Invest in ME

Invest In ME (IiME) introduced the meeting and, just before handing over to Dr Spence, invited Anne Savage to inform the meeting about Hepatitis-B vaccination problems and symptoms which are similar to ME. Dr Spence is a person with ME like many in the audience, and the agenda for the talk, that included a coffee break followed by a questions session. It was noted that there were paper and pens available for anyone to write questions, if they preferred, but Dr Spence was happy to take questions from the floor at the end of the talk.

At the beginning, Dr Spence acknowledged people who had helped organise the event and those who had been fundraising in Hampshire from 2005-6, including Invest In ME (IiME). As he said, without supporters doing sponsored parachute jumps, and sponsored runs and walks, and without IiME’s Cuppa for ME events, the work that he was about to discuss would never have been done. Everyone involved in fundraising was thanked. He considered it important to thank IiME for their support as a Corporate Friend of MERGE, in parallel to a number of similar organisations.

Dr Spence reminded the audience that he was not a medical practitioner but a clinical scientist who - before contracting ME - had been a Principal Clinical Scientist at the University of Dundee. He has had ME for 24 years and was forced to retire early on health grounds around 15 years ago. He was a very fit guy, playing squash in the premier league and golf with a “scratch handicap” but has never played since the day he fell ill. He is presently a Senior Research Fellow (honorary) in the University of Dundee, as well as Chairman of MERGE. The university has been very supportive of MERGE, with Dundee (a city about the same size as Southampton) having approximately 700 patients with ME. The contents of the talk were split into four sections:

MERGE was created with the help of senior bank executive Bob McRae, Roger Jefcoate CBE and the Countess of Mar, with the principal aim of energising research into this neglected illness. Its principal aim is to commission and fund high-quality scientific (biomedical) investigation into the causes, consequences and treatment of ME, but it also has a mission to "Energise ME Research" since - uniquely- raising the awareness of the illness and the need for biomedical research has to go hand in hand with researching it.

One important but under-recognised role of MERGE is to bring the possibility of researching ME/CFS to the attention of scientific researchers, no easy task for an illness that is so often wrongly referred to as “psychosocial”.
MERGE receive some - but not nearly enough - applications for research funding through the web-site, where short- and large-forms of application pro forma application forms are available, depending on the sums of money requested. Also, the charity has a database of historical archive research papers, that can be made available to researchers if requested.

It has come a long way since 2000 - it now has some 17 Group Friends, 15 Corporate Friends, and is undertaking a standing order campaign - but it has a long way to go to become like Action Research or Cancer Research UK! It is important to recognise that the ideals of MERGE and IiME are the same - “research” is the key message - and that the ME world desperately needs young, fresh and vibrant organisations with new ideas and approaches to come on the scene and shake things up. As Dr Spence said, the arrival of the 21st century is a great excuse for us all to move forward together.

It is important to recognise that it is difficult to get research done and that getting funding is not the only problem. In fact, there are four main problems.

a) Diagnosis

The first problem, and perhaps the principal problem, is that ME/CFS is not a “clean” diagnosis. Indeed, the terms Myalgic Encephalomyelitis (ME) and Chronic Fatigue The Core Problem is: We lack a “clean diagnosis” for M.E. Syndrome (CFS) mean different things to different people. None of the professionals in medical schools use the term “ME”, they use CFS since the 1994 definition of CFS - flawed though it is - has come to be the dominant catch-all definition. There are no teaching classes in medical schools on ME/CFS, in fact in the Medical School at the University of Dundee, Dr Spence gives two voluntary lectures each year to fourth-year medical students. This problem colours all debate on ME, but the essential point is that although the term 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 CFS has been adopted by medical journals and healthcare professionals. At present, the composite term ME/CFS is used, though in fact it represents the uneasy union of two strange bedfellows. In addition, we find ourselves in a situation where misuse of terminology by the mass media is common.

Chronic Fatigue is a symptom, not a disease, and most people suffer fatigue at some point. Perhaps 4% of the population have “chronic fatigue”. Now that represents about 2.5 million people in the UK. In the slide on the right the greatest portion of the circle represents the 'set' of patients with chronic fatigue (CF); Overlapping conditions and symptoms used for M.E. but you can see that the set of patients with CFS (i.e., those with '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). This ME slice might include “Sudden on-set”/”Viral ME on-set”/”Acute on-set” cases. 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 (i.e., experimental subject) in a particular diagnostic category.

Then there are conditions like Fibromyalgia (FMS), where in certain countries the overlap is complete with ME/CFS. For example in Sweden, what they call FMS, we call ME and vice versa, but usually a characteristic of FMS is the existence of painful “trigger-points” in very specific places. Pesticide exposure can cause a lot of ME-like symptoms, and again people with Borrellia (Lyme Disease) develop symptoms akin to the “rag-bag of non-specific symptoms that defines CFS. Overlapping diagnostic criteria for M.E. Then there are a far larger group of people with a number of psychological problems, somatoform disorders such as Atypical Depression, that can be in some definitions of CFS.

However, the question is, “Does it matter?” Well it does matter because in research we need all the healthy “controls” to be separable from the patients, as shown in the figure, right. So that when a patient comes in and a blood sample is taken, a clear distinction can be found between ME/CFS patients and healthy people of the same age and sex. However, the lower figure on the right illustrates real data, where the healthy people providing the control measurements are overlapped by a much greater spread of results from people with ME/CFS, which is what we actually see. Obviously, the average values for the two groups are distinctly different but what does it mean for the test? Well, it discriminates some patients quite well but there are a number that cannot be differentiated from the normal control spread. So, there is a dire need for more precise clinical assessment to reduce the possibility of overlap.

Professor Leonard Jason of Chicago University published in 2005 [1] an excellent review on the need for sub-grouping of the over-broad “diagnostic category” CFS which can catch widely different groups of patients in its net. As he said, “This review suggests that there is a need for greater diagnostic clarity and that this might be accomplished by subgroups that integrate multiple variables including genetic, neurological, psychological and biological domains.” This illness is very big, very complicated and we are not going to solve anything by pushing everyone in to one large group called CFS At present, what patients are left with is a “devalued” diagnosis consisting of (in one researcher’s words) a “...ragbag of common non-specific symptoms with many causes, mistakenly labelled as a syndrome”.

The medical community bears some of the responsibility for invalidating ME/CFS as a real condition”; and what Professor Anthony Komaroff (who was one of the people who set up the case definition) stated was:

“None of the participants in creating the 1988 CFS case definition and name ever expressed any concern that it might trivialize the illness. We were insensitive to that possibility, and we were wrong.”

Yet, patients and their carers are left with a diagnosis that is easy to trivialise - and this is profoundly wrong.

b) Funding

There are two main ways that biomedical research gets funded: government and charities, and in fact charities in the UK provide some 80% of all research funding. There has been very little funding of biomedical research from Sources of funding for research in the UK government agencies for ME/CFS, and while there are many general medical charities, such as the Wellcome Foundation, Action Research and the Nuffield Foundation, none (as far as Dr Spence is aware, has funded ME/CFS biomedical research which is not seen as a “high-enough priority”. We need to have a debate about the priorities for research. The MRC has £400M per annum, which although it sounds a lot includes funding for large expensive items like buildings and MRC Research Centres. In fact, one UK Cancer charity raises about £385M each year, the same size as the MRC budget. The ME world has to do the same if the illness is to be cracked. For example, when MERGE talks to someone planning to do some research, it struggles to find £20k, yet one researcher can cost £35k per annum, so you don’t buy much for £20k. There are two other ME/CFS charities funding research in the UK: the CFS Research Foundation which is presently doing sterling work funding Dr Jonathan Kerr in London for research into gene expression in peripheral blood mononuclear cells. This team has found an existing drug - an unnamed "immunomodulatory drug" which has already been tested - that may act on the metabolic pathways that seems to underpin the changes in gene use. The work also involves the development of a laboratory blood test, since it has discovered differences in blood proteins related to the changes in the use of genes. This is great stuff, and so heartening to all of us with ME ourselves. The other organisation funding research is the ME Association, which has recently supported Dr John Gow in Glasgow, looking at the differential gene expression in CFS patients, to whose work MERGE has also contributed.

c) The dominance of the “psychosocial” model of the illness

The psychological lobby has received an awful lot of funding from the government and other sources. They have had a very good marketing strategy because they have tapped into the charity sector to help to access central funding. The MRC have a special CFS award scheme on their web-page, and one can only hope that some of the resources will be used to fund biomedical researchers. Now psychological research has a role in human health, but it is not going to help patients with severe neurological ME. As an example, “Graded Exercise is affective at reducing the degree to which patients focus on their symptoms”, is a quote taken from a review recently published in The Lancet (28 January 2006), and hopefully some of the many criticisms of this review will be published in the printed issue of this journal soon. One recent paper (Deale et al 2001) using cognitive behavioural therapy for patients concluded that CBT though providing some benefits “is not a cure” - but such comments are unfortunately rarely highlighted by the psychosocial lobby.

d) High Quality Biomedical Research is Ignored

On the whole, biomedical research into ME/CFS is ignored by the medical publications, which is really annoying. In fact, a whole talk can be taken-up just explaining the brain research that has been conducted recently. In addition, there has been much research on muscle and immune cells. Christopher Snell in 2005 reported that the results of exercise capacity and immune function in male and female patients with CFS “implicate abnormal immune activity in the pathology of exercise intolerance in CFS and are consistent with a channelopathy involving oxidative stress and nitric oxide-related toxicity”. This could explain why people with ME/CFS can’t exercise, as there is a limit, beyond which you cannot train. If we look at the gene array we do find some abnormalities, but if patients with ME/CFS, exercise then we find a lot more abnormalities. Another useful study that has been virtually ignored was by Lange, reported in the journal Neuroimage in 2005; this showed that ME/CFS patients use significantly more areas of the brain to process auditory information, (using Modified Paced Auditory Serial Addition Test (mPASAT) testing techniques) than a healthy person. Dr Spence then showed pictures from Magnetic Resonance Imaging (MRI) brain scans compared for control patients and patients with ME/CFS that indicated areas of reduced blood flow - indeed, myalgic encephalomyelitis might be a good name for such “brain-muscle” anomalies.

Diagnosis really is a problem, since without sensitive and correct diagnostic criteria patients are consigned to the “CFS dustbin” when they might in fact have other illnesses. How many people in the audience had ever had full clinical assessments to exclude other conditions? Indeed, there was a small study in Dundee years ago in which 100 consecutive patients referred with a diagnosis of Post Viral Fatigue Syndrome (PVFS), which is yet another name for ME, were re-examined and found in about a third of the cases to have some other diagnosis, including Addison’s disease, poly myalgia rheumatica and depression.

It is now clear that muscles produce high levels of reactive oxygen species (ROS) generation via several pathways, and that therefore skeletal muscles produce high levels of free radicals after exercise, an increase that is maintained for some time thereafter. One of the most interesting scientific papers in ME/CFS for a long time was by Jammes in 2005, and it concluded that “The response of CFS patients to incremental exercise associates a lengthened and accentuated oxidative stress together with marked alterations of the muscle membrane excitability”. These experiments are now being repeated and extended by MERGE-funded researchers at Caledonian University in Glasgow.

There has also been interest in the cytokine IL6, which produces muscle fatigue after exercise. Arnold in 2002 showed that injecting IL6 in to CFS patients produced aches and fatigue, whereas this did not occur in the control patients within the first 6 hours after the injection. A group at Strathclyde University is interested in IL6 and its receptors and has been awarded a grant to compare responses over 24 hours of CFS patients and an equivalent control group, starting in 2006.

Dr Spence revealed that blood vessel endothelium was one of his particular interests, and he showed a number of Single Positron Emission Computer Tomography (SPECT) images of blood flow in the brain of normal patients (where blood flow to the brain is broadly symmetrical) and then compared them with ME/CFS patients (where there are many areas of high and low flow, often not symmetrical. The regions of irregular blood flow extend to multiple vascular territories, and these phenomena were first reported in 1994 in a paper by Schwarz et al who concluded that “the findings in CFS are consistent with the hypothesis that CFS, like ADC, results from viral infections of neurons, glia, or vasculature ”. The blood flow to the brain is highly regulated, unlike in a muscle, so differences can be highly significant, and so MERGE is keen to fund some research in this area.

The next area of interest is that people feel ill when they are upright, which is known as Orthostatic Intolerance. Dr Peter Rowe and others around 1994 found that ME/CFS patients had significant cardiovascular responses to standing upright, manifested by changes in vascular volume/heart rate/blood pressure. Some researchers have suggested that the cardiovascular changes to upright tilt were simply cardiovascular deconditioning, but nothing could be further from the truth.

In an article entitled “Standing Up For ME” in The Biologist in 2004, Professor Julian Stewart, and Dr Spence outlined some of the “physical” arguments surrounding this aspect of the illness. The first thing to recognise is that the blood pressure in most ME/CFS patients is maintained by a significant increase in heart rate, at least in the early stages of upright posture.
Professor Stewart of New York has published some interesting data on what happens to ME/CFS patients when they are upright, and it shows that there is a group of patients whose leg blood is low when lying down and it increases when upright, a wholly abnormal response and indicative of a shift of vascular volume towards the legs. Images of the leg of an 18 year old woman suffering from ME were shown when in the supine and upright position to illustrate the increased blood flow (redness of colour). This whole area of orthostasis is extremely complex and little understood. Might there be a problem with peripheral blood vessels in ME/CFS patients?

Well, since 2000, the group at the University of Dundee has been looking at how skin blood vessels respond to the endothelium-dependent vasodilator, acetylcholine. To do this we use a novel instrument, a laser Doppler scanner which images blood flow in the skin. In ME/CFS patients, blood vessels are sensitive to acetylcholine driven through the skin; i.e. the skin blood vessels dilate more than expected, a novel if not unique finding (i.e., most diseases show the opposite response to acetylcholine, which is a blunted or decreased blood flow). A review of this work has been published (Spence et al. Prostaglandins, Leukotrienes and Essential Fatty Acids 2004), and MERGE has continued to fund research on this aspect of ME/CFS given its importance to understanding some of the unusual vascular phenomena which characterise the illness, and this work - including on role of nitric oxide, prostacyclin and endothelium-derived hyperpolarising factor in promoting acetylcholine sensitivity - is continuing.

As previously mentioned, there have also been significant developments in gene expression in ME/CFS patients which have occurred recently, from Dr Jonathon Kerr in London and Dr John Gow in Glasgow to Prof Susan Vernon in Atlanta, USA. They are working on similar approaches, and their findings seem to confirm the findings mentioned above, particularly the isoprostane and apoptosis results. We were delighted to be able to contribute towards Dr Gow’s research for a project on the characterisation of differential gene expression in ME/CFS patients, in conjunction with the ME Association. As you know, Dr Gow is uncovering several things, including increased cell membrane prostaglandin-endoperoxidase synthase activity with downstream changes in O₂ transport; increased macrophage activation; and cellular apoptotic pathway activation.

What had spurred her and Kathleen McCall to form IiME during the summer of 2005 was that she read about a young man called Casey Fero, who was 23 years old when he died in July 2005. He had been diagnosed with ME at the age of 9 years. Invest in ME are in contact with Pat Fero, who lives in Wisconsin in the USA, and they have agreed to work together to bring everyone together to address this world-wide problem. In the UK there are five times more people with ME than with HIV/AIDS, for which the government provided ring‑fenced money for research but they have provided nothing for ME biomedical research. So it is up to people like us to make that connection.

For the first time in many years, there is optimism about the potential for biomedical advances in ME research. A range of groups are beginning to report physiological abnormalities in many patients with ME/CFS, showing what can be achieved if scientific effort and funding are targeted towards biomedical research, leading to therapeutic intervention and treatment. However, Dr Spence stressed that his purpose here is not to answer questions, but to show that biomedical investigation 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. He and his colleagues are currently formulating new hypotheses and designing new experiments in order to unravel the significance of acetylcholine sensitivity, increased oxidative stress, increased early death of neutophils etc, in the ME/CFS patients. Experience has convinced them, however, that funding will be difficult to maintain, and that the funding strategy for ME must mirror that of cancer research which obtains 85-90% of its revenue from private sources and ground-level fundraising. It is a huge task, but he hopes achievable for all our sakes.

Invest in ME thanked Dr Spence for the fantastic talk and noted that Dr Spence mentioned a few things that are crucial: that ME is a hidden national and world-wide scandal; that to make a difference takes people,” like us who cannot not do anything anymore.”

People were invited to join IiME and to encourage doctors to attend the ME Conference on 12 May 2006, where a lot of the researchers that have been mentioned will be speaking, and Dr Jonathan Kerr says that he will be giving exciting news of developments.

Invest in ME also asked the audience to,” Please write to your MPs demanding that you get the same sort of treatment that other people deserve and expect for their illnesses; ME is very serious and people are dying of this illness.”

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