS/ME is a disease primarily of people in upper/middle socioeconomic groups. Our experience in Yerington, Dr. Snow's in New Zealand (see Snow, Chapter 11,this symposium), and reports from upstate New York (34; see Bell, Chapter 19, this symposium) and Australia 24 would suggest that the apparent predominance of patients in upper socioeconomic strata is more a matter of referral patterns than incidence. This illness may be more readily identified in very motivated active individuals, often in a situation where even a moderate change in life style is much more handicapping because of the goals and motivations of the patient. Such a pattern, described in sheepherders by Dr. Snow, may affect the apparent epidemiologic pattern in the United States.

Evaluation of Clinical Trials Identification of active therapeutic agents is an important area of research that requires considerable expertise. Thus far, several studies have shown gamma globulin to have temporary benefit in some p a t i e n t s 4 o , 4 i and antidepressants may also be efficacious in improving sleep patterns4i but other agents, such as A c y c l o v i r , 4 2 have been disappointing. Epidemiologists have played major roles in the development of clinical trials in a number of areas, such as cancer chemotherapy, and their assistance in clinical trials involving CFS could be particularly helpful in view of the importance of case definition, study design, and statistical evaluation of the results. The placebo effect in clinical trials is quite s t r o n g 4 2 and the utilization of the cross-over method whereby the patient serves as his/her own control is one that appears particularly well suited to CFS trials. Anecdotal studies on a few patients or uncontrolled thera-

Genetics.—A third risk factor appears to be genetic predisposition, suggested by an association with allergies. Several studies, such as those of Jones and Straus,1? describe signs and symptoms of allergy in approximately 75% of patients with apparent EBV associated CFS.

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using the comprehensive center approach that is now being used for cancer patients. Closer communication between investigators in the field and in the laboratory are critical, particularly in the workup of clusters. Laboratory investigators need to alert field workers to the appropriate biologic specimens and field workers need to collect and transmit to the laboratory full clinical and epidemiologic data. Specific check lists should be developed for each cluster, with particular attention to cognitive disorders since these findings are often striking but need to be carefully and systematically evaluated.

peutic trials should be viewed with suspicion in view of the variable course of this illness. Summary As our understanding of CFS improves with the multifaceted approach represented by the many studies described in this symposium, it is important that attention be paid to scientific principles. This meeting has shown increased attention to case definition, selection of controls, objective measurements, etc. which have set the stage for improved communication among various disciplines and investigators in various countries. Further standardization of terminology and techniques are now needed to accelerate the collection of useful data. Among the issues to be addressed are: (a) more detailed definition of study populations; (b) standardization of data collection, including neuropsychiatric, as well as immunologic data; (c) development of serum banks with standardized data collection to allow comparison of different populations; (d) development of more detailed protocols for patient identification, perhaps

Other manuscripts in this symposium have addressed these and other issues important to the control of CFS. The opportunity to facilitate collaborative efforts afforded by symposia such as this one should continue to improve our understanding of this complex problem. Aknowledgement: The author thanks Dr. Stephen E. Straus for helpful comments.

References 1. Holmes GP, Kaplan JE, Nelson MG, et al: Chronic fatigue syndrome: a working case definition. Annlnt Med 1988;108:387389.

8. Miller G, Gorgen E, Rowe D, et al: Selective lack of antibody to a component of EB nuclear antigen in patients with chronic active Epstein-Barr virus infection. J Infect Dis 1987;156:26-35.

2. Tobi M, Morag A, Ravid Z, et al: Prolonged atypical illness associated with serologic evidence of persistent Epstein-Barr virus infection. Lancet 1982;1:61-64.

9. Henle W, Henle G, Andersson J, et al: Antibody responses to Epstein-Barr virus-determined nuclear antigen (EBNA)-l and EBNA-2 in acute and chronic Epstein-Barr virus infection. Proc Natl Acad Sci USA 1987;84:570-574.

3. DuBois RE, Seeley J, Brus I, et al: Chronic mononucleosis syndrome. South Med J 1984;77:1376-1382.

10. Levine PH, Krueger GRF, Kaplan M, et al The postinfectious chronic fatigue syndrome. In: Ablashi DV, Faggioni A, Krueger GRF, et al, eds. Epstein Barr Virus and Human Disease. Crescent Manor, NJ:Humana Press; 1989:405-438.

4. Jones JF, Ray CG, Minnich LL, et al: Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses; elevated anti-early antigen antibodies. Ann IntMed 1985;102:1-7.

11. Jeffreys T. The Mile High Staircase, Hodder and Stoughton, Auckland, 1982.

5. Straus SE, Tosato G, Armstrong G, et al: Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Int Med 1985;102:7-16.

12. Gilliam AG: Epidemiologic study of epidemic diagnosed as poliomyelitis, occurring among personnel of Los Angeles County General Hospital during the summer of 1934, bulletin 240. Washington, DC, US Public Health Service, Division of Infectious Diseases, Institute of Health, 1938; 1-90.

6. Straus SE: The chronic mononucleosis syndrome. J Infect Dis 1988;157:405-412. 7. Jones JF, Straus SE: Chronic Epstein-Barr virus infection. Ann Rev Med 1987;38:195-209.

13. Sigurdsson B, Sigurjonsson J, Sigurdsson JH, et al: A disease epidemic in Iceland simulating poliomyelitis. Am JHyg 1950;52:222-238.

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Paul H. Levine, MD

14. White DN, Burtch RB: Iceland disease: a new infection simulating acute anterior poliomyelitis. Neurology 1954;4:506-516. 15. Sigurdsson B, Gudmundsson KR: Clinical findings six years after outbreak of Akureyri disease. Lancet 1956;1:766-767. 16. The Medical Staff of the Royal Free Hospital: An outbreak of encephalomyelitis in the Royal Free Hospital Group, London, in 1955. Br Med J 1957;2:895-904. 17. Galpine JF, Brady C: Benign myalgic encephalomyelitis. Lancet 1957;1:757-758. 18. Poskanzer DC, Henderson DA, Kunkle EC, et al: Epidemic neuromyasthenia: an outbreak in Punta Gorda, Florida. NEngl

28. Holmes GP, Kaplan JE, Stewart JA, et al: A cluster of patients with a chronic mononucleosis-like syndrome. JAMA 1987;257:2297-2302. 29. DaughertySA, Henry BE, Peterson DL,etal: Chronic fatigue syndrome in Northern Nevada. Rev InfDis 1991; 13:S39-S44. 30. Salahuddin SZ, Ablashi DV, Markham PD, et al: Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 1986;234:596-601. 31. Placerville Record, July, 1986. 32. Roueche B, ed. In the Bughouse. In: The Orange Man. Boston: Little, Brown and Co.; 1965:95-115.

J Med 1957;257:356-364. 19. Shelokov A, Habel K, Verder E, et al: Epidemic neuromyasthenia: an outbreak of poliomyelitislike illness in student nurses. NEngl J Med 1957;257:345-355. 20. Acheson ED: The clinical syndrome variously called benign myalgic encephalomyelitis, Iceland disease and epidemic neuromyasthenia. Am J Med 1959;26:569-595.

33. Dale JK, Straus SE: The chronic fatigue syndrome: Considerations relevant to children and adolescents. Adv in Pediatric Infectious Diseases 1992;7:63-68. 34. Bell KM, Cookfair D, Bell DS, et al: Risk factors associated with chronic fatigue syndrome in a cluster of pediatric cases. Rev InfDis-, 1991; 13:S32-S38.

21. Dillon MJ, Marshall WC, Dudgeon JA, et al: Epidemic neuromyasthenia: outbreak among nurses at a children's hospital. Br Med J 1974;1:301-305.

35. Trevor RB, Cluff LE, Peeler RN, et al: Brucellosis I. L a b o r a t o r y - a c q u i r e d a c u t e i n f e c t i o n . Arch Int Med 1959;103:381-397.

22. Behan PO, Behan WMH, Bell EJ: The postviral fatigue syndrome—an analysis of the findings in 50 cases. J Infect 1985;10:211-222.

36. Cluff LE, Trevor RW, Imboden JB, et al: Brucellosis II. Medical aspects of delayed convalescence. Arch Int Med 1959;103:398-405.

23. Henderson DA, Shelekov A: Epidemic neuromyasthenia: clinical syndrome? N Eng J Med 1959;260:757-764.

37. Imboden JB, Canter A, Cluff LE, et al: Brucellosis III. Psychologic aspects of delayed convalescence. Arch Int Med 1959;103:406-414.

23a. Aoki T., Usuda Y., Miyakoshi H., et al: LNKS: Clinical and immunologic features. Nat Imun Cell Growth Regul 1987;6:116-128.

38. Imboden JB, Canter A, and Cluff LE: Convalescence from influenza. Arch Int Med 1959;108:115-121. 39. Demitrack M, Dale J, Straus E, et al: Evidence for Impaired Activation of the Hypothalamic-Pituitary-Adrenal Axis in Patients with Chronic Fatigue Syndrome. J Clin Endocrinology and Metabolism 1992;73:1224-34.

24. Lloyd AR, Hickie I, Boughton CR, et al: Prevalence of chronic fatigue syndrome in an Australian population. Med J Australia 1990; 153:524-528. 25. GunnWJ, Randall B,ConnellD: Progress Report: Chronic fatigue syndrome surveillance and long term follow-up system. Centers for Disease Control and Abt Associates, 1991.

40. DuBois RE: Gamma globulin therapy for chronic mononucleosis syndrome. AIDS Res 1986;2:S191-S195.

26. The Sacramento Bee, Mystery sickness hits Tahoe, October 11, 1985, pp Bl.

41. Gantz NM, Holmes GP: Treatment of patients with chronic fatigue syndrome. Drugs 1989;38:855-862.

27. Barnes DM: Mystery disease at Lake Tahoe challenges virologists and clinicians. Science 1986;234:541-542.

42. Straus SE, Dale JK, Tobi M, et al: Acyclovir treatment of the chronic fatigue syndrome: lack of efficacy in a placebo controlled trial. N Eng J Med 1988;319:1692-1698.

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Section 7

Children and Students with M.E. / CFS

David S. Bell, MD

Children with M.E. / CFIDS: Overview and Review of the Literature

Chapter 19

David S. Bell

Children w i t h Myalgic Encephalomyelitis / Chronic Fatigue-Immune Dysfunction Syndrome: Overview and Review of the Literature David S. Bell MD, FAAP Department of Pediatrics, Cambridge Hospital and Mount Auburn Hospital, 1493 Cambridge Street, Cambridge, Massachusetts 02139 USA Dr. Bell has spoken throughout the United States and internationally on M.E. / CFS. His publications on CFS have appeared in numerous journals, including Annals of Internal Medicine, American Journal of Epidemiology, and Journal of Infectious Diseases. Abstract Myalgic Encephalomyelitis / Chronic Fatigue Immune Dysfunction Syndrome (ME I CFIDS) is a serious chronic illness that affects children as well as adults, occurring in epidemics or as sporadic cases. In children the illness is rare under the age offive and presents most commonly at puberty. Males and females are equally affected. Long term morbidity is common because ofpersisting somatic symptoms, prolonged school absence and abnormal cognitive function. The most common misdiagnosis in children with ME / CFIDS is school phobia.

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Of the more than fifty epidemics described, many have been community based outbreaks involving large numbers of children. Several of these outbreaks are reviewed, as well as the literature on Juvenile Primary Fibromyalgia Syndrome, which may represent the same condition. The 1985 epidemic in Lyndonville, New York is reviewed, and 104 patients were identified who retrospectively met the current disability and symptom criteria of the Centers for Disease Control. Forty-four patients were children, representing 42% of the total. Of the children, 35% had an acute onset of symptoms while 65% had a gradual onset of symptoms. All children were followed for at least 27 months, and only 8 children (18%) described complete resolution of symptoms and considered themselves well. ity of papers are reports of epidemics involving both children and adults. Several reports have emphasized possible etiologic agents and have included data on children as well as adults. Examples of this type of study are the papers implicating Enterovirus and Epstein-Barr virus. There have been several reports on Primary Juvenile Fibromyalgia Syndrome in the rheumatology literature which bear striking similarities to ME/CFIDS. Finally, there have been scattered editorials or case reports concerning ME/ CFIDS in children. Papers from this last category will not be discussed in this paper.

I. Overview Myalgic Encephalomyelitis (ME), also known as Chronic Fatigue-Immune Dysfunction Syndrome (CFIDS) is a discrete clinical entity of numerous signs and symptoms affecting children as well as adults. The majority of published reports concerning ME/CFIDS have concentrated on the adult population, but some studies have reviewed the pediatric presentation 12 . The purpose of this paper is to review the clinical presentation of 44 children affected during the Lyndonville, New York outbreak, and to review the literature concerning this illness in children.

The greatest obstacle in evaluating the literature on ME/CFIDS is the varying approach in diagnosis and clinical description. Some authors have concentrated on neurologic symptoms, as in the early clusters associated with acute anterior poliomyelitis. Other descriptions have stressed the rheumatologic symptoms, such as the reports of primary juvenile fibromyalgia syndrome. ME/CFIDS needs to be more precisely defined so that future outbreaks may be quickly recognized and appropriate etiologic and epidemiologic studies may be carried out. The reader is referred to several comprehensive reviews for a more thorough discussion of ME/CFIDS in adults 3 8.

In general, the symptoms of ME/CFIDS in children are similar to those of adults. Differences from the adult presentation include a greater incidence of gradual onset of symptoms, and a more equal sex distribution. Children, especially younger children with gradual onset describe less fatigue, perhaps because of a relative lack of a healthy reference activity level. School difficulties are common because of prominent somatic symptoms, prolonged school absence, and cognitive disturbances. Perhaps the most common misdiagnosis in the school age child is depression or school phobia. While children may manifest emotional symptoms after the onset of their illness, the pattern of these symptoms differs from primary depression. School phobia is frequently diagnosed because of school absence and a relatively normal physical and laboratory examination. However, children with ME/CFIDS fail to show evidence of separation anxiety. In addition, family dynamics are normal, and there is no precipitating emotional event frequently seen in school phobia. The diagnosis of school phobia should not be a "diagnosis of exclusion", and should not be made without evidence of a primary emotional disturbance.

From 1983 through 1987 an outbreak of ME/CFIDS occurred in upstate New York, centered around the rural farming community of Lyndonville on the southern border of Lake Ontario. During this period over two hundred persons developed an illness characterized by a specific symptom complex. Over thirty persons, including at least eight children, have developed the illness since December 1987 and are not included in this survey.

The literature on ME/CFIDS in the paediatric age group has fallen into several categories. The major-

The diagnostic criteria originally used to establish the diagnosis are based upon this specific symptom

II. C l i n i c a l P r e s e n t a t i o n i n Lyndonville, N e w York

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complex9. These criteria were developed in 1986, prior to the current criteria established by the Centers for Disease Control10. The 104 patients included in this survey were retrospectively selected so as to conform to the CDC criteria of fatigue severity and symptom pattern. However, the majority have not had the extensive exclusionary laboratory tests as required by the CDC criteria. It is estimated that at least an equal number of persons, not included in this review, developed a similar symptom complex which was mild and/or of short duration.

had an acute onset of the illness with a "flu-like" illness. There was no sex prevalence observed in the type of onset. Fifteen of the children (34%) were between the ages of 9 and 11 at the time of onset (Table 2). The dates of onset of all cases, adult and children, are presented in Table 3. Twenty nine of the children in this study (66%) have had at least one other family member with a similar symptom complex. Table 2 Age at Onset, Lyndonville Outbreak (Children only)

Table 1 Number of Cases

Diagnostic Criteria 1. Symptoms P r e s e n t for at least 6 months. 2. Six of Eight Major Symptoms Fatigue Neurologic Symptoms Headache Joint Pain Muscle Pain Lymph Node Pain Sore Throat Abdominal P a i n

0-5

6-8

9-11

12-14

15-17

18

3. Or 5 of 8 Major plus 2 of 3 Minor Symptoms Eye P a i n / Photophobia

Age at Onset

Fever / Chills / Night Sweats Rash

Table 3 Lyndonville, NY Outbreak: Date of Onset One hundred four patients were selected, and all met the "Lyndonville Criteria" shown in Table 1. Of the 104 patients, 44 were children, representing 42% of the total. Of these 44 children, 29 (66%) met all eight major symptom criteria, 7 (16%) had seven major symptoms, and 8 (18%) had six major symptoms. 37 children (84%) had at least two of the three minor symptom criteria. In this study, no child required the inclusion of minor symptom criteria to make the diagnosis. Comparison of adults and children in the Lyndonville outbreak showed a similar pattern of symptoms, but children had a greater number of individual symptoms than adults (data not shown).

Number of Cases 30 25 20 15 10 5

0 Seventeen of the children were male (39%) while 27 were female (61%). The majority (66%) had a gradual onset of symptoms over several months, while 34%

Cases

1-6/83 1-6/84 1-6/85 1-6/86 1-6/87 1-6 7-12/83 7-12/84 7-12/85 7-12/86 7-12/87

Date of Onset

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All children described numerous symptoms which fit a consistent pattern. All complained of marked fatigue and headache, and most had neurologic complaints including loss of short term memory, dyslogia, paresthesias, weakness, dizziness and word finding difficulties. Most had a disturbed sleep pattern characterized by non-restorative sleep and episodes of hypersomnolence, insomnia or both. Other prominent symptoms included joint and muscle pain, abdominal pain, recurrent sore throat, lymphodynia, eye discomfort and sensation of abnormal temperature. The frequency of symptoms in these children is shown in Table 4. Table 4

III. E p i d e m i c s of M.E. / CFIDS I c e l a n d (Akureyri) D i s e a s e

Lyndonville Epidemic Symptoms in 44 Children Fatigue Headache Neurologic Memory Loss Dyslogia Sore Throat Abdominal Pain Muscle Pain Joint Pain Lymphodynia Photophobia Eye Pain Rash "Fever" Night Sweats Emotional Change Chills Dysuria

illness and 3) a history of drinking unpasteurized milk prior to onset of illness. Numerous other factors, including socio-economic status, exposure to pesticides, type of drinking water, and location of dwelling (rural or town) were not significant. While cultures of raw milk from cows and goats in the area revealed Camplobacter, Yersinia enterocolitica, Shigella and Salmonella species, there have been no significant outbreaks of illness caused by these pathogens. The link with unpasteurized milk remains unexplained.

While there have been reports of epidemics of ME/ CFIDS extending back to the 1930's, perhaps the largest and best recognized epidemic to involve children occurred in Akureyri on the Northern coast of Iceland in 1948. The illness, reported by Sigurdsson et al12, became known as Iceland Disease and affected over 1000 persons, nearly half of them children. The epidemic began in the winter of 1948 with three confirmed cases of acute anterior poliomyelitis and spread rapidly through the town of Akureyri and the surrounding countryside. Overall 6.7% of the town and 0.8% of the rural population became ill. Children were prominently involved and children in the 15 to 19 year old age group had the highest attack rate. Women were more commonly affected than men except in children where the incidence was nearly equal. Multiple cases were seen within households, and more than 30% of the cases occurred in the upper grade schools. The illness was felt to be infectious with an incubation period of 5 to 7 days.

100% 100% 98% 70% 68% 95% 93% 89% 82% 82% 82% 80% 80% 68% 48% 45% 43% 27%

In an earlier description of some of the children involved in this epidemic1, most had marked difficulties in school performance, and many had family and social disruption. School difficulties were most marked in those children with an acute onset of symptoms. Laboratory evaluation in these children revealed that 25% had no antibody to Epstein-Barr virus (EBV).

Clinical descriptions emphasized neurologic symptoms stemming from the original assumption that poliovirus was the cause. The acute course was characterized by low grade fever, malaise, paresthesias, exhaustion, and sweating. Flaccid and asymmetric paresis would occur, occasionally followed by atrophy. Little or no respiratory or gastro-intestinal symptoms were noted. The course was prolonged and marked by relapses with many cases being bedridden for months. Eye discomfort, memory loss, sleep disturbance, emotional lability and arthralgias occurred. Follow-up of fifty seven cases seven to ten months later showed that only 11% had become

In a case control study of 21 children and 42 age and sex matched controls11, three factors significantly separated cases and controls: 1) past history of allergies and/or asthma 2) family members with similar

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totally well. Most patients resumed work, but 19% had residual weakness. Fatigue occurred in 37% while 42% had "nervousness." Attempts to isolate an infectious agent were not successful.

spread of this illness, and family clustering was noted. In one family five of seven children were ill. Two of eleven patients had abnormal CSF with elevations in cell count and protein. Elevated urinary creatinine excretion was present in most of thirteen tested. At follow up fifteen months later, no patient was entirely well, although most had improved.

Adelaide, Australia E p i d e m i c At almost the same time, an epidemic of classical poliomyelitis occurred in Adelaide, South Australia 13 affecting 1350 persons. During the epidemic, however it became clear that another illness was present which did not fit the diagnostic expectations of polio. This variant affected children, with 45% of all cases being under 15 years of age. The onset of this illness would be either abrupt or gradual. It was characterized by "lassitude", muscle aching and weakness, headache, sore throat, abdominal symptoms, paresthesias, fever, blurring of vision and urinary retention. A chronic course was common among these patients with muscle pain, psychologic symptoms, and poor concentration predominating. There were no deaths. This illness varied from acute anterior poliomyelitis in several respects: 1) the CSF was normal 2) rapid improvement of weakness but prolonged recovery 3) prominent psychologic symptoms, dyslogia, and myalgia. A variant of poliovirus was proposed to be the cause.

The Cumberland, E n g l a n d E p i d e m i c In 1955 a physician, Dr. A. L. Wallis, in Cumberland noted a large epidemic of Iceland Disease, or Royal Free Disease as it was then called, and described his findings in a paper which was submitted as a doctoral thesis 15 . The epidemic involved 233 persons over a six month period, half of them children. Males were affected more frequently than females among children while in adults this ratio was reversed. It appeared to be an infectious illness with a 5 to 7 day incubation period. Most cases were mild, resolving within one month, but some patients had extended illness marked by relapses and remissions. The most prominent symptoms included fatigue, headaches, myalgia, dizziness, "dry throat", tender and enlarged lymph nodes, sore eyes and blurred vision. Other symptoms included abdominal discomfort, diarrhea, nausea, dysesthesias, night sweats, sleep disturbance, and difficulty with concentration. There were no obvious differences in the pediatric presentation from that of adults.

Kingston / U p p e r N e w York State E p i d e m i c Another epidemic of "Iceland Disease" involving children was described by White and Burtch in 1953 in northern New York State 14 . The first cases presented in the summer of 1950 and were assumed to be acute anterior poliomyelitis or abortive poliomyelitis. However, because of prominent dysesthesias and muscle aching and the absence of marked weakness and wasting, the illness was subsequently assumed to be Iceland disease.

The P u n t a Gorda, Florida E p i d e m i c In 1957 an epidemic of ME/CFIDS occurred in Punta Gorda, Florida16 involving 21 persons, several of them children. The onset was insidious with fatigue, headache, neck pain and mental confusion with exacerbations from one to four weeks after onset. Nineteen patients were hospitalized or bed ridden. Follow-up after five months demonstrated a prolonged, irregular course. In a community survey, there were no cases identified under the age of 9, while eleven cases from ages 10-19 were identified, an attack rate of 7.7%.

Forty seven patients were described, eleven of whom were considered to have true poliomyelitis. Of the remaining, nineteen were chosen for intensive study, fifteen women and 4 men ranging in age from nine to forty five years of age. The onset was more commonly gradual than acute. Prominent symptoms included muscle aching, transient weakness without wasting, transiently decreased tendon reflexes, paresthesias, headache, photophobia, depression and lymphadenopathy. Personal contact seemed to be involved in the

The Great Ormond Street E p i d e m i c In 1978, Dillon17 describes an outbreak of ME/CFIDS involving 145 adults which occurred in 1970 at the Hospital for Sick Children, Great Ormond Street,

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subsequently called the "Tapanui flu", involved 28 cases. Thirty six percent were children under the age of 15, 3 between the ages of 5 and 10, and 7 between 10-15 years of age. All had fatigue and mood changes, and most had abdominal pains, joint and muscle pain, headache and change in sleep pattern.

London. In a supplementary note, seven children were described with what appeared to be the same illness. The report detailed the symptoms of five boys and two girls, with the average age of onset 11.7 years. The children had a protracted course, and two were still ill two years after onset. There appeared to be contact with other family members with the same constellation of symptoms. Prominent symptoms were headache, fatigability, lethargy, back and muscle pains, sore throat, nausea, abdominal pains. On physical examination, pharyngitis, lymphadenopathy and mild pyrexia were noted. It is of interest that in the primary epidemic, which affected 15% of the nursing staff and 3% of the medical staff, no inpatient children were noted to have become ill.

IV. Sporadic ME/CFIDS - Enterovirus, Epstein-Barr v i r u s There have been numerous reports describing ME/ CFIDS in studies which have concentrated on possible specific etiologic agents. In the United States, these papers have tended to concentrate on EpsteinBarr virus, while experience in Great Britain, Australia, and New Zealand have concentrated on the enteroviruses. In one paper, DuBois and his colleagues 21 described 2 children among 14 patients who were selected because of prominent fatigue, fever, myalgia, depression, pharyngitis and lymphadenopathy. Epstein-Barr virus anti-Early Antigen was noted to be higher in patients than in controls.

In 1980 May et al18 described an epidemic in Southampton and attempted specifically to address the lingering questions of psychogenic origin which had persisted in the twenty years since the Royal Free epidemic. The outbreak occurred in spring of 1979 in the Southampton Girls' School and was studied using a personality questionnaire. Forty five children became ill, with an average age of 13.2 years. They had 8.1 separate symptoms and were bed-ridden 14.2 days, many with a prolonged convalescence. With the exception of one child with mononucleosis, virologic studies were negative.

Sporadic Cases The following year, Jones et al22 published a paper involving forty four patients, eighteen of whom were children under 15 years of age. The cases appeared to be sporadic rather than epidemic. The report demonstrated elevated Epstein-Barr virus anti-Early Antigen antibodies, with 39 of 44 elevated compared to healthy controls. Both of these papers described ME/ CFIDS to a medical audience who had been largely unaware of reports of ME in other countries.

The conclusions of this study were that 1) there was no evidence of stress as a predisposing factor 2) "Altered medical perception" was a factor in diagnosis while "neuroticism" was not. Also of interest was that of the children considered "well" at the time of the epidemic, many had fatigue, myalgia, sore throat, and headache.

In 1985 Salit23 described fifty patients with sporadic postinfectious neuromyasthenia, 5 of whom were adolescents. The study is of interest as a systematic attempt was made to identify the organism responsible for the initial infectious episode. The results suggested an association with the following agents: EBV in 16; Coxsackie B virus in 4; Giardia lamblia in 2; Mycoplasma pneumoniae in 2; Toxoplasma gondii in 2; Hepatitis A virus in 1; Herpes zoster virus in 1; Cytomegalovirus in 1 and unknown in 22. One patient had evidence of simultaneous infection with both EBV and Coxsackie B virus.

Ayrshire E p i d e m i c In January 1980 an outbreak of ME/CFIDS occurred in Ayrshire19 involving 22 cases, two of whom were children aged 8 and 10. The specific symptoms for the children were not recorded but symptoms of the patients in general were similar to other descriptions. It was noted that 82% had elevated neutralizing antibody titers to Coxsackie B virus. West Otago E p i d e m i c

Two recent papers have attempted to look at the epidemiology of ME/CFIDS from the perspective of

The West Otago, New Zealand outbreak of 198220,

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laboratory testing requests. In a study by Ho-Yen24 381 cases were diagnosed retrospectively based upon information contained in virology requests. Based upon this data, they concluded ME/CFIDS is very common in children, perhaps more common than infectious mononucleosis, and that boys are as likely to be affected as girls. In a separate paper, Wilson and co-workers25 presented 39 children with a clinical diagnosis of ME evaluated for antibodies to Coxsackie B virus. The clinical symptoms of the children involved were fatigue, myalgia, headache, limb pain, anorexia, weakness and extended school absence. Males and females were equally affected.

presentation (acute or insidious), muscle weakness; sore throat or lymphatic pain. Physical examination demonstrated "tender points" on muscle palpation. Routine laboratory studies were "normal", but immunological studies were not performed. At follow-up of an average of 18.8 months, complete recovery was seen in 5%, improvement in 55%, while 40% retained moderate symptoms. The authors emphasized that while the symptoms of anxiety and depression were present, they did not appear to be etiologic, and none of the children had school phobia. They emphasized the need for accurate diagnosis.

V. Primary J u v e n i l e Fibromyalgia Syndrome VI. Conclusions Note has been made of similarities between ME/ CFIDS and Primary Fibromyalgia Syndrome (PFS)26, with similarities in symptomatology, sleep physiology and immunology. In a few papers involving PFS in children27"31, symptoms other than muscle tender points have been described. It is possible that Primary Fibromyalgia Syndrome represents a group of patients with ME/CFIDS where muscle tenderness is the most prominent symptom.

This illness, called Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), or Chronic Fatigue-Immune Dysfunction Syndrome (CFIDS), appears to affect children as frequently as it does adults. However, attention has been directed primarily toward adults with this disorder, perhaps because of several factors: 1) The illness in children may be milder 2) children may be more "adaptable" to chronic symptoms 3) a gradual onset of symptoms is more common in children thus making diagnosis more difficult, and 4) an adult who has lost the ability to support a family commands more attention than a child with prolonged school absence. While considerable discussion has revolved around hysteria, depression and school phobia, there has been no evidence in any of the published studies in children to suggest these factors as etiologic.

In February 1985, Yunus and Masi27 described a group of 33 children who presented for rheumatological evaluation as having Juvenile Primary Fibromyalgia Syndrome (JPFS). These evaluations were conducted along the same lines as adult PFS with detailed descriptions of "tender points" and joint symptoms, but also included a description of accompanying symptoms. The average age was 12.3 years at onset with a predominance of females (31 female, 2 male). Of these children the following was observed: generalized aches and pains 97%; stiffness 79%; subjective soft tissue swelling 61%; waking up tired 100%; poor sleep 67%; general fatigue 91%; anxiety 70%; depression 55%; chronic headaches 54%; paresthesias 36% and irritable bowel symptoms 27%. No mention was made of cognitive difficulties, type of

Several common factors are observed in the studies of ME/CFIDS in children: 1) The presence of a specific pattern of symptoms, 2) Nearly equal sex distribution, 3) High attack rate at puberty, 4) High family incidence, 5) School, family and social disruption, and 6) Prolonged morbidity. Clearly, more studies on the pediatric population are indicated.

VII. R e f e r e n c e s 1. Bell DS, Bell KM. The post-infectious chronic fatigue syndrome: diagnosis in childhood. In Ablashi DV, Faggioni A, Kreuger GRF, et al (eds). Epstein-Barr Virus and H u m a n Disease. Clifton, NJ: Humana Press 1989; 412-7.

2. Gordon N. Myalgic Encephalomyelitis. Dev Med & Child Neurol 1988;30:673-82.

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3. Acheson ED. The clinical syndrome variously called benign myalgic encephalomyelitis, Iceland disease, and epidemic neuromyasthenia. Am J Med 1959; 26:569-95.

17. Dillon MJ. Epidemic neuromyasthenia at the Hospital for Sick Children, Great Ormond Street. London. Postgrad Med J 1978; 54: 757-64, 814-8.

4. Behan PO, Behan WMH: Epidemic Myalgic Encephalitis. In ClinicalNeuroepidemology CliffordF,Ed., Pitmansl980; 374-383.

18. May PBR, Donnan SPB, Ashton JR, Ogilvie MM, Rolles C J. Personality and medical perception in benign myalgic encephalomyelitis. Lancet 1980, ii; 1122-4.

5. Henderson DA, Shelokov A. Epidemic neuromyastheniaClinical Syndrome. N Eng J Med, 1959, 260 : 757-64.

19. Fegan KG, Behan PO, Bell EJ. Myalgic Encephalomyelitisreport of an epidemic. J Roy Col. Gen. Pract. 1983:33; 335-337.

6. Komaroff AL. Chronic fatigue syndromes: relationship to chronic viral infections. J Virol Methods 1988; 21: 3.

20. Poore M ,Snow P, Paul C. An Unexplained Illness in West Otago. NZ Med J 1984; 97:351-4.

7. Behan PO, Behan WMH. Postviral Fatigue Syndrome. CRC (Critical Reviews in Neurobiology) 1988 4:2; 157-178.

21. DuBois RE, Seeley JK, Brus I, Sakamoto K Ballow M, Harada S Bechtold TA. Chronic Mononucleosis syndrome. South Med J. 1984, 77: 1376.

8. Ramsay AM. Myalgic Encephalomyelitis and Postviral Fatigue States. 1988 2nd Edition; London: Gower Medical 9. Bell DS, Bell KM. Chronic fatigue syndrome: diagnostic criteria.[letter] Ann Intern Med. 1988. 109 (2):167. 10. Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, et al. Chronic fatigue syndrome: A working case definition. Ann Intern Med 1988;108:387-89.

22. Jones J J, Ray C G, Minnich L L, Hicks MJ, Kibler R, Lucas DO. Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated antiearly antigen antibodies. Ann Intern Med. 1985; 102:1-6. 23. Salit IE. Sporadic postinfectious neuromyasthenia Can Med Assoc J 1985; 133: 659-63. 24. Ho-Yen Darrel.The epidemiology of post viral fatigue syndrome. Scott Med J 1988; 33(6):368-9.

11. Bell KM, Cookfair D, Reese P, Bell D, Cooper L. Risk Factors with chronic fatigue syndrome in children. [Abstract], Am J Epidemiol. 1988; 128:899.

25. Wilson PM, Kusumaker V, McCartney RA, Bell EJ. Features of Coxsackie B virus (CBV) infection in children with prolonged physical and psychological morbidity PsychosomRes 1989; 33(1): 29-36.

12. Sigurdsson B, Siguijonsson J, Sigurdsson JH, Thorkelsson J, Gudmundsson KR. A Disease Epidemic in Iceland simulating Poliomyelitis. Am J Hyg. 1950; 52: 222-238.

26. Buchwald D, Goldenberg DL, Sullivan JL, Komaroff AL. The "chronic active Epstein-Barr virus infection" syndrome and primary fibromyalgia. Arthritis Rhum, 1987; 30:1132-6.

13. Pellew RAA. A Clinical description of a disease resembling poliomyelitis, seen in Adelaide, 1949-1951. Med J Aust June 1951; 944-6.

27. Yunus MB, Masi AT. Juvenile primary fibromyalgia syndrome. Arthritis Rheum 1985; 28 138-145.

14. White DN, Burtch RB. Iceland Disease A New Infection Simulating Acute Anterior Poliomyelitis. Neurology 1954; 4:506-516.

28. Calabro JJ. Fibromyalgia (Fibrositis)in Children. Am JMed 1986; 81 (Suppl 3A): 57-9.

15. Wallis AL. An Investigation into an unusual disease in Epidemic and sporadic form in a general practice in Cumberland in 1955 and subsequent years. University of Edinburgh doctoral Thesis 1957..

29. Yunus MB, Aches and pains: is it juvenile fibromyalgia syndrome? Diagnosis August 1984; 93-102. 30. Pellegrino MJ, Waylonis GW, Sommer A. Familial occurrence of primary fibromyalgia. Arch Phys Med Rehabil 1989; 70: 61-3.

16. Poskanzer DC, Henderson DA, Kunkle EC, Kalter SS, Clement WB, Bond JO. Epidemic neuromyasthenia: An outbreak in Punta Gorda, Florida. NEng J Med 1957;257:356-64.

31. C i c u t t i n i F, L i t t l e j o h n GO. F e m a l e a d o l e s c e n t rheumatological presentations: the importance of chronic pain syndromes. Aust Paediatr J 1989; 25: 21-4.

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Section 8

General Review

Richard H.T. Edwards, PhD, FRCP

A Multidisciplinary

Approach to Investigating

and Treating Patients with CF

Chapter 20

Richard H. T. Edwards

A Multidisciplinary Approach to Investigating and Treating Patients with Chronic Fatigue Richard H.T. Edwards, PhD, FRCP, University of Liverpool Muscle Research Centre, Department of Medicine, University of Liverpool, P.O. Box 147, Liverpool L69 3BX United Kingdom Acknowledgements: The research programme into the physiology of muscle fatigue directed by the author has at various times been supported by the Wellcome Trust, Muscular Dystrophy Group of Great Britain and Northern Ireland, ICI Pharmaceuticals and Mersey Region Health Authority. The outstanding work of the research collaborators cited is specially acknowledged. Previous to Professor Edwards' present position as Head of the Department of Medicine at the University of Liverpool, he was the Co-Director of the Jerry Lewis Muscle Research Centre at the Royal Post-graduate Medical School, Honorary Consultant Respiratory Physician to the Hammersmith Hospital, Professor of Human Metabolism at the University College Hospital Medical School in London, and past President of the European Society for Clinical Investigation. Professor Edwards was awarded the Robert Bing Prize of the Swiss Academy of Medical Sciences for development of new techniques for analyzing muscle weakness and fatigue.

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The Clinical and Scientific Basis of M.E. / CFS

Introduction The constellation of symptoms comprising the 'Chronic Fatigue Syndrome' (CFS) are well known and were the subject of a recent Oxford Consensus Meeting l . There, CFS was defined as a syndrome characterised by disabling mental and physical fatigue, of definite onset (i.e. not life long) and associated with other symptoms e.g. myalgia, mood and sleep disturbance. As a matter of practical definition the diagnosis can be made if fatigue has been present for more than six months and for more than fifty percent of the time. The condition may overlap with the (acute onset) postviral fatigue syndrome2 in which there is evidence (corroborated by laboratory studies) of past or continuing viral infection3. The condition (Table 1) currently known as 'Myalgic Encephalomyelitis' (M.E.) bears some similarity to the 'Effort Syndrome' (as it was known to Sir Thomas Lewis earlier this century) 4 as one of a group of disorders manifesting the symptoms of weakness, fatigue and exercise intolerance 5 . Table 1 Summary of Myalgic Encephalomyelitis from the ME Association Onset - Viral infection (Epidemic or scattered cases) Headache Sore throat General aches and pains Dizziness Chronically - Profound fatigue Muscle weakness Muscle tenderness Coldness of extremities Impaired memory and concentration Intense malaise and extreme debility Relapses usually triggered by periods of excessive physical or mental activity.

atic physiological analysis of muscle fatigue. Clinical investigations and exercise testing show evidence of a physiological basis for symptoms such as breathlessness or palpitations as a feature of "unfitness" due to lack of exercise5-10, n . A detailed study was carried out to investigate the possibility of a persistent viral infection and a further study was done to explore, within the context of a General Medical Clinic, the possible psychological factors underlying, perpetuating or amplifying the impairments in mental or physical performance. The results of these comprehensive studies suggest a means of explaining the mechanisms of symptom production (irrespective of the actual cause: viral or psychogenic) to provide a basis for positive diagnosis, reassurance and sympathetic, confident management.

Objective S t u d i e s of Muscle Structure a n d Function The physiological basis of human muscle fatigue was the subject of a Ciba Foundation Symposium12 in which the relative importance of 'central'13'14 and 'peripheral' 1616 mechanisms in the genesis of fatigue and, in the case of the latter, the importance of "metabolic" or "electrical" factors in various types of exercise was debated. A clinically relevant classification is whether the fatigue (defined as failure to sustain force or power output) is of central origin i.e. due to a failure to maintain the recruitment of high threshold motor units or peripheral, due to failure of neuromuscular transmission, sarcolemmal excitation, or excitation-contraction coupling (Table 2). Our earlier studies included a review of 109 patients presenting with the symptom of unexplained myalgia17. A large proportion of these patients could now be classified as having M.E. Exclusion of the cases of inflammatory or metabolic myopathy on the basis of percutaneous muscle biopsy with studies of histomorphology and histochemistry18'19 showed then, as now, that M.E. patients have few significant pathological abnormalities in muscle or, if they do occur, the changes are such as may be seen on percutaneous biopsy in the large population of normal subjects (especially athletes) studied by ourselves and others 20 in the UK, North America and Scandinavia. Among the reported abnormalities including minor atrophic changes are sometimes

Advice: Rest

Other symptoms are loss of ability to concentrate, disturbed sleep, dizzy spells and disturbances of the autonomic system causing such effects as feeling feverish or cold. Patients with postviral fatigue syndromes (including M.E.) fall into this category. Our work over several years6'7,89 provides a system-

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Richard

H.T. Edwards,

PhD,

FRCP

A Multidisciplinary

those reported ("moth-eaten" Type I fibres) as occurring in the related syndrome of 'Primary Fibromyalgia'21- 22.

Physiological Definitions and Classification of H u m a n Skeletal Muscle Weakness a n d Fatigue 8 , 9

r e c t l y p r o p o r t i o n a l t o t h e c r o s s - s e c t i o n a l a r e a of t h e c o n t r a c t i l e e l e m e n t s of t h e m u s c l e ) . F a i l u r e to s u s t a i n force or p o w e r o u t p u t C a u s e s of F a t i g u e

Fatigue

Possible

Central

Definition

Mechanism

Less force with 'maximal'

Failure to sustain

voluntary contractions than

maximal recruitment of

with maximal electrically

of motor units or firing

stimulated contractions or

frequency.

as evidenced by the 'Twitch Interpolation Technique' Peripheral

Same force loss with voluntary as with electrically stimulated contractions a) High Frequency Fatigue

Impaired neuromuscular transmission or conduction of muscle action potential

b) Low Frequency Fatigue

and Treating

Patients

with

CF

The recovery from exercise was followed with repeated assessments of muscle function over the next 48 hours to check whether the symptom of prolonged fatigue after exercise could be attributed to some delayed or slowly recovering physiological process but there was no evidence of undue fatigue (when compared with age and sex matched normal controls) at the end of exercise nor a slower rate of recovery. Muscle function was normal when patients were complaining of the protracted fatigue after exercise. The reported abnormal tendency to develop intracellular acidosis with moderate aerobic exercise in muscle as demonstrated by magnetic resonance spectroscopy in a patient with postviral fatigue syndrome29 is scarcely surprising given the observed (nonspecific) reduction in mitochondrial enzyme activity30 seen in chronic fatigue patients (Figure 1, courtesy of Dr P MacLennan). In this connection, it has proved interesting to make a comparison with the metabolic and physiological responses to exercise seen in patients with a biochemically defined defect of mitochondrial oxidative metabolism. Such a 'paradigm' case was studied in detail31'32. Other useful indicators of muscle inflammation or damage (ESR and plasma creatine kinase activity respectively) are invariably normal or not raised to the levels indicative of actual muscle pathology in CFS patients.

W e a k n e s s - F a i l u r e to g e n e r a t e force (N.B. I n m a x i m a l l y a c t i v a t e d c o n t r a c t i o n s , force is di-

Type of

to Investigating

activation of their muscle as indicated by the 'Twitch Interpolation Technique'15,27. The possible objection of using the Adductor Pollicis as a model for the function of larger muscle groups and the limitation of the electrical stimulation technique for the assessment of fatigue induced by isometric contractions 26 have been overcome in subsequent studies 28 in which objective measurements were carried out in the quadriceps after fatiguing cycle ergometer exercise.

Table 2

Fatigue

Approach

Impaired excitationcontraction coupling

The symptom of fatigue before exercise could not be logically attributable to any metabolic defect of muscle, even if a specific one had been described, because it is characteristic of metabolic myopathies 18 that pain and fatigue occur during and after but not before exercise. From these considerations, it can be concluded that there is insufficient evidence to attribute the fatigue of CFS to any form of primary myopathy. Even if 'secondary' changes in muscle occur, they cannot logically be held responsible for the symptom of fatigue since objective testing shows muscle function to be normal 26,28 .

The EMG evidence of abnormal jitter 23 ' 24 and the occasionally observed evidence of a resolving viral polymyositis25 are not diagnostic and neither can adequately explain the symptom of fatigue which, when analysed systematically (Table 2), is found to be 'central' rather than a consequence of any 'peripheral' impairment of muscle26. There is no appreciable muscle wasting other than that which might be attributed to inactivity in the most severe cases and there is usually no evidence of weakness as tested with brief (5 sec) maximal voluntary contractions though some patients may fail to achieve maximal

221

The Clinical and Scientific Basis of M.E. / CFS

Evidence of postural hypotension or of a dependent shift of blood volume is easy to seek at the bedside by measuring pulse rate followed by blood pressure first in the lying then standing posture 5 . The former is obvious while the latter is indicated by an excessive rise (more than 20 beats per minute) in pulse rate. This will be helpful in planning treatment, for the patient taking sufficient exercise to reap the therapeutic benefit. In such cases the following may be tried: a) support stockings (or tights) to reduce pooling of blood in dependent capacitance vessels; b) Dihydroergotamine as a venoconstrictor to achieve the same purpose; c) Fludrocortisone to increase sodium retention and thus achieve blood volume expansion and a small rise in resting mean blood pressure.

Formal Exercise Testing may reveal abnormal responses in acute viral or bacterial infections34'35 but, in CFS patients, testing usually reveals a reassuring response to submaximal power outputs, but a reduction in the maximal work rate, achieved usually with a submaximal heart rate indicating cessation of exercise before reaching the physiological limit11-36. Rating of Perceived Exertion (RPE) with the Borg scale reveals that CFS patients rate submaximal power outputs higher than normal suggesting an increased 'gain' for the perception of physiological signals associated with exercise. It is worth determining that there is a postural element i.e., that patients may feel more fatigued by sitting or standing for a long period and better if lying horizontal.

80

D

A

A A

• n O

40

• O

• 6

Normal controls

A •

• A

A q D

A 0 o

Figure 1

palmitate oxidation (nmol/min/g)

Fatigue syndrome, no pain

cytochrome c oxidas< (umol/min/g)

i

50

25

Fatigue syndrome, pain on exercise O Fatigue syndrome, pain at rest and on exercise Mitochondrial enzyme activities in patients with myalgia and chronic fatigue showing non-specific general reduction in activity. (Results from patients attending Muscle Clinic at the Royal Liverpool Hospital - analyses by techniques published previously (30). Normal control values are means +/ - S.D.; n=13)

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Richard H.T. Edwards, PhD, FRCP

A Multidisciplinary

Viral Aetiology

Approach to Investigating

and Treating Patients with CF

Psychological and Psychiatric Assessment in CFS

A seriously considered possible aetiology of the disease is that there is a persistent viral infection in the muscles and elsewhere. Present evidence points to the enteroviruses 3,37,38 and the assumption is that there is an inadequate immune response to the infecting virus. The suggested impaired response may quite possibly involve the T-cell response as cellmediated immunity is important in control to prevent persistence of virus infection, but eventually this fault is rectified and the patient recovers. Definite evidence of viral infection has been found in a variable proportion of patients in that there may be high IgM antibody titres to Coxsackie viruses, indicating recent infection24. Viral protein has been found in the serum of patients and Coxsackie virus has also been isolated from the stools of patients. Circulating immune complexes containing IgM have also been found in a fair proportion of patients 37 . Viral RNA has been found in muscle biopsies of patients with postviral fatigue syndrome39,40.

The psychological/psychiatric aspects of CFS are a matter of current debate especially as to whether M.E. is a new entity or 'neurasthenia' in a new guise45,46. What is needed now is a systematic unbiased assessment of the present psychological health of CFS patients and then to seek to identify 'risk factors' in terms of underlying personality traits as suggested in the case of the 'Post Polio Syndrome'47 and susceptibilities, with attention to initiating stressful life events and the developing factors which subsequently determine illness behaviour. Structured interviews were carried out in consecutive CFS patients and in ambulant patients with myopathy (Becker and Facioscapulohumeral muscular dystrophy and inactive polymyositis) of similar age distribution. Scores on a questionnaire to measure mental fatigue, Spielberger's State Trait Anxiety Inventory, Hospital Anxiety and Depression Scale and Present State Examination/Catego were used as the main outcome measures 48 . Psychiatric symptoms were significantly more common in CFS patients than those with myopathy. A variety of psychiatric diagnoses were made (Table 3) supporting the belief that fatigue is a common nonspecific psychiatric symptom. Whether any or all of these can be attributed to being the cause or the consequence of the CFS is not known.

There is no doubt that a viral infection can be a precipitating factor or a complication of a reduced immunity as when active Epstein Barr virus was reported to occur in PVFS41. We considered it would be interesting to compare41 CFS patients with patients with muscle diseases who were also involved in the psychological assessment. Circulating immune complexes containing IgG and IgM and the lymphocyte proliferation in response to Concanavilin A and to Coxsackie B virus were determined but there were no changes which could lend support to the belief that there could be a specific viral aetiology for CFS. Itis evident that there is a substantial proportion of patients who do not have any history or other evidence of viral infection.

Table 3 Psychiatric Diagnoses in Chronic F a t i g u e S y n d r o m e Summary Results 47 The breakdown is as follows: Depression Phobic Anxiety S t a t e Somatoform Disorders Anxiety State Subcases of Anxiety a n d Depression

A very similar constellation of symptoms to those complained of by CFS patients may be seen in the 'Post Polio Syndrome'43 (interestingly a consequence of another enterovirus infection) and after head injury44. If a viral aetiology is found to be important at least in some patients, it is possible that the feature common to several aetiologies is diffuse (microscopic) brain damage which has significant psychological if not psychiatric consequences.

'Pure' Chronic F a t i g u e Syndrome without associated psychiatric diagnosis Chronic Fatigue with associated psychiatric diagnosis

223

24% 12% 6% 6% 27%

25%

75%

The Clinical and Scientific Basis of M.E. / CFS

psychological/psychiatric state. The rehabilitation programme encompasses detailed explanations of the pathophysiology in layman's terms and instruction on relaxation and control of breathing 54 .

An I n t e g r a t e d P h y s i o l o g i c a l Interpretation There may be grounds for suggesting49 that the psychosomatic disorder manifested in the CFS is an example of'Somatisation' 50 where the thresholds for distinction between physical and psychiatric illness have become blurred. That patients with CFS have heightened perception of physiological signals during exercise is evident as may be observed of the heightened cutaneous and muscle sensibility on clinical examination. Evident too is the tendency for patients to suffer from the consequences of consciousness of hitherto unconscious (automatic) central motor control functions 51 . Thus walking very slowly may deprive the patient of the learned automaticity of the motor skills, including balance and coordination necessary for normal gait. Failure to relax antagonists compromises the function of agonists and may cause muscle pain due to inappropriate use. Similarly the 'nonrestorative sleep' which may also affect immune responsiveness 52 can be associated with myalgia on waking, or before exercise may result in continued activity of a small percentage of muscle fibres with physiological and metabolic overuse to a degree which is seen in the related condition of 'Primary Fibromyalgia' 21,22 . CFS may thus be more a true functional disorder i.e. a disorder of physiological regulations rather than a disease resulting from a discrete pathology. It is clear however that lesions of the brain can result in a striking increase in the conscious effort necessary to perform simple, familiar everyday tasks 53 . Such an explanation is useful for operational purposes in designing and explaining a positive programme of support and rehabilitation.

Finally, there is guidance on the proper conduct of a graduated exercise programme designed to overcome the effects of inactivity55 and to re-educate motor performance skills. Exercise is also valuable in returning autonomic controls which are often disturbed in CFS, e.g. postural control of heart rate and blood pressure, thermal regulation involving skin blood flow and control of sweating. Sometimes it may be helpful to recommend that the patient keeps an activity diary in which the day's physical and mental exertions are recorded together with a note as to the extent of physical and mental fatigue such as in the diary currently available from the M.E. Association. It may also be useful to give encouragement to seek to regularise sleep patterns, if possible without the use of drugs such as hypnotics or antidepressants 2 - 56 (though in our experience this has helped only a small proportion of CFS patients) by going to sleep and waking (if necessary by setting an alarm clock) at a set time so that diurnal physiological rhythms may be kept as normal as possible. If a patient finds an exercise session too much, either on a given day or is unable to continue with the programme on subsequent days, the intensity of the exercise chosen initially was too great and should be reduced. It is not accepted however that exercise is harmful to the extent that patients have to stay in bed for days or weeks afterwards; no known physiological disturbance or medical condition does this. In such an event a search must be made into the psychological reaction to the exercise and why such a low physical stress appears to impede progress in rehabilitation. Certainly it is well known that muscles have a great capacity to adapt to increased use57 with benefit to peak performance but especially endurance and this can provide a valuable positive feedback on the road to recovery.

A P o s i t i v e A p p r o a c h to M a n a g e m e n t The first step is to convince the patient that there is no mystery concerning the origin of their symptoms; they are 'real' and not 'imaginary' in that they have a recognizable physiological basis. Next it is necessary to adopt a firm "the buck stops here" approach to management so that the commitment of the patient may be engaged. The multidisciplinary approach currently used in my medical clinic covers assessments of the relevant medical conditions, viral and immunological screens as well as percutaneous muscle biopsy and measurement of muscle function. Coupled with this is the formal assessment of the

CFS can be of very variable duration ranging from months to many years, but eventually most people do recover24. In this, a close working relationship with physiotherapists is important 5 - 54 . Finally, it is important to educate doctors and health

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Richard H.T. Edwards, PhD, FRCP

A Multidisciplinary

professionals that CFS is a condition which can be diagnosed on positive grounds and not just by excluding others. It is not necessary to refer patients for complex, expensive investigations of muscle. It is not

Approach to Investigating

and Treating Patients with CF

a primary muscle disease and it would be to the patients' advantage for them to be given sympathetic but firm reassurance and confident advice on their first contact with the medical profession.

References 1. Editorial. Consensus on research into fatigue syndrome. Brit Med J (1990) 300: 832.

13. Waller AD. The sense of effort: a n objective study. Brain (1981) 14: 179-247.

2. Smith DG. Understanding ME. (1989) London: Robinson Publications.

14. Bigland-Ritchie B, Jones DA, Hosking GP, Edwards RHT. Central and peripheral fatigue in sustained m a x i m u m voluntary contractions of h u m a n quadriceps muscle. Clin Sci (1978) 54: 609-614.

3. Yousef GE, Bell EJ, Mann GF, Murugesan V, Smith DG, McCarthy RA and Mowbray JF. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet (1988) i: 146-150.

15. Merton PA. Voluntary strength and fatigue. J Physiol (1954) 123: 553-564.

4. Lewis T. The soldier's heart and the effort syndrome. London: Shaw & Sons 1918. Effort syndromes.

16. Cooper RG, Edwards RHT, Gibson H and Stokes M. H u m a n muscle fatigue: frequency d e p e n d e n c e of excitation and force generation. J Physiol. (1988) 397: 585599.

6. Edwards RHT, Young A, Hosking GP, and Jones DA. Human skeletal muscle function: description of tests and normal values. Clin Sci Mol Med (1977) 52: 283-290.

17. Mills KR and Edwards RHT, Gibson H and Stokes M. H u m a n muscle fatigue: frequency d e p e n d e n c e of excitation and force generation. J Physiol. (1988) 397: 585599.

5. Newham D and Edwards RHT. Physiotherapy (1979) 65: 52-56.

7. Edwards RHT and Jones DA. D i s e a s e s of skeletal muscle. In: Handbook of Physiology: Skeletal Muscle. Eds Peachey D, Adrian RH & Geiger SR. American Physiological Society. Baltimore: Williams & Wilkins (1983) pp 633-672.

18. Mills KR, Newham DJ and Edwards RHT. Muscle Pain. In : Textbook of Pain Ed Wall PD and Melzack R. (Second Edition) Edinburgh: Churchill Livingstone (1989): pp420-432. 19. Dietrichson P, Coakley J, Smith PEM, Griffiths RD, Helliwell TR and Edwards RHT. Conchotome and n e e d l e p r e c u t a n e o u s b i o p s y of s k e l e t a l m u s c l e . J Neurol, Neurosurg. Psychiat. (1987)50: 1461-1467.

8. Edwards RHT. N e w t e c h n i q u e s for studying h u m a n muscle function, metabolism, and fatigue. Muscle & Nerve (1984)7: 599-609. 9. Jones DA and Edwards RHT. Muscle strength and metabolism. In: Recent Achievements in Restorative Neurology 2: Progressive Neuromuscular Diseases. EdMDimitrijevic, B Kakulas and G Vrbova. (1986) Basel: Karger. 123-138.

20. Doyle D. Muscle biopsies in Postviral Fatigue Syndrome. The Nightingale (1990) 1 (3): 9 (Abstract). 21. Henriksson KG, Bengtsson A, Larsson J, et al. Muscle biopsy findings of possible diagnostic importance in Primary Fibromyalgia (Fibrositis, Myofascial Syndrome). Lancet (1982) ii: 1395.

10. Riley MS, O'Brien C J, McCluskey DR, Bell NP and Nicholls DP. Aerobic work capacity in patients w i t h chronic fatigue syndrome. (1990) In press

22. Henriksson KG. Muscle p a i n in neuromuscular disorders and primary fibromyalgia. Eur J Appl Phsyiol (1988) 57: 348-352.

11. McCluskey DR. Aerobic work capacity in patients with Chronic Fatigue Syndrome. The Nightingale (1990) 1(3): 21 (Abstract).

23. Jamal Ga, Hansen S. Electrophysiological studies in the post-viral syndrome. J Neurol, Neurosurg, Psychiat. (1985)48: 691-694.

12. Edwards RHT. Human muscle f u n c t i o n and fatigue. In: Human Muscle Fatigue: Physiological Mechanisms. (Ciba Foundation Symposium 82) London: Pitman Medical, (1981) pp 1-18.

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24. Behan PO, Behan WMH and Bell EJ. The postviral fatigue syndrome an analysis of the findings in 50 cases. J. Infection (1985) 10: 211-222.

37. Mowbray JF. E v i d e n c e for chronic enterovirus infection in ME. (1990) The Nightingale 1(3): 22 (Abstract).

25. Schwartz MS, Swash M, and Gross M. B e n i g n postinfection polymyositis. Brit med J (1978) 2: 12561257.

38. Calder BD, Warnock PJ, McCartney RA & Bell EJ. Coxsackie B viruses and the post-viral sydrome: a prospective study in general practice. J. Roy. Col. Gen. Prac. (1987) 37: 11.

26. Stokes MJ, Cooper RG and Edwards RHT. Normal strength and fatiguability in patients w i t h effort syndrome. Brit med J (1988) 297: 1014-1017.

39. Archard LC. Molecular virology of muscle disease: Persistent virus infection of muscle in patients with postviral fatigue. The Nightingale (1990) 1(3): 5 (Abstract).

27. Chapman SJ, Edwards RHT, Greig C, Rutherford O. Practical application of the Twitch Interpolation Technique for the study of voluntary contraction of the quadriceps muscle in man. J Physiol (1984) 353: 3P.

40. Archard LC, Bowles NC, Behan PO, Bell E J and Doyle D. Postviral Fatigue Syndrome: Persistence of enterovirus RNA in muscle and elevated creatine kinase. J Roy Soc Med (1988) 81: 326-329.

28. Gibson H, Carroll N, Coakley J and Edwards RHT. Recovery from maximal exercise in Chronic Fatigue States. Eur. J. Clin. Invest. (1990) 20: A29.

41. HotchinNA, Read R, Smith DG and Crawford DH. Active Epstein-Barr virus infection in post-viral fatigue syndrome. J Infection (1989) 18: 143-150.

29. Arnold DL, Bore PJ, Radda GK, et al. E x c e s s i v e intracellular acidosis of skeletal muscle o n exercise in a patient with a post-viral exhaustion/fatigue syndrome. Lancet (1984) i: 1367-1369.

42. Milton JD, Edwards RHT and Clements GB. Immune r e s p o n s i v e n e s s in Chronic Fatigue Syndrome. Postgrad. Med. J. (1991) 67: 532-537. 43. Halstead LS, Wiechers DO, Rossi DC. Late effects of poliomyelitis: Case reports. In: Late Effects of Poliomyelitis. Eds Halstead LS & Wiechers DO Miami: Symposia Foundation, (1985).

30. Wagenmakers AJM, KaurN, Coakley JH, Griffiths RD and Edwards RHT. Mitochrondrial metabolism in myopathy and myalgia. In "Advances in Myochemistry" ed G. Benzi. London: John Libby Eurotext pp. 219-230.

44. Lishman WA. P h y s i o g e n e s i s and p s y c h o g e n e s i s in the'Post Concussional Syndrome'. Brit J Psychiatry (1988) 153: 460-469.

31. Edwards, RHT, Wiles CM, Gohil K et al. Energy Metabolism in Human Myopathy. In: Disorders of the Motor Unit. Ed D Schotland. New York: John Wiley. (1982)55:715728.

45. David AS, Wessely S and Pelosi AJ. Postviral fatigue syndrome: time for a n e w approach. Brit Med J (1988) 296: 696-699.

32. Griffiths RG and Edwards RHT. Energy metabolism in human muscle studied by 31P MRS. In: Biochemical aspects of physical exercise. Ed. G. Benzi, L Packer and N Siliprandi. Amsterdam: Elsevier (1986) pp 261-272.

46. Wessely S. Old w i n e in n e w bottles: Neurasthenia and 'ME'. Psychological Medicine (1990) 20: 35-53.

33. Wiles CM, Jones DA, and Edwards RHT. Fatigue in human metabolic myopathy. In: Human Muscle Fatigue: Physiological Mechanisms. (Ciba Foundation Symposium 82) London: Pitman Medical (1981) 264-282.

47. Bruno RL and Frick NM. Stress and "Type A" behaviour as precipitances of Post-polio sequelae: the Felican/ Columbia Survey. In: Research and Clinical Aspects of the Late Effects of Poliomyelitis. Eds. Halstead LS & Wiechers DO Birth Defects: Original Article Series. (1987) 23, (4), pp 145155.

34. Friman G. Effect of acute infectious disease o n isometric muscle strength. Scand J Clin Lab Invest (1977) 37: 303-308.

48. Wood GC, Bentall RP, Gopfert M and Edwards RHT. A comparative psychiatric assessment of patients with Chronic Fatigue Syndrome and Muscle Disease. Psychol. Med (1991) 21,619-628.

35. Friman G. Effects of acute infectious disease o n circulatory function. Acta Med Scand (1977) Supp 19: 4041.

49. Edwards RHT. Muscle Fatigue and Pain. Acta Med. Scand. (1986) Suppl. 711: 179-88.

36. Carroll N, Gibson H, Coakley J and Edwards RHT. Cycle ergometry in patients w i t h chronic fatigue syndromes. Eur. J. Clin. Invest. Suppl. (1990) 20: A29.

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A Multidisciplinary

50. Lipowski ZJ. Somatization: A Borderland b e t w e e n Medicine and Psychiatry. CMAJ. (1986) 135. 609-614. 51. Granit R. Constant Errors in the Execution and Appreciation of Movement: Brain (1971) 95: 649-660. 52. Moldofsky H. The significance of sleep- w a v e physiology and immune functions to chronic fatigue syndrome (CFS) and Fibromyalgia. The Nightingale 1 (3): 22 (Abstract). 53. Brodal A. Self-observation and Neuro-anatomical considerations after a stroke. Brain (1973) 96: 675-694.

Approach to Investigating

and Treating Patients with CF

55. Greenleaf JE, and Kozlowski S. Physiological conseq u e n c e s of r e d u c e d physical activity during bed rest. Exercise and Sport Sciences Reviews. (1982) 10: 84-119. 56. Vallings R. Myalgic Encephalomyelitis - A Consideration of Treatment. The New Zealand Family Physician. (1989) Summer 9-13. 57. Saltin B and Gollnick PD. Skeletal muscle adaptability: significance for metabolism and performance. In: Handbook of Physiology: Skeletal Muscle. Eds Peachey D, Adrian RH & Geiger SR. American Physiological Society. Baltimore: Williams & Wilkins (1983) pp 555-631.

54. Harvey J. Breath of Fresh Air o n Chronic Fatigue. Therapy Weekly. (1990) 16: 6.

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Chapter 21

Anthony L. Komaroff

A Review of Myalgic Encephalomyelitis / Chronic Fatigue Immune Dysfunction Syndrome / Post-Viral Fatigue Syndrome (M.E. / CFIDS / PVFS) in America Anthony L. Komaroff, MD Department of Medicine, Brigham and Women's Hospital, School, Boston MA

Harvard Medical

This work was supported by grants 1R01AI26788 and 1R01AI27314from the National Institute of Allergy and Infectious Diseases, and grants from the Minann and Rowland Foundations. Dr. Anthony Komaroff is an academic general internist who has been studying ME / CFIDS/PVFS for the past six years. He follows a large group ofpatients with this illness, and has an active program of research. He has been primarily interested in studying possible etiologic agents, and neuroimmunologic dysfunction in this syndrome.

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Abstract

Yet another subgroup of patients with chronic fatigue, presumably a small fraction, do not fit the pattern of any recognized physical disease, but do have features that suggest an "organic" disorder. Over the past 100 years, the medical literature has included descriptions of several ill-defined clinical syndromes that produce chronic fatigue: neurasthenia1, post-viral fatigue syndrome 2 , chronic mononucleosis35, severe chronic active EBV infection 6 7, myalgic encephalomyelitis 89 , fibrositis or fibromyalgia10,11, and more recently chronic fatigue syndrome12. Dr. Hyde discusses this history in more detail. In recent years, there has been much speculation that these syndromes may be secondary to chronic viral infection. The syndromes go by different names, but share so many clinical and laboratory features that some believe they may be the same illness: that is, they may share a final common pathogenetic pathway. In this manuscript, I will assume that they are all the same illness, and refer to them all by the shorter name, chronic fatigue syndrome (CFS).

Myalgic encephalomyelitis (M.E.), chronic fatigue immune dysfunction syndrome (CFIDS), and postviral fatigue syndrome (PVFS) are characterized by chronic, debilitating fatigue lasting greater than six months, with associated chronic and recurrent fever, pharyngitis, myalgias, adenopathy, arthralgias, difficulties in cognition and disorders of mood. In the majority of patients, the illness starts suddenly with an acute, apparently infectious illness. In such cases, the term "post-viral" fatigue syndrome (PVFS) is often used. Preliminary work suggests that various laboratory abnormalities may be seen more often in patients with CFS than in healthy individuals, including atypical lymphocytosis, monocytosis, elevation of heptocellular enzymes, low levels of antinuclear antibodies, elevated levels of IgG, elevated numbers of B cells, elevated CD4/CD8 T cell ratio, and low levels of immune complexes. Preliminary clinical and serologic studies suggest an association of CFS with enteroviral infection, Epstein-Barr virus (EBV) and the recently-discovered h u m a n herpesvirus-6 (HHV 6). No viral agent has yet been shown to play a causal role in the illness.

In my judgment, the similarities in the clinical descriptions of patients in all these groups are more impressive than the differences. The average patient is in his or her thirties, but the age at onset ranges from childhood to the elderly. Approximately 70% of the patients are women. The patients generally are middle-class, but all socioeconomic groups are represented. The main symptom is fatigue. Some patients are regularly bedridden or shut-in, unable to work. Many can work only part-time. Before they became ill, the patients perceived that they typically were more energetic than most of their friends.

It is likely that this illness can be triggered by a heterogeneous group of forces and circumstances. An attractive model is: immune dysfunction is produced as a consequence of exogenous lymphotropic viruses, environmental toxins, stress or depression; the immune dysfunction leads to the reactivation of dormant, latent infectious agents; the reactivated infectious agents produce morbidity through cytodestructive action; the immunologic response to exogenous and endogenous agents, such as the elaboration of various cytokines, may also produce some of the morbidity of the illness; both a past atopic history, and a past history of major affective disorder, may make an individual vulnerable to this illness.

In contrast to most patients seen in a general practice with chronic fatigue, the great majority of patients with CFS experience the sudden onset of an illness that then becomes chronic. Typically, the patients with chronic fatigue syndrome state that their chronic illness began on a particular day, with an acute "infectious" illness characterized by fever, pharyngitis, adenopathy, myalgias and related symptoms. Often, the onset is a respiratory tract infection characterized by sore throat, cough, myalgias and fever. Sometimes the onset is a gastrointestinal infection, with the predominant symptoms being nausea, diarrhea, and vomiting. Sometimes both respiratory and gastrointestinal symptoms are present. On occasion, the initial illness is acute infectious mono-

M.E ./CFID S/PFS: A D e s c r i p t i o n Practising physicians frequently see patients seeking care for the complaint of chronic fatigue. Most of the time, formal or informal evaluation leads to the conclusion that the patient is depressed, or anxious, or both. On unusual occasions, the patient may be suffering from a well-recognized "physical" disease such as an occult malignancy or thyroid disease.

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nucleosis, with the classic clinical, hematologic and serologic findings. On occasion, the initial illness is dominated by neurologic findings: headache, photophobia, marked cognitive disturbance, profound vertigo and ataxia, visual impairment, paresis, or seizures. This acute illness never seems to fully resolve. While its character may change over time, and its severity may vary, a state of chronic ill health ensues. The principal symptoms, and their frequency, are summarized in Table 1.

In our experience, patients with acute neurologic events (primary seizures, ataxia, focal weakness, transient blindness) have clinical and laboratory findings very similar to those of the larger group of patients with chronic fatigue, except for the neurologic events themselves.

Table 1 Frequency of Chronic Symptoms and Signs* Symptom / Sign

Frequency

Fatigue Low-grade fever Myalgias Depression Headaches Pharyngitis Impaired cognition Sleep disorder Anxiety Adenopathy Nausea Arthralgias Diarrhea Cough Odd skin sensations Rash Weight loss Weight gain Low basal body temperature (95.0 - 97.6F)

75-100% 60-95% 30-95% 70-85% 35-85% 50-70% 50-70% 15-70% 50-70% 40-60% 50-60% 40-60% 30-40% 30-40% 30-40% 30-40% 20-30% 50-70%

were typically not a chronic problem in the years before the onset of their illness, but became common after the illness began. We ask patients to make this distinction explicitly. Here are the frequency of several common chronic symptoms after the illness began vs. before the illness began: arthralgias (76% vs. 6%); morning stiffness (62% vs. 3%); distractibility (82% vs. 4%); forgetfulness (71% vs. 2%); dizziness (61% vs. 4%); paresthesias (52% vs. 2%); sleep disorder (90% vs. 7%); irritability (68% vs. 4%); depression (66% vs. 7%).

On past medical history, the only clearly striking finding is a high frequency of atopic or allergic illness (in approximately 50%), as was first highlighted by Jones and his colleagues1314, and confirmed by Straus16. On physical examination, unusual and abnormal findings are observed in 15-50% of our patients: fevers; unusually low basal body temperature (below 97 F); posterior cervical adenopathy; and abnormal tests of balance (Romberg and tandem gait). On standard hematologic testing, preliminary evidence indicates that results outside the normal range are seen in 15-50% of patients: relative lymphocytosis and relative lymphopenia; atypical lymphocytosis; monocytosis; and elevated sedimentation rate. These results have not yet been formally compared to results in a control group of healthy patients.

10-20%

* Adapted from the experience of the author, plus others 16-18 .

In our experience, two particularly remarkable findings are chronic post-exertional malaise and recurrent, often drenching night sweats. The postexertional malaise is characterized not only by symptoms that could represent deconditioning, pain and weakness of the involved muscles, but also by exacerbation of'systemic" symptoms, e.g., fever and adenopathy. The patients state that these symptoms and others

230

Standard serum chemistry testing is remarkable only for modestly elevated transaminases on one or more occasions in a quarter of the patients we have seen. None of these patients has had serologic evidence of active infection with hepatitis A, B or C virus. On immunologic testing, we and others14-16 21 have found evidence of subtle and diffuse dysfunction: partial hypogammaglobulinemia (25-80%); partial hypergammaglobulinemia (10-20%); low levels of autoantibodies, particularly antinuclear antibodies (15-35%); low levels of circulating immune complexes

Anthony L. Komaroff, MD

A Review of ME / CFIDS / PVFS in America

(30-50%); elevated ratios of helper/suppressor Tcells (20-35%); reduced EBV-specific cytotoxic T-cell activity; reduced in vitro synthesis of interleukin-2 and interferon by cultured lymphocytes; increased IgE-positive T and B cells; deficient functional activity of natural killer cells; anergy or hypoergy by skin testing; and elevated levels of various cytokines. Some investigators have found increased levels of circulating interferon, whereas others have not. Straus demonstrated a significant increase in levels ofleucocyte 2', 5'- oligoadenylate synthetase activity, an enzyme induced during acute viral infections18.

plays a p r i m a r y role in the pathogenesis of CFS: most patients have normal antibody levels to EBV. Furthermore, there is clinical and laboratory evidence that other herpesviruses also can be reactivated in this illness; antibody to measles virus also may be higher 27 . Therefore, it seems most likely that the EBV serologic results in most patients with chronic fatigue syndrome represent s e c o n d a r y evidence of some immunologic perturbation, rather than a primary pathogenetic role for EBV. Nevertheless, secondary reactivation of EBV may not be just an epiphenomenon, as will be discussed shortly.

Viruses a n d Chronic F a t i g u e S y n d r o m e

The recently-discovered human herpesvirus-6 is an interesting candidate for a pathogenetic role in some cases of chronic fatigue syndrome, primarily because it is lymphotropic and gliotropic28"30. There appears to be a serologic association of this virus with both chronic fatigue syndrome and fibromyalgia31"33, although some studies have not found such an association. Studies to assess active replication of HHV 6 are now underway. At this time, the evidence seems most consistent with the hypothesis that this virus may be secondarily reactivated in this syndrome, as are other viruses; however, a primary role for HHV6 in the pathogenesis of this illness remains possible.

As each of the chronic fatigue syndromes we have discussed has found its way into the medical literature, it has brought with it the speculation that the illness was initiated by an infectious agent. The speculation has centered most often on viruses, although Salit has suggested that non-viral infectious agents also can trigger a similar post-infectious malaise22. Myalgic encephalomyelitis was thought for some time to be produced by a less virulent strain of poliovirus. Recently Mowbray has kept alive the possibility that enteroviral infection may indeed be associated with some cases of CFS, by demonstrating circulating enteroviral antigen more often in patients than in control subjects23. Archard has found enteroviral RNA in muscle from patients, as well24.

In this decade of the human retroviruses, it was inevitable that there should be some speculation linking retroviruses to chronic fatigue syndrome. We and others have found no evidence that any of the known human retroviruses are involved with this syndrome. Furthermore, we have found no evidence of reverse transcriptase activity in the supernatants of primary lymphocyte cultures from a number of our sickest patients. Nevertheless, our diagnostic assays could have failed to recognize a retrovirus that was not T-lymphotropic, and/or was primarily lytic.

Antibody to Epstein-Barr virus has been measured in many patients, and higher levels of VCA-IgG and EA-Ab generally have been found in patients than in healthy control subjects; also, antibody to EBNA is absent in 10-30% of patients, whereas this is thought to be quite unusual in seropositive healthy individuajsi6-i8,25 Moreover, it has been shown that antibody to EBNA-1 is absent in 10-30% of patients; it is absent more often in the more severely ill patients. Absence of antibody to EBNA-1 is very rarely seen in patients convalescing from acute infectious mononucleosis, or in patients with cancer. It is, however, seen frequently in children with AIDS26.

CFS a n d P s y c h o l o g i c a l Illness Most patients seeking medical care for chronic fatigue probably are suffering from a primary affective disorder (depression and/or anxiety), and probably do not have CFS34 35. What is the role, if any, of affective disorders in CFS? This is a difficult issue to study, since the affective disorders are defined in part by symptoms that could also reflect a "physical" illness. Our experience

In the few cases of CFS that start with acute infectious mononucleosis, it is reasonable to assume that EBV may be playing a central role in the CFS. In other cases, there is no strong evidence that EBV

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suggests that most patients with CFS perceive themselves as becoming secondarily depressed and/or anxious following the (usually sudden) onset of their illness: 80-90% initially deny suffering from depression or anxiety in the years prior to their illness. Yet more intensive interviewing by a trained interviewer, using the Diagnostic Interview Schedule, suggests that affective illness predated the onset of CFS in a somewhat greater number of patients (unpublished data).

immune dysfunction and active viral infection, it may never be possible to determine whether the affective disorder, the immune dysfunction or the viral infection came first. Rather, the practical question is what form of therapy will be most effective: psychotherapy, pharmacotherapy of the affective disorder, "immune modulating" pharmacotherapy, anti-microbial therapy, or some combination of these. A Model F o r The P a t h o g e n e s i s of CFS

Even if it were true that patients with CFS more frequently have an affective disorder that predates the onset of chronic fatigue, what might that mean? The classic Descartian notion of mind-body duality has led some to conclude that the symptoms in patients with CFS reflect no physical abnormality, just a heightened awareness of and concern about physical sensations, possibly coupled with a desire to attribute their dysfunctional state to a physical illness.

Knowledge about CFS is limited. The available data permit many models, but provide strong support for none of them. My own current view of this illness is reflected in Figure 1. At the core of CFS, I suspect, is an immunologic disturbance that allows reactivation of latent and ineradicable infectious agents, particularly viruses. The reactivation of these viruses may only be an epiphenomenon. However, I feel it is more likely that, once secondarily reactivated, these viruses contribute to the morbidity of CFS — directly, by damaging certain tissues (e.g., the pharyngeal mucosa), and indirectly, by eliciting an on-going immunologic response. In particular, the elaboration of various cytokines (e.g., interferon-alpha and interleukin-2) as part of this on-going immunologic war may produce many of the symptoms of CFS — the fatigue, myalgias, fevers, adenopathy, and even the disorders of mood and cognition. This is suggested by the finding of increased levels of various

I am more inclined to view affective disorders as biologically-determined disorders of neurochemistry. "Mind" and "body" are not separate and discrete, but linked. Neurochemical disorders can affect immune function and, in turn, neurochemistry can be perturbed by the immune system. Biological forces that increase the likelihood of affective disorder also may increase vulnerability to disorders of immunity. In patients with CFS, who have a current and/or past affective disorder, and who also have evidence of

Figure 1 Current Favorite Model Atopy (Allergy) Epiphenomenon Lymphotropic Viruses Toxins

Reactivate Latent Viruses (HHV 6, EBV, Enteroviruses)

Compromise Immunity

Activate Immune System ((Cytokines)

Stress Symptoms Chronic Affective Disorder Disability

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cytokines in CFS and related conditions36 38, and the experience with infusing cytokines made by recombinant DNA techniques for various therapeutic purposes 39 45.

What triggers the immune dysfunction in the first place? It is likely that many factors could do so: an atopic diathesis, exogenous lymphotropic infectious agents, environmental toxins, stress and, as argued earlier, the biology of an underlying affective disorder. It seems unlikely that a single explanation, such as a single infectious agent, explains this complex illness.

Whatever the course, the symptoms of CFS lead to some degree of debility in every patient. As with any illness, the degree of debility must be due, in part, to psychological factors.

References 12. Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: A working case definition. Ann Intern Med 1988;108:387-9.

1. Paul O. DaCosta's syndrome or neurocirculatory asthenia. Br Heart J 1987;58:306-15. 2. Behan PO, Behan WMH, Bell EJ. The postviral fatigue syndrome — an analysis of the findings in 50 cases. J Infect 1985;10:211-22.

13. Olson GB, Kanaan MN, Gersuk GM, Kelley LM, Jones JF. Correlation between allergy and persistent Epstein-Barr virus infections in chronic-active Epstein-Barr virus-infected patients. J Allergy Clin Immunol 1986;78:308-14.

3. Isaacs R. Chronic infectious mononucleosis. Blood 1948;3:858-61.

14. Olson GB, Kanaan MN, Kelley LM, Jones JF. Specific allergen- induced Epstein-Barr nuclear antigen-positive B cells from patients with chronic-active Epstein-Barr virus infections. J Allergy Clin Immunol 1986;78:315-20.

4. Komaroff AL. The "chronic mononucleosis" syndromes. Hosp Pract 1987;22:71-5. 5. Straus SE. The chronic mononucleosis syndrome. J Infect Dis 1988;157:405-12.

15. Straus SE, Dale JK, Wright R, Metcalfe DD. Allergy and the chronic fatigue syndrome. J Allergy Clin Immunol 1988;81:791- 5.

6. Edson CM, Cohen LK, Henle W, Strominger JL. An unusually high-titer human anti-Epstein Barr virus (EBV) serum and its use in the study of EBV-specific proteins synthesized in vitro and in vivo. J Immunol 1983;130:919-24.

16. DuBois RE, Seeley JK, Brus I, et al. Chronic mononucleosis syndrome. South Med J 1984;77:1376-82. 17. Jones JF, Ray CG, Minnich LL, Hicks MJ, Kibler R, Lucas DO.Evidence for active Epstein-Barr virus infection in patients with persistent unexplained illnesses: Elevated antiearly antigen antibodies. Ann Intern Med 1985;102:1-7.

7. Schooley RT, Carey RW, Miller G, et al. Chronic EpsteinBarr virus infection associated with fever and interstitial pneumonitis. Clinical and serologic features and response to antiviral chemotherapy. Ann Intern Med 1986;104:636-43.

18. Straus SE, Tosato G, Armstrong G, et al. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern Med 1985;102:7-16.

8. Acheson ED. The clinical syndrome variously called benign myalgic encephalomyelitis, Iceland disease and epidemic neuromyasthenia. Am J Med 1959;4:569-95.

19. Tosato G, Straus S, Henle W, Pike SE, Blaese RM. Characteristic T cell dysfunction in patients with chronic active Epstein-Barr virus infection (chronic infectious mononucleosis). J Immunol 1985;134:3082-8.

9. Henderson DA, Shelokov A. Epidemic neuromyasthenia — clinical syndrome. New Engl J Med 1959;260:757-64. 10. Yunus M, Masi AT, Calabro J J , Miller KA, Feigenbaum SL. Primary fibromyalgia (fibrositis): Clinical study of 50 patients with matched normal controls. Sem Arth Rheum 1981;11:151- 71.

20. Caligiuri M, Murray C, Buchwald D, et al. Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome. J Immunol 1987;139:3306-13.

11. Goldenberg DL. Fibromyalgia syndrome: An emerging but controversial condition. JAMA 1987;257:2782-7.

21. Murdoch JC. Cell-mediated immunity in patients with myalgic encephalomyelitis syndrome. NZ Med J 1988;101:511-2.

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34. Kroenke K, Wood DR, MangelsdorffAD, Meier NJ, Powell JB. Chronic fatigue in primary care. Prevalence, patient characteristics, and outcome. JAMA 1988;260:929-34.

22. Salit IE. Sporadic postinfectious neuromyasthenia. Can Med Assoc J 1985;133:659-63. 23. Yousef GE, Bell EJ, Mann GF, et al. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet 1988;1:146-50.

35. Manu P, Lane TJ, Matthews DA. The frequency of the chronic fatigue syndrome in patients with symptoms of persistent fatigue. Ann Intern Med 1988;109:554-6.

24. Archard LC, Bowles NE, Behan PO, Bell EJ, Doyle D. Postviral fatigue syndrome: persistence of enterovirus RNAin muscle and elevated creatine kinase. J Royal Soc Med 1988;81:326-9.

36. Wallace DJ, Margolin K. Acute-onset fibromyalgia as a complication ofinterleukin-2 therapy. Arth Rheum 1988;31:S24. 37. Peter JB, Wallace DJ. Abnormalities of immune regulation in the primary fibromyalgia syndrome. Arth Rheum 1988;31:24.

25. Tobi M, Morag A, Ravid Z, et al. Prolonged atypical illness associated with serologic evidence of persistent Epstein-Barr virus infection. Lancet 1982;1:61-64.

38. Cheney PR, Dorman SE, Bell D. Interleukin-2 and the chronic fatigue syndrome. Ann Intern Med 1989;110:321.

26. Miller G, Grogan E, Rowe D. Selective lack of antibody to a component of EB nuclear antigen in patients with chronic Epstein-Barr virus infection. J Infect Dis 1987;156:26-35.

39. Muss HB, Costanzi J J , Leavitt R, et al. Recombinant alpha interferon in renal cell carcinoma: a randomized trial of two routes of administration. J Clin Oncol 1987;5:286-91.

27. Holmes GP, Kaplan JE, Stewart JA, Hunt B, Pinsky PF, Schonberger LB. A cluster of patients with a chronic mononucleosis-like syndrome: Is Epstein-Barr virus the cause?. JAMA 1987;257:2297-2302.

40. Quesada JR, Talpaz M, Rios A, Kurzrock P, Gutterman JU. Clinical toxicity of interferons in cancer patients. J Clin Oncol 1986;4:234-43.

28. Salahuddin SZ, Ablashi DV, Markham PD, et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 1986;234:596-601.

41. Erstoff MS, Kirkwood JM. Changes in the bone marrow of cancer patients treated with recombinant interferon alpha 2. Am J Med 1984;76:593-6.

29. Josephs SF, Salahuddin SZ, Ablashi DV, Schacter F, Wong-Staal F, Gallo RC. Genomic analysis of the human Blymphotropic virus (HBLV). Science 1986;234:601-3.

42. Rosenberg SA, Lotze MT, Muul LM, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine activated killer cells and interleukin 2 or high dose interleukin 2 alone. N Engl J Med 1987;316:889-905.

30. Ablashi DV, Salahuddin SZ, Josephs SF, et al. HBLV (or HHV-6) in human cell lines. Nature 1987;329:207.

43. Belldegrun A, Webb DE, Austin HAI, et al. Effects of i n t e r l e u k i n 2 on r e n a l function in p a t i e n t s receiving immunotherapy for advanced cancer. Ann Intern Med 1987;106:817-22.

31. Buchwald D, Saxinger C, Goldenberg DL, Gallo RC, Komaroff AL. Primary fibromyalgia (fibrositis) and human herpesvirus-6: a serologic association. Clin Res 1988;36:332A.

44. Denicoff KD, Rubinow DR, Papa MX, et al. The neuropsychiatric effects of treatment with interleukin 2 and lymphokine activated killer cells. Ann Intern Med 1987;107:293-300.

32. KomaroffAL, Saxinger C, Buchwald D, Geiger A, Gallo RC. A chronic "post-viral"fatigue syndrome with neurologic features: serologic association with human herpesvirus-6. Clin Res 1988;36:743A.

45. Ettinghausen SE, Puri RK, Rosenberg SA. Increased vascular permeability in organs mediated by the systemic administration of lymphokine activated killer cells and recombinant interleukin 2 in mice. J Nat Cancer Inst 1988;80:178188.

33. Ablashi DV, Josephs SF, Buchbinder A, et al. Human Blymphotropic virus (human herpesvirus-6). J Virol Meth 1988;21:29-48.

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Foundation

Post-Viral Fatigue Syndrome Research in Glasgow, A Review

Chapter 22

Peter O. Behan

Post-Viral Fatigue Syndrome Research in Glasgow A Review of Lectures given by Professor Peter O. B e h a n Review by The Nightingale Research Foundation Staff The following is a review of some of the work of Peter O. Behan M.D. and his associates in Glasgow, Scotland. Dr. Behan is Professor of Clinical Neurology at the University of Glasgow at the Institute of Neurological Sciences, Southern General Hospital, Glasgow. His ideas represent years ofexperience and the joint work of his team , perhaps the best funded and the most dedicated clinical and scientific group studying M.E. / CFS in Europe. Dr. Behan is preparing his own chapter for this book but it has not arrived at the time of printing. The following chapter is taken from Dr. Behan's speeches over the past three years and does not represent his most recent research and publications (see following page). Although we have made every effort to reproduce Professor Behan's ideas in a manner to be consistent with his various speeches, we do not pretend that this chapter represents Professor Behan's present views on Post Viral Fatigue Syndrome (PVFS). The world of PVFS, M.E. / CFS is undergoing continual flux, with new discoveries announced almost monthly. We refer the reader to the Index Medicus for the most recent papers from Dr. Behan's group. Nowhere in his writings or speeches can we find a precise definition of PVFS. However, the elements in the encapsulated definition that we publish here have been discussed by Professor Behan and we have salvaged them from several of his speeches and papers. It may not be his exact and present formulation. Dr. Peter Behan was born in County Kildare, Ireland, studied at Leeds University in the Midlands in England and did his doctorate at Harvard. He and his wife Dr. Wilhelmina Behan, reside in Glasgow. Dr. Behan refers to M.E. /CFS as Post-Viral Fatigue Syndrome (PVFS). He feels that the U.S. term, CFS, is too broad and inclusive. Dr. Behan's research interest has included the immunological aspects of muscle and nervous diseases. He is a co-author of the text, Clinical Neuroimmunology, and is editor of the Journal ofNeuroimmunology. He serves on the editorial board of Autoimmunity and is a member of the Medical Advisory Board, Epidemic ME Association of London, the Association of British Neurologists and the British Society of Immunology.

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Post-Viral Fatigue Syndrome (PVFS) Definitions Preconditions Post-Viral Fatigue Syndrome (PVFS): Unless you start with some reference point, such as a definite or probable initial precipitating viral infection, it is difficult to know what you are studying.

(2) PVFS is an endemic disorder occurring sporadically and occasionally occurring in epidemics. (3) The patient should have a prior well-adjusted, premorbid personality with a good past work record.

(1) The disease should have as its onset a viral infection, preferably with laboratory evidence of this infection.

(4) PVFS results in a 50% or more reduction in the individual's ability to carry out previous levels of work, school or social abilities.

PVFS Defining Characteristics: Essential Features

(7) Cardiac symptoms may occur, usually with a very rapid pulse and with missing beats. On objective testing, some patients are found to have infection or disturbance of the myocardium or pericardium.

(1) There is central fatigue (arising in the brain) with poor exercise tolerance. (2) There is hypothalamic dysfunction. (3) There is sleep disturbance that, in a child, frequently resembles sleeping sickness.

(8) Idiopathic cyclic oedema is common in women with monthly periodic weight gains of up to 12 lb.

Frequently Occurring Features

(9) Vestibular symptoms may occur. They do not have true vertigo but have difficulty or imbalance in walking

(4) There may be myalgia in a specific topographical distribution. The usual areas are the neck, trapezius and intercostal muscles. This pain in some cases simulates heart disease because the pain is so severe and so acute.

Exclusions: to define the research population clearly , patients should be excluded if they have: (1) a previous or pre-existing history of psychiatric disease (2) any other organic illness not associated with PVFS (3) any pre-existing chronic infectious illness

(5) There are sometimes psychiatric symptoms that mimic endogenous depression with a diurnal variation (6) Gastrointestinal symptoms are common and may be synonymous with irritable bowel syndrome

The following review of Dr. Behan's research group's work is based upon lectures given in: Los Angeles, California in 1990,1 London England, 1990,2 and in Hamilton Ontario in late 1991.3 Some ofthe original tapes are available on request from Dr. Jay Goldstein4 in California, and Miriam Gallacher, of the Hamilton Wentworth M.E. Association in Hamilton Ontario.5 Transcripts are available from The Nightingale Research Foundation.6 We have made every effort to record as faithfully as possible, either the exact words or intent ofDr. Behan's statements. For more extensive review articles on the Glasgow group's work, see references 7 and 8. Abnormal EMG Studies In the London epidemic of 1955 abnormal EMG studies 910 were noted, but there was criticism from

some sources that these abnormal findings could possibly be self-induced artifacts simulating disease.

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Dr. Jamal 11 , senior neurophysiologist in Professor Behan's research centre, perfected a technique invented by Professor Stalberg of Sweden12 and demonstrated that patients with PVFS who had a lesion either in the nerve, the terminal dendrites or in the neuromuscular junction, developed "jitter". Jitter represents a lack of congruity in the action potentials of two proximate muscle fibres. Professor Behan notes that these findings are extraordinarily abnormal and highly significant in 75% of 40 patients studied. The importance of this finding is that jitter is entirely objective and cannot be simulated. 13 This test merely points out that there is something wrong with the muscle, but it doesn't tell you what's wrong.

was any association with Class 1 or Class 2 HLA antigens. They were not able to find any association. They also looked at hypo-reactivity because it is known that there is a hypo-reactivity to certain viral vaccines in PVFS. Again they found no homozygosity in the DR antigen cluster and there was no lymphocyte hyporeactivity. Professor Behan notes that individuals in Holland have claimed that there is a specific monoclonal antibody that reacts with the DR region. It doesn't react with DP, DQ or DR, but is said to be a marker for activated lymphocytes and to act on cells from patients with Post-Viral Fatigue Syndrome. Professor Behan's group received the monoclonal antibody from the originators and tested it and found no association whatsoever. In fact, it was totally inactive in the cases they have looked at.

Immunological Abnormalities Professor Behan recently stated that immunological abnormalities are not specific, that there are not any basic primary immune abnormalities; they are secondary to other events.

Normal Interleukins

(Immune abnormalities are discussed in detail in his excellent paper, The postviral fatigue syndrome7. Dr. Behan notes under immunological results that in vitro lymphocyte function was highly abnormal, bmh)

Professor Behan noted that Dr. Smith of the Medical Council Research Unit measured reaction time of interferons, and the various effects of interferon on the brain. Professor Behan's group wanted to know if there was any relationship of circulating interferon, circulating interleukins or cytokines either in the CSF or in the serum. Were there inhibitors of these substances present that would allow them, for example, avoid detection? The measurement of all of these interleukins both in the cervical spinal fluid and in the serum was entirely negative in Behan's group's study.

Also in the paper by L. Morrison14, Dr. Behan's group writes: "These phenotypic changes provide laboratory evidence of immunological abnormalities in this syndrome, and, we suggest, may be consistent with persistent viral infection." HLA Study (human leukocyte antigen)

(This appears to be a reversal ofDr Behan's position, where certain enormous interleukin increases were observed and noted at the CIBA conference in London in 1989. bmh)15

Professor Behan's group has studied the genetic make-up of patients who develop PVFS since there may be an increased susceptibility among patients who possess certain DR antigens. This would explain why the illness may have some familial origin or clustering.

Abnormal Muscle Biopsy Professor Behan observes that the muscle looks normal even to an experienced muscle pathologist, However when one looks at it very carefully, there is a difference in the distribution of muscle fibre types that can be measured. In addition there is an abnormality of the mitochondria, that become very large and deformed.

PVFS may be expressing a specific epitope (antigenic determinant) in the FHC region. This change can be induced in normal individuals with the introduction of interferon. Dr. Behan's group conducted a study of 100 patients in a tissue typing laboratory in Glasgow to see if there

Seventy percent of muscle tissue from biopsies of both children and adult PVFS patients were shown

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to have type 2 predominance with type 2 atrophy. They have not found that type 2 fibre atrophy occurs with disuse even with patients with their leg in a plastic cast. He notes that an Australian researcher has published that disuse does not cause type 2 predominance nor does it cause type 2 fibre atrophy. Professor Behan states that if you look carefully at the muscle, you will find the occasional muscle fibre necrosis, but it occurs without any cellular reaction.

there are cases of fat lipid storage myopathy, which means the mitochondria have packed in following a viral infection. In Ray's syndrome, following varicella, influenza B, as well as in coxsackie and other enteroviruses, patients also develop mitochondrial abnormalities in muscle liver and in the brain. Now we have looked at the mitochondria both of muscle and the mitochondria of liver and both of them are abnormal in our typical PVFS cases.

They observe occasional paracrystaline inclusions in muscle biopsies.

In summary: In mitochondrial myopathies, which are inherited, recent reports show that in several syndromes that there are lesions in the mitochondria of the hypothalamus and that there are quite distinct neuro-endocrine abnormalities. Professor Behan believes that this might explain the mitochondria lesions they have found in muscle. Similar lesions of course can be seen in the brain and specifically can occur in the hypothalamus.

(This material is published in The post-viral fatigue syndrome ,19848in which the authors note there were widely scattered necrotic muscle fibres without any sign of inflammatory reaction and increased size and numbers oftype 2 fibres. Mitochondria were increased with occasional tubular inclusions . bmh) Abnormal Mitochondria and Myalgia

Dr. Behan's , as yet unpublished, grossly abnormal mitochondria are very similar to the abnormal mitochondria shown by Dr. Elaine DeFreitas in her Sarasota, Florida speech of March 1992. These were greatly enlarged with abnormal cristi and possible viral inclusion. This is similar if not identical to Professor Behan's findings.

Professor Behan notes that mitochondria are related to cellular energy and that they can be adversely affected by acute viral infections, by alcohol, by toxic processes such as strychnine and they are adversely affected in PVFS patients suggesting that there is some derangement of the energy-producing mechanisms of the cell.

Magnetic Resonance Spectrography (MRS) PVFS muscle demonstrates massive early lactic acidosis that is persistent in over 40 cases examined by Professor Behan's group3. The Ph falls considerably and the ADP remains normal after exercise indicating that there is something wrong with the chemistry of breaking down glycogen into sugar to give energy. The cause is not known but this could suggest that there is an enzyme derangement in the actual cell within the mitochondria. However, although they can measure this muscle abnormality it is not of great enough severity to account for the degree of fatigue in PVFS. He believes that the fatigue is caused primarily by a neurotransmitter abnormality in the brain and to a lessor degree by a peripheral muscle derangement.

He also notes that electron microscopy at the muscle membrane level in the sub-sarcolemal portion reveals grossly abnormal swollen mitochondria and extraordinary inclusions of fat. Small compartments occur in these mitochondria. This mitochondrial compart mentalization syndrome occurs with small hyalin matrix bodies in the compartments. Some mitochondria look entirely necrotic. The number of abnormal mitochondria with abnormal para-crystaline inclusion bodies bear a direct statistical relationship to the patients with myalgia. Professor Behan finds that there is an aberration of the interdigitalization of the cristi. This type of pathological mitochondrial anatomy is sometimes seen in patients with severe febrile viral infections. The role of the mitochondria in the contribution to the disease process is not known.

Dr. Behan notes that NMR was carried out on a number of PVFS patients at Oxford University. They exhibited early excessive and persistent lactic acidosis after exercise. There was low intercellular PH and normal ATP after exercise, indicating excessive

Abnormal Muscle and Liver Mitochondria In the literature,

particularly with chicken pox,

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glycolytic activity. There was obviously a muscle cell metabolic lesion to cause this.

brain stem lesions or in sarcoidosis, the test was positive.

Verifiable information comes from a paper published by D. Arnold16 [This paper referred to a single patient who fell ill with chicken pox. To my knowledge, there has been no publication of the 40 positive cases mentioned by Dr. Behan . bmh.(Also see chapter, this text concerning MRS that is essentially in agreement with Dr. Behan's observations.)]

In eighteen patients examined: 9 were 3 were 4 were 2 were

very abnormal, borderline, unable to take the test, and, normal.

Professor Behan states that if you give these patients an injection of steroid, fluid output will return to normal if they have Addison's disease and stay abnormal for PVFS.

Water Loading Test Professor Behan states that there are similarities between PVFS and Addison's disease. Addison's disease is a disease in which there is failure of the adrenal glands to produce steroids. These cases, if they were very severe, would have died before the advent of steroids, but if they were sub-clinical, then they would have complained of depression, asthenia, weakness and fatigue. They would be identical to the symptomatology he finds in Post-Viral Fatigue Syndrome. There is a test for this defect called the water loading test.

Hypothalamic Hormone Abnormality According to Professor Behan, that the problem appears to be that the hypothalamus in PVFS patients must have receptors that turn off a hormone called the antidiuretic hormone (ADH). When this hormone is turned off the kidneys excrete urine. The levels of ADH in PVFS patients follows a very irregular pattern. This hormone comes from the area of the supraoptic and paraventricular nucleus in the hypothalamus. There is a derangement in this area in PVFS patients. It appears to be the same derangement found in irritable bowel syndrome and also idiopathic cyclic oedema.

According to Professor Behan, like Addison's disease patients, PVFS patients compared to normals tend to be unable to excrete a given water load in a specific time. If cortisone is given, PVFS patients still show this defect whereas Addison's patients will return to a normal excretion pattern. This is a reasonable screening test, in that it tends to be persistently abnormal.

He notes that Professor of Neurology Dr. Raymond Adams at the Mass. General Hospital, at Harvard, in his textbook on neurology advocates it as a simple test for differentiating organic from functional fatigue.

Professor Behan states that it is a simple test that requires no expertise. This group studied a series of 18 consecutive PVFS cases who came to their clinic.

Abnormal Axis

These patients were hospitalized and made to fast overnight. Smoking was not permitted. They were asked to empty their bladder immediately before the test and to lie flat throughout the test unless they were to void. At 8:00 AM, 8:15 AM and 8:30 AM, they took 500 mis. of body temperature water. The urine was then collected every hour for three hours. A normal result occurs if the output is greater than 80% of normal capacity at the end of three hours.

Hypothalamic-Pituitary-Adrenal

Professor Behan observed that when they looked at hypothalamic pituitary adrenal axis tests, these patients are also extraordinary. Six of the eighteen cases had very high basal cortisone levels, one of four of them had high basal prolactin levels. They have subsequently collected a number of cases investigated for prolactinoma. There have been high basal gonadotrophin levels in one, and a flat gonadotrophin response in another one and no hypoglycemia response when you have used double the amount of insulin that you would normally use in six. So this test indicates that there is something the matter with the hypothalamus in a subtle way. These results are

Their results were found to be very abnormal. When they looked at patients with organic disease, such as diabetes mellitis, multiple sclerosis with

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The products were looked at by agarose gel, athenium bromide stain and slot block assays and by hybridizations to both the internal probe of P 32, and dysontogenic.

striking. There is something wrong in the hypothalamus pituitary adrenal axis. Rat models indicated hypothalamic changes in the region of the paraventricular nucleus. When the brains of PVFS patients who had committed suicide or the brains of patients who had suffered from poliomyelitis years before were examined, they had similar brain injury in the area of the paraventricular nuclei.

If one looks at the various coxsackie, polio and echo viruses, for the sequences observed, one can see those that are positive. Professor Behan notes that the controls were entirely negative. An agarose analysis of the various enteroviral PCR products to the various coxsackie and entero viruses were positive.

(This material discussing the abnormal hypothalamic hormones was reviewed by Dr Peter Behan in a symposium in Los Angeles, exactly 23 months prior to the paper published by Demitrack and Steven Straus in December 1991.18 The authors in that paper gave no mention of Dr Behan's paper, bmh.)

A slot blot analysis of enterovirus PCR products probed with digoxygenin labelled internal probe, the P2 was also positive.

Enterovirus Sequences in PVFS Muscle In another series of polio, echo and various other entero-viruses showing the PCR product, a very distinct band occurs right acrossin a certain blot analysis of the previous gel probed with digoxygenin labelled P2 probe. The slot blot assay of human muscle PCR products was probed with the radioactive P32 labelled P2 probe.

Professor Behan's group asks the question: are there enterovirus sequences in PVFS muscle? They investigated muscle for sequences of the coxsackie virus B genome using oligo-peptide sequences. Forty out of a hundred cases were positive. Their probe and primers were taken from the region of the oligo nucleotide sequences The non-transferable region was the sight chosen for the polymerase chain reaction. The reason for choosing this site was that this site has 80% homology with other enteroviral types.

Strict precautions against contamination were followed including using different laboratories, different pipettes, control tubes with unaffected RNA and no RNA in sequences, so there was no question of contamination, nor of carrying products across. They continue to examine to find which cells are affected. Are they muscle cells, macrophages or other cells? Professor Behan states that muscle cells and also certain white blood cells were involved.7

First they checked if their probe was working by infecting normal tissue culture cells with various enteroviruses. Others were infected with measles virus and others with nothing. Then in a blinded fashion they were able to check if their probe could separate enterovirus RNA in cell cultures from that containing abnormal measles cultures. Their probe proved successful.

Some of this material was published in the Gow paper I7 that noted that: "Overall, significantly more patients than controls had enteroviral RNA sequences in muscle, 53% v. 15%. ...Conclusions- Persistent enteroviral infection of muscle may occur in some patients with postviral fatigue syndrome and may have an aetiological role."

He states that RNA was extracted from a PVFS muscle biopsy. They then did agarose gel visualization of 28 and 18 S RNA bands to see that one had pure RNA. The next step was a complementary DNA PCR amplification of an endogenous gene. This is a housekeeping gene, a tyrosine kinase gene. If this was present, then they did PCR amplification of this gene. They then did complementary DNA PCR amplification of the enterovirus sequences using the primers mentioned.

(Dr .Behan noted that the 53% recovery resulted from a single needle muscle biopsy per patient and when more than one needle biopsy was made per patient the yield of virus recovery was actually higher. This is not noted in the paper, bmh)

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Lymphocyte Protein Synthesis Abnormalities

affects these receptors to PVFS patients (We believe this may have been buspirone. bmh) He states that within 10 minutes of receiving this chemical, these PVFS patients became intensely ill during the next hour or two with diarrhoea, vomiting, sweating, collapse and mood changes. When they gave this drug to 20 normal patients, who did not have PVFS, absolutely nothing happened to them.

When one cultures lymphocytes, with vita hemaglutanin, and measure the incorporation of radiolabelled iso-lucine over the first 24 hours, there is virtually a flat curve when compared to controls. Simply, patients with PVFS lymphocytes do not incorporate as much leucine as healthy controls. Professor Behan notes that Professor Peters in London has shown a similar feature in muscle cells with a failure to incorporate protein at normal anticipated levels. This suggests that something is wrong with intracellular protein synthesis but it does not tell you what is wrong.

They then gave this drug that acted on the hypothalamus of PVFS patients and measured their prolactin levels. Within 10 minutes their prolactin levels started to rise in a grossly abnormal manner. Again, when they gave this drug to normal non-PVFS patients there was no abnormality in their prolactin response.

Parkinson's Disease It is Dr. Behan's opinion that, in PVFS patients, there are gross abnormalities of 5-hydroxytryptamine and possibly L-dopa. This could explain their blood abnormalities, their sleep dysfunction, their depression. These same substance may be abnormal in M.S. patients.

Occasionally, Professor Behan's group observe young patients who, after a viral infection, develop all of the symptoms of PVFS, but in addition get Parkinson's disease. He mentioned a clear cut case in a 19 year old girl from Belfast and a 21 year old woman from Dundee. They have collected a series of them. He states that the Parkinson's disease lasts for about a year or so and they look exactly the same as old people in a geriatric home with Parkinson's disease.

Serotonin, 5-Hydroxytryptamine Agonist Professor Behan states that there is a problem in treatment for this defect. Since the body has been deprived of a normal level of 5-hydroxy-tryptomine for many years and will have altered its normal homeostasis, introduction of these agents will then create abnormal clinical responses until you get back to your previously healthy levels. He believes that drug trials will be very difficult in that initially they will cause these patients to be worse. However they would expect that after 2-4 weeks the patient should begin to feel better.

In Akureyri, in northern Iceland it has been found that there is a statistical increase in Parkinson's disease in the patients who fell ill with PVFS in 1948. This disease is related to dopa and also to 5hydroxytryptamine receptors. (Associated Parkinson's disease is not always as innocuous as mentioned here. Dr Behan does not mention the children who fell ill with classical Parkinson's disease in the Akureyri area epidemic in 1948, and then went on after a few years, to die of Parkinson's disease before reaching adulthood.19 We have also noted what appears to be an increased incidence of Parkinson's disease in spouses of M.E. / CFS patients but we have not done a good statistical investigation, bmh)

If a 5 HT agonist is given to a normal person, the symptoms ofPVFS can be reproduced. 5HT1 blockers appear to have some benefit in the treatment of PVFS patients. Hopefully, the results of Professor Behan's trial will tell quite clearly that it works. In his hands, at the moment, these medications seem to be highly advantageous in a very large number of people.

5-Hydroxytryptomine Other treatments to date that they have tried have been to no avail.

Professor Behan's group came up with the idea that there was an intense perturbation or abnormality of some of these hormones, in particular, the neurotransmitter 5 hydroxytryptomine. They then tried a relatively harmless substance, a 5 HT agonist, that

[It is my understanding that Dr Behan has mentioned to individuals in Ontario that the twopharma-

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ceuticals that he is presently investigating and which he believes hold promise for PVFS patients are the following: (1) Sertraline Hydrochloride, (Pfizer) known as Zoloft in North America and Lustral in Great Britain. This is a serotonin (5 hydroxytryptomine) reuptake inhibitor. It down regulates brain norepinephrine and serotonin receptors in animals. It is marketed as an antidepressive. (2) Buspirone Hydrochloride (Bristol-Myers-Squibb) known as Buspar in Canada. This is marketed as an anxiolytic. It has an affinity for brain D2 Dopamine receptors and acts both as an agonist and antagonist and on the 5HT1A receptors where it acts as an agonist. If a trial of these medications is to be considered, please take note of the initial effects of this drug noted above. Medical supervision is essential. Also a forthcoming publication anticipated from Dr. Behan should further clarify this information, bmh] Essential Fatty Acids Professor Behan's group has found abnormalities in essential fatty acids in PVFS patients It is known that essential fatty acids can be useful in diabetic neuropathy in humans and greatly improve cardiac dysregularities in mice. In PVFS patients essential fatty acids can be helpful but are not a cure. In the paper by Behan et al20, the authors stated that: "At one month, 74% of patients on active treatment and 23% of those on placebo assessed themselves as improved over the baseline....At three months the corresponding figures were 85% and 17%, since the placebo group had reverted towards the baseline state, while those in the active group showed continued improvement. There were no adverse events. We conclude that essential fatty acids provide a rational, safe and effective treatment for patients with postviral fatigue syndrome." Magnesium

This statement is made on the basis of a lot of debate, a lot of experimentation and a lot of talking to people who really know and have experience of treating with magnesium. Professor Behan reiterates that "it is total utter bogus and of no value whatsoever. It is beyond me, why the editor of The Lancet allowed the paper to be published. 3 Immunizations Professor Behan was asked, does immunization have any effect on someone who has postviral fatigue syndrome? He stated that there have been no studies done on this, so there's no one to his certain knowledge who can authoritatively say yes or no, but "we have seen some patients, particularly those who have received hepatitis (B) immunizations, who get much worse. We've also seen them get much worse following yellow fever." He stated that if you wanted to be immunized and it's of no importance whether you're immunized or not, then he would stay away from it. But if it's essential, if you're going to an area where diseases were endemic, in the jungle in Africa or in South America, then clearly you should require immunization, but other than that it would be very prudent to leave it alone until further information is available. 3 Pregnancy Professor Behan stated that he knew of no effect on unborn children {of mothers who have been ill prior to pregnancy with PVFS). Several of his patients have asked whether they should they become pregnant or not. A few of them have been made much worse, in that their symptoms have obviously caused great distress during the pregnancy, but by far the greatest response has been that the illness has disappeared, usually by about the 3rd month of pregnancy. There are innumerable cases on record where the illness has cleared up totally and completely in some, unfortunately in others it has come back. He also stated that some of them have developed quite severe post-natal depression, but generally speaking, pregnancy has an excellent effect on them. Professor Behan notes that pregnancy has an excellent effect on several disorders including certain cases of multiple sclerosis, some cases of myasthenia gravis, and some more autoimmune diseases. But when you go back and analyse it, people have not

Dr. Behan stated in Hamilton, Ontario that the whole question of magnesium treatment is bogus and it would be a waste of time even to consider it.

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been able to predict who are the ones who are going to get better and who are the ones who may in fact even get worse.3 Generally speaking, they tend to get better.

schooling. He relates how their schooling fell off dramatically. He recounted that in those cases that he had seen, the mothers mentioned that their children had aches and pains. If they were good at athletics, that fell off extraordinarily, and they refused to play games. He observed that in Scotland these children were handed over to psychologists and to psychiatrists who said it was a matter of behaviour, and the net result is that these children did in fact, in his opinion, suffer enormously and were never treated properly.

Children Professor Behan noted that in children below the age of 7 or 8, PVFS is extremely rare. They don't seem to be affected. If they are affected, they behave in a different way. But after the age of 7, they certainly are affected and the symptoms in children are identical to the symptoms in adults.

Further Diagnostic Criteria He noted that there was an outbreak of this illness in a small community in Scotland and it was the children who brought it to the attention of the physicians insofar as the school teachers at school noticed that a number of their pupils had difficulty with their

To complement the diagnostic statements made by Dr. Behan and reconstructed into the two tables at the beginning of this chapter, please also refer to the Diagnostic Criteria in Dr. J a m a i s paper in this text (Chapter 47).

References 11. J a m a l G , Hansen S, Electrophysiological studies in the post-viral fatigue syndrome, Journal of Neurology, Neurosurgery and Psychiatry 91985) 48; 691-694.

1. National Conference on Chronic Fatigue Syndrome and Fibromyalgia, Feb 16 - 18,1990 Los Angeles, California 1990. 2. London England, 27 October 1990, Lecture given to the members of the M.E. Association of Great Britain.

12 Stalberg E, Ekstedt J, Broman A, The electromyographic j i t t e r in normal h u m a n muscles, Electroenceph. Clin. Neruophysiol., (1971) 31: 429-438.

3. St Joseph's Hospital , Hamilton Ontario, 21 September 1991, Lecture to several of the M.E. Associations of Southern Ontario, organized by Miriam Gallacher of the Hamilton Wentworth M.E. Association, 90 Malton Drive, Hamilton, ON L9B 1E9 Canada.

13. Dr Jamal's paper, see this book, Chapter 40. 14. Morrison LJA, Behan W, Behan P, Changes in natural killer cell phenotype in patients with post-viral fatigue syndrome, (1991) Vol 83, pages 441-6.

4. Jay Goldstein M.D., Director of Chronic Fatigue Syndrome Institutes of Anaheim Hills and Beverly Hills, 500 South Anaheim Hills Rd„ Suite 206, Anaheim Hills, CA 92807 USA.

15. CIBA London Conference, CIBA Foundation, 41 Portland Place, London, England, October 11, 1988.

5. Miriam Gallacher, R.N., Hamilton-Wentworth M.E. Association

16. Arnold D, Radda G, Bore P, Styles P, Taylor D, Excessive intracellular aidosis of skeletal muscle in a patient with a postviral exhaustion/fatigue syndrome, The Lancet (1984) 23 June, 1367-9.

6. The Nightingale Research Foundation, 383 Danforth Ave., Ottawa, Canada, K2A 0E1.

17. Gow J, Behan W, Clements G, Woodall C, Riding M, Behan P, Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome, BMJ, (1991), 23 March, Vol 302, 692-6.

7. Behan P, Behan W and Bell E, The postviral fatigue syndrome, an analysis of the findings in 50 cases, Journal of Infection, (1985) 10, 211-222. 8. Behan P, Behan W, Post-viral fatigue syndrome, CRC Critical Reviews in Neurobiology, (1988) Vol 4, Issue 2, pages 157-178.

18. Demitrack M, Dale J, Straus E, et al: Evidence for Impaired Activation of the Hypothalamic-Pituitary-Adrenal Axis in Patients with Chronic Fatigue Syndrome. J Clin Endocrinology and Metabolism 1992;73:1224-34.

9. Medical Staff of the Royal Free Hospital, An outbreak of encephalomyelitis in the Royal Free Hospital Group, London, in 1955, The British Medical Journal, (1957) October 19, pages 895-904.

19. Bergmann private communication with B. Hyde, Reykjavik, Iceland, 1988. 20. Behan P, Behan W, and Horrobin D, Effect of high doses of essential fatty acids on the postviral fatigue syndrome. Acta Neurol Scand (1990) 209-216.

10. Richardson AT, Some aspects of the Royal Free Hospital epidemic, Annals of Physical Medicine,(1956) July, pages 81-9.

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Section 9

Evaluating the M.E. / CFS Patient

Jay Goldstein, MD

How Do I Diagnose a Patient with Chronic Fatigue Syndrome?

Chapter 23

How Do I Diagnose a Patient with Chronic Fatigue Syndrome? Jay Goldstein, MD Director, Chronic Fatigue Syndrome Institutes of Anaheim Hills and Beverly Hills Anaheim Hills, California, 92807 USA Dr. Jay Goldstein has been involved in research on Chronic Fatigue Syndrome and treatment ofpatients with this disorder for several years. He has coordinated a team of researchers who study the disease from the level of viral DNA to functional examinations of the brain. Viewing the symptoms of Chronic Fatigue Syndrome as a cascade of dysregulation of immunotransmission, he has tried to develop rational scientific therapies based on this hypothesis. Struck with the similarity in presentation of Chronic Fatigue Syndrome and Fibromyalgia, he has recently been attempting to unify approaches to both of these difficult problems. Dr. Goldstein was the recent organizer of the highly successful LA symposium on CFIDS / Fibromyalgia. There are several symptoms which may serve to distinguish Chronic Fatigue Syndrome from other illnesses. Virtually all of the symptoms can be understood if the disease is viewed as a limbic encephalopathy in a dysregulated neuroimmune network:

When I first began to see such patients, I believed their symptoms were so distinctive that no other illness could produce them. I now realize that a small percentage of patients will have other disorders, and that I cannot depend on the patient's previous physician to necessarily have ruled them out. Autoimmune diseases, primary sleep disorders and pelvic pathology are probably the main illnesses to have been overlooked. The physician must do a thorough history and physical examination unless the patient is warned in advance that it is the responsibility of his referring or primary care physician to do so, and that I will be functioning only as a consultant.

1) The fatigue is made worse by exercise. Very few patients report feeling better after strenuous exercise. There are probably fatigue receptors in the limbic system which are dysfunctional. They may be stimulated by cytokines which are produced in increased amounts by exercise. In Chronic Fatigue Syndrome, the quantities or types of cytokines pro-

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merous diseases, but very few diseases produce recurrent sore throats, even though examination of the oropharynx is usually normal.

duced may be abnormal or the receptors for them may be dysregulated. In many individuals, the cytokines may begin a cascade of immunochemical events, since severe fatigue or exacerbation of all the CFS symptoms do not begin for several hours after exercise, or perhaps not until the next day.

8) Nasal allergy is a common premorbid disorder which is usually exacerbated by the onset of CFS. Are nasal mucosal mediators such as substance P, somatostatin, histamine, and calcitonin gene-related peptide subject to retrograde axonal transport into the limbic system via the piriform cortex?

2) Cognitive dysfunction is extremely common. Impairment of short-term memory, a hippocampal function, is most frequently seen. Sometimes the symptoms are obvious, other times it may manifest by the patient's admission that he goes into another room and frequently forgets why he did. Getting lost while driving, impaired concentration and difficulty in word finding are often discussed.

9) The presence of the 18 tender points of fibromyalgia is the only reliable physical finding in Chronic Fatigue Syndrome. They should be examined in each patient suspected of having the disorder. If they are present, the diagnosis of Chronic Fatigue Syndrome can be made with much more confidence.

3) Mood disorders are also quite common. A recent onset of panic disorder, which is probably a limbic derangement, is rather diagnostic. Premorbid mood disorders may indicate a poor prognosis, as may length and severity of illness, and also the absence of an acute precipitating event, especially an infectious one with documented physical and laboratory abnormalities.

10) Night sweats, although seen in other diseases, are also quite common in Chronic Fatigue Syndrome and are probably caused by impaired hypothalamic temperature regulation. 11) Premenstrual Syndrome (PMS), usually severe, is almost uniformly encountered in women with Chronic Fatigue Syndrome. Many of the symptoms are similar to Chronic Fatigue Syndrome, and PMS is probably a hormonally entrained cyclic disorder of limbic gonadal steroid receptors.

4) A disorder of initiating and maintaining sleep is characteristic. A patient will state, "I can't shut my mind off no matter how tired I am." Sleep fragmentation and non-restorative sleep are typical. Hypersomnia is more frequently encountered in the initial stages of the illness. Frequent vivid nightmares are common.

12) Other disease associations such as irritable bowel syndrome, polycystic ovarian disease, thyroiditis, and endometriosis are probably part of the Chronic Fatigue Syndrome. Loss of libido and erectile dysfunction are also quite typical. It is a rare woman with Chronic Fatigue Syndrome who has not had hair loss, usually diffuse and non-scarring.

5) Intermittent blurring of vision with normal ophthalmalogic examination is the most frequently cited visual complaint, along with photophobia. 6) Few CFS patients are able to tolerate alcohol. A small amount, even a few sips will make patients intoxicated, sleepy, produce severe hangovers, and even relapses. If the mode of action of alcohol on the brain were better understood, the pathophysiology of CFS would be also. In mouse embryo hippocampal neurons, ethanol specifically inhibits NMDA receptor activation. Such inhibition may contribute to the neural and cognitive impairment associated with intoxication and the NMDA receptor involved in CFS.

13) Dyspnea on minimal exertion, air hunger and hyperventilation are frequently seen. I believe these symptoms are a result of abnormal input from the central nucleus of the amygdala to the pneumotaxic centre in the pons. Single pulse stimulation of this nucleus results to an immediate switch to inspiration. 14) Complaints of sensitivities (not allergies) to medications, food and environmental agents are quite common. It is possible that some antigens may be directly transported from the oropharynx to the brain, that abnormal antigen presentation may occur in the

7) Malaise and myalgia are characteristic of nu-

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How Do I Diagnose a Patient with Chronic Fatigue Syndrome?

TREATMENT APPROACHES 1) A n t i - i n f e c t i v e

H-2 Blockers Cognitive-behavioural therapy Antidepressants and strategies for treatment-resistant depression: Lithium, buspirone, thyroid hormone, MAOI's Anticonvulsants: carbamazepine, valproate, clonazepam Calcium channel blockers Biofeedback Altering trigeminal nerve afferents to thalamic nuclei Cognitive restructuring techniques Acupuncture MgS04 to block the NMD A receptor and as a vasodilator Naltrexone Precursor therapy Pain management Nutritional counselling Hydergine and other nootropics S-adenosyl methionine Vitamin B-12 Diamox Amantadine and ACE inhibitors to raise encephalin levels Cyclobenzaprine (Flexeril) for Fibromyalgia Leuprolide acetate (Lupron)

Antiviral agent against reactivated herpes viruses if detected by culture or PCR. Other antiviral agents for "Agent X" Antibiotics to treat sinusitis, borrelia, mycoplasma Antifungal drugs for possible Candida GI invasion Antiparasitic for Giardia and other possible agents 2) I m m u n o m o d u l a t o r y H-2 blockers Ampligen Kutapressin Gamma globulin, IM or IV Lentinan & LEM Thymic hormones Transfer factor Isoprinosine DTC Peptide T Alpha interferon Herbal Products, e.g. echinacea, astragalus Graduated exercise Gamma linoleic acid Zinc Antihistamines )— Steroids and cromlyn sprays....)— For allergic Hyposensitization )— rhinitis Allergen avoidance Sinus Surgery Leuprolide acetate (Lupron)

4) O t h e r Multivitamins Antioxidants Coenzyme Q10 Resting Avoid sunshine, immunizations, alcohol, stress, overexertion DHEA

3) N e u r o m o d u l a t o r y Improving DIMS and alpha-delta sleep with TCA's, fluoxetine, trazodone, ritanserin.

skin test for delayed hypersensitivity. CFS patients usually have very low sed rates. I do not do routine chest x-rays, although occult neoplastic disorders or sarcoidosis, as well as fungal diseases could be missed. If the patient has the proper geographic exposure, I will do Lyme titers, and stools for ova and parasites. In a patient without significant lymphadenopathy, I do not order viral titers for anything.

limbic system of the CFS patients, and that there is a dysregulated limbic response to substances such as insulin, alpha fibroblast growth factor, interleukin1 beta, and tumour necrosis factor alpha which are secreted post prandially. Some patients report feeling better after they eat, often only with certain types of foods. Others are unable to eat almost anything without a worsening of symptoms. Exogenous psychotropic substances in foods, such as opioids or benzodiazepines, may play a role.

Level II: A u t o i m m u n e investigation. I order a lupus panel to investigate the possibility of autoimmune diseases. Antithyroid antibodies, when present in h i g h t i t e r s , m a y i n d i c a t e s u b c l i n i c a l hypothyroidism, particularly important when contemplating thyroid hormone augmentation of antidepressant therapy. The presence of circulating immune complexes is another indication of immune dysfunction. Serum copper is often elevated, although ceruloplasmin and 24-hour urine copper are normal. None of my patients has yet had a low red

Laboratory investigations can be done in levels: Level I: Rule out other diseases. This caution can be taken to great extremes, with $5,000 lab bills and imaging of virtually every body part. My Level I includes a CBC, urinalysis, SMA-20, thyroid profile with TSH, sedimentation rate, antinuclear antibody, ferritin, HIV serology, and a multitest CMI

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The Clinical and Scientific Basis of M.E. / CFS

blood cell magnesium. IgA levels and IgG subclasses are ordered if I am contemplating gamma globulin therapy.

All of these brain mapping techniques are functional or physiological. In this regard, scanning before and after exercise provides more information consistent with the patient's disease process. BEAM (QEEG) scanning is an excellent preliminary step and not overly expensive. SPECT scanning is helpful diagnostically and detects mid-brain as well as the cortical features of the disease process, and also may justify vasodilator therapy with calcium channel blockers, Diamox, or magnesium sulphate, which also produces a voltage-dependent block of the NMDA receptor. PET scanning can also suggest other areas of the brain amenable to neuropharmalogic intervention. All of these modalities are helpful in documenting an organic mental disorder.

Level III: Immune system investigation. I like to know if my patient has an activated immune system and how he might respond to immunomodulatory therapy. I order IL-2 receptor levels because patients with elevated levels may respond better to intravenous immunoglobulin, soluble T-8 receptor levels, a T cell "Levy" panel, and a natural killer cell function assay. I order a single lymphocyte immune function assay if Kutapressin treatment is to be considered. I find T and B cell subsets and mitogen stimulation tests in general to not be helpful. Viral cultures and PCR for putative CFS-associated agents are available to me now and, hopefully, will be generally disseminated in the future. Sensitivity testing of anti-viral drugs may also be important.

Level V: Neuropsychological testing, if it reveals the characteristic encoding deficit seen in CFS, will be helpful diagnostically and will also suggest appropriate cognitive restructuring intervention.

Level IV: Brain Imaging. Brain functional imaging is an important part of my workup if the patient's insurance will pay for it or if the patient can afford it. Topographic brain mapping is useful if I am considering anticonvulsant or stimulant therapy.

Testing with the MMPI can reveal a typical CFS profile. Functional capacity evaluation by an occupational therapist is helpful ifthe patient will be applying for disability as well as suggesting approaches for retraining and conditioning.

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How Do I Diagnose a Patient with Chronic Fatigue Syndrome?

Dr. Goldstein's CFS Symptom checklist This symptom checklist is not sufficient to diagnose Chronic Fatigue Syndrome unless other disorders have been ruled out by appropriate assessment. A.

Did your illness begin: abruptly gradually about how long ago?

B.

Did your illness begin with a flu-like episode? yes no If yes: were lab tests done? what tests? were abnormalities found?

Were you treated for psychological problems prior to the onset of this illness? yes no If yes: psychotherapy? medication:

yes

no

Rate the severity of your symptoms from 0 to 10. 1.

Fatigue (100%) - usually made worse by physical exercise.

2.

Cognitive function problems (80%) a) attention deficit disorder b) calculation difficulties c) memory disturbance d) spatial disorientation e) frequently saying the wrong word

3.

Psychological a) b) c) d) e)

4.

Other nervous system problems (100%) a) sleep disturbance b) headaches c) changes in visual acuity d) seizures e) numb or tingling feelings f) dysequilibrium g) lightheadedness - feeling "spaced out" h) frequent unusual nightmares i) difficulty moving your tongue to speak j) ringing in ears k) paralysis 1) severe muscular weakness m) blackouts

problems (80%) depression anxiety - which may include panic attacks personality changes- usually a worsening of a previous mild tendency emotional lability (mood swings) psychosis (1%)

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The Clinical and Scientific Basis of M.E. / CFS

_n) _o) _p) _q) _r) _s)

intolerance of bright lights intolerance of alcohol alteration of taste, smell, hearing non-restorative sleep decreased libido twitching muscles ("benign fasciculations")

5.

Recurrent flu-like illnesses (75%) - often with chronic sore throat.

6.

Painful lymph nodes - especially on sides of neck and under the arms (60%).

7.

Severe nasal and other allergies - often worsening of previous mild problem (40%).

8.

Weight change - usually gain (70%).

9.

Muscle and joint aches with tender "trigger points" or fibromyalgia (65%).

10 .

Abdominal pain, diarrhea, nausea, intestinal gas- "irritable bowel syndrome" (50%).

11 .

Low grade fevers or feeling hot often (70%).

12 .

Night sweats (40%).

13 .

Heart palpitations (40%).

14 .

Severe premenstrual syndrome - PMS (70% women).

15 .

Rash of Herpes Simplex or Shingles (20%).

16 .

Uncomfortable or recurrent urination - pain in prostate (20%).

17 .

Other symptoms a) b) c) d) e) f) g) h) i) j) k) 1) m) n) o) p) q) r) s) t)

rashes hair loss impotence chest pain dry eyes and mouth cough TMJ syndrome mitral valve prolapse frequent canker sores cold hands and feet serious rhythm disturbances of the heart carpal tunnel syndrome pyriform muscle syndrome causing sciatica thyroid inflammation various cancers (a rare occurrence) periodontal (gum) disease endometirosis easily getting out of breath ("dyspnea on exertion") symptoms worsened by extremes of temperature multiple sensitivities to medicines, food and other substances

* Some of the above statistics were compiled with the assistance of data provided by Daniel Peterson, M.D. and Paul R. Cheney, M.D., Ph.D.

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MD

The Evaluation

of Adults with Chronic Fatigue .

Chapter 24

Dedra

Buchwald

The Evaluation of Adults with Chronic Fatigue: A Review of Laboratory and Psychological Findings Dedra Buchwald, MD Department of Medicine, University of Washington Seattle, Washington Dr. Buchwald received her medical degree from the University of California, San Diego and completed a Kaiser Fellowship atBrigham and Women's Hospital, Harvard Medical School. After completion of her post-graduate training, she assumed her current academic position at the University of Washington in the Department of Medicine, Division of General Internal Medicine. She presently directs the Chronic Fatigue Clinic and the Refugee Clinic at Harborview Medical Center, a major university-affiliated teaching institution. Dr. Buchwald has received external support for her work on Chronic Fatigue Syndrome and has authored and co-authored articles on various aspects of this illness. This work was supported by grant R01A126788from the National Institute of Allergy and Infectious Diseases and by a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression.

review of these findings and recommendations for the evaluation of adults with chronic fatigue.

During the past several years, much attention has been focused on an illness called chronic fatigue syndrome (CFS). CFS is a disabling systemic illness characterized by severe persistent fatigue often associated with fevers, pharyngitis, myalgias, headache, neurocognitive difficulties, sleep disturbances and depression. Although the cause of CFS remains obscure, findings from a growing body of literature suggest that immunological abnormalities, infectious agents, particularly viruses, and psychological factors may play important roles. The following is a

Laboratory F i n d i n g s 1. Standard Laboratory Tests Although a diversity of laboratory abnormalities have been reported (mostly in uncontrolled studies), there have been no consistent findings associated with CFS. On standard hematologic testing,

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The Clinical and Scientific Basis of M.E. / CFS

a third of patients78'10"1216 (AL Komaroff, unpublished data; AL Komaroff, D Buchwald, unpublished data). They are typically found in low concentrations without other evidence for lupus. Studies of immunoglobulin levels have yielded inconsistent findings as both decreased, and less commonly increased, immunoglobulins of the IgA, IgD, IgG or IgM class have been reported3'6'7'12141819 (AL Komaroff, unpublished data; AL Komaroff, D Buchwald, unpublished data). An average of 53% of patients have low levels of circulating immune complexes 4512 (AL Komaroff, unpublished data), but only a minority of patients show depressed complement4"7 and none have clinical manifestations of immune-complex mediated disease. A mitogen-induced d i m i n u t i o n in immunoglobulin synthesis in vitro has also been reported in 10% of CFS patients.

leukocytosis and leukopenia are each seen in approximately 20% of patients 1-3 (AL Komaroff, unpublished data; AL Komaroff, D Buchwald, unpublished data). A relative lymphocytosis has been described in up to 71% of patients 2 4 8 (AL Komaroff, unpublished data). Atypical lymphocytes have been reported in 0-30%2,4,5,7,9"12 (AL Komaroff, unpublished data; AL Komaroff, D Buchwald, unpublished data) and in serial studies, in about 50% of patients (AL Komaroff, unpublished data). Similarly, in one series, 48% of patients demonstrated monocytosis (AL Komaroff, unpublished data). Some investigators have reported elevated erythrocyte sedimentation rates in CFS patients 2 ' 4 ' 6,71213 and approximately 15% have positive heterophile or monospot tests 5 ' 6 ' 8101213 . Other standard testing has revealed that 20% of patients have modestly elevated transaminases 6 8'1214 (AL Komaroff, unpublished data; AL Komaroff, D Buchwald, unpublished data).

Several groups have noted abnormalities in the lymphokine and interleukin responses of CFS patients. Leukocyte activity of the interferon-induced enzyme, 2'5'-oligoadenylate synthetase was elevated in a small number of CFS patients 12 20 and circulating interferon has been infrequently detected1,5'10'12'21'22. Although one study found reduced synthesis of gamma interferon and interleukin-2 by mitogen-stimulated lymphocytes 2 3 , o t h e r s have found elevated interleukin-2 levels in CFS24.

Table 1 Frequency of Selected Laboratory Abnormalities in Adults Hematologic Leukocytosis Leukopenia Lymphocytosis Atypical lymphocytes Positive heterophile

00000-

21% 26% 71% 30% 50%

0411 030 20

32% 100% -40% 73% -40% 100% 54%

Abnormalities of lymphocyte number and function have also been noted. Both elevated and diminished numbers of T4 and T8 cells425 (AL Komaroff, unpublished data) and increased and decreased T4/T8 ratios have been found1,6,910,25 (AL Komaroff, unpublished data; AL Komaroff, D Buchwald, unpublished data). As with T-cells, both increased and decreased numbers of B-cells have been reported 5,21 (AL Komaroff, unpublished data; AL Komaroff, D Buchwald, unpublished data). In studies of lymphocyte function, up to 54% of patients are anergic3,5,6,12,26, and significantly delayed hypersensitivity to multiple antigens has been demonstrated 26 . Decreased responsiveness in vitro to standard mitogen stimulation assays has also been reported1,4,5,8,10. A recent controlled study found a significant reduction in the display of CD3, a common membrane structure found on T cells27. Since CD3 interacts with antigen and is considered i m p o r t a n t in the transduction of T cell activation signal, this finding suggests a mechanism for the T cell dysfunction observed in CFS.

Immunologic Positive antinuclear antibodies Decreased immunoglobulin classes Increased immunoglobulin classes Circulating i m m u n e complexes Increased T4/T8 ratio Decreased T4/T8 ratio Anergy Decreased n u m b e r of n a t u r a l killer cells Decreased n a t u r a l killer cell function

73%

0 - 100%

2. Immunologic Abnormalities Unusual and often conflicting findings have been noted in many immunologic studies (Table 1). Of the various circulating autoantibodies reported, the most common are antinuclear antibodies, detected in up to

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The Evaluation of Adults with Chronic Fatigue .

Natural killer cell deficiencies in CFS have been confirmed in a number of independent laboratories. Decreased numbers of natural killer cells and reductions in the normally dominant (NKH1 positiveT3 negative) subset have been reported in up to 73% of patients 14,28 . Natural killer cell function has been found to be increased11, decreased1,23,28 and normal 5 as measured by cytolytic activity against a number of different target cell lines. Diminished cytolytic activity resistant to interleukin-2 stimulation, particularly against Epstein-Barr virus infected cells, has been documented in many patients with CFS28. These abnormalities of natural killer cell phenotype and function are interesting given the central role played by these cells in viral infection, particularly infections with the herpes virus family.

lymphotropic virus or human immunodeficiency virus1,3,16 (AL Komaroff, unpublished data; AL Komaroff, D Buchwald, unpublished data). 4. Allergy Testing Allergies are a common feature of CFS10,12'4142. Several investigators have explored this association in adults and found increased cutaneous reactivity to allergens, increased levels of circulating IgE and IgE-bearing T and B cells, greater lymphocyte responsiveness to allergens and increased numbers of Epstein-Barr nuclear antigen bearing B cells in response to stimulation with specific antigens 43 44. The mechanisms linking allergy and CFS remain unknown. 5. Muscle Studies

3. Infectious Agents Muscle studies of chronic fatigue following a viral infection have demonstrated normal muscle enzymes4 and the absence of antibodies to the acetylcholine receptor45. Most patients studied had muscle biopsies showing type II fiber atrophy or necrosis, tubular and mitochondrial structural abnormalities 446 and 75% had abnormal single fiber electromyography 45 . Excessive intracellular acidosis by nuclear magnetic resonance spectroscopy has also been reported 4 47. In contrast, studies of metabolic and enzymatic markers of muscle activity in CFS demonstrated no evidence of a defect in the intermediary energy pathway48. Likewise, normal muscle strength, endurance and recovery49,50 and normal cardiac function at rest 51 have been documented by a variety of techniques . However, on graded exercise testing (which is effort dependent), CFS patients have a markedly limited exercise capacity characterized by an inability to achieve their target heart rate, a lower exercise heart rate and an abbreviated exercise duration.

CFS has been reported following infections with several different agents 7 . Although early studies linked Epstein-Barr virus and CFS, further investigations and evidence from two seroepidemiologic surveys have indicated that Epstein-Barr virus is unlikely to be an etiologic agent in most cases of CFS29,30,31. Many studies have found elevated IgG to viral capsid antigen and early antigen, generally in the absence of IgM to viral capsid antigen2,3,6,8,10,12" 14,16,19,32-35. however, there is extensive overlap between patients and healthy control subjects. A low or absent antibody to the nuclear antigen, thought to be an unusual finding in healthy seropositive individuals, has been found in some CFS patients5'81012"1419. The enteroviruses have also been implicated as possible etiologic agents in CFS. Two intriguing studies report finding circulating enteroviral antigen36,37 and IgM complexes in the majority of patients, and isolation of the virus in 22%37. Moreover, enteroviral nucleic acid has been found in muscle cells more often in patients with CFS than in control subjects38.

In summary, the laboratory abnormalities observed in adults with CFS are diverse, sometimes conflicting and frequently modest in degree. While some findings have been consistently reported by multiple investigators, others have been noted by only one group and await confirmation. The most interesting laboratory findings in CFS are those involving the immune system. While there is evidence of diffuse immunologic dysfunction, with some parameters reflecting deficient function, and others indicating hyperactivity, it has not been shown that these findings

It has been suggested that several latent viruses — herpes simplex, cytomegalovirus, measles virus 33 and human herpesvirus-639,40 — may be reactivated in patients with CFS. If true, it is unclear whether this reactivation of latent viruses contributes to the morbidity of CFS, or whether it is an epiphenomenon. In addition, several investigators have found no evidence of infection with h u m a n T-cell

255

The Clinical and Scientific Basis of M.E. / CFS

explain symptomatology of CFS, nor correlate with changes in symptoms over time. It also remains to be seen whether these findings distinguish CFS patients from those with other illnesses which can present with a similar clinical picture. Most likely, when more systematic "blinded" studies using healthy control subjects are performed, some of the "abnormalities" currently thought to be characteristic of CFS will disappear. Psychological Findings Some early reports describe neuropsychologic symptoms in young adults with prolonged illness following infectious mononucleosis or other acute infections52" 55 . The reports which heralded the current interest in CFS describe depression and "psychosocial problems" as prominent components of the syndrome10'12. Although psychological distress was presumed to result from the stress of chronic illness or from neurotoxic effects of viral infection, subsequent investigations have suggested a role for psychologic factors. At present, controversy remains regarding a primary or secondary role for psychiatric disorder in CFS.

daily activity. Although no laboratory tests are diagnostic in CFS, a reasonable laboratory test battery to evaluate patients with possible CFS would include: a complete blood count, with manually performed differential white blood cell count; erythrocyte sedimentation rate; chemistry panel; thyroid function tests; antinuclear antibodies; in some cases, circulating immune complexes and immunoglobulin levels (IgG, IgA and IgM) may be warranted. Extensive serological testing for viruses is not usually helpful in identifying a causal link between fatigue and persistent or reactivated viruses. Consideration must be given to a psychological evaluation, searching, in particular, for anxiety and depression. Whenever possible, the use of a comprehensive standardized, interviewer-administered instrument such as the Diagnostic Interview Schedule is recommended. This evaluation should be useful in supporting a diagnosis of CFS, or in ruling out other diseases that produce chronic fatigue. Table 2

Frequency of Psychiatric Dysfunction in Adults Recent investigations have consistently found a high prevalence of psychiatric disorder, primarily depression, in adult CFS patients (Table 2)11'56"61. Those studies, which included control groups, demonstrate a higher prevalence of psychiatric disorder in patients than in control subjects. Among those with both chronic fatigue and psychiatric disorders, approximately half experienced an episode of the psychiatric disorder prior to the onset of chronic fatigue58,60'61. Furthermore, in a specialty fatigue clinic, it was found that 95% of patients did not meet the Centers for Disease Control criteria for CFS56,57. Over 70% of the excluded patients had fatigue symptoms severe enough to meet criteria, but each was excluded because the psychiatric disorder was thought to be responsible for the fatigue syndrome.

Author

Assessment

Psychiatric

Used

Disorder in CFS Current

Manu

Lifetime

Psychiatric Disorder in Controls Current

Lifetime

DIS

59%

77%

N/A

N/A

DIS

N/A

75%

N/A

N/A

SADS

72%

N/A

36%

N/A

DIS

67%

N/A

N/A

29%

DIS

45%

86%

6%

48%

(56,57) Kruesi (58) Wessely (59) Taerk (60) Katon (61)

Recommended Evaluation DIS - National Institute of Mental Health (NIMH) Diagnostic Interview Schedule SADS - Schedule for Affective Disorders and Schizophrenia

A detailed history, careful physical examination, and selected laboratory tests are indicated in all patients with chronic fatigue that is significantly affecting

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The Evaluation of Adults with Chronic Fatigue .

Note added in proof Klimas62 has recently reported multiple abnormalities of cellular immunity in 30 CFS patients, including a diminution in natural killer cell cytotoxicity, gamma interferon production and lymphoprolifera-

tion after mitogen stimulation. Other findings were an increase in the percentages of suppressor-cytotoxic T cells, activated T8 cells and number of B cells and a decrease in the suppressor- inducer subset of T4 cells.

References 12. Straus SE, Tosato G, Armstrong G, Lawley T, Preble OT, Henle W, Davey R, Pearson G, Epstein J, Brus I, Blaese RM. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Int Med 1985;102:7-16.

1. Aoki T, Usuda Y, Miyakoshi H, Tamura K, Herberman RB. Low natural killer syndrome: Clinical and immunologic features. Nat Immun Cell Growth Regul 1987;6:116-28. 2. Kaslow JE, Rucker L, Onishi R. Liver extract-folic acidcyanocobalamin vs. placebo for chronic fatigue syndrome. Arch Intern Med 1989;149:2501-3.

13. Kroenke K, Wood Dr, Mangelsdorff AD, Neier NJ, Powell JB. Chronic fatigue in primary care: prevalence, patient characteristics, and outcome. JAMA 1988;260:929-34.

3. Lloyd AR, Wakefield D, Boughton CR, Dwyer JM. Immunological abnormalities in the chronic fatigue syndrome. Med J Aust 1989;151:122-4.

14. Roubalova K, Roubal J, Skopovy P, Fucikova T, Domorazova E, VonkaV. Antibody response to Epstein-Barr virus antigens in patients with chronic viral infection. J Med Virol 1988; 25:115- 22.

4. Behan PO, Behan WMH, Bell EJ. The postviral fatigue syndrome - an analysis of the findings in 50 cases. J Infect 1985;10:211- 22.

15. Lane TJ, Manu P, Matthews DA. Prospective diagnostic evaluation of adults with chronic fatigue. Clin Res 1988;36:714A.

5. Borysiewicz LK, Haworth SJ, Cohen J, Mundin J, Rickinson A, Sissons JGP. Epstein- Barr virus-specific immune defects in patients with persistent symptoms following infectious mononucleosis. Quarterly J Med 1986;58:111-21.

16. Prieto J, Subira ML, Castilla A, Serrano M. Naloxonereversible monocyte dysfunction n patients with chronic fatigue syndrome. Scand J Immunol 1989;30:13-20

6. DuBois RE, Seeley JK, Brus I, Sakamoto K, Ballow M, Harada S, Bechtold TA, Pearson G, Purtilo DT. Chronic mononucleosis syndrome. South Med J 1984;77:1376-82. 7. Salit IE. Sporadic postinfectious neuromyasthenia. Med Assoc J 4385;133:659-63.

17. Weinstein L. Thyroiditis and "chronic infectious mononucleosis" N Eng J Med 1987;317:1225-6. 18. Read R, Spickett G, Harvey J, Edwards AJ, Larson HE. IgGl subclass deficiency in patients with chronic fatigue syndrome. Lancet 1988;1:241-2.

Can

8. Tobi M, Morag A, Ravid Z, Chowers I, Weiss VF, Michaeli Y, Ben- Chetrit E, Shalit M, Knobler H. Prolonged atypical illness associated with serological evidence of persistent Epstein-Barr virus infection. Lancet 1982;1:61-4.

19. Tosato G, Straus S, Henle W, Pike SE, Blaese RM. Characteristic T cell dysfunction in patients with chronic active Epstein-Barr virus infection (chronic infectious mononucleosis). J Immuno 1985;134:3082-8.

9. Hamblin TJ, Hussain J, Akbar AN, Tang YC, Smith JL, Jones DB. Immunological reason for chronic ill health after infectious mononucleosis. Br Med J 1983;287:85-8

20. Morag A, Tobi M, Ravid Z, Revel M,Schattner A. Increased (2'- 5')-oligo-a synthetase activity in patients with prolonged illness associated with serological evidence of persistent Epstein-Barr virus infection. Lancet 1982;1:744.

10. Jones JF, Ray G, Minnich LL, Hicks MJ, Kibler R, Locas DO. Evidence for active Epstein- Barr virus infection in patients with persistent, unexplained illnesses: elevated antiearly antigen antibodies. Ann Int Med 1985;102:1-7.

21. Ho-Yen DO, Carrington D, Armstrong AA. Myalgic encephalitis and alpha-interferon. Lancet 1988;1:125. 22. Lloyd A, Abi Hanna D, Wakefield D. Interferon and myalgic encephalomyelitis. Lancet 1988;1:471.

11. Gold D, Bowden R, Sixbey J, Riggs R, Katon WJ, Ashley R, Obrigewitch R, Corey L. Chronic fatigue: A prospective clinical and virologic study. JAMA 1990;264:48-53.

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23. Kibler R, Lucas DO, Hicks MJ, Poulos BT, Jones JF. Immune function in chronic active Epstein-Barr virus infection. J Clin Immunol 1985;5:46-54. 24. Cheney PR, Dorman SE, Bell DS. Interleukin-2 and the chronic fatigue syndrome. Ann Intern Med 1989;110:321. 25. Linde A, Hammarstrom L, Smith CIE. IgG subclass deficiency and chronic fatigue syndrome. Lancet 1988;1:885-6. 26. Murdoch JC. Cell-mediated immunity in patients with myalgic encephalomyelitis syndrome. NZMedJ 1988;101:511-2.

36. Halpin D, Wessely S. VP-1 antigen in chronic postviral fatigue syndrome. Lancet 1989;1:1028-9. 37. Yousef GE, Bell EJ, Mann GF, Murugesan V, Smith DG, McCartney RA, Mowbray JF. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet 1988;1:146-7. 38. Archard LC, Bowles NE, Behan PO, Bell EJ, Doyle D. Postviral fatigue syndrome: persistence of enterovirus RNA in muscle and elevated creatine kinase. J Royal Soc Med 1988;81:326-9. 39. KomaroffAL, SaxingerC, BuchwaldD, Geiger A, GalloRC. A chronic "post-viral" fatigue syndrome with neurologic features serologic association with human herpes virus-6. Clin Res 1988;36:743A.

27. Subira M, Castilla A, Cireira M, Prieto J. Deficient display of DC3 on lymphocytes of patients with chronic fatigue syndrome. J Infect Dis 1989; 160:165-6. 28. Caligiuri M, Murray C, Buchwald D, Levine H, Cheney P, Peterson D, Komaroff AL, Ritz J. Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome, J Immunol 1987;139:3306-13.

40. Wakefield D, Lloyd A, Dwyer J. Human herpes virus 6 and myalgic encephalomyelitis. Lancet 1988; 1:1059. 41. Jones JF, Straus SE. Chronic Epstein-Barr virus infection. Ann Rev Med 1987;38:195- 209.

29. Hellinger WC, Smith TF, Van ScoyRE, Spitzer PG, Forgacs P, Edson RS. Chronic fatigue syndrome and the diagnostic utility of antibody to Epstein-Barr virus early antigen. JAMA 1988;260:971-3.

42. Straus SE, Dale JK, Wright R, Metcalfe DD, Allergy and the chronic fatigue syndrome. J Allergy Clin Immunol 1988;81:791-5.

30. Horwitz CA, Henle W, Henle G, Rudnick H, Latts E. Longterm serological follow-up of patients for Epstein-Barr virus after recovery from infectious mononucleosis. J Infect, Dis 1985;151:1150-3.

43. Olson GB, Kanaan MN, Gersuk GM, Kelley LM, Jones JF. Correlation between allergy and persistent Epstein-Barr virus infections in chronic-active Epstein-Barr virus infected patients. J Allergy Clin Immunol 1986;78:308-14.

31. Lamy ME, Favart AM, Cornu C, Mendez M, Segas M, Burtonboy G. Study of Epstein Barr virus (EBV) antibodies: IgG and IgM anti-VCA, IgG anti-EA and IgG anti-EBNA obtained with an original microtiter technique: -Serological criterions of primary and recurrent EBV infections and followup of infectious mononucleosis; - Seroepidemiology of EBV in Belgium based on 5178 sera from patients. Acta Clin Belgica 1982;37:281-98.

44. Olson GB, Kanaan MN, Kelley LM, Jones JF. Specific allergen- induced Epstein-Barr nuclear antigen-positive B cells from patients with chronic-active Epstein-Barr virus infections. J Allergy Clin Immunol 1986;78:315-20.

32. Buchwald D, Sullivan JL, Komaroff AL. Frequency of 'chronic active Epstein-Barr virus infection' in a general medical practice. JAMA 1987;257:2303-7.

46. Warner CL, Cookfair D, Meffuer R, Bell D, Ley D, Jacobs L. Neurologic abnormalities in the chronic fatigue syndrome. Neurol 1989;39 (suppl):420.

33. Holmes GP, Kaplan JE, Stewart JA, Hunt B, Pinsky PF, Schonberger LB. A cluster of patients with a chronic mononucleosis-like syndrome: Is Epstein-Barr virus the cause? JAMA 1987;257:2297-2302.

47. Arnold DL, Bore PJ, Radda GK, Styles P, Taylor DJ. Excessive intracellular acidosis of skeletal muscle on exercise in a patient with a post-viral exhaustion/fatigue syndrome. Lancet 1984;1:1367-9.

34. Hotchin NA, Read R, Smith DG, Crawford DH. Active Epstein- Barr virus infection in post-viral fatigue syndrome. J Infect 1989;18:143-50.

48. Byrne E, Trounce I. Chronic fatigue and myalgia syndrome: mitochrondrial and glycolytic studies in skeletal muscle. J Neurol Neurosurg Psychiatry 1987;50:743-6.

35. Waters-Peacock N, Wray BB, Ades EW. A prospective study: Evaluation of the antibody- dependent cell mediated cytotoxicity assay in chronic active Epstein-Barr syndrome. J Clin Lab Immunol 1988;27:11-2.

49. Lloyd AR, Hales JP, Gandevia SC. Muscle strength, endurance and recovery in the post- infection fatigue syndrome. J Neurol Neurosurg Psychiatry 1988;51:1316-22.

45. Jamal GA, Hansen S. Electrophysiological studies in the post- viral fatigue syndrome. J Neurol Neurosurg and Psychiatry 1985;48:691-4.

258

Dedra Buchwald,

MD

The Evaluation

50. Stokes MJ, Cooper RG, Edwards RHT. Normal muscle strength and fatigability in patients with effort syndromes. Br Med J 1988;297:1014-7.

of Adults with Chronic Fatigue .

57. Manu P, Matthews DA, Lane TJ. The mental health of patients with a chief complaint of chronic fatigue: a prospective evaluation and follow-up. Arch Intern Med 1988;148:221317.

51. Montague TJ, Marrie TJ, Klassen GA, Berwick DJ, Horacek 58. Kruesi MJP, Dale J. Straus SE. Psychiatric diagnoses in patients who have chronic fatigue syndrome. J Clin Psychiatry 1989;50:53-6.

BM. Cardiac function at rest and with exercise in the chronic fatigue syndrome. Chest

1989;95:779-84.

52. Greenfield NS, Roessler R, Crosley AP. Ego strength and length of recovery from infectious mononucleosis. J N e r v M e n t Dis 1959;129:125-28.

59. Wessely S, Powell R. Fatigue syndromes: a comparison of chronic "postviral" fatigue with neuromuscular and affective disorders. J Neurol Neurosurg Psychiatry 1989;52:940- 8.

53. Bender CE. Recurrent mononucleosis. JAMA 1962;182:954-6. 54. Issacs R. 1948;3:858- 61.

Chronic infectious mononucleosis.

60. Taerk GS, Toner BB, Salit IE, Garfmkel PE, Ozersky SO. Depression in patients with neuromyasthenia (benign myalgic encephalitis). Int J Psychiat Med 1987;17:49-56.

Blood

61. Katon WJ, Buchwald DS, Simon GE, Russo JE, Mease PJ. Psychiatric illness in patients with chronic fatigue and rheumatoid arthritis. J Gen Intern Med 1991; 6:277-85.

55. Kasl SV, Evans AS, Niederman JC. Psychosocial risk factors in the development of infectious mononucleosis. Psychosom Med 1979;41:445-6.

62. Klimas NG, Salvato FR, Morgan R, Fletcher MA. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol. 1990; 28:1403-10.

56. Manu P, Lane TJ, Matthews DA. The frequency of the chronic fatigue syndrome in patients with symptoms of persistent fatigue. Ann Intern Med 1988;109:554-6.

259

The Clinical and Scientific Basis of M.E. / CFS

Chapter 25

Alexander C. Chester

Chronic Fatigue of Nasal Origin: Possible Confusion with Chronic Fatigue Syndrome Alexander C. Chester III, MD, FACP Clinical Professor of Medicine, Georgetown University Medical Center Foxhall Internists, PC Suite 348, 3301 New Mexico Avenue, NW, Washington, DC 20016 USA Dr. Chester has studied at Georgetown University, Washington, University of Salzburg, Austria as well as Columbia University, New York. Dr. Chester has been involved in many societies, including The Osier Society, National Kidney Foundation, Council on Clinical Nephrology, Dialysis and Transplantation and The ClinicoPatholgical Society. Dr. Chester has held many prestigious positions including the President of The Osier Society and he presently holds the position of the Secretary and Treasurer of the Hippocrates-Galen Society. William Osier described three types of fatigue. The first is a weakness experienced in the muscles and limbs caused by neurologic or muscle illness. The second, a "lassitude felt on slight exercise" is associated with systemic disease. Finally, a "painful weariness" or the feeling of being "knocked out" after minimal exertion is the type generally noted in unexplained chronic fatigue. 1

could result in the severe complications occasionally associated with sinusitis. Conversely, sinusitis has been noted as the initial symptom of CFS and may serve as a possible trigger. The possibility that nasal problems can precipitate a more complex disease, possibly of viral origin, is suggested by an outbreak of multiple sclerosis following sinusitis. 4

The last type of fatigue is characteristic of both chronic fatigue syndrome (CFS) and fatigue of nasal origin.2'3 Upper respiratory complaints are noted in both. Unlike CFS, nasal disease with its related sinusitis, is eminently treatable and should be thoroughly considered in the differential diagnosis of unexplained fatigue. Additionally, failure to treat

In the practice of general internal medicine, chronic fatigue is responsible for approximately 25% of visits. 5 Less than half of these are clarified with a diagnosis leaving the syndrome of unexplained chronic fatigue as one of the largest problems in the outpatient population. 6 Psychologic explanations are

260

Alexander C. Chester, MD, FACP

Chronic Fatigue of Nasal Origin: Possible Confusion with Chronic Fatigue

often suspected but proof or consensus is lacking. Unlike the fatigue of a typical organic illness, however, the patient does not in general feel best in the morning, "wearing down" as the day goes on. Moreover, unlike most physical illnesses, there are no known laboratory markers. The physical examination is likewise unremarkable.

Syndrome

tested. Significant unexplained fatigue for greater than one month, unrelieved by rest, was noted in 68 patients (study group). Findings were compared to the remaining 239 (control). Women contributed 60% of the study group and 41% of the control (p 50%)

No.

%

Muscle fatigue Emotional labilityf Myalgiaft Cognitive disturbancettt Headache Giddiness, disequelibrium Autonomic dysfunctiontttt Auditory disturbances* Reversal of sleep rhythm Visual disturbances** Parasthaesia, hypo &hyperasthaesia Intercostal myalgia/weakness Fasciculation, spasm, myoclonus Clumsiness***

420 411 336 323 310 302 289 289 268 260 256 247 239 235

100 98 80 77 74 72 69 69 64 62 61 59 57 56

Less commonly

No.

%

psychoactive, antiarthritic or steroid drugs in 21 (5%). Laboratory

results

Haematology and biochemistry Screening tests were normal with the following exceptions: 55/420 (13%) had leucocyte counts below normal range (3,500 x 109/1) with occasional atypical lymphocytes and 22/420 (5%), abnormal liver function tests, of whom two had hepatitis A. Two further p a t i e n t s had undiagnosed p e r s i s t a n t hyperbilirubinaemia. CBV serology The sera of 205 patients with diagnostic features of M.E. seen before 1985, were tested by NT: 68/205 (33%) had titres indicative and 35/205 (17%) suggestive of recent CBV infection. Subsequently, 124 patients were additionally tested by the enteroviral IgM ELISA system. Applying the diagnostic criteria established by McCartney et al.,7 38/124 (31%) had evidence of recent/active enteroviral infection. Sixteen patients in our study, who were retested annually for three years, showed persistently raised CBV NTs and intermittently positive enteroviral IgM . Other viral

investigations

found( 40):

< 20 years old = 11% > 20 years old • 89%

(Rough calculations)

Roughly 80% of the tests we receive are from adults, and more than 99% of adults over 39 years of age are VCA-IgG positive. For this reason the tests chosen

for adults are VCA-IgG and EA (EBNA) and VCA Immunoglobulin M (IgM) are done mostly in children and teenagers, where primary infections are suspected.

293

» The Clinical and Scientific Basis of M.E. / CFS

Figure 2 E n t e r o v i r u s e s Isolation a n d Serologic D i a g n o s t i c R e s u l t s (3,225 viruses) Over N i n e Years from Ontario P a t i e n t s

Total Enteroviruses . Diagnosed

700 - -

-a 600

Untyped" EM only

--

X

Coxsackies

Echovi ruses 500

400

300 - -

200

100 - -

80-81

81-82

82-63

83-84

84-85

85-86

86-87

87-88

88-89

YEAR

We consider an EA > 40 to indicate a recent, or relatively recent active infection (primary or reactivation); a VCA > 640 with EA < 40, a relatively recent active infection but less recent; positive VCA-IgMs have been positive only rarely in our adults; EBNAs

have been almost constantly positive in adults, indicating those high VCAs or present EAs were due to reactivations. It is very difficult to interpret EBV serology significance in cases with "fatigue" of more than six months' duration, or of several years' duration.

294

B. McLaughlin, MD

Virology Laboratory Diagnosis of Chronic Fatigue Syndrome

Table 1 EBV Serology of Ontario Patients: A Nine-Year Review

1981-82 1982-83 1983-84 1984-85 1985-86 1986-87 1987-88 1988-89

Total Tested

VCA+ EA > 40

11,492 7,419 7,878 10,600 16,835 22,409 33,734 28,669

1,676 2,688 1,540 3,499 4,335 5,193 6,984 5,193

VCA > 640 EA < 40

IgM VCA+

Seroconversions

1,652 1,953 2,706 2,633 5,292 4,891

31 16 59

39 42 56

138,646

with EA < 40, and specimens with EA > 40 represent about equal numbers in 1983-84. The percentage of EA > 40 increases while the EA < 40 decreases in 1984, 1985, 1986, and 1987. In 1988-89 (Table 2), they are restored to the proportions of 1983-84. It seems that between 1983 and 1988 the number of recent reactivations was higher. Although it is impossible to draw accurate conclusions from such data, it seems that some event occurred between 1983 and 1988 to cause EBV reactivations.

Figure 1 shows the large, steady increase in demand for the test. The media's influence on demand has been very noticeable following programs on TV and radio, and publications in popular magazines and newspapers on chronic fatigue, chronic EBV infections, the "Yuppie Plague", "Lake Tahoe Disease," etc. If we look at the percentage of significant results (Figure 1), we see that specimens with VCA > 640

Table 2

EBV Serology of Ontario P a t i e n t s : March, April, May 1989 >640 >40

Seroconversions

IgM

Total

10 33 22 40 40 41 83

29 49 38 78 73 90 177

2 3 0 0 0 1 1

3 4 0 0 1 0 0

503 689 459 612 555 492 1,192

1,095

309

622

7

8

5,373

20.3%

5.7%

12.3%

Age

VCA < 40 EA < 40

40-320 128640 40

232 150 50 39 36 19 64

180 341 274 325 273 218 583

47 109 75 130 132 123 284

Total

687

2,605

%

12.7%

48.4%

40-320 >40

295

0.1%

» The Clinical and Scientific Basis of M.E. / CFS

Table 3 N i n e Years of E n t e r o v i r u s Isolation R e s u l t s from Ontario P a t i e n t s 80/81 C 0 m b i n e d

V. Coxs A, nt 5 I. Coxs A 9 14 & Coxs B 1 S. B2 9 B 3 31 B 4 30 B5 6 B6 95

C 0 m b i n e d

Echo 2 3 5 6 V. 7 I. 9 & 11 s. 13 14 17 18 21 22 24 25 29 30

Polio 1 2 3

82/83

84/85

85/86

86/87

87/88

13

18

7

17 28 27 160

11 10 3 1

1 3 1 1

21 1 4 17 8 3

70

68

245

43

13

54

3 3 3

2

1 1

2

5

3

1

43 7

1 5 1

2 4

11 25

13 15

1

1 5

1

14

14 2 15 8

4 13 36 2 1

45

2

83/84 6 8 3 10 6 13 22

6

2 1 5 8

1

88/89

Total

3 4

11 101 4 73 114 133 207 1

11

4

1

1 6 22 23

2 5 71 6 18

10 6

2

5

5 1 1 2 1

6 3 10 2

1 1 1

22 V. 0 I. n 1 y

81/82

1 5

7

8

17

17

54

87

4,v

l,v l.v 6,v

2,v

4

8

2

l,v

1

66

102

34

1

2 13 53 23 79 72 105 1 10 8 6 3 10 3 12 20

12

411

l,w

2 4 12

2,v

2

644

1,V

19 ( l w , 18v)

V. 0 I. n 1 y

EMOnly 124

172

109

138

Ent, nt

TOTAL

99

266

90

111

149

290

321

192

566 621 952

78

124

172

109

135

78

248

556

411

303

2,139

242

238

204

262

412

361

671

500

327

3,225

Legend nt = not typed v = vaccinal EM = Electron Microscopy

w - wild

V.I. & S. = Virus Isonation & Serology

296

B. McLaughlin, MD

Virology Laboratory Diagnosis of Chronic Fatigue Syndrome

Enteroviruses

results are difficult to interpret in the absence of precise clinical or immunization history, which we were unable to collect.

Dr. Byron Hyde has earlier discussed the etiologic significance of polio, coxsackie and echoviruses as causes of CFS. We reviewed the enteroviruses diagnosed in our laboratory during the last 9 years. A total of 3,225 (Table 3) diagnoses were made. These are virus diagnoses made by isolating viruses in cell cultures while some were detected only by electron microscopy. They represent mostly cases of viral meningitis, "summer flu," sore throat, fever, myalgia, pleurodymia, febrile rashes, and diarrhea, and they were essentially detected in late summer and early winter. Typing of these enteroviruses is time-consuming and was not always done, but we see a peak of Coxsackie B5 in 1984-85 and Echovirus 7 in 1986-87.

Discussion The laboratory data reviewed here are of 2 different types. For EBV, the number of specimens received were certainly influenced by the media, and the percentage of significant results were provided by the laboratory. For enteroviruses, the number of actual viral isolates from clinical specimens should not have been influenced by media "hype" but should reflect the epidemiologic patterns of these viruses. Still, both EBV reactivations and enteroviruses infections increased between 1983 and 1987, a phenomenon that seems to confirm the impressions of Dr. Mildon and Dr. Hyde in their review of their Ontario patients. It is impossible to draw further conclusions from these very general data, but they do merit further investigation.

Figure 2 shows the increase in enterovirus detection between 1984 and 1987, with a decline in 1987-88. Enteroviruses are always present in Ontario, with type variations and epidemic peaks varying from year to year, which again makes interpretation of these data difficult. Serology for polio and coxsackie in patients said to be suffering with CFS was analyzed for the first 6 months of 1989 and showed frequently high titres for polio, especially Polio 3 (Table 4). The

Editor's note: The marked clinical increase ofM.E. / CFS noted in Canada between 1984-1987 cannot be explained by the Ontario Ministry ofHealth's relative lack ofincrease of EBV findings, but could be explained by the observed increased Coxsackie B viruses in 1984 and marked increase in Echo viruses in 1984-87. Dr. McLaughlin and Dr. Yousef, neither aware of the other's work, both noted Coxsackie B5 and Echo 11 as the major enteroviral infectious agents during the period under their particular and unrelated studies.

Table 4 Chronic F a t i g u e / Myalgic E n c e p h a l o m y e l i t i s E n t e r o v i r u s Serology J a n u a r y - J u n e 1989 High Titres to 1 or 2 Viruses (>1:512)

Coxsackie Coxsackie Coxsackie Echovirus

Dr. McLaughlin notes significant indications of Echovirus 7, 9 and 11. She apparently did not test for Echo 1. Dr. Yousef also notes specific increased recovery of Echo 1, 9 and 11. Echo 11 appears to be specifically correlated with the same type period of 1985-1987 by both researchers. The sum total of positive enteroviral tests are more consistent with the 1984-1987M.E./CFS epidemic than any individual enterovirus. This correlation does not confirm that enteroviruses were the cause of the 1984-1987 M.E. / CFS epidemic but does place the enteroviral group of viruses as potential causes of this epidemic period.

1 3 18

Polio 1 Polio 2 Polio 3 B2 B3 B4 9

1 3 3 1 30

Total tested % with High Titres

1269 11%

297

The Clinical and Scientific Basis of M.E. / CFS

Chapter 29

Mauro

Bendinelli

The Immunosuppressive Effects of Group B Coxsackievirus Infections Mauro Bendinelli, MD, PhD and Donatella Matteucci, BS Virology Section, Department of Biomedicine, University of Pisa. Address: Dr. M. Bendinelli, Dipartimento di Biomedicina, Via S. Zeno 35, 56127 Pisa, Italy. In addition to his academic position, Dr. Bendinelli is Director of the Department of Biomedicine and head of the Clinical Virology Unit of the University ofPisa as well as being Professor ofMicrobiology. His main research interests are: pathogenesis and immunopathogenesis of viral infections; immunobiology of Coxsackieviruses and retroviruses; viral-induced immunodeficiencies. Dr. Bendinelli is also the Co-editor ofthe series "Infectious Agents of Pathogenesis" for Plenum Press, New York, as well as several scientific journals. D. Matteucci has been a research assistant at the Virology section of the Department of Biomedicine of the University of Pisa since 1976. Her research interests include: interactions of murine retroviruses and coxsackieviruses with the host's immune system, mechanisms of coxsackievirus persistence in infected cells, biology and pathogenesis of feline immunodeficiency virus and other feline retroviruses. 1. Introduction Group B coxsackieviruses (CBV) encompass six different serotypes that belong to the genus Enterov i r u s of the family P i c o r n a v i r i d a e . These impor-

tant human pathogens are small, naked icosahedral, positive single-stranded RNA viruses that usually cause common enteric infections throughout the world

298

M. Bendinelli, MD, PhD and D. Matteucci, BS

The Immunosuppressive

Effects of Group B Coxsackievirus Infections

Subsequent studies were carried out using adult inbred BALB/c mice infected with CBV-3. Using monodispersed spleen cells stimulated in vitro with selected antigens, it was observed that, within a few days from infection, primary antibody responses to thymus-dependent antigens were depressed by 50 to 80%. In contrast, secondary responses to the same antigens were essentially spared (Bendinelli et al., 1982).

but may also produce a wide range of well characterized acute clinical illnesses, including aseptic meningitis and other diseases of the central nervous system, acute myocarditis and pericarditis, and epidemic pleurodinia (also known as epidemic myalgia or Bornholme disease). In addition, CBV have been implicated in the etiology of a number of other infections such as congenital malformations, acute pancreatitis and orchitis, exanthemata, chronic cardiopathies, and type 1 diabetes (Bendinelli and Friedman, 1988). Recently, they have been considered as possible etiological agents of myalgic encephalomyelitis (M.E.) (Bell et al., 1988).

Attempts to understand the mechanisms for the reduced immunoresponsiveness of infected spleen cell cultures yielded the following results: i. spleen cells responded well to thymus-independent antigens and, when supplemented with non-B cells from uninfected mice, also to thymus-dependent antigens;

CBV-induced Immune Deficiency One aspect of CBV pathogenecity that, until recently, had been entirely overlooked is their detrimental action on the functions and integrity of the immune system. Recent studies, however, have clearly shown that experimentally infected mice may present a markedly reduced immune response to unrelated antigens and a severe degree of lymphoid involution, and that human lymphocytes exposed to CBV in vitro also exhibit a reduced responsiveness. In addition, in vitro studies have shown that, with the exception of serotype 6 (CBV-6), CBV can readily establish carrier-type persistent infections in cultures of immortalized human lymphocytes. These data may be relevant to the etiopathogenesis of M.E., as from the very beginning it has been suspected that the disease is associated with disordered regulation of the immune system (Behan et al., 1985).

ii. activated nonspecific T suppressor cells were present in the infected spleens, although the level of suppressive activity detected in individual mice did not correlate with the degree of immunodepression exhibited by the same animals; iii. supplementing with splenic or peritoneal macrophages from normal mice restored the responsiveness of infected spleen cell cultures; iv. adding splenic macrophages from infected spleens did not reintegrate the responsiveness of macrophagedepleted spleen cell cultures from normal or infected animals; v. addition of cell-free CBV-3 to normal spleen cultures did not reproduce the immunosuppressive changes exhibited by spleen cells obtained from infected mice.

This paper summarizes the studies performed in mice in the attempt to understand the mechanisms underlying CBV-induced immune deficiency and then reviews published evidence suggesting that CBV can be immunosuppressive in humans.

Taken together, these findings indicate that CBV3-induced immunosuppression is sustained by defects in the ability of accessory cells to cooperate normally with lymphocytes and, possibly, also to the activation of nonspecific T suppressor cells. In contrast B lymphocytes do not seem to represent a major target of immunosuppression (Bendinelli et al., 1982).

2. Animal S t u d i e s In early experiments, adult random bred Swiss mice were infected with the six CBV, as well as with three group A coxsackievirus (CAV) serotypes, and then challenged with unrelated immunogens. Animals infected with CBV-1, 3, 6 and CAV-15 exhibited a reduced antibody responsiveness. CBV-3 also suppressed the ability of mice to mount a normal cellmediated contact sensitivity response to the skin sensitizer oxazolone (Bendinelli et al., 1975).

In addition to such functional alterations, the immune system of CBV-infected mice undergoes a marked anatomical involution. Thymus, spleen and

299

»

The Clinical and Scientific Basis of M.E. / CFS

lymph nodes gradually lose weight and cellularity. Histologically, the thymus showed an early depletion of cortical thymocytes and loss of distinction at the corticomedullary junction, followed by cellular depletion of the medulla. In the peripheral lymphoid organs, cellular depletion was characterized by a parallel decline of the various cell classes and subclasses studied, except for an early temporary rise of T cells with suppressor phenotype. Fibrosis was the eventual outcome in all organs (Matteucci et al., 1985). How the functional and anatomical alterations of the immune system observed in CBV infected mice are generated remains an enigma. A direct adverse effect of locally replicating virus, due to viral cytopathology or less obvious changes, is generally believed to contribute to the genesis of many virus-induced immune deficiencies (Specter et al., 1989). However, attempts to grow CBV in freshly harvested murine lymphoid cells were unsuccessful. Moreover, infectious center assay detected few, if any, productively infected cells in central and peripheral lymphoid organs. Only the bone marrow contained substantial numbers ofvirus-producing cells (Matteucci et al., 1985). Direct immunofluorescence with monoclonal antibody to CBV-3 evidenced production of viral molecules in scattered cells (usually less than 1%) whose nature remained elusive (Garzelli et al., 1988). It seems possible that virus-infected cells are a small subpopulation of lymphoid cells or blood vessel cells or other cell types (Easton and Eglin, 1988). In this context, it is worth mentioning that in vitro the murine lymphoid cell line YAC-1 could be persistently infected with CBV-3 (Cao and Schnurr, 1988) in a manner similar to the human lymphoid cell lines discussed below. In these cultures, infection was perpetuated by a minority of susceptible cells whereas most of the cells were resistant to the carried virus. It is therefore possible that murine lymphoid cells are inherently resistant to CBV but become susceptible under particular physiological conditions. Even if one assumes that local viral replication in a few cells is responsible for immunosuppression and lymphoid involution, it remains to be established how the damage is amplified. Two possibilities come to mind: one is that the infected and presumably lysed cells have important trophic functions (Garzelli et al., 1989). The other is that local infection triggers

300

a chain of progressive autoaggressive events. Interestingly, attempts to alleviate the lymphoid involution by administering a number of immunopotentiating compounds led to a paradoxical exacerbation of manifestations (Matteucci et al., 1985). Similar results were obtained by treating mice with bacterial lypopolisaccharide (LPS), a well known polyclonal B cell activator (unpublished data). Recently, we have investigated the role played by selected cytokins in the generation of the immune derangements produced by CBV-3 infection in mice. The amounts of interleukin (IL) 2 and gamma-interferon (IFN) produced by concanavalin A stimulated spleen cells were reduced in the early stages of infection but highly enhanced after the onset of lymphoid involution. At this time IL 1 production by LPS-treated adherent spleen cells was also enhanced. Basal titres of circulating tumor necrosis factor (TNF)alpha were transiently increased early after infection, while LPS-induced levels remained considerably increased for several days. Serum from infected mice inhibited the proliferation of lymphoid cells in vitro at higher dilutions than that of normal mice, but this activity could not be attributed to TNFalpha. On the other hand, the administration of antimurine TNF antibody failed to protect mice against CBV-3-induced lymphoid involution and lethality. Thus, although it could not be excluded that altered cytokine physiology might play a major role in CBV3-induced immunological damage, no single alteration appeared responsible for lymphoid involution (Bendinelli et al. 1990). 3. H u m a n S t u d i e s To the authors' knowledge, there are no published reports on the behaviour of standard clinical immunology parameters in CBV-infected patients. Neither is there evidence that CBV can replicate extensively in the lymphoid organs of humans. In fact, the histopathology of human lymphoid tissues during CBV infections is generally poorly understood. There are, however, scattered clinical reports indicating that these viruses can worsen concomitant infections and facilitate disease production by opportunistic agents. An example is the case of fulminant pulmonary coccidioidomycosis described in a child co-infected with CBV-4 (Gururaj et al., 1984).

M. Bendinelli, MD, PhD and D. Matteucci, BS

The Immunosuppressive

Recently, studies have been performed on the ability of human peripheral blood mononuclear cells (PBMNC) exposed to CBV in vitro to support viral replication and to effect their normal functions. In one study, it was found that CBV-3 replication in human PBMNC was essentially restricted and could not be enhanced by mitogen stimulation. Polyclonal blastogenic and antibody responses of lymphocytes were not significantly affected (Hyypia et al., 1988). In similar studies by us, a considerable degree of variability was observed in the permissiveness of PBMNC from individual donors to the six CBV serotypes. Such variations appeared unrelated to donor age and gender and showed no relation to the presence and titre of anti-CB V neutralizing antibody in the donor sera. PBMNC presented a reduction of mitogen-driven proliferation whose extent varied from 20 to 50%, again depending not only on viral serotype and dose but also on the PBMNC donor. The depressive effect of CBV-6 was particularly pronounced and consistent. Suppression was not mediated by the antiproliferative properties of IFN produced by the PBMNC in response to CBV challenge, as it could not be prevented by the addition of high titre anti-alpha and/or beta-IFN antibodies. The suppression was only partially reversed by the addition of large amounts of recombinant human IL 2 (Conaldi et al., 1988).

Effects of Group B Coxsackievirus Infections

proliferation were evident over the entire period of incubation, despite the high viral titres produced. This was of interest because CBV are generally considered highly cytocidal, as virions are liberated in a burst when the host cell lyses at the end of the replication cycle. On the whole, lines of B-lymphocytic origin appeared somewhat more susceptible to CBV infection than Tcell lines and their permissiveness appeared to be independent on the presence of the Epstein-Barr virus genome that reportedly influences B cell susceptibility to other viruses (Creager et al., 1981). A further level of variation was observed when the lymphoid cells were exposed to different clones of a same CBV immunotype. At 37°C all clones grew well, even though the effects on culture viability varied considerably, but certain small plaque clones proved unable to replicate significantly at 39.5°C.

The cell type(s) among human PBMNC which support a low degree of CBV replication is still unclear. By immunofluorescence, it was found that viral antigens were mostly located in adherent cells (Hyypia et al., 1988). It should be noted, however, that human lymphoid cells may be permissive for CBV replication. We examined the response of a number of lymphoid cell lines of the B and T lymphocyte lineage to infection by the six CBV immunotypes (Matteucci et al., 1985). The outcome of infection varied but complete restriction of CBV replication was infrequent. Among the virus-cell combinations studied, variation in permissiveness was reflected in the peak titre of virus produced as well as in the time of first detection of progeny virus and in the time of peak yield (that ranged between day 1 and 4). Variation was also observed in the effects on cell viability. CBV6 was the only immunotype which regularly led to complete destruction of the cultures. The other CBV caused partial or minimal damage. In many instances, no visible adverse effects on cell culture viability or

301

Several days after CBV infection, many lymphoid cell cultures were still producing virus but showed no morphologic changes or loss of proliferative capacity. By passaging these cultures serially, long-term persistent infections were readily established. The infected cells continued to grow and shed high titres of virus for months and years. For example, the MOLT4 cell line persistently infected with CBV-3 is still propagated in our laboratory after over 5 years from its establishment. In earlier studies performed with nonlymphoid cells, CBV had shown no tendency to persist unless virus inhibitors were added exogenously (reviewed in Bendinelli and Friedman, 1988). Lymphoid cell lines may liberate IFN and other lymphokines spontaneously or following induction. However, exhaustive attempts to demonstrate virus inhibitors during the acute and persistent phases of CBV infection in MOLT-4 cells were unsuccessful. Persistence in these cells was shown to be maintained by a carrier culture mechanism involving virus spread through the medium and replication among a minority of susceptible cells that appeared to emerge continuously from a population ofresistant cells. The genetic or phenotypic basis of the MOLT-4 cell heterogeneity that permits a permanent virus-cell equilibrium have however remained unclear. As permissiveness to CBV and other picornaviruses is known to be controlled mainly at the absorption-penetration step (reviewed in

» The Clinical and Scientific Basis of M.E. / CFS

Crowell et al., 1988), differences at this level might be implicated. Akin viruses which have been shown to give persistent infections in vitro include the three polioviruses andechovirustype6. In lymphoid lines, polioviruses were shown to establish a carrier culture mechanism (Carp, 1981) but, in neuroblastoma cells, the mechanism seemed different since viral antigens could be detected in all the cells of the persistently infected cultures (Colbere-Garapin et al., 1989). Echovirus 6 persistence was described in the human amnion WISH cell line and appeared to be maintained by a steady state mechanism in which all the cells contained defective genome-size viral RNA which was synthesized continuously and incorporated into defective virions unable to infect cells because they were devoid of two structural proteins (Righthand and Blackburn, 1989). Generally, viral persistence is a dynamic process. In all the above systems, as well as in CBV infected human lymphoid cells, viral persistence was associated with evolution of the persisting virus and of the persistently infected cells. For example, the human MOLT-4 lymphoid cell line persistently infected with CBV-3 remained normally susceptible to unrelated viruses but became progressively more resistant to the parental virus and, to a lesser extent, to other CBV serotypes. On the other hand, during persistence, the virus evolved an increased cytopathogenicity for the original MOLT-4 cells and a reduced ability to replicate in other cell lines. The virus recovered from the media of persistent cultures also differed from the parental virus in the size of plaques produced on indicator cells, in the ability to replicate at s u p r a o p t i m a l t e m p e r a t u r e s and in a n i m a l pathogenicity. Although these changes did not seem to contribute significantly to the establishment of persistence as they evolved gradually while the conditions leading to persistence were already established within a few days after virus infection, they may be instrumental in the stabilization and maintenance of the carrier state. In vitro models of viral persistence have provided important clues to the understanding of how viruses are implicated in the generation of chronic and pro-

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gressive diseases. Persistence of infectious CBV in vivo has never been unequivocally demonstrated even though prolonged virus shedding is not rare. This may reflect the fact that the presence of persistent or latent virus infections in intact tissues may be extremely difficult to demonstrate. However, CBV persistence has been implicated in the genesis of chronic CBV-induced cardiomyopathies both in animal models and in humans and CBV specific RNA sequences have been detected in chronically diseased hearts by dot blot or in situ hybridization (Archard et al., 1988; Kandolf et al., 1988). Furthermore, related viruses such as echoviruses have been shown to produce long-term infections of the CNS (Griffith et al., 1977). The cell type(s) where CBV might persist in vivo is still undetermined but lymphoid cells are likely candidates as many viruses have been shown to persist preferentially in lymphoid tissues of chronically infected hosts (Specter et al., 1989). It may be of clinical interest that CBV persistence in lymphoid cells could be terminated by treatment with virus-specific antibody and, even more effectively, with IFN (Bendinelli et al., 1987). 4. Closing R e m a r k s For many years, CBV were believed to produce only acute infections and to induce tissue damage and disease exclusively by direct cytopathology. As recently discussed in several reviews (Bendinelli and Friedman, 1988; Wolfram and Rose, 1989), it is now increasingly recognized that CBV infections do instead share many complexities traditionally associated with infections by enveloped viruses which are generally considered more sophisticated pathogens. They can persist for prolonged periods and possibly indefinitely in patients, produce subtle changes of infected cells, cause chronic pathology, trigger immunopathological damage to infected tissues, and initiate autoimmune phenomena. Thus, while many aspects of pathogenesis remain little understood, there is no doubt that, in CBV infections, the immune system plays a much more complex role than it was originally thought. A detailed understanding of the interactions CBV establish with the host's immune system might provide clues to the etiology and pathogenesis of several cryptogenesic diseases, including M.E.

M. Bendinelli, MD, PhD and D. Matteucci, BS

The Immunosuppressive

Effects of Group B Coxsackievirus

Infections

References 1. Behan P.O., Behan W.M.H., and Bell E.J., 1985, The post viral fatigue syndrome - An analysis of the findings in 50 cases, J. Infect. Dis.10, 211-222.

cardiac tissue by in situ hybridization, J. Gen. Virol. 69: 285-291.

11. Eglin R.P., 1988, The detection of coxsackievirus RNA in

2. Bell J.E., Assaad F., and Esteves K., 1988, Neurologic disorders, In Coxsackievirus. AGeneral Update (Bendinelli M., and Friedman H., eds.), Plenum Press Corporation, New York, pp. 318-337.

12. Garzelli C., Basolo F., Matteucci D., Prabhakar B.S., and Toniolo A., 1989, Picornavirus-induced immunosuppression, In Virus i n d u c e d Immunosuppression (Specter S., Bendinelli M., Friedman H., eds.), Plenum Press Corporation, New York, pp. 217-234.

3. Bendinelli M., and Friedman H.(eds.), 1988, Coxsackieviruses: A General Update, Plenum Press Corporation, New York, p. 430.

13. Griffith J.S., Katz S.L., and Moore M., 1977, Persistent enterovirus infections in agammaglobulinemia, in Microbiology 1977 (Schlesinger D., ed.) American Society for Microbiology, Washington, D.C.

4. Bendinelli M., Matteucci D., Conaldi P.G., and Soldaini E., 1990, Bacterial endotoxin as a probe to investigate virusinduced immunodeficiencies. Adv.Exp.Med.Biol. 256:511523.

14. Easton A. J., Gururaj V.J., Marsh W.W., and Aiyar S.R., 1984, Fulminant pulmonary coccidioidomycosis in association with coxsackie B4 infection, Clin. Pediatr.24: 406-408.

5. Bendinelli M., Matteucci D., Toniolo A., Patane A.M., and Pistillo M.P., 1982, Impairment of immunocompetent mouse spleen cell functions by infection with coxsackievirus B3, J. Inf. Dis. 146: 797-805.

15. Hyypia T., Vainionpaa R., and Akerman K., 1988, Interaction of measles and coxsackie B3 viruses with human peripheral blood mononuclear cells, Proc. 9th E u r o p e a n Immunology Meeting, Rome, 14-17 September.

6. Bendinelli M., Ruschi A., Campa M., and Toniolo A., 1975, Depression of humoral and cell-mediated immune responses by coxsackieviruses in mice. Experientia 31: 1227-1229.

16. MatteucciD.,PagliantiD., Giangregorio A.M., Capobianchi M.R., Dianzani F., and Bendinelli M., 1985, Group B coxsackieviruses readily establish persistent infections in human lymphoid cell lines, J. Virol. 56: 651-654.

7. CaoY., and SchnurrD. S., 1988, Persistent infection of YAC1 cells by coxsackievirus B3, J. Gen. Virol. 69: 59-65.

17. Matteucci D., Toniolo A., Conaldi P.G., Basolo F, Gori Z., and Bendinelli M., 1985, Systemic lymphoid atrophy in coxsackievirus B3-infected mice: Effects of virus and immunopotentiating agents, J. Inf. Dis. 51: 1100-1108.

8. Carp R.I., 1981, Persistent infection of human lymphoid cells with poliovirus and development of temperature-sensitive mutants, Intervirology 15: 49-56.

18. Righthand V.F., and Blackburn R.V., 1989, Steady-state infection by echovirus 6 associated with nonlytic viral RNA and an unprocessed capsid polypeptide, J. Virol. 63: 5268-5275.

9. Colbere-Garapin F., Christodoulou C., Crainic R., and Pelletier I., 1989, Persistent poliovirus infection of human neuroblastoma cells, Proc. Natl. Acad. Sci. 86: 7590-7594.

19. Specter S., Bendinelli M., and Friedman S., 1989, Virusinduced immunosuppression, Plenum Press Corporation, New York, p. 477.

10. Conaldi P.G., Matteucci D., Soldaini E., Guidi M., and Bendinelli M., 1988, Interactions of group B coxsackieviruses with immunocytes, In N e w Concepts in Viral Heart Disease; Virology, Immunology and Clinical Management (Schulteiss H.-P., ed.), Springer-Verlag, Berlin, pp. 195-204

20. Wolfram L.J., and Rose N.R., 1989, Coxsackievirus infection as a trigger of cardiac autoimmunity, Immunol. Res. 8:61-71.

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Chapter 29

H.R.H. The Princess of Wales and James Mowbray Photograph courtesy of Zhang Hong Yi

Evidence of Chronic Enterovirus Infections in M.E. James F. Mowbray, FRCP Professor of Immunopathology, Department of Immunopathology, St. Mary's Hospital Medical School Norfolk Place, London W2 IPG, England Dr. James Mowbray is an Immunologist with special interests in transplantation and reproductive Immunology as well as problems of chronic virus infections. He showed 10 years ago that the enteroviral antigens in the blood of patients with ME and viral myocarditis were the same. His research group have shown that a material fraction of ME patients have chronic infection with enteroviruses which could be recovered from the GI tract using special techniques. Dr. Mowbray has very wide experience of viral / immunological studies of ME patients and their management. Editor's note: Since neither Dr. Mowbray nor Dr. Yousef have sent their manuscripts, the following is a transcript taken from a tape recording of Dr. Mowbray's lecture at Cambridge, and then corrected by Dr. Mowbray. We have reproduced Dr. Yousef s published paper that corresponds roughly to his Cambridge paper. For a better review of Dr. Mowbray's group's important work, please refer to Chapter 32 of this text and also Post-Viral Fatigue Syndrome, 1991, John Wiley & Sons, Jenkins and Mowbray. What I want to do first is to try to explain what I'm talking about and then discuss the evidence that has accumulated in my laboratory over the last few years, largely about enteroviruses in M.E.

We're all aware of some chemical causes of fatigue syndromes. Interestingly, one of them is germanium, a heavy metal which is actually being used by some people as a treatment for M.E. Germanium toxicity produces serious renal involvement. Renal damage produces myalgia, diminished muscular effort capabilities and certain cognitive difficulties. It looksalittle bit like M.E.,but isclearlyof achemical nature. Cancer, particularly cancer chemotherapy produces severe muscle fatigue symptoms. But we're

If we were to consider all fatigue syndromes, there would be a lot of potential candidates. Within all fatigue syndromes, we would find some non-infectious ones and infectious ones. We would find things like cancer, which produces a fatigue syndrome.

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really concerned with the infectious fatigue syndrome. The oldest and best established of those is tuberculosis and those of you who lived in the era when tuberculosis was a common disease know that it produced severe prostrating fatigue with extremely poor muscle capability throughout the disease. But one of the things I wanted to point out is that as the infection got better, these symptoms decreased. Giardiasis is a condition with which a number of patients return from other parts of the world. It is an infection which produces a severe fatigue syndrome. This may be very protracted because it is a chronic illness. Now, in order to produce a chronic fatigue syndrome caused by an infection, the infection must be chronic. There are not many chronic virus infections. So, if you were to look at the virus caused chronic fatigue syndrome which we call ME or post infectious, protracted viral infectious syndrome, there would not be very many candidate viruses, and the viruses which appeared out of the woodwork are those which have the capability of producing long term chronic infection. I don't mean latent or dormant but active infection. Something like the flu is not going to produce a disease for more than a few days. Yet, if we were to look at the acute illness of flu, it has much of the characteristic symptomatology found in the more protracted chronic fatigue syndrome. Now the definition that I am concerned with of ME has those things: There is muscle fatigue on exercise, with slow recovery going to the point of exhaustion. It sometimes takes days or weeks to recover after severe exhaustion. There are also cognitive difficulties, difficulties in concentration, short term memory and particularly nominal dysphasia which I think is a thing always worth looking for as the patients frequently don't notice it. Their families and their medical attendants may notice it more frequently.

acute onset with a flu-like illness or an insidious onset. In terms of rates of recovery and virology and all the other things we've looked at, there does not seem to be any striking difference between the two groups. Now it has already been suggested today that possibly there might be mediators of some of the symptoms as a result of an infection, or as somebody earlier said, as a result of an immune response. Well, both virus infections and immune responses generate cytokines. Lymphokines, those things specifically associated with immune response, can occur with agents other than viruses. However, the alpha and beta interferons are produced by virus infected cells, not by the immune response to them. It appears that alpha interferon as well as gamma interferon which is produced by lymphocytes, both produce on administration the well-known interferon toxicity syndrome which is produced by giving pure interferon. It had been described very accurately by one of the patients who was receiving the treatment as being just like a flu but without the bunged-up nose. They got all the other things; the difficulties in thinking, the myalgia, the anhedonia, (the lack of pleasure in life while they've got it) and really all the symptoms, with the exception of the severe muscle pain limiting exercise. They've got all of those as a result of the administration of either gamma or nongamma interferon. So it may be that a virus infection by infecting cells may result in the interferon production. The immune response to it will result in the production of other things such as interleukin 1 and interleukin 2, which has been referred to this morning, although interleukin 2 doesn't really produce as much in the way of symptoms as does recombinant interferon. Part of this syndrome is pain in muscle and in joints as well as simply in muscle, and that was one of our very early starting points in looking at patients who had ME and also happened to have myocarditis. We found that most of them had circulating complexes with IgM antibodies bound to an antigen. Those, of course, are the sort of complexes which are most frequently associated with polyarthralgia. The joints may be mediated by complexes. A lot of the central nervous system effects may be mediated by cytokines of various kinds. But there is always the possibility that virus infection of the central nervous system or virus infection of the muscle may produce the effect locally as well. And in the enteroviruses we have a

One of the very few physical signs in this condition is that they frequently show very slow accommodation, particularly from near gaze to the distance. This may be associated with hippus during the time of re-accommodation, in which the pupil is seen to expand and contract over a period of fifteen - thirty sixty seconds before it finally settles down. So that's the group of patients we've been concerned with. We have not minded whether they've had an

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group of viruses which have, although they are found in the enteron (they're found in the gastrointestinal tract), are myotropic and neurotropic and some of the strains are also cardiotropic. So they're quite good candidates and the only problem would appear to be that it was assumed that chronic virus infection with enteroviruses was a rarity. You see enteroviruses, unlike most other sorts of viruses, have no mechanism for integration into the nuclear material in the cell and they have no mechanism for dormancy. So the only way to keep the infection going is by having active infection of cells, cell death, release of infectious particles, infection of new cells, and a cycle continuing that way. You cannot have latency. So if you find evidence that there is virus protein around, for instance, it means that there must be virus replication around. It's quite different from a situation of the herpesviruses, which in fact integrate and may lie dormant for eighty years before appearing as reactivation of a herpes zoster virus. Now, what was the evidence, apart from the outbreaks, that there were enteroviruses involved in ME? There was evidence from neutralizing antibody titres with people saying "Oh yes, look, some of them have very high titres against whatever few neutralizing antibodies were looked at" (usually against five or occasionally six coxsackie B viruses out of a possible 72 enteroviruses). Circulating immune complexes we found were present in about 2/3 of the patients whether they had myocarditis or not. And then Professor Banatvala's development of IgM antientero viral antibodies really made a lot of difference because it was now possible to get some idea whether the infection was continuing or recent. The presence of neutralising antibody shows only the past history of the patient. It then became obvious that there were IgM anticoxsackie antibodies in a significant fraction of the ME patients whenever you looked at them. They were there month by month, or year by year, suggesting that the infection was continuing. If we actually look at the neutralising antibody, there's a paper that Professor Banatvala and I actually never got around to finishing as the evidence was pretty poor. The best evidence is from a study of one hundred extremely carefully worked out patients with ME in which the neutralizing titres to one of the Coxsackie B viruses that the highest neutralizing titre is recorded here, and there is the matched group

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of control patients who were matched for living on the same road, the same sex, and same decade of age. You see it's pretty unimpressive. Fairly impressive maybe for the few patients here and there, but for the most part it was pretty poor evidence. If you are not concerned with an outbreak where you isolate the particular strain, it was not very good evidence that they've got better immune responses (higher antibody levels) to Coxsackie B than the rest of the population. You could say that, as there are over 70 serotypes of enteroviruses, that they don't have the other one, but there is no evidence to prove that supposition. So we set out to try and see if we could show that the patients were infected with a virus. To do that, we looked at the normal cyclic of virus which is in the gut. And, as Betty Dowsett said earlier on, you cannot isolate viruses normally in enteroviral infection for more than a few weeks, because of the development of IgA antibodies secreted into the gut, which are neutralizing antibodies. This neutralizes the virus so that you can't calculate it. So we had to develop a technique for finding the virus in the presence of antibody. What we did was to take enteroviruses and deliberately neutralize them with IgA antibodies (human IgA antibodies from human breast milk of people who had a lot of anti entero antibodies), then taking the neutralized virus to an acidic wash, so that the antibody would come off the virus again. Since the viruses are gastro-intestinal viruses, they can infect through the stomach. They don't mind the acid condition. So separate the antibody from the virus. Then, in the alpha-centrifuge, centrifuge the virus to the bottom, leaving the antibody at the top and culture the bottom. Doing this, we were able to get enterovirus isolates from people. Only in a very few people did we get isolates just by culturing the feces directly, the reason being that the studies were done in the beginning of May 1986 to the beginning of May 1987 and the summer enterovirus season in Britain doesn't really start until the end of May continuing to the end of October. The weather then becomes too cold for the survival of enteroviruses in the population and they disappear to warmer climates for the winter (like much of the population at home). If you go to Central Africa, you'll meet maybe three or four or five enteroviruses a year. In

Evidence of Ch ronic Enterovirus Infections in M.E.

James F. Mowbray, FRCP

Britain, you generally only meet one, unique to the summer cold, and you meet it between the end of May and the end of October. So we chose a time when they weren't around very much and we took patients with ME and matched controls and what happened was that, in two of the patients and two of the controls, direct viral cultures were possible. They were probably people who had transient intestinal carriage even though they were a bit early in the season. They did not have evidence that virus proteins were present in the blood and the virus was not recoverable subsequently. So these are those with transient carriage. However, we did find in 22% of the patients that it was possible to culture a virus (only after removing neutralizing antibody). So they had an infectious virus and they had symptoms for a minimum of two years and a maximum of twenty-six years in this group. Most of them demonstrated enteroviral infection lasting between two and eight years. That shows that they had a virus but it doesn't show that they were persistently infected with a virus, which is part of Koch's postulate; the disease has to be associated with a virus and it has to be associated both in time and geographically, and the removal of the virus would be associated with disappearance of symptoms. But there's always the chance that someone could get the infection but you can't, for some reason, culture it. So we went back a year later and did the same thing again. In each patient in which we cultured a virus for two years, it was the same serotype of virus. I think that's a vital recording element that you would expect to have, that it is, a persistent infection with that virus. It is not a reinfection occurring at intervals. Monoclonal Antibody The other thing we did was to develop a monoclonal antibody which detected one of the virus proteins. That protein is not very variable between all of the enteroviruses and there is on it one epitope, which is the same in all enteroviruses. We have developed a monoclonal antibody against that epitope. So then if you look at the small RNA virus, it makes one messenger strand, one protein. The protein is then keyed by protealytic in the enzymes within the cell and also coded for by the virus. It splits into frag-

ments and of these fragments, one of them, the VP1, one of the captured proteins, is then used for the architecture of the virus and one spot of this doesn't do anything. So now we can have an antibody which will react with the VP1 of any enterovirus; echoes, coxsackie A, coxsackie B, polio, it reacts with all of them. This just shows you on a dot-blot that it doesn't react with a lot of controls, but reacts to a whole slew of enteroviruses. Now using that antibody, label the antibody with Peroxidase and add it to a blood sample that contains antibodies to VP1, and may contain VP1 itself if there is an infection there. If there is an infection there and the antigen is there, if we look at the labelled enterovirus and wait long enough, the complexes will dissociate and reassociate and the labelled antibody will become incorporated into the complex. Then, using polyethylene glycol under carefully controlled conditions, you can precipitate the complex and leave the free antibody behind. You've made half your label. From that you can calculate how much VP1 there was present in the sample. This technique proved useful because it was possible to do a lot of assays and detect any enterovirus. Whereas, if you were to look for even things like IgM antibodies to enteroviruses, you would need to do thirty or forty tests to cover the whole range of overlapping antigenicity to the enteroviruses. Looking back at what we published after we had done the culture work, looking at the amount of VP1 label that was precipitated, in any patient, a lot of patients were above three standard deviations above the normal and there were quite a few below, this being the normal control range and these being other inflammatory and infectious disease samples that were coming in to the department at the time. One ofthose is a patient with the condition called epidemic mastoiditis or viral labrynthitis. Some other of those patients would also prove to be positive and it looks quite likely that some of those epidemic labrynthitis outbreaks might happen to be going through viruses. Now I said we frequently found people with circulating/renewing complexes in ME. This was our starting point some eight or nine years beforehand. You will see that, if you take the ones who are complex positive, a lot of them have VP1 detectable. If you take the ones that are complex negative, there are only a couple. Normal controls have hardly any. 307

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Now let's look at the ones who are "culture positive" or "culture negative", having acidified the virus preparation in the stool. You will see a capture of positive ones with two exceptions of VPI positive and a capture of negative. There are some positives that are a bit low level. There may have been too little virus there for us to capture them into. Those two negatives are the two who had virus cultures which were positive without acidification. Another thing was that in people who had the virus for a few days it was passing through, it was not a chronic infection. They just had intestinal carriage at the time. So, getting back to where I was, we had a technique for measuring the virus present in the blood and it could only be there if there was an infection there. There was no dormancy or latency not an antibody. It's like measuring hepatitis B surface antigen and hepatitis. It may find the virus. We have samples that came from Tony Komaroff, a physician in New York, some from Byron Hyde, and a rather poor selection of US normals, but we found in this, as we had in the UK samples, that there's quite a big fraction of people who were positive on all of the series except the chap in New York. It's hidden behind the controls, but he managed to do something which is very difficult to do, which is take a number of people with the syndrome and not find any of them with high VPI. I never did ask him what the secret of his success is but I would quite like to know. I'm going to mention cross-postulates. Well, here is the last of the cross-postulates that I really wanted to talk about. I'm showing two patients on whom we have done serial VPl's as they recover. You can ask the patients if they're better and they'll tell you. If you do so and if you have some markers for improvement, you will find that the correlation of the VPI with improvement is quite considerable. In other words, as their symptoms increase, the amount of virus protein detected in their blood also increases. Some patients (they are the subjects of a still incomplete trial) respond extremely well to IgG (normal or pooled human IgG). The chap in green in the back didn't have anything. You can see that over the months his VPI level is falling as he responds.

and he was virtually symptom free existence for about six weeks. He then went on to regular IgG treatment. But you will see at the time after the IgG is given, the VPI disappears, and will recur, if not in four weeks, then it will be back in eight weeks to essentially the same level it was before. So, there is agreement between the level of VPI and the degree of symptoms. If you take people who have been better, or pretty nearly better, whose VPl's have fallen down to levels we can't detect who then go out and overdo it and exhaust themselves, it's one of those relapses. Now, time after time, we find we can get their VPI better although it had disappeared previously. So, Koch's postulate is to a large extent verified. The other one that Koch stated is that, in the organism, the infection is where the disease is. Well, of course that's clearly not true if you think of tetanus or diphtheria. But one would like to know whether the virus is present, in the tissues involved, in the brain, and in the muscle. It is easy to get muscle biopsies, difficult to get brain samples. Here we have a muscle of a patient with adult polymyositis. Yousef and David Eisenberg show, in a paper, how adult polymyositis had enteroviruses. And here you will see muscle cells in a very inflamed muscle area frequently stained with Peroxidase,-Peroxidase which is on the monoclonal antibody and is looking for VPI and finds VPI over there as an infection, a very acute infection. There's virus replication, there's damage going on, muscle enzymes are high, cellular infiltration is present and you will find virus present there easy to see. If, however, we look in the ME patient's muscle, we will not find any VPI infected muscle or muscle cell with VPI. If, however, we use a probe for the virus RNA which has biotin on it, you can stain the tissue for the viral RNA and get peroxidase stain if the viral genes are there in the muscles. You can then see infected cells (those infected by virus) and they are rare. They represent 1/100 to 1/200 fibres only, that have virus detectable in them. So that any change in muscle performance due to virus infection would not be expected to involve a decrease in the total muscle function. That is one of the reasons why, for those of you who heard Richard Edwards last night, it's so important to realize that the actual performance of

Treatment w i t h IgG This man had an injection of IgG given at that time

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the muscle is normal. It is the neuromuscular work which is the problem. But the changes in muscles are present and we found them (Len Archard is going to be talking much more extensively about that this afternoon) but there is virus only in a very few muscle cells. So in at least one of the sites it's there in a large fraction of the patients with ME, and as the ME goes away, the virus goes away and indeed we've never been able to get positive virus cultures from people after recovery either. I think the evidence for enteroviruses as a main cause of ME is very good. I think Koch's postulates are pretty well answered. Were there an appropriate anti-viral gene therapy, you could complete the proposition by saying I will treat the patients, make them lose their virus, and see if the disease gets better. And that is the sort of approach we're going to have to use, no matter which virus is considered. I've skipped over a slide which is the result of work by Dorothy Crawford and David Smith and they've studied reactivation of Epstein Barr virus in the same group of patients (a very well worked out group of M.E. patients) who had also been studied by us for

the enteroviruses. The result is really quite striking - 65% of them have high levels of detectable VP1 and in the remaining 35%, 20% of them have early Epstein-Barr IgG and some high VCA antibodies as evidence of reactivation. But none of them has both which makes causality from a virus infection much more likely than that some strange alteration in the immune response that made them liable to pick up a couple of viruses. That still leaves 15% in which no evidence of Epstein-Barr virus or an enterovirus was obtained, and that may be due to sensitivities in the technique, or it may be due to other viruses which might cause M.E. Possible Viral Cause of M.E. But I would stress that if you're going to show causality and more than one virus is involved, you should only find one virus in each patient and if you find two or three viruses together in each patient, then you would suggest that maybe some sort of immunodepression was going on. But, at the moment, that is not the situation, so: enteroviruses first, Epstein-Barr virus next, and we don't know about the remaining 15%. Thank you very much.

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Chapter 29 This article is reprinted courtesy of The Lancet, Ltd., GE Yousef, GF Mann, DG Smith, EJ Bell, V Murugesan, RA McCartney, JF Mowbray, "Chronic Enterovirus Infection in Patients with Postviral Fatigue Syndrome", © The Lancet Ltd., January 23, 1988, i:146-50.

Chronic Enterovirus Infection in Patients with Postviral Fatigue Syndrome G.E. Yousef, G.F. Mann, D.G. Smith, E.J. Bell, V. Murugesan, R.A. McCartney, J.F. Mowbray Department of Pathology, St. Mary's Hospital Medical School, London; Enterovirus Reference Laboratory and Regional Virus Laboratory, Ruchill Hospital, Glasgow; London School of Hygiene and Tropical Medicine; and General Practice, Horndon-on-the-Hill, Essex Summary 76 patients with the postviral fatigue syndrome (PVFS) and 30 matched controls were investigated. Virus isolation was attempted from concentrated faecal samples by direct culture and after acid dissociation of virus from antibody. Positive cultures of enteroviruses were obtained from 17 (22%) patients and 2 (7%) controls. An enterovirus-group-specific monoclonal antibody, 5-D8/1, directed against the VP1 polypeptide, was used to detect enteroviral antigen in the circulation, either free or complexed with antibody. VP1 antigen was detected in the serum of 44 (51%) of a further group of 87 PVFS patients. The number of patients positive for VP1 antigen was greater (42/44) when IgM complexes were detectable than when they were not (2/23). 1 year later, the 17 patients of the first group of 76 with positive cultures were again studied. The same virus was again isolated from 5 (29%), 13 (76%) had detectable IgM responses to enteroviruses, and 9 (53%) were positive for VP1 antigen in the serum. These results show that chronic infection with enteroviruses occurs in many PVFS patients and that detection of enterovirus antigen in the serum is a sensitive and satisfactory method for investigating infection in these patients. Introduction An association between previous infection with Coxsackie B viruses and the chronic postviral fatigue syndrome (PVFS), also called myalgic encephalomyelitis, has been suspected. 1 Similar associations have been reported between these viruses and recurrent perimyocarditis and chronic peripheral muscle disease,2-4 mainly on the basis of retrospective findings of significantly increased titres of neutralising antibodies to Coxsackie B viruses. 5

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These viruses are myotropic and involved in acute muscle disease. 6 Persistent enterovirus infection has now been demonstrated by the detection of genomic sequences of Coxsackie B virus in muscle biopsy samples from patients with dermatomyositis, polymyositis, and chronic myocarditis.7.8 Chronic enterovirus infection has also been reported in cases of chronic myopathy and myositis.4.9 Significant levels of IgM antibodies specific for Coxsackie B virus have been found in patients with chronic PVFS,10 which strengthens the serological evidence for a role of enteroviruses in this syndrome. We report here chronic enterovirus infection in a group of patients with PVFS. Subjects a n d M e t h o d s Subjects The patients had a history of at least 6 months and up to 12 years of excessive muscle fatigue on exercise accompanied by myalgia, with or without an acute viral infection at onset. All patients had dysphasia, difficulty with concentration, and short-term memory, and most had difficulty in accommodation. No patient had evidence of neurological disease, and physical examination was normal. When possible the patients enlisted a neighbour of similar age and sex to act as a control. Isolation of V i r u s e s from F a e c e s Stool specimens were obtained from 76 PVFS patients (group A) and 30 controls during the third week of May, 1986. Specimens reached the laboratory within 24 h of collection and were stored at -70°C.

Chronic Enterovirus Infection in Patients with PVFS

Galal Yousef, MD et al

100 ml of a 20% faecal suspension was prepared from every specimen and the supernatant clarified. 11 Supernatants were centrifuged at 150 000 g for 2 h and the pellets resuspended in 4 ml of'Medium 199' (Gibco). Virus was cultured by two techniques, direct culture and with acid centrifugation. Flasks of Vero cells and Hep2 cells were drained of growth medium, inoculated with 0.5 ml of the concentrated faecal sample, and the inoculum adsorbed for 2 h at room temperature. The inoculum was decanted, and 30 ml of maintenance medium (Melnick B)11 added to the flasks which were then incubated at 37°C. The cultures were examined daily for a viralinduced cytopathic effect (CPE) for 3 weeks, during which time two blind passages were done. Positive flasks were harvested when 75% CPE was seen. For acid centrifugation, 1.5 ml 0.1 mol/1 glycine/HCl buffer, pH 2.4, was added to 2.5 ml of the concentrated sample and the pH readjusted to 2.4 with 0.5 mol/ 1HC1 before incubation at room temperature for 3 h. The acidified mixture was centrifuged over a 30% sucrose cushion at pH 2.4 for 2h at 150 000 g. The optimum concentration of sucrose required for separation of virus and antibody had been determined previously. The supernatant and sucrose were removed and the pellet was resuspended in 1 ml medium 199. The suspension was adjusted to pH 7 by addition of 0.5 mol/lNaOH, and then inoculated into two flasks. 1 Figure 1

The sensitivity of the system for dissociating IgG and IgA neutralising antibodies from virus had been determined before use. Suspensions of Coxsackie B2 virus containing 100 plaque-forming units per ml were neutralised by overnight incubation at 4°C with dilutions of previously titrated serum or breast-milk from a lactating woman who was hyperimmune to Coxsackie B2 virus. The neutralised suspensions of the virus were treated 2 and "plaqued" by the technique of Dulbecco.12 The overall efficiency of virus recovery after acid centrifugation was 50%, estimated by plaque counts. All positive cultures were presumptively identified by the characteristic morphology of enterovirus-induced CPE and by electron microscopy,6 and confirmed by indirect immunofluorescence with a monoclonal antibody, 5-D8/1, directed against the enteroviral group-specific protein of VP1.13 Intersecting antiserum pools were used to identify the serotypes of the isolates by a staindard neutralisation test. 14 Stool samples were obtained 12 months later from all the patients from whom enteroviruses were isolated, and the entire process of virus isolation and identification repeated. 36 normal healthy individuals matched by age, sex, and geographical location were included at this time as a new set of controls.

Detection of Immune Complexes

43 kD

Circulating IgM immune complexes in serum samples obtained from a different series of 87 PVFS patients (group B) were estimated by precipitation with 2% polyethylene glycol (PEG). Precipitated IgM was measured by single radial immunodiffusion against monospecific antibody to human IgM.15 Positive samples were those with precipitated IgM more than 2 SD above the mean of 612 normal healthy controls.

30 kD

21 kO 14 kD

ST

M

YF HA A7

A9

P1

B5

B3

E22

E11

ST

Detection of Enterovirus-specific ' IgM Antibodies

F i g u r e 1 - Western blots of proteins from a range of enteroviruses and other unrelated viruses probed with 5-D8/1 molecular antibody.

Enterovirus-specific IgM responses in patients with positive stool cultures were measured by the pantibody-capture ELISAfor Coxsackie B IgM.10 These assays were done 12 months after the initial virus isolation.

Enterovirus peptide reacting with 5-D8/1 has molecular wight of34-37 kD and has been shown by radioimmunoprecipitation to be VP1. ST= molecular weight standards, M=measles, YF=yellow fever, HA=hepatitis A, A7=Coxsackie A7, A9=Coxsackie A9, Pl=poliovirus I, B5=Coxsackie B5, B3=Coxsackie B3, E22=Echo-22, and E l l = E c h o - l l .

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» The Clinical and Scientific Basis of M.E. / CFS

Characterisation of Monoclonal Antibody 5-D8/1

sera of all group A patients with positive cultures after acid centrifugation and compared with the results from 16 group A patients who were culture negative.

The monoclonal antibody 5-D8/1, produced against heat-inactivated Coxsackie B5 virus, reacted with the VP1 polypeptide of all tested enteroviruses except hepatitis A virus. This antibody specifically detects a single enteroviral protein, and the antibody does not react with any virus that is not an enterovirus (fig l). 13 In a separate study, 5-D8/1 was used to screen 130 field isolates of a wide range of enteroviruses in a dot-blot enzyme immunoassay. 95% of the isolates were conveniently and correctly identified as enteroviruses. 16 Table 1 Virus Isolation from F a e c e s of PVFS P a t i e n t s (Group A) and Contois Culture technique

PVFS patients (n=76)

No. of patients: After direct culture Only after acid centrifugation

15 (20%)

Total

17 (22%)

2 (3%)

Controls (n=30)

2 (7%) 0* 2(6.7%)

*PVFS vs controls: x 2 = 5.9, p13. T h e s e s e e m to b e m o r e e v i d e n t i n l o n g - s t a n d i n g c a s e s 8 , so i t is, i n a n y case, u n l i k e l y

Acknowledgements

t h a t a B cell deficiency w o u l d h a v e b e e n e v i d e n t i n

The authors wish to record their appreciation to the Australia-New Zealand Myalgic Encephalomyelitis Society (New Zealand) Inc., who supported this work, and to the human volunteers who took part in the clinical study.

the main study group. T h e S p e a r m a n r a n k c o r r e l a t i o n s , h o w e v e r , m a y inc l u d e a n u m b e r of s p u r i o u s l y s i g n i f i c a n t r e s u l t s . A l t h o u g h t h e control g r o u p c o n t a i n e d no c o r r e l a t i o n s w h a t s o e v e r a t t h e 5% level, u p to 10 or m o r e could b e e x p e c t e d on a r a n d o m b a s i s o u t of a l m o s t 230. Cor-

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Michael J. Holmes, MD

Paired Age, Sex and Ethnically Matched Studies of Peripheral Blood Leucocyte Profiles...

References 1. Bell, E. S., McCartney, R. A. and Riding, M. H. (1988). "Coxsackie -B viruses and Myalgic Encephalomyelitis." J. Royal Soc. Med. 81: 329-331.

12. Murdoch, J. C. (1988). "Cell mediated immunity in patients with myalgic encephalomyelitis." N.Z.J.Med. 101: 511-514. 13. Read, R., Spickett, G., Harvey, J., Edwards, A. J. and Larsen, H. E. (1988). "IgGl subclass deficiency in patients with chronic fatigue syndrome." Lancet. 1: 241-242.

2. Dale, J. K., Straus, S. E., Ablashi, D. V., Salahuddin, Z. S., Gallo, R. C., Nishibe, Y. and Inoue, Y. K. (1989). "The InoueMelnick virus, Human Herpesvirus Type 6 and the Chronic Fatigue Syndrome." Ann. Int. Med. 110 (1): 92-93

14. Straus, S. E., Dale, J. K., Wright, R. and Metcalfe, D. D. (1988). "Allergy and the Chronic Fatigue Syndrome." J. Allergy Clin. Immunol. 81: 791-795.

3. Holmes, G. F., Kaplan, J. E., Stewart, J. A., Hunt, B., Pinsky, P. F. and Schonberger, L. B. (1987). "A cluster of patients with a chronic mononucleosis-like syndrome: Is Epstein-Barr virus the cause?" J.A.M.A. 257: 2297-2302.

15. Tosato, G., Straus, S. E., Henle, W., Pike, S. E. and Blaese, R. M. (1985). "Characteristic T cell dysfunction in patients with chronic active Epstein-Barr virus infection (chronic infectious mononucleosis)." J. Immunol. 134: 3082-3088.

4. Odds, F. C. (1988) in "Candid