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A presentation by ME Research UK Chairman Dr Vance Spence to the Group on Scientific Research into Myalgic Encephalomyelitis (Gibson Parliamentary Inquiry), on 7th June 2006 at Portcullis House, Westminster, UK.
There are a great many sick people out there — and some have had ME for many years, myself included. Yet, they have not lost their spirit, and the fact that this Group has been established is a testament not only to scale of the problem but to their feistiness and persistence in the face of great adversity.
The slide shows the terms of reference for the group — including an assessment of “
the progress of scientific research on ME since the publication of the Chief Medical Officer’s Working Group Report into CFS/ME in 2002” — and I propose to address this specific remit in three sections, as well as I can in the time available:
- Progress since Chief Medical Officer’s report
- Scientific publications
- Specific Reasons for lack of progress
- Case definition
- Influence of the biopsychosocial model
- Biomedical research findings undervalued and unsupported by funding
- How can we move forward?
Progress since CMO report
Looking at progress in scientific research since January 2002, we can see that it has been patchy and relatively small-scale. The MEDLINE database lists 783 Chronic Fatigue Syndrome publications from anywhere in the world during the past 52 months, and of these 55 are clinical trials, only 6 of which were from the UK. Looking at vaguely-defined experimental studies, only 57 were from the UK in this time: most of these came from the London Medical Schools in which the biopsychosocial model predominates, while 10 discrete studies emanated from 2 privately-funded research groups and another 6 were one-off studies at various locations.
This pattern hardly constitutes an engine room for biomedical investigation of the illness, and compares unfavourably with other illnesses (e.g., in the 52 months there have been 6231 publications on multiple sclerosis and 48,110 on diabetes). So, my claim is that overall ME/CFS research in the UK (and worldwide) is very small scale, that there are comparatively few biomedical studies, and that while hypotheses abound there is often little data to support them. Any objective observer would conclude that the Chief Medical Officer’s report of 2002 has had a minimal effect on the drive to uncover the causes of ME/CFS.
Specific Reasons for lack of Progress
There are many reasons for the lack of progress, but given the time constraint I propose to mention briefly three central issues: problems with case definition, the influence of the biopsychosocial model overlaid on the illness, and the lack of attention (both in professional and funding terms) given to biomedical research findings.
Case definition issues
ME and CFS and ME/CFS mean different things to different people. As I say over and over again, this problem colours all debate on ME, yet rather like the whiteness of a wall it is often not recognised as a colour at all. Much of the background has been described in written submissions to the committee and in previous presentations, but the essential point is that although the term myalgic encephalomyelitis (ME) — involving an infectious onset, specific neuromuscular symptoms and signs, and a unique post-exercise component — has a scientific history involving epidemic and sporadic forms, ME today has come to be seen as a lay term used by patient organisations and patients themselves, while chronic fatigue syndrome (CFS) has been adopted by medical journals and healthcare professionals, and there are even several CFS case-definitions which select for different patient groups! At present, the composite term ME/CFS is used, though the conjunction of the two terms is still problematic.
This next slide is an attempt to describe the problem graphically — though we must be aware that this is only schematic, a way of visualising the problem which may be more or less complex in reality.
While the greatest portion of the circle represents the set of patients with chronic fatigue (CF) — which might represent between 1 and 4% of the population — you can see that the set of patients with CFS (i.e., those with 6 months’ fatigue plus 4 symptoms) is much smaller (estimated to be 0.2 to 0.4% of the population in the CMO report of 2002), while those with ME as described in the older scientific literature might represent a subset of CFS itself, since post-exercise fatigue is a key element in their illness (population estimates are unavailable for this subset since healthcare professionals no longer diagnose ME per se). The important point is that the each slice melds into the next, and that, in the absence of a full clinical assessment, the popular press, healthcare professionals and medical researchers may easily be deceived about the placing of a particular patient in a particular diagnostic category. For researchers the problem is particularly acute since what confidence can they have in the diagnostic discreteness of their patients when the diagnostic construct CFS is so broad?
The diagnostic mess that is ME/CFS is illustrated by our own research in 2004 which found that distinct differences could be found between three groups of patients all of whom fulfilled criteria for the 1994 CDC Fukuda definition of CFS. As this paper (Kennedy et al, 2004) says, “
The specificity of the CFS case definition should be improved to define more homogeneous groups of patients for the purposes of treatment and research.” This view was echoed by Prof. Leonard Jason who published in 2004 an excellent review on the need for subgrouping of the over-broad diagnostic category CFS.
Influence of the biopsychosocial model of ME/CFS
The Chief Medical Officer’s report of 2002 defined the biopsychosocial model as a “
…model of pathophysiology, applicable to all disease, suggests that once an illness has started its expression is affected by beliefs, coping styles, and behaviours, while consequential physiological and psychological effects act in some ways to maintain and/or modify the disease process”. The operative words in that definition are “applicable to all disease”, for its non-specific therapeutic techniques, such as cognitive behavioural therapy (CBT), are indeed used in many illnesses for symptom management. But in most illnesses psychosocial techniques are adjuncts to contemporaneous biomedical research, whereas in ME/CFS the biopsychosocial model seems to have developed a life of its own, hoovering up attention and funding, apparently at the expense of biomedical investigation. It is for this reason that we said in a letter to the Lancet in May 2006:
The central point… is that, for patients with chronic fatigue syndrome (and there are some 20,000 members of support groups in the UK alone), the biopsychosocial model offers relatively little, yet it dominates the canvas in terms of research funding and exposure in professional journals instead of being a small part of the overall clinical and scientific picture. (Abbot NC, Spence VA. Lancet 2006; 367:1574)
The evidential basis of the CBT model for ME/CFS, shown in the slide above, consists of 8 discrete randomised controlled trials, 3 negative for the intervention and 5 positive. While there are arguments for and against each of these trials, I think we can agree that this constitutes a far-from-impressive evidence base, particularly when set beside other evidence bases and beside patients’ reports and surveys.
What I want to stress is that the biopsychosocial model — which even its supporters admit is not a cure — is very influential. It colours the perception of the illness across the board — from official reports, such as the Chief Medical Officer’s report mentioned above, to government agencies such as the Department of Work and Pensions which is producing its new electronic guidelines at present, to research funding bodies such as the Medical Research Council. Indeed, the Medical Research Council has recently provided substantial funding for two biopsychosocial investigations — the FINE Trial (designed to increase activity and challenge dysfunctional illness beliefs), and the PACE (Pacing, Activity and Cognitive behaviour therapy) trial — yet, as far as we know, has rejected most if not all applications for funding for biomedical investigation.
I end this section with a quote from an editorial in the British Medical Journal in 2002, and highlight the crucial phrase: “
there is a consensus among patients that if resources were allocated towards rigorous material empirical biochemical research it would be… preferable in their eyes to promulgating an… incomplete paradigm as though it were a cure”.
Biomedical research findings undervalued and unsupported by funding
The third reason for lack of progress is that biomedical research findings into ME/CFS get ignored and undervalued. Yet they exist, and there is substantial evidence that, despite the apparent heterogeneity of the patient group, biomedical researchers can uncover a range of interesting anomalies. I have time here to discuss only a few key areas.
A) BLOOD FLOW TO THE BRAIN
A singular paper that has greatly interested me over the years came in 1994, reporting the remarkable finding of reduced blood flow in the brain. The authors concluded that brainstem perfusion of 43 ME/CFS patients was significantly lower than controls (p<0.0001) and patients with major depression (p<0.005). Isn’t it important that this work be reproduced and extended?
B) ORTHOSTATIC INTOLERANCE
In an article entitled ‘Standing Up For ME’ in The Biologist in 2004, Professor Julian Stewart and I outlined some of the physical arguments surrounding orthostatic intolerance in the illness. This whole area of orthostasis is extremely complex and little understood. Might there be a problem with peripheral blood vessels in ME/CFS patients? Shouldn’t we find out?
The ME Research UK-funded unit at University of Dundee has found a pattern of significantly increased oxidative stress in ME/CFS patients that are related to symptoms, and these findings have now been supported by at least four other research groups worldwide who have also shown excessive free radicals in blood, urine and muscle tissues of ME/CFS patients. Isn’t it important to discover the source(s) of these molecules, whether from excessive immune activity, chronic infections or abnormalities within muscle tissue?
There is also evidence that patients have detectable abnormalities in neutrophils (the most abundant of white blood cells) — specifically a larger proportion of dying (apoptotic) cells than in healthy subjects — consistent with an activated inflammatory process which is possibly the consequence of a past or present infection. Might some people with CFS have a chronic inflammatory disorder, albeit an unusual one?
E) GENE STUDIES
Recent developments in gene research in ME/CFS have suggested dysregulation of genes involved in immune pathways, supporting the many reports in the literature of immune dysregulation in the pathogenesis of ME/CFS. This research in the UK has been supported by smaller ME/CFS charities and private individuals, but why not by central agencies such as the Medical Research Council with class 1 funding?
Furthermore, fascinating one-off results covering many of the prominent symptoms of ME/CFS continue to be published by research groups worldwide: these include reduction of brain serotonin transporters in relation to pain (Yamamoto et al, 2003), delayed gastric emptying (Burnett et al, 2004), and altered muscle excitability in response to exercise (Jammes et al, 2005). One particular recent one-off finding I’d like to highlight concerns the finding of increased vascular stiffness in ME/CFS patients from my own Unit at the University of Dundee, which fits in with our provisional hypothesis that at least some ME/CFS patients might have increased cardiovascular risk.
My purpose here is not to answer the questions above, but to show that biomedical investigations can uncover, within a proportion of ME/CFS patients, biological anomalies that might well help to explain many of the clinical features associated with the illness, and might also indicate areas for therapeutic treatment. The key point that I want to make to the committee is that breakthroughs in biomedical research generally follow funding (since without it there is no possibility of starting the exploration!). Yes, many investigations to date have been low-level, and in none of these areas are the findings conclusive as yet. But some (or all) of these areas might well lead to a breakthrough in understanding and treating the illness, and without support for biomedical research we will never find out.
Since it is left to the smaller charities to progress the agenda, we do what we can as shown in the slides listing ME Research UK’s current funded projects. But much more could and should be done. And the first step is for the larger funding agencies including the Medical Research Council to cease being hypnotised by non-curative incomplete paradigms and to begin prioritising basic biomedical research.
The Way Forward
In conclusion, we wish to make the following points:
- Doing nothing is not an option
- Thousands of people remain chronically unwell since the CMO report
- The perception that biopsychosocial models are the answer to ME/CFS should be challenged
- The Biomedical Research Agenda should be expedited by ring-fencing central funds for basic biomedical research, and by inviting ‘new blood’ researchers into the field
- Recent gene work is a good example of what can be done if resources can be found to get to the root of the problem