FATIGUE 2000 : INTERNATIONAL CONFERENCE

FATIGUE 2000 : INTERNATIONAL CONFERENCE
Friday & Saturday 23-24 April 1999

HISTORY OF ME/CFS

Dr.Charles Shepherd, Medical Director of ME Association

ME/CFS is frequently portrayed as being a new disease of the late 20th century. However, case reports of fatigue syndrome with very similar symptomatology date back to at least 1750 when Sir Richard Manningham published his description of febricula or little fever (1).

Following a number of relatively small outbreaks starting in the 1930s, the syndrome began to acquire a variety of different names based on either geographical location (eg Icelandic disease) or the clinical and presumed pathological features (eg myalgic encephalomyelitis / ME and post-viral fatigue syndrome/PVFS in the UK or chronic fatigue and immune dysfunction syndrome/CFIDS in the USA).

During the 1980s CFS (as it was subsequently labelled in 1988 by members of the International CFS Study Group (2)), became the subject of intense medical debate, particularly in relation to possible pathoaetiology, psychiatric co-morbidity and management.

ME / CFS has now achieved official recognition from the World Health Organisation (International Classification of Diseases, 10, G93.), the National Institutes of Health in the USA and the Department of Health in the UK. Even so, it continues to remain an enigma or 'no go area' for much of the medical profession.

REFERENCES

1) Manningham R (1750) The symptoms, nature, causes and cure of the febricula or little fever: commonly called the nervous or hysteric fever; the fever of spirits; vapours, hypo, or spleen. 2nd edition. J Robinson, London, pp 52-53. 2) Holmes GP, et al (1988) Chronic fatigue syndrome: a working case definition. Annals of Internal Medicine, 108, 387 - 389.

THE EPIDEMIOLOGY OF CFS / ME

Dr Derek Pheby, Unit of applied Epidemiology, University of the West of England, Frenchay Campus.

Research studies into the epidemiology of CFS/ME have come to widely differing conclusions regarding the incidence and prevalence of the disease. While this certainly indicates in part natural variation in its occurrence between different populations, it is also likely to have a large artefactual component, reflecting differences in research methodologies, sampling techniques, and case definitions. This point is illustrated by reference to published research. The difficulties of undertaking epidemiological research in respect of a condition like CFS/ME are discussed. Such difficulties arise essentially from the very heterogeneous character of the disease, both in respect of its clinical features, which are largely unspecific in nature, and also of its causes. The shortcomings of extant clinical research definitions for epidemiological purposes are reviewed, and a way forward for epidemiological research is proposed.

Dr Derek Pheby is Director of the Unit of Applied Epidemiology in the Department of Environmental Health & Science at the University of the West of England, Bristol. He has a long term interest in Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis and was a member of the National Task Force. He was also a member of the Expert Advisory Group of the Department of Social Security and is currently a member of the Key Group of the Chief Medical Officer's Working Group on CFS/ME. He is a scientific advisor to the ME Association, Action for ME and CHROME. His other scientific interests are in cancer epidemiology (he was for six years Director of the South Western Regional Cancer Registry), health informatics, health services research and environmental epidemiology.

ME AND INFECTION

Gow JW, Behan WMH, Simpson K, & Behan PO. Glasgow University Dept of Neurology, Southern General Hospital, Scotland.

Myalgic encephalitis (ME) or chronic fatigue syndrome (CFS) is often associated with a viral-like episode. Over the last decade many infectious agents have been implicated in ME but no single agent has been consistently isolated in a significant number ofcases. We have recently searched for six infectious agents in tissue from patients with ME including varicella zoster virus, hepatitis B, Borna disease virus, enteroviruses, influenza B and brucella. The study was carried out in order to confirm or eliminate these organisms as possible persistent agents producing chronic disease.

Sixty-four patients with ME were monitored over a two year period and the results compared to those from 34 age/sex matched controls. Patients undenvent a full clinical screening, peripheral blood mononuclear cells (PBMC's) were isolated and, in a number of cases, cerebrospinal fluid or a liver biopsy were taken. Polymerase chain reaction (PCR) amplification and RT-PCR together with Southern blot analyses were performed on the PBMC's.

RESULTS

All samples from the controls were negative. Three samples from patients were positive for VZV, 4 for hepatitis B, 2 for BDV and 2 for brucella. None of the infectious agents were present in a significant number of cases of ME and none of the patients had evidence of dual infection. Overall, 18% of the patients had evidence of infection although that figure is reduced to 14% if the VZV-positive cases are considered to be due to a sub-clinical reactivation oflatent virus rather than a recent infection.

In addition, 64 ME patients and 69 controls (with a variety of muscle disorders) were asked if they had been vaccinated against hepatitis B prior to the onset of their illness, since this vaccine has also been suggested as a possible aetiological agent. None of the controls but 3 of the 64 patients (4.7%) had been vaccinated.

These results do not support a chronic role for the six infectious agents (VZV, hepatitis B, enteroviruses, influenza B and brucella ) in ME.

This study was funded by the ME Association and the Linbury Trust.

IMMUNOLOGICAL ABNORMALITIES AND THE ANTI-VIRAL Rnase L PATHWAY IN CHRONIC FATIGUE SYNDROME

K.De Meirleir (presenter), I. Campine, P.De Becker, C.V. Herst - Vrije Universiteit Brussel R. Suhadolnik, N. Reichenbach, S. HoI-vath, D. Peterson - Temple University, Philadelphia C. Bisbal, T. Salehzada, B. Lebleu - CNRS Montpellier

Several viral infections have been associated with CFS, but no single micro organism has been demonstrated to be the etiological agent until now. However, immunological activation and altered cellular immunity, decreased NK cell cytotoxicity, viral reactivation and abnormal cytokine production are well documented immunological disturbances in this syndrome.

A very important finding is the persistent upregulation of the 2-5A Synthetase/Rnase L system with a significant increase of the 2-5A Synthetase activity, higher concentration of 2-5A oligonucleotides and increased Rnase L activity. Suhadolnik et al, have also discovered a new low molecular form of Rnase L (LMW) in severely disabled CFS patients. Furthermore, it has been shown that this LMW Rnase L is responsible for the elevated Rnase L activity in PBMCs of CFS patients (Horvath et al).

We thoroughly examined a group of 752 pafients who fulfilled the CDC criteria for CFS, in nearly 5% of this group the syndrome was precipitated by a blood transfusion a few weeks prior to a flu-like syndrome that later proved to be the acute onset of their CFS. This can strengthen the viral theory, especially since some of these "post-transfusion" CFS patients had an elevated LMW x 1O/LMW Rnase L ratio.

Along with an increase in the amount of LMW Rnase L in PBMCs of CFS patients, we also note a sharp increase in bronchial hyper responsiveness which might partly explain the dyspnoea observed in these patients. The exact role of the immune system and Rnase L system in this phenomen has yet to be established. We will show the results of a study where we examined several immune parameters in relation of the presence or absence of bronchial hyper responsiveness in a large subgroup of CFS patients.

Kenny De Meirleir MD PhD (Physiology) Certified in Internal Medicine, Cardiology and Rehabilitation Full Professor of Medicine and Physiology Director Fatigue Clinic and Sports Medicine Clinic, V.U.B. Brussels Director Cardiac Rehabilitation Centre A.Z. V.U.B. Brussels

NEUROENDOCRINE STUDIES IN CHRONIC FATIGUE SYMPTOMS

Dr Anthony J Cleare, Senior Lecturer in Psychological Medicine, Guy's King's and St Thomas' school of Medicine, London.

Neuroendocrine hypotheses of Chronic Fatigue Syndrome (CFS) suggest that changes in hormone regulation may contribute to symptoms or be part of the underlying pathophysiology in CFS. Our group has now finished a series of studies suggesting that non-depressed, medication-free CFS patients have increased central serotonergic function and reduced adrenal axis function. Extensive studies of the growth hormone axis have revealed no significant changes. We have now finished a placebo-controlled crossover trail of low dose hydrocortisone as a potential treatment for CFS. Result showed that doses of 5-10 mg of hydrocortisone led to a marked improvement in fatigue in 28% of patients compared to 9% on placebo. Importantly, we found no evidence of compensatory adrenal suppression during the short-term (1 month) duration of treatment. This latter study provides evidence that low cortisol levels may be related to symptom production in CFS. What remains to be seen is whether low cortisol is a primary feature of CFS or a secondary effect of chronic illness.

Dr Tony Cleare is currently a Senior Lecturer in the Department of Psychological Medicine at Guy's King's and St Thomas' school of Medicine and the Institute of Psychiatry, London. He also holds an honorary consultant position at the Maudsiey Hospital in London. After obtaining a degree in psychology from University College London, he trained in medicine at Guys Hospital Medical School in London. His postgraduate training was in psychiatry at the Bethlem Royal and Maudsley Hospital. He has published approximately 50 papers on a variety of aspects of psychology and psychiatry. In 1998 he obtained a PhD looking at neuroendocrine aspects of affective disorders. Ongoing research interests include: linking neurochemical abnormalities with psychological function; and the numerous effects of the endocrine system on psychological function.

His current clinical practice includes a special interest in chronic fatigue syndrome.

SLEEP PROBLEMS AND CHRONIC FATIGUE SYNDROME

Dr Richard Morris, Senior Lecturer in Psychiatry, University of Manchester.

Introduction

The clinical importance of sleep problems; apart from the subjective unpleasantness of not sleeping, remains unclear.

Descriptive Studies

Questionnaire and polysomnograph (EEG) studies suggest that:

1) 90% CFS patients complain of unrefreshed sleep;
2) 50% CFS patients take more than one hour to fall asleep;
3) 60% CFS patients wake in the night for more than one hour.

60% of CFS patients without major depression have diagnosable sleep disorders of initiating or maintaining sleep, but this figure falls to 25% in CFS patients without anxiety or depressive symptoms. Patients wake for a variety of reported reasons and this waking appears to disrupt slow wave sleep. There is evidence of abnormal circadian rhythm in CFS patients analogous to people suffering from jet lag or the adverse effects of shift work.

Clinical Importance

Sleep problems appear to rarely precede the onset of CFS symptoms. Patients with CFS and sleep abnormalities are more distractible and have problems with memory and sustained attention compared to CFS patients without sleep problems. Abnormalities in the sleep-wake cycle appear to worsen function and maintain the symptoms of CFS. Recent rehabilitative treatment approaches to CFS have been successful when sleep-wake cycle problems have been corrected. Neuroendocrine studies suggest that CFS patients without psychiatric disorder have abnormalities in cholinergic, noradrenergic and somatomedin function. Studies are in progress or planned to determine if correction of these abnormalities improve symptoms and function in CFS, possibly by improving the quality of the sleep in CFS patients.

Conclusion

Sleep problems appear to be an integral part of the clinical presentation of a substantial proportion of CFS patients. In some CFS patients, sleep problems are severe enough to further compromise function and require treatment in their own right.

Dr Richard Morriss is a Senior Lecturer in Psychiatry at the University of Manchester and Honorary Consultant Psychiatrist at the Guild NHS Trust in Preston. Previously he was trained in psychiatry in Leeds, Baltimore in the United States and Oxford, where he carried out his first study into chronic fatigue syndrome in 1990.

He has completed a number of research studies includin g sleep investigations and treatment studies in chronic fatigue syndrome. Dr Morriss provides a general adult psychiatry service in his current post. He will be taking up post as Professor of Psychiahy at the University of Liverpool from 1st August 1999.

COGNITIVE PROBLEMS IN CHRONIC FATIGUE SYNDROME

Alison J Wearden, Department of Clinical Psychology, University of Manchester, Withington Hospital, Nell Lane, Manchester M20 8LR.

Patients with CFS report problems with memory and concentration and often say that this is one of the most troubling aspects of the condition. Early research tested the performance of CFS patients on many types of tasks using batteries of tests, in order to find out whether patterns of deficits existed that resembled those seen in other, better understood, conditions. However, this approach did not prove very productive, partly because cognitive deficits were rarely found on many of the tests used. This may have been because the tests used were not designed specifically to examine fatigue-related performance deficits and were not sufficiently sensitive to pick up the cognitive problems of CFS patients. More recent research has concentrated less on the question of what causes CFS cognitive problems and more on trying to develop explanation of the processes which may be involved when such problems occur. This paper will review the (short) history of research into cognitive problems in CFS, assess and comment upon the current state of knowledge, and make some suggestions as to directions for future research.

Alison Wearden studies Psychology at Manchester University, worked as Probation Officer, and spent a few years at home with her 3 sons before starting research on CFS. She has worked on cognitive problems in CFS and is also interested in family factors in CFS and other conditions.

HEALTH OF UK SERVICEMEN WHO SERVED IN THE PERSIAN GULF WAR

Dr Khalida Ismail, Clinical Lecture in Liaison Psychiatry, Gulf War Illnesses Research Unit, Guy's, King's and St Thomas' School of Medicine.

Following the Gulf War 1990-1991, anecdotal reports began to emerge in the United States and then in the United Kingdom, that some GulfWar veterans were suffering from a diverse range of symptoms and disorders, some of which appeared to have a clinical picture that resembled chronic fatigue.

At the Gulf War Illnesses Research Unit at King College Hospital, we have carried out a cross sectional postal study on three random samples of current and ex servicemen; those who served in the Gulf War, those who served in Bosnia on Peace Keeping Duties, and those who did not served in either connict (Era cohort).

The most significant finding was that the Gulf War cohort reported symptoms and disorders about twice as often as those in the Bosnia and Era cohorts. These symptoms included fatigue, pain, sleeping difficulties, headaches, memory problems and joint pains. Gulf War veterans were more likely than Bosnia veterans to have substantial fatigue, as well as more likely to report other health outcomes.

Potentially harmful hazards were reported more frequently by the Gulf War cohort. All hazards, ranging from pesticides, seeing dead bodies, skin contact with diesel fuels, vaccinations against biological warfare, were statistically associated with having more symptoms and the various health outcomes, irrespective of whether or not they went to the Gulf.

Although the Gulf War veterans report more symptoms, the pattern of symptom reporting is no different in Gulf, Bosnia and Era cohorts.

Our study demonstrated that Gulf War veterans are suffering from more ill health than other military groups but we could not find evidence of a single new illness or a single cause. Our study is just one piece of the jigsaw and further research is clearly needed.

BLOOD-BRAIN BARRIER BREAKDOWN IN MYALGIC ENCEPHALOMYELITIS

Behan W, Gow J.W, Curtis F. Department of Pathology and Neurology, Wester Infirmary, Glasgow, G11 6NT, Scotland.

ABSTRACT: A new approach to finding the cause of myalgic encephalomyelitis (ME,CFS) has been suggested by recent work on the Gulf War Syndrome: scientists in Israel showed that severe stress, physical or mental, could produce breakdown of the blood-braio-bamer (BBB) and detectable changes in brain function in experimental animals. They proposed that the same thing happened in army recruits.

We realised immediately tbe relevance of thir wark: the bram is usually protected by the BBB from agents present in the rest of the body. If the barrier is broken, small amounts of substances outside the brain, not expected to affect it, could produce brain injury.

In the case of ME ow hypothesis is that a person already under physical or mental stress, is exposed to an agent (e.g. virus or toxin) which crosses the BBB, enters the brain, and produces long-term dysfunction manifest as fatigue and lack of concentration.

We have developed a rat model based on physical stress i.e. swimming. Several rat strains were examined before we found that tbe most suitable are Brown Norway and PGVG. Characterization of stress-induced changes in neuronal function and cytokipe production is now underway.

CLINICAL OVERVIEW OF THE TREATMENT OF CFS/ME WITH AMPLIGEN

David R. Strayer, William A. Carter, Hemispherx, Biopharma Inc., USA and Kenny De Meirleir, Vrije Universiteit, Brussels, Belgium.

Our objective was to review physical and quality of life improvements derived from four separate clinical studies of Ampligen in Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME). Chronic Fatigue Syndrome is a symptom complex characterized by both chronic physical debilitation as well as impairments in concentration and short-term memory. Although the etiology of CFS remains elusive, abnormalities in immune function and viral reactivation have been reported. We have investigated the role of a double-stranded RNA, Ampligen, which acts as a biological response modifier with both antiviral and immunomodulatory activity. We have examined the utility of measuring components of the Rnase L pathway and have also initiated studies of physical activity in CFS using activity monitors(AM). The aggregate of the four clinical trials reviewed, three open-label and one placebo-controlled, includes 171 individuals meeting the CDC case definition for CFS. The results of these four clinical studies, which utilized similar Ampligen dosage levels, duration of therapy and data endpoints and collection intervals, were analyzed.

Following 24 weeks of therapy, the most consistent finding was the degree of improvement evinced by the Karnofsky Performance Scores (KPS) and the Exercise Treadmill Testing (ETT). For the 124 Ampligen patients the average KPS improvement was 14.5 (jl% mean improvement over baseline) vs 3.7 (10%) for the 47 placebo subjects. ETT percentage changes were 41% and 17% (2 minutes and 1/3 minute gains) for Ampligen (p=0.0001, paired t-test) and placebo (p=0.063), respectively. A Pearson's correlation coefficient between the percent change in KPS vs. ETT was .69 (p=0.0001) for Ampligen and .04(p=0.78) for placebo groups. Wilcoxon ranskum tests showed that the probability that the medians for KPS percent change differ by chance for the Ampligen and placebo groups was 0.0001. Examination of the relationship between Rnase L and clinical benefit revealed that changes in Rnase L correlated with improve cognition perception (SCL-90-R) for the Ampligen group (R=0.52, p=0.0012), but not for the placebo group (R=0.13, p=0.44); Finally, activity monitors (AM's) were employed to provide an index of severity of CFS. Prior to treatment, segmentation of normal controls and CFS patients was well delineated with no CFS patient achieving a daily score of over 250,000 activity units (based on a weekly average), while no normal control expressed a daily score of less than 250,000. Correlation between baseline KPS and AM scores was 0.83 (p-0.0001). Changes in AM with Ampligen therapy also correlated well (Pearson Correlation Coefïicient = 0.89) with KPS improvements (p<0.05). In these studies the twice weekly (200-400mg) Ampligen treatments produced no evidence of cumulative toxicities. No clinically significant abnormalities were revealed in blood chemistry, coagulation, or haematological parameters.

In summary, results of four separate studies using Ampligen in CFS firmly demonstrates the therapeutic advantages of the treatment asrevealed using the KPS, ETT and SCL-90-R. Both physical performance and cognition improved significantly during treatment in these four clinical trials and the treatment was generally well-tolerated.

COGNITIVE BEHAVIOURAL TREATMENT OF CHRONIC FATIGUE SYNDROME: RANDOMISED CONTROLLED TRIALS

Dr Trudie Chalder, Academic Dept. of Psychological Medicine, King's College School of Medicine and the Institute of Psychiatry.

Ten years ago very little was known about the aetiology or treatment of chronic fatigue syndrome (CFS). Views regarding aetiology appear to be as divided now as they were then, with people ascribing to either a physical or psychological cause. These attitudes are based on an unhelpful dualistic mode ofunderstanding illness/disease. An approach which avoids dualistic argument is based on a three systems model of undeistanding CFS in which physiological, behavioural and cognitive responses are assumed to be important in precipitating and maintaining the illness. Behavioural and cognitive interventions based on these sound theoretical principles are used to reduce both disability and symptoms in people with CFS. Although two randomised controlled trails have demonstrated the effectiveness of cognitive behaviour therapy (1,2) and one has shown that graded exercise can be effective (3), not all trials have been as positive (4,5). The aim of this lecture is to review the evidence for CBT and exercise and to examine how effective the treatment is when applied in everyday clinical practice, outside the confines ofa randomised controlled trail.

1. Deale A, Chalder T, Marks I, Wessely S. A randomised controlled trial of cognitive behaviour versus relaxation therapy for chronic fatigue syndrome. American Journal of Psychiatry 1997; 154:408-424. 2. Sharpe M, Hawton K, Simkin S, Surawy C, Hackmann A, Klimes I et al. Cognitive behaviour therapy for chronic fatigue syndrome; a randomized controlled trial. British Medical Journal 1996;312:22-26. 3. Fulcher K, White P. Randomised controlled trial of graded exercise in patients with chronic fatigue syndrome. British Medical Journal 1997;314:1647-1652. 4. Lloyd A, Hickie I, Wakefield D. A double blind placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. American Journal of Medicine 1990;89:561-567. 5. Wearden A, Momss R, Mullis R, Strickland P, Pearson D, Appleby L, et al. (1998). A double-blind, placebo controlled treatment trial of fluoxetine and a graded exercise programme for chronic fatigue syndrome. British Journal of Psychiatry.

Trudie Chalder currently works as a Senior Lecturer in the Dept. of Psychological Medicine at Guy's, King's and St Thomas' School of Medicine (GKT), London. She is a cognitive behavioural psychotherapist and has an MSc in Health Psychology and a PhD in Psychology which is related to the area of fatigue in primary care. She has worked as a clinician and a researcher in the area of chronic fatigue and Chronic Fatigue Syndrome (CFS) for about 10 years. Her interest in CFS began while she was working as a full-time therapist at the National Hospital for Neurology and Neurosurgery where she started to assess and treat adults with the condition. In the few years she has developed an interest in adolescents and with colleagues has adapted the approach she uses with adults to suit the needs of teenagers and their families. Her research interests include the epidemiology of fatigue as well as its development and treatment.

ALLERGY IN CFS

Professor Jonathon Brostoff

Patients with CFS are selected by virtue of chronic fatigue and their associated symptoms. Using the various criteria of selection of CFS patients, a number of these associated symptoms are often accepted as part and parcel of the total CFS symptomatology. These symptoms consist of irritable bowel, arthralgia, headache, chemical sensitivity and ofcourse fatigue.

A sample of patients with CFS studied at the Middlesex Hospital clearly show that many of the above symptoms respond extremely well to environmental intervention - usually an elimination diet and nutritional supplements. Thus, headache, imtable bowel and arthralgia could be called "add-on" symptoms, not actually part of the CFS syndrome itself. A small proportion of"TATT" patients are in fact food sensitive and are suffering from the opioid excess syndrome.

A further group of symptoms have been associated with "somatisation" but in reality many of these are due to hyperventilation. Data will shown how hyperventilation can mimic many of the so-called classic CFS/ME symptoms.

Lastly, other causes of the CFS symptomatology have been clearly identified. In essence, many patients with chronic inaammatory conditions are tired and complain of Symptoms similar to CFS. A particular sub-group are female patients with a long histoIy of candidiasis who respond well to dietary intervention, nutntional supplementation and anti fungaltherapy. These patients will be clearly defined and are worthy of further study.

Professor Jonathon Brostoff is currently Professor of Allergy and Environmental Health at University College London and the Director of the Centre for Allergy Research. He trained at Oxford and St Marys Hospital in London. After being Registrar to Dr A W Frankland, he subsequently became Reader in Clinical Immunology and Physician in charge of the Allergy Clinic at the Middlesex Hospital. His textbook "Food Allergy and Intolerance" with Prof Stephen Challacombe, is the major reference text for doctors and scientists working in this field. He is internationally recognised as a specialist in the field of food intolerance.

MELVIN RAMSAY MEDALLIST LECTURER

Benjamin H. Natelson MD went to college and medical school at the University of Pennsylvania where he was elected to the Alpha Omega Alpha Medical Honor Society. Subsequently he trained in neurology at the Albert Einstein College of Medicine in the Bronx and did two postdoctoral fellowships (Behavioural Neurosciences at Cornell University Medical Center in White Plains NY and Experimental Psychology at Walter Reed Army Institute of Research). In 1974, he moved to the New Jersey Medical school and its affiliate the East Orange VA Medical Center where he moved up the ranks to full Professor in 1981.

Natelson has had continued VA support since 1974 for his work on animal models on the effects of stress in precipitating or exacerbating underlying organic illness as well as on animal models of chronic stress. In 1989, he began a small private practice caring for patients with unexplained fatiguing illness. Shifting his focus from his animal work to this medical problem, he used pilot data in an application to establish a CFS Co-operative Research Center in NJ. That application was funded in 1991, and the center was renewed 4 years later. Data from that civilian center were important in establishing a VA group to evaluate the hypothesis that Gulfveterans had CFS. A proposal to open a parallel center to study Gulf veterans with unexplained illness was funded in 1994, and Natelson is the medical director ofthat center. Thus NJ is the only site to receive federal funding establishing center to study severe fatiguing illness in both veterans and civilians.

Natelson has authored or co-authored over 170 papers reporting empiric data on his animal and human studies as well as 2 books - the most recent of which concerns fatigue was released by Yale University Press last spring.

EVIDENCE FOR GLUTATHIONE DEFICIENCY IN CHRONIC FATIGUE SYNDROME

Paul R Cheney MD, PhD

Chronic Fatigue Syndrome has recently been linked to activation of a novel, low molecular weight (37 Kda) Rnase L (1). Such activity would be expected to significantly impair key enzyme systems important to human function. Recent studies have also suggested that xenobiotic toxicity plays a substantial role in the symptoms of chronic fatigue syndrome (2). Urinary xenobiotics which are likely of gut microbial origin, correlate with the severity of and types of symptoms associated with chronic fatigue syndrome. We will present evidence of impairment of glutathione synthesis and function in chronic fatigue syndrome. Dysfunction in this key detoxification system would be expected to cause portal circulation toxicity as well as other xenobiotic toxicity now reported for chronic fatigue syndrome.

1. Suhadolnik, JR; Peterson, DL; O'Brien, K; Cheney PR et al. "Biochemical Evidences for a Novel Low Molecular Weight 2-SA-Dependent Rnase L in Chronic Fatigue Syndrome" Journal oflnterferon and Cytokine Resenrch, 17:377-385 (1997)

2. McGregor, NR; Dunstan, RN et al. "Preliminary Determination of a Molecular Basis to Chronic Fatigue Syndrome" Biochemical and Molecular Medicine, 57:73-80 (1996)

Paul R Cheney MD, PhD is the Director of The Cheney Clinic which exciusively serves the Chronic Fatigue Syndrome (CFS) patient community located on Bald Head Island, North Carolina. For over ten years, Dr Cheney has been a pioneering clinical researcher in the field of Chronic Fatigue Syndrome. He has published numerous articles in peer reviewed medical journals, and lectured around the world on chronic fatigue syndrome. He is an internationally recognised authority on the subject of CFS and was a founding Director of the American Association of Chronic Fatigue Syndrome (AACFS), a professional association of scientists and clinicians from around the United States interested in doing research on chronic fatigue syndrome.

Dr Cheney holds a PhD from Duke University in Physics and is a graduate of Emoly University School of Medicine in Atlanta, GA. He is a board certified internist and has held a number of research positions in tumour immunology at the Center for Disease Control (CDC) in Atlanta and in the departments of pharmacology and radiation oncology at Emory University School of Medicine. Dr Cheney was Chief of Medicine at Mt. Home Air Force Base Hospital in Mt. Home, Idaho and Chief of Medicine at Lakeshore Hospital on the north shore of Lake Tahoe in Incline Village, NV. For the three years before starting The Cheney Clinic in Charlotte, NC in 1990, Dr Cheney was a senior staff physician at the Nalle CIinic in Charlotte, the largest multispeciality group practice in the southeastern United States.

Dr Cheney has been interested in many aspects of CFS. He has authored or co-authored publications and scientific presentations in many fields relevant to CFS including: Immunology, Virology, Clinical Epidemiology, Metabolism, Neuropsychology & Neuroendocrinology, Exercise Physiology, Computerized EEG brain mapping; Clinical Treatment Trials using: Ampligen as a biological response modifier in CFS Configured Nutrition as treatment for CFS

PROBLEMS FACING FAMILIES WITH CHILDREN WITH ME/CFS IN THEIR DEALINGS WITH MEDICAL PROFESSIONALS

Dr Nigel Speight, Consultant Paediatrician, Durham. As a pediatric adviser to each of the main ME support organisations, the author has been asked to give second opinions on pediatric cases of ME/CFS from all over the UK as a result of parental dissatisfaction with local medical management. Common themes include:-

1. Failure to diagnose ME/CFS in the first place leading to:- 2. Referral to Child Psychiatry as a routine, and in a manner unacceptable to families. 3. Inappropriate pressure to attend school when the child is too unwell. 4. Lack of support for Home Tuition.

There is a possibility that (3) and (4) have become more common following the recommendations in the section on childhood ME/CFS in the report from the Royal Colleges.

In addition to these "negative"failings, in a small but important number of cases, families have been referred by their paediatricians to social services as cases of emotional abuse and neglect, non-school attendance and Munchausen syndrome by proxy. In the opnion of the author, in each of the cases that he has been involved in, these actions have been inappropriate and have constituted "child abuse by professionals".

FATIGUE IN CNS DISORDERS

Dr Abhijit Chaudhuri DM MD MRCP (UK), Clinical Lecturer in Neurology at the Institute of Neurological Sciences, University of Glasgow.

Fatigue is common in many CNS disorders and is often under-reported. It is a major symptom in Parkinson's disease (PD) and may occur long before other signs of the disease are evident. Fluctuating fatigue, paroxysms of sweating, impaired concentration and increased resting energy expenditure are common to both PD and patients with chronic fatigue syndrome (CFS). Fatigue is common in post-stroke patients, multiple systems atropthy, Alzheimer's disease and multiple sclerosis (MS). Irrespective of the severity of their neurological disability, patients with MS experience nuctuating fatigue that shares similar features with fatigue in CFS, including temperature sensitivity. Fatigue occurs in chronic infective meningitis, sleeping sickness and HIV encephalopathy. Hypothalamic disorders typically produce fatigue and paroxysmal fatigue occurs in migraine and other neurological channelopathies. Fatigue is characteristic of disorders which affect both central and peripheral nervous systems, such as motor neurone disease, mitochondrial cytopathies and myotonic dystrophy.

Treatment of fatigue in CNS disorders is difficult because of our lack of understanding of the neural mechanisms and substrates that may cause fatigue. Dopaminergic agonists have been used with partial success to treat fatigue in PD, MS, CFS and post-polio syndrome. Treatment with antidepressants is generally effective improving fatigue in major depression, although antidepressant therapy is seldom effective in other neurological disorders producing fatigue including CFS. Our current research supports the role of neurotransmitters, particularly dopamine, in the genesis of fatigue but other mechanisms, e.g. neuronal depression and cytokine effects are also likely to be involved.

Dr Abhijit Chaudhuri DM MD MRCP (UK) is a clinical lecturer in neurology at the Institute of Neurological Sciences, University of Glasgow. He has been working with Professor Peter Behan since 1996 and is doing his PhD on chronic fatigue syndrome. He qualified as a neurologist from Bombay, India, where he received his clinical training from Dr Nadir E Bharucha. He did his MD thesis on the effect oflow dose Aspirin on platelet aggregability and ischaemic cerebral stroke. His MD thesis was on the effect of social and cultural beliefs on long-tenn anti-epileptic drug compliance. Dr Chadhuri was invited speaker on a symposium on chronic fatigue syndrome in XVI World Congress of Neurology held in Buenos Aires in 1997. He has published more than 20 papers in peer-reviewed scientific Journals. He was also the recipient of the first inaugural Pfizer prize on biological psychiatry in 1997.

CHRONIC FATIGUE SYNDROME: ACQUIRED NEUROLOGICAL CHANNELOPATHY

Professor Peter O Behan & Dr Abhijit Chaudhuri

Many symptoms of chronic fatigue syndrome (CFS), including severity of fatigue, may be periodic, fluctuant and induced by physical and mental activities, including trauma and stress. The fatigue in CFS is distinct from the fatigue of neuromuscular disorders but is similar to that found in disorders of the central nervous system such as multiple sclerosis, Parkinson's disease and multiple system atrophy. Although fatigue is a common symptom ofdepressive disorders, it is not clear that CFS patients differ from patients with inajor depression in their symptoms, biological markers such as steroid metabolism and response to standard anti depressant drug therapy. In addition, specific tests aimed at quantitating the neuroendocrine responses mediated through the hypothalamus and brain stem reflexes, show robust differences between normal controls, patients with depression and patients with CFS. In this talk, it is proposed that dysfunctional ion channels in cell membrane are the key abnormality in CFS and may underlie the neuroendocrine abnormalities reported in this condition. Changes in the neuronal ion channel function from time to time offer a rational basis to explain nuctuating fatigue and related symptoms. Finally, ion channel abnormality leading to selective neuronal instability may be the common disease mechanism in CFS and other paroxysmal disorders affecting brain functions such as migraine and epilepsy.

POST POLIO SYNDROME

Dr W R C Weir, FRCP FRCP (Ed)

What we now recognise as Chronic Fatigue Syndrome can clearly be triggered by many antecedent illnesses, from specific virus infections through to bacterial and even protozoal infections. The occurrence and recognition of Post Polio Syndrome may well be yet another variant of the overall clinical phenomenon of CFS. The possible mechanisms of the illness will be discussed with some historical reference to Post Polio Syndrome itself, the immunology of infectious disease and a given individual's response to infection in certain circumstances may well be at the basis of this distressing disorder.

Dr W R C Weir, Consultant Physician, Royal Free & Coppetts Wood Hospitals. Hon. Senior Lecturer in Infectious Diseases, Royal Free Hospital Medical School Hon. Senior Lecturer, Clinical Tropical Medicine, London School of Hygiene & Tropical Medicine Research interests include the pathophysiology of severe malaria and the Immunology of Chronic Fatigue Syndrome.

A CLINICAL TREATMENT MODEL FOR CHRONIC FATIGUE SYNDROME PATIENTS

During this session, Dr Hyams will present a practical approach to manage Chronic Fatigue Syndrome (CFS) patients, based on the generally accepted understanding of the pathophysiology underlying CFS.

The model is designed to treat patients multi-systemically, including neurological rehabilitation, appropriate immune modulation intervention, managing the underlying metabolic dysfunction and addressing the neuroendocrinological changes occurring in this illness. Occasionally, dental and/or gastroenterological interventionmay be required. Dr Hyams will outline a methodical approach to treat patients and this type of model is used both in the USA as well as in Europe. Teitelbaum et al have confirmed clinically significant results of patients being treated on a multi-modality treatment programme and this appears to yield better results than any single treatment modality, on its own.

Dr Hyams will emphasise management based on clinical outcome studies as well as suggested treatments discussed at peer reviewed conferences. He will also discuss the paradigm shift occurring in the management of chronic illnesses such as CFS involving integrative approaches combining orthodox medicine and the need for scientifically based nutritional medicine. During this discussion, he will allude to some nutritional approaches, although this will be dealt with more extensively during the separateworkshop to be held on Sunday 25th April. Reference will be made to some of the proposedclinical treatment trials which will hopefully commence in this country shortly.

This treatment model is currently being introduced to the fatigue service at the National ME Centre as well as the Havering Hospital Trust.

Dr Hyams is specialised in the management of chronic fatigue syndrome, fibromyalgia and related disorders. He is currently appointed as the Assistant Clinical Director of the National ME Centre and also one of the specialists treating this disorder as part of the Havering Hospitals Trust. He is originally South African and directed a large specialised clinic, exclusively serving the CFS population in the Johannesburg/Pretoria regions. He was offered a prestigious position directing research into CFS at the Cheney Clinic in North Carolina, USA. Dr Hyams and Dr Cheney worked together for two years before he took up his current post. Dr Hyams wrote for the CFIDS Chronicle, the American Journal of the CFIDS Association of America, on a regular basis. He has also lectured extensively on CFS and co-authored publications and scientific presentations in fields relevant to CFS. Dr Hyams has also been involved in the Ampligen trials in the USA and will be involved in the introduction of Ampligen to this country. Dr Hyams was elected onto the scientific advisory council of the CFIDS Association while in America and he has also served as Chairman of the CFS Association of South Africa and also the National Research Foundation. Dr Hyams has been recently interviewed by Action for ME.

THE MANAGEMENT OF CFS - THERAPY OVERVIEW

Diane L Cox MSc, Dip COT, Senior Lecturer, Faculty of Health, South Bank University, London. Formally Head OT and Co-ordinator of CFS Service at the Essex Centre for Neurological Sciences.

Over the last two days, we will have heard all that is current in the aetiology, epidemiology, clinical content, diagnostic criteria and clinical management of CFS and allied fatigue syndromes. The research is essential to ensure practice is evidence based. However, most medical practitioners and therapists need practical guidance on how to assist the patient to manage the illness on a day to day basis. This presentation aims to do that.

The common patterns that develop in response to the symptoms and the structured programme of intervention will be presented. The specifics of the CFS service and in particular Occupational Therapy Lifestyle Management, will be discussed (1) and the perceived outcomes of patients who have completed the inpatient (2) and outpatient group programmes will be presented.

1. Cox DL 1999 Chronic Fatigue Syndrome: An Occupational Therapy Programme. Occupational Therapy International. 6;1:52-64

2. Cox DL, Findley W 1998 The Management of Chronic Fatigue Syndrome in an Inpatient Setting: Presentation of an approach & perceived outcome. British Journal Occupational Therapy 61;9:405-409

PSYCHIATRY AND CFS

Dr Sean Lynch

The contribution of psychiatric assessment to the management of patients with chronic fatigue and chronic fatigue syndrome, is described from the perspective of the current literature and a multidisciplinary fatigue clinic.

The Leeds Fatigue Clinic has two assessment arms, infectious diseases and liaison psychiatry, each of which receives over 300 referrals per annum. Over 50% of referrals are found to meet both UK and CDC criteria for CFS (Sharpe et al 1991, Fukuda et al 1994). Many management difficulties for psychiatrists in the clinic are related to patients who fail to meet these criteria, but have a significant complaint of chronic fatigue.

Between 1997-8, a sample of 270 consecutive attenders at the Leeds Fatigue Clinic were contacted and sent a postal questionnaire battery. This was designed to assess illness perception, mood, fatigue and somatic complaints and used validated measures reported in other studies (Powell et al 1990, Blenkiron et al in press). 60% were found to have concurrent psychiatric morbidity, with DSM-IV major depression being the diagnosis in 40% of the sample. One surprising aspect of the study was that there was a wide spectrum of illness perceptions in this group, and 30% had highly variable mood symptoms, not strictly conforming to DSM-IV affective disorder criteria, but more closely conforming to the concept of "recurrent brief depression". This confirms the heterogeneity of such clinical samples an in particular of mood syndromes in CFS patients.

These findings are reviewed in the context of the published literature on the nosology and current treatments for mood disorders, chronic fatigue and the chronic fatigue syndrome.

Key words:- Psychiatric assessment, treatment, recurrent brief depression, chronic fatigue syndrome.

VESTIBULAR AND NON-VESTIBULAR SPATIAL DISORIENTATION IN PATIENTS WITH FATIGUE SYNDROME

Michael A Gresty MRC Human Movement and Balance Unit, National Hospital for Neurology and Neurosurgery, London. Leslie J Findley MRC Human Movement and Balance Unit, National Hospital for Neurology and Neurosurgery, London. Neurosciences Unit, Havering Hospitals NHS Trust.

Strong illusions of motion of either the self or the visual and tactile surrounds which one may term "vertigo" are usually, and quite rightly, diagnosed as due to vestibular disorder. Vague illusions of motion and disorientation also arise from disordered somatosensory signals, eg. "cervical vertigo" and in a wide range of neurochemical, eg. hormonal, disorders, but in these the sensations are less compelling and tend not to be associated with the vaso-vagal sequalae so typical ofa vestibular episode. Rarely recognised in medicine, but commonplace in the aerospace scenario there are also functional causes of spatial disorientation and vertigo which are thought to be due to a "heightened" perception of the quotidian instabilities in the world around us. In pilots, disorientation is most often triggered by stress in unusual flight circumstances. A similar disorientation syndrome can also be identified in patients wherein it may also stress related or epiphenomenal to the central disease process. This kind of disorientation in patients Thomas Brandt refers to as "phobic postural vertigo". Functional spatial disorientation imitates mild vestibular or somatosensory vertigo and thus leads to a problem of differential diagnosis, particularly in the viraemic patient.

Anecdotally a substantial number of patients with fatigue complain of symptoms of spatial disorientation, including vertigo and imbalance. Accordingly, we have screened a selection of 19 patients (18 female) who presented vertiginous symptoms for objective signs of neuro-otological disease with the purpose of making a differential diagnosis of the causes of their disorientation. The patients were seen over a period of two years and had specific assessments of ocular motility, posture, gait and cochleo-vestibular function. The results were analysed in particular relationship to stress, migraine, endocrinological factors, duration of disease and mode of onset (viral, vestibular symptoms).

Definite signs of peripheral vestibular disease were present in 5 patients including 2 with benign paroxysmal positional vertigo. One patient had central vestibular sign ofsustained positional nystagmus. In three patients, we had the strong suspicion of vestibular disease but without hard signs (not surprising because we do not have a "complete" method of vestibular assessment). The presence ofvestibular signs was correlated with a viral onset to the fatigue state. In the remaining patients, a diagnosis of functional disorientation "phobic postural vertigo" was made. Incidentally, an orthogonal components factor analysis, with rotation, of the statistics and observations of this group of patients revealed two subgroups, with main differentiating factors being a short versus a long duration of illness, independent of patients age (range 13-62 years). This finding suggests that the natural histories of"fatigue states" may follow two rather different dynamics.

These results help rationalise treatment. Cognitive therapy is of utmost importance in gening the patient to understand functional disorientation. In the armed forces, it is treated with intensive desensitising and retraining immersion. The role ofvestibular disease as a possible cause of fatigue is suggested by our observations but as yet unproven. However it is of note that an aspect of an attack of vertigo is an element of disconnection from the normal sensation of being in touch with the real world. This experience is frightening; provoking depression, withdrawal and anxiety and will undoubtedly exacerbate patients' problems.

CONCEPTS AND PROBLEMS WITH CFS

Professor Leslie J Findley TD MD OLJ FRCP FACP

In the last two decades, sporadic chronic fatigue syndrome has become recognised as a clinical entity accepted by all the major medical authorities. It's recognition was aided by the work of the Task Force Report 1994 (Westcare) and the conjoint report of the Royal Colleges of Physician, Psychiatrists and General Practitioners 1996. The latter report, whilst criticised by some, stated categorically chronic fatigue syndrome was a common problem, had to be recognised and treatment facilities provided. It recognised that the bulk oftreatment would be provided from primary care.

In spite of such considerations and recommendations, a substantial minority of doctors still either fail to accept, recognise or are able to offer advice on the management of CFS.

In the absence of an accessible biological marker, diagnosis depends on fulfilling criteria. What is generally accepted now is the CDC criteria (Fukuda et al 1994) which in essence states "CFS is an acquired state of substantial fatigue persisting for more than six months - other recognised causes offatigue having been excluded. It separates CFS from primary fatigue, that being a lifelong debility.

Conceptually CFS can be considered an umbrella diagnosis for a heterogeneous group of conditions with central fatigue as the core "problem". CFS is invariably associated with reversible cognitive impairment and commonly associated with myalgia. A common association with other unrelated conditions, supports the concept of genetic predisposition. The triggering factors of infection and/or stress are commonly observed.

The relationship of chronic fatigue syndrome to the commonly associated food intolerances/allergies and psychological disturbances, will be explored during this conference.

As a neurologist my biased viewpoint is that chronic fatigue syndrome represents a profound disturbance of functioning of the central nervous system and its connections through the neuroendocrine and neuroimmune systems. CFS is a major source of morbidity in our society. Of those referred for specialist assessment, 30-50% improve in the medium term but some studies suggest that less than 10% return to premorbid levels of functioning.

Professor Findley is currently a Consultant Neurologist at the Essex Neurosciences Unit based in Oldchurch Hospital, Romford, Essex. He is a Professor of Health Sciences (Neurology) in the faculty of Health Science at South Bank University. He is also adjunct Professor of Neurology at the University of Kansas Medical School, Kansas, USA. He received his undergraduate and postgraduate training in general medicine at the University of Sheffield. The postgraduate neurological training was done at the National Hospital of Neurology & Neurosurgery and St Marys Hospital, London.

His main research interests are Movement Disorders, in particular tremor and Fatigue Syndromes. He is Medical Advisor to the National Tremor Foundation(UK). He is European President of the International Tremor Foundation (Kansas, USA). He is Director of Fatigue Services for Havering Hospitals Trust (NHS). He is Honorary Clinical Director for the National Centre for ME and Centre for Fatigue Syndromes a charity set up to compliment the NHS services. He is Honorary President of the Melvin Ramsay Society, a Society for the scientific study of Fatigue syndromes.

MANAGEMENT PROBLEMS WITH CHILDREN & YOUNG PEOPLE

Dr Alan J Franklin, FRCP, DCH

These are some of the problems that can be encountered.

1. Medical Problems: Recognition, diagnosis, misinterpretations of symptoms, preconceived ideas, disbelief, inexperience of lack of physical signs, lack of knowledge and experience, failure to see and understand the child's world, fear of missing another (treatable) condition, over- investigation, inept referral, mistaken view of child protection concepts.

2. Educational Problems: Lack of physical and intellectual stamina. Cognitive difficulties in concentration, word blindness, short term memory, comprehension, writing, vision, hand control, inability to read. Problems with school premises - steps, long distances between buildings, "bells and smells". Poor understanding of the illness and the effects of travel, sustained attention and physical difficulties by stall at all levels.

3. Psycho-social Problems: Emotional lability, frustration, anger, disappointment, lowered self esteem, sense of failure, loss of hope, depression, loss of social contact with staff and with peers, lack of contact with the world outside.

4. The Way Forward: Better knowledge, better referral patterns, making time to listen, talk and review.