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ME a misunderstood and much maligned disease

by Dr Derek Pheby(more info)

listed in cfs me long covid, originally published in issue 12 - May 1996

Myalgic encephalomyelitis (ME) is an illness which for years has divided the medical profession, yet no-one who has experienced it, or who has had the responsibility of caring for a family member who has had the misfortune to suffer from it, can have any doubt as to the real suffering and distress that it can cause.

Among doctors, the reasons for differences of opinion are not difficult to discern. The lack of readily demonstrable physical signs on clinical examination, and of abnormalities on routine laboratory investigations, has led many to conclude that the disease does not exist outside the minds of those who claim to suffer from it, and that it should not be regarded as a specific clinical entity. Others share the same viewpoint regarding the lack of clinical features of the disease and of specific abnormalities on laboratory investigation, but argue from this basis that, since the disease exists within the minds of sufferers, it must be regarded not as a specific clinical entity, but of psychological origin.

A further school of thought among doctors takes the view that the disease is a genuine physical entity, and that the reason why abnormalities are not demonstrated by routine clinical examination and laboratory investigations is that, as normally practised, these are too crude to demonstrate what are fairly arcane and subtle, though nonetheless real, changes.

Ten years ago, doctors who subscribed to this latter view were few and far between. Often they found themselves part of a beleagured minority, which encountered a response from colleagues little short of ridicule. Such a response, one may conclude, is a long way from the spirit of enlightened enquiry, free from preconceptions, that should characterise a science-based, liberal profession. Not only that, but in recent years, scientific research has made it increasingly clear that the initial premise on which such sceptical views were founded (viz. that there were no specific changes demonstrable in patients with the disease) has become increasingly untenable. The underlying viral aetiology of the condition is well established , although there is considerable divergence of view as to the particular viruses thought to be responsible, with British opinion tending to favour enteroviruses, and American opinion the Epstein-Barr viruses. In reality both are likely to be involved, and to interact in ways not yet fully understood. Changes have been demonstrated involving neuromuscular structure and function, the hypothalamic-pituitary axis, and brain perfusion.

Studies of neuromuscular function have indicated various histopathological features of the disease at the cellular level, including fibre changes, glycogen depletion and mitochondrial abnormalities, which appear to be correlated with the severity of symptoms. Overall, though, these changes are not associated with any marked degree of contractile failure. However, in well-characterised, severely ill patients, such changes may well underlie the common feature of excessive muscle fatiguability after exercise.

Abnormalities of the hypothalamic-pituitary axis have been demonstrated in a number of studies. Demitrack et al1 noted a reduction in ACTH release in response to corticotrophin releasing hormone, while Bakheit et al2 found that prolactin secretion in response to buspirone challenge was more marked in patients with chronic fatigue syndrome than in patients with depressive illnesses or in normal controls. Other studies have shown diminished release of growth hormone in response to dexamethasone stimulation in patients with chronic fatigue syndrome. Overall, the disturbances to the hypothalamic-pituitary axis in CFS differ markedly from those found in depression, which also affects the hypothalamic-pituitary axis, while recent research by Costa and others3 has indicated quite characteristic patterns of brain vascular perfusion which, again, are quite different from those found in depressive illnesses or among normal controls.

Such research findings, though, are still the preserve of a handful of sophisticated research units, and require advanced skills, sophisticated techniques and expensive equipment to demonstrate them, and are not yet available in routine clinical practice. It will be some time, therefore, before they are available to help the average patient, who may well therefore, unless very fortunate, have to endure the disbelief, and in many cases, contempt, of doctors who, like St Thomas the Apostle, are unwilling to accept the reality of anything unless they can see the stigmata.

Since it has not yet been possible to identify a single, specific underlying pathological lesion which characterises the illness, it has to be defined as a syndrome, on the basis of its clinical features. However, its clinical presentation is very heterogeneous. This has led to problems of definition which have impeded research, both in terms of epidemiology (to determine possible causal associations, and the overall burden of the disease in the community) and of clinical research, since it is very difficult to draw general conclusions from studies involving groups of patients who may well not be representative of ME sufferers as a whole.

In epidemiological studies, incidence rates per 100,000 population vary by a factor of nearly a thousand, from around 4 to upwards of 3,000. The lower figure represents, for example, the results of studies conducted by the Communicable Diseases Center, Atlanta, Ga., largely on the basis of a telephone survey, and in the UK on the basis of analysis of hospital referrals4. The higher figure was achieved in a general practice based study in the West of Scotland5. The variations may be attributed to four main sets of reasons, viz:-

(I) Biological variation between populations.

(II) Semantic reasons.

(III) Methodological differences.

(IV) Heterogeneity of the disease.

Some part of the observed variation in incidence rates may be attributable to the real differences that exist between different populations. Both epidemic and sporadic cases of the disease clearly occur, so not only is there variation in incidence between populations, but also within populations through time. Acheson6 reviewed fourteen major outbreaks that have occurred in the past sixty years, and demonstrated attack rates of between 2 and 20%, which is clearly a far higher incidence rate than that attributable to sporadic cases. Epidemic cases appear to be more common in women, and in young adults, though the disease occurs at all ages. The age and sex distribution may merely reflect the composition of the relatively closed communities in which many of the outbreaks occurred.

On this basis, they confirm the peak incidence occurring in young adults and females, assert a lifetime involvement of between 3 and 7% of the exposed population in the UK and the USA, and point to an association with social class, with professionals being more frequently affected than others. However, in the study by Calder and Warnock5, in which such a high incidence rate was reported, no one symptom was reported by more than about half of the presenting patients. Fatiguability and tiredness were the most commonly reported symp toms. Myalgia, the next most common, was reported by only about a third of patients. Presenting symptoms were grouped into twenty-one categories, suggesting considerable variation in clinical presentation. Acheson's review of outbreaks showed that common clinical features in all those studied included headache, myalgia, paresis, other features suggestive of nervous system damage, mental symptoms, and generally low or absent fever.

A vigorous, robust and readily implementable case definition is a sine qua non for epidemiological studies. There have been a number of attempts to achieve such a definition, culminating in this country in that proposed by the Oxford consensus meeting of 1990 8 . A definition developed in America, under the aegis of the Centres for Disease Control (CDC)9 suggests two major criteria for the disease. The first of these was:-

"New onset of persistent or relapsing, debilitating fatigue or easy fatiguability 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 six months".

The second major criteria was the absence of around thirty other conditions, including chronic psychiatric disorders.

Some of the apparent variations in reported incidence and prevalence rates arise from case definitional differences related to differences in the purposes of the particular studies reported. Very low reported rates are in most cases due to the case definition adopted being appropriate for analytical but not for descriptive studies.

There is semantic confusion over names and definitions which reflects the fact that the disease itself is heterogeneous. In order to clarify questions arising from the heterogeneity of the disease, Armon and Kurland10 have proposed a flow chart to enable more homogeneous subgroups to be identified and characterised. If more homogeneous and readily identifiable subgroups could be identified, this would facilitate epidemiological research into the syndrome. By contrast, Yeomans and Conway11 conclude that the difficulties of definition arise from the multi dimensional nature of the dis ease, and that a problem-orientated approach would define the disease with respect to its social and psychological, as well as its physical, dimensions. It is difficult to see, how such an approach to definition could be readily incorporated in epidemiological studies.

It is clear from the above account that a great deal of epidemiological report remains to be done. Most existing studies lack comparability, for the reasons outlined above, and some of the most useful sources of data which exist, in the form of case series compiled by individual clinicians, while invaluable as a basis for analytical studies, are restricted in the usefulness in descriptive studies by their lack of a population base. The UK is a ideal location for descriptive epidemiological studies, since the organisation of primary care by allocation of the population to practice lists means that incidence and prevalence rates can be readily calculated in studies undertaken within the primary care sector. It follows that valuable insights could be gained by a major epidemiological study within general practice, conducted on a longitudinal basis to overcome the problem of seasonal variation in incidence, and on the basis of case identification by non-stringent criteria but eliciting data to enable cases conforming to various current definitions to be identified. The Oxford definition should be a major focus of interest, but modified to avoid the need for invasive investigative procedures. Such a study would enable an objective view to be formed as to the scale of the syndrome as a public health problem, and the impact of definitional differences on incidence and prevalence rates to be determined.

Other work that needs to be done, in addition to case-control studies to shed further light on possible causative factors, is in the area of health services research rather than epidemiology, in order to assess the impact of the disease on health services and welfare provision, by examining in detail the health and welfare needs of patients, and current levels of support.

A recent Consensus conference was held at the Department of Health which brought together medical and scientific experts in many fields to consider these issues. Despite different perceptions and disparate backgrounds, a measure of agreement was achieved which was perhaps surprising in the circumstances. The final report is still in preparation, but should, one hopes, provide a more enlightened basis than in the past for the study of the condition and the treatment of sufferers.


DEMITRACK MA, et al Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J. Clin. Endocri I & Metab., 1991, 73, 1224-1234.
BAKHEIT, AM, et al Possible upregulation of hypotha lamic 5HT1a receptors in patients with post viral fatigue syndrome. Brit. Med. J., 1992, 304, 1010-1012.
COSTA, DC, et al, "Postviral Fatigue Syndrome" Brit. Med. J., 1992, 304, 1567.
BEHAN P O, BEHAN W M H, BELL E, "The Postviral Syndrome - an analysis of the findings in 50 cases" J. Infect. 1985, 10: 211-222.
CALDER BD, WARNOCK PJ, McCARTNEY RA, BELL EJ. "Coxsackie B viruses and the post-viral syndrome" J.R. Coll. GP, 1987, 37, 11-14.
ACHESON ED "The Clinical Syndrome variously called Benign Myalgic Encephalomyelitis, Iceland Disease and Epidemic Neuromyasthenia" Nightingale Foundation Symposium (ed. Byron Hyde), 1992, pp. 129-157.
RAMSAY AM, DOWSETT MB. "Myalgic Encephalomy elitis then and now; an epidemiological introduction" Nightingale Foundation Symposium, op. cit., pp 81-84.
SHARPE MC, et al. "A report - chronic fatigue syndrome : guidelines for research" J. Roy. Soc. Med. (1991), 84, 118-121.
HOLMES GP, et al. "CFS: A working case definition" Ann. Intern. Med. (1988), 108, 387-9.
ARMON C, KURLAND IT. "Chronic fatigue syndrome: issues in the diagnosis and estimation of incidence" Rev. Inf. Dis. (1991), 13, S68-S72.
YEOMANS JDI, CONWAY SP. "Biopsychosocial aspects of chronic fatigue syndrome (myalgic encephalomyelitis)" J. Infect. (1991), 23, 263-269.


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About Dr Derek Pheby

Dr Derek Pheby, Epidemiologist, former member of the Chief Medical Officer’s Working Group on CFS/ME and former trustee of Action for ME is currently Project Coordinator at National CFS/ME Observatory. He may be contacted on

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