Author

Dr Vance Spence, Senior Research Fellow, Vascular Diseases Research Unit, Department of Medicine, University of Dundee, and Chairman of ME Research UK

Presentation

A presentation given on 3rd October 2003 at the workshop ‘New developments in the biology of ME/CFS’ at the West Park Conference Centre, University of Dundee

Welcome to everyone attending this research workshop on ME/CFS. As far as we know, this is the first time that the Royal Society of Edinburgh has funded a workshop on the biomedical aspects of this illness. As Dr Kennedy has discussed, the day is divided into two sections, dealing with vascular aspects in the morning and new biochemical developments in the afternoon.

However, my role is to provide an overview of the difficulties surrounding the illness, especially for those of you who are coming fresh to the topic from other scientific areas and specialties. One of our aims is to bring together experts from a variety of disciplines, some with little or no experience of ME/CFS, as we attempt to energise research into this condition with new ideas and novel approaches to solving its inherent problems.

The most widely-used definition of ‘Chronic Fatigue Syndrome’ is that developed in 1994 by a consensus conference: the CDC-1994 definition (1). This was developed in response to criticisms that previous definitions (including the CDC-1988) were too restrictive. It requires the presence of chronic fatigue of six months duration which is persistent or relapsing, of new or definite onset, not substantially alleviated by rest, not the result of ongoing exertion, resulting in a substantial reduction in activities, and leading to substantial functional impairment.

In addition, at least four of the following are required: sore throat, cognitive symptoms, tender lymph nodes, muscle pain, multi-joint pain, headaches, unfreshing sleep and post-exertional malaise. Cognitive or neuropsychiatric symptoms may be present, but the definition excludes clinically important medical conditions such as melancholic depression, substance abuse, bipolar disorder, psychosis and eating disorders. Some would argue that I could just mention this definition and sit down again; but, in fact, it is part of the problem, and it is worth examining why that is so.

As you can see, the definition relies on ‘fatigue’ as its major criterion. For that reason, many patients who fall under this diagnostic label hate the name — they call it the F-word — since, for many of them, ‘fatigue’ per se is not the major problem, and does not best represent how they would explain their condition. Thus, this CDC-1994 definition is now widely recognised to have a number of limitations: symptoms are mainly self-reported (e.g., the clinical signs required in the CDC-1988 definition have been removed); the terminological criteria are vague (e.g., fatigue, malaise, unrefreshing sleep, etc.); the specificity of the definition is poor, allowing heterogeneous groups of patients (e.g., those with somatoform disorders, fibromyalgia syndrome, etc.) to co-exist under the one umbrella term (23); and it makes no attempt to differentiate patients on the basis of severity of illness or level of functional disability.

Indeed, there is a growing realisation that the current CDC-1994-defined ‘CFS’ term is an impossibly inclusive diagnostic construct, begging Simon Loblay (4) to ask the ontological question: “Is CFS a recognisable disease entity with a unique pathophysiology, or is it a ragbag of common non-specific symptoms with many causes, mistakenly labelled as a syndrome?

As an example, our work in Dundee has compared three groups of patients each fulfilling theCDC-1994 criteria; namely, patients with ME, those with Gulf War Syndrome and patients with a definite history of exposure to organophosphate pesticides. We showed clear differences between the groups in terms of measured parameters, including muscle pain, and physical and mental status (5). Importantly, a high proportion of people in each group had measurable signs of muscle weakness in arms or legs (Figure), indicating that clinical signs can, in fact, be found in these patients if physicians take care to do a full physical examination. Future work will explore such important findings.

Figure 1. Muscle Power in the Legs

Figure 1. Muscle Power in the Legs

There have been other definitions, apart from the CDC-1994 (Fukuda) one (Table 1). The most recent attempt to revise the definition is based on clinical experiences with very large numbers of patients (6). It will, however, be some time before this new ‘Canadian’ description of ME/CFS replaces the CDC-1994 definition in clinical and research practice.

When comparing scientific studies, it is important to bear in mind that different definitions of ME/CFS may have been used, and this complicates interpretation and comparison of data. It can also be seen from Table 1 below that there have been several attempts in the past decade to define diagnostic criteria for the illness. Each definition has been problematic reflecting, in part, the special interest of the author, and taking little account of the extensive literature, prior to 1988 (Table 1), that made the case for myalgic encephalomyelitis as a distinct clinical entity based on reports of epidemic and endemic cases.

Table 1. Diagnostic criteria (adults) for ‘CFS’-like illness 1988–2003
Diagnostic criteria
‘Canadian’ Expert Consensus Clinical Case Definition for ME/CFS, 2003
US Centers for Disease Control and Prevention, 1994 (1) CFS
World Health Organization, 1994 (non-clinical)
‘Oxford Criteria’ UK, 1991 (7) CFS
Australia, 1990 (8) CFS
London, 1990 (9) ME
US Centers for Disease Control and Prevention, 1988 (10) CFS
Previous literature
Epidemic Neuromyasthenia, 1978 (11)
Myalgic Encephalomyelitis, 1959 (12)
Epidemic Neuromyasthenia, 1959 (13)

What was this condition ‘Myalgic Encephalomyelitis’ that existed before 1988, before it was subsumed within the CFS construct, and which is still referred to by patients in the lay literature as ME? Myalgic encephalomyelitis was first defined by Acheson (14). It had been found to occur in epidemic and sporadic forms, and was believed to result from a continuing or persisting viral infection. It has been defined as a systemic illness characterised by marked muscle fatigability (not just weakness); muscle pain, tenderness and swelling; variable involvement of the central nervous system (ataxia and cranial nerve involvement); muscle weakness and/or sensory changes due to neuronal damage; impairment of memory; sleep disorders, etc.; vascular involvement (orthostatic tachycardia, pallor); reticulo-endothelial dysfunction; and recurrences of flu-like symptoms with myalgia.

From 1934 to 1990, there were at least sixty-three outbreaks of epidemic proportions, all well documented, and distributed geographically in North America (29 outbreaks), the UK (16), the rest of Europe (11), Australasia (4), Africa (2) and Asia (1). One of the most studied, and possibly the most controversial, of these outbreaks occurred at the Royal Free Hospital, London, in 1955, during which 292 people were affected. Indeed, outbreaks may still be occurring, and some of the patients who currently come under the CDC-1994 CFS definition have clinical features similar to the classical description of post-infectious ME patients defined above.

The fact that we are still aware of these details is in no small measure due to Dr J Gordon Parish, who is attending this workshop today. Dr Parish has, over many years, collected reports of these outbreaks of ME (1516), and has a complete archive of the relevant literature.

Given the heterogeneous nature of the term CFS, and the different ways of defining it, it is probably no surprise that many of the biomedical studies conducted into the illness — a relatively small number given the scale of the problem — have had inconclusive results. Despite this, however, a range of abnormalities have been found by a number of different research groups, and these are summarised in Table 2 below.

Today’s workshop will concentrate on the vascular and biochemical aspects of ME/CFS, but ME Research UK intends to facilitate further workshops concentrating on other aspects of ME/CFS pathophysiology, such as muscle metabolism and function, and neuroimaging and brain function.

Table 2. Physiological and biochemical abnormalities found in groups of patients meeting the broad criteria for ‘CFS’
Biochemical
Oxidative stress (1718192021)
Dysregulation of anti-viral pathways, i.e., abnormal activity of the anti-viral immune responses (222324)
Vascular (relating to the circulation)
Endothelial dysregulation, i.e., abnormal responses of small blood vessels selectively to acetylcholine (252627)
Altered brain perfusion, i.e., areas of reduced blood flow in the brain (2829)
Orthostatic hypotension, i.e., physiological changes to blood pressure/cardiovascular mechanisms on standing (3031)
Brain
Metabolic abnormalities, e.g., alterations of brain choline (important in brain function) (323334)
Muscle
Altered metabolism, e.g., changes in muscle composition or use of fuel (3536)
Abnormal response to exercise (3738)
Enteroviral sequences in muscle, i.e., evidence of a persisting virus in some CFS patients (39)

References

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