ME Research UK — Energising ME Research

New Horizons 2008: International Conference on ME/CFS Biomedical Research

The speakers
New Horizons

Hosted and organised by ME Research UK, and co-sponsored by the Irish ME Trust, the New Horizons 2008: International Conference on ME/CFS Biomedical Research took place on 6th May 2008 at the Wellcome Trust Conference Centre on the Genome Campus at Hinxton near Cambridge, UK, an outstanding custom-designed venue designed to attract the world’s leading scientists to debate issues at the forefront of new scientific discovery.

Building on the success of last year’s conference at Heriot-Watt University, Edinburgh (read the report here), the day brought together researchers from around the world, healthcare professionals, representatives from local support groups, and delegates from ME/CFS charities. The full day’s programme consisted of invited keynote lectures from scientists from Scotland, England, USA, Canada, Belgium, Sweden and Australia.

IMET

The media coverage of the conference was far greater than in previous years — thanks to Bob Ward and Sarah Emberson who volunteered their professional PR services to “energise media awareness” — and media coverage included the following:

Order your copy of the 4-DVD set (morning and afternoon) of the presentations by contacting our headquarters; the cost is £5 (including P&P within the UK) for the four-DVD set. You can pay by cheque (made payable to “ME Research UK”), and orders can also be taken by credit/dedit card over the phone. (You can also send a set as a gift direct to your GP, consultant or other healthcare professional.

Morning session

Roger Jefcoate
Roger Jefcoate CBE

Delegates were welcomed by Sue Waddle who was chairing the conference with Prof. Nancy Klimas and Bob McRae. The conference proper was opened formally by Roger Jefcoate CBE, co-founder of ME Research UK with Dr Vance Spence and Bob McRae, and a Patron of the charity. Roger explained that he felt greatly privileged to be welcoming delegates to such a prestigious event, and went on to describe how he came to be involved in ME and in funding research into the illness. For all of his working life, he has actively promoted technology for disabled people, including developing the world’s first remote control system for severely disabled people at the National Spinal Injuries Centre, Stoke Mandeville Hospital, a system that is still freely available through the National Health Service, with thousands of happy users and carers nationwide. In 1983, he started a trust to fund adapted computers for severely disabled people, some of whom were housebound or even bedbound with ME; and in 1998 he was asked by Dr Vance Spence to fund a vital laser Doppler scanner for the ongoing biomedical research at Dundee University with Professor Jill Belch and Dr Faisel Khan. At nearly £30,000, this donation for the laser Doppler scanner remains the largest ever donation his charity has given. He continued:

As you all well know, people with ME suffer grievously, often with little support or understanding, sometimes isolated and ignored by the very institutions that should be helping — such as the National Health Service and the Benefits Agency. Indeed, it is a matter of continuing astonishment to me that for so severe an illness, biomedical research is so underfunded, including by agencies such as the Medical Research Council which should be the first port of call. ME Research UK has become a beacon of hope for many patients, some of whom — I know from personal experience — have lived for many years in this sea of darkness and despair. It is heartening to see, therefore, the range of experts who have volunteered to come and share with us their efforts to explore the biomedical basis of the illness. A report to the Chief Medical Officer of England in 2002 said that a programme of research on all aspects of ME/CFS was urgently needed, and that improvement of health and social care was an urgent challenge. We hope that this conference will concentrate minds on scientific aspects of this illness.

Nancy Klimas and Sue Waddle
Nancy Klimas and Sue Waddle

The first keynote lecture was by Prof. Nancy Klimas (pictured left, with Sue Waddle) of the University of Miami School of Medicine and the Miami VA Medical Center, who directs the UM/VAMC Gulf War and Chronic Fatigue Syndrome Research Center, which focuses on better understanding of the neuro-immune-endocrine interactions in both these complex disorders. Her presentation was entitled “Clinical Aspects of ME/CFS”, and her key initial emphasis was on the need to move beyond “case definitional” issues of ME and CFS towards assessing patients (sub-grouping) on the basis of clinical tests and symptom clusters as outlined in the Canadian Consensus Definition of 2003, of which she was a co-author. In her view, the post-exertional nature of symptoms are key, but it is also important to identify sleep anomalies, pain and autonomic dysfunctions which can be prevalent.

After reviewing the epidemiology — suggesting that there could be one million people with CFS in the USA — she described a model for the development of the illness. The model postulates a genetic predisposition (supported by past work on HLA DR haplotypes), which encounters a triggering event or infection, leading to the production of immune, endocrine or neuroendocrine mediators, resulting in a poor health outcome and persistence of illness. As she explained, chronic immune activation has long been thought to be a component of CFS, and T-lymphocytes appear to be chronically activated. Indeed, CD8 cells in patients typically demonstrate an increase in activation markers (CD38, HLA-DR) and a reduction in CD8 suppressor cells. Also, there is evidence that the homeostasis between the cell-mediated or T helper (Th1) immune response and the humoral (Th2) immune response is disrupted in CFS, as well as evidence of increased pro-inflammatory cytokine expression (TNF-a, IL1, IL6).

Prof. Klimas reviewed the evidence for viral persistence and reactivation (e.g., enterovirus, HHV6 and EBV), and then discussed the evidence for endocrine dysfunction, such as reduced cortisol output via several mechanisms (though many possible confounding factors such as deconditioning, sleep, and medication make final conclusions difficult). As regards autonomic dysfunction in ME/CFS, this has been measured as neurally mediated hypotension, orthostatic hypotension, parasympathetic dysfunction, sympathetic overactivation — and she indicated that Dr Julia Newton’s presentation later in the day would go into these aspects in greater depth.

The way forward

Gene expression microarray data has become a highly productive tool for better understanding CFS research, and Prof. Klimas described recent studies, including the differential expression of 35 genes for T-cell activation, neuronal and mitochondrial regulatory abnormalities. Again, pre–post exercise challenge gene studies have indicated differences in genes that regulate ion transport and intracellular cell functions, and it may be that evaluation of gene expression profiles will allow for pathophysiologic subgrouping of patients. Advances in the field should result in targeted therapies to impact immune function, HPA axis regulation and persistent viral reactivation in CFS patients.

The next keynote lecture was given by Dr Jo Nijs, an academic physiotherapist with special interest in chronic pain and ME/CFS who works at the Vrije Universiteit Brussel, Belgium, and the University College of Antwerp where he is Head of the Division of Musculoskeletal Physiotherapy.

Dr Nijs gave an overview of his recent paper on “Intracellular immune dysfunction in ME/CFS: state-of-the-art and therapeutic implications” (published in Expert Opin Ther Targets 2008; 12:281–289), in which he examined the accumulating evidence in support of intracellular immune dysfunction in the illness. From an in-depth review of the scientific literature, he and his colleagues concluded that proteolytic cleavage of the native RNase L enzyme is characteristic of dysregulation of intracellular immunity in people with ME/CFS, although the origin of the dysregulation is unexplained at present. There is increasing evidence for upregulation of various aspects of the 2-5A synthetase/RNase L pathway and for immune cell apoptosis in ME/CFS. The dysregulation and upregulation of the 2-5A synthetase/RNase L pathway in ME/CFS are not just epiphenomena: evidence in support of their clinical importance has been provided. Conflicting data of the functioning of the PKR enzyme in blood cells of ME/CFS patients have been reported, possibly reflecting various stages of the illness or distinct subgroups. Intracellular immune impairments are related to poor exercise performance, but future research should reveal the exact nature of this association.

Jo Nijs
Jo Nijs

Dr Nijs explained that it seems plausible that decreased natural killer cell function, the presence of infections and intracellular immune dysfunctions are interrelated parts of the ME/CFS pathophysiology, but these potential interactions still need to be unravelled. More insight into the exact nature of these interactions is likely to come from well-designed drug treatment studies. Particularly needed are studies examining the effects of drug treatment in conjunction with exercise interventions. Since post-exertional malaise is one of the major problems with exercise therapy in ME/CFS, drugs might be able to diminish the side effects of exercise interventions, possibly leading to improved compliance and effectiveness.

In the final presentation of the first session, Dr Gregor Purdie, a general practitioner and GP Adviser to NHS Dumfries and Galloway, described service development and patient pathways from the perspective of the practising clinician. Dr Purdie has been actively involved in moves towards setting up a Scottish Clinical Network on ME/CFS, the outcome being “responsive, empathetic, patient-centred care of high quality delivered by clinicians who have kept abreast of the latest research, with seamless working between primary, secondary and tertiary care”. As regards achieving such a network, he stressed that we need to ask ourselves who is to do this, when and how. At present in the pyramid of care most of the burden is taken up up by ME/CFS and other voluntary organisations at the base, but ideally it would be dispersed throughout the pyramid in a multidisciplinary approach involving consultants, primary care and healthcare support staff, with Centres of Excellence as a key aspect of the overall mix.

In the following session, Dr Byron Hyde (pictured), from Nightingale Research Foundation, Ottawa, Canada, outlined some of his conclusions from his years seeing ME and CFS patients. He explained that unlike physicians in other countries, he operates inside the Canadian healthcare system within which he can order any blood, urine or tissue test free of charge for any Canadian citizen, including MRI and SPECT imaging.

Byron Hyde
Byron Hyde

His talk began by outlining myalgic encephalomyelitis which he described not as a syndrome but a disease process causing a diffuse measurable pathophysiological injury of the brain (CNS). He showed SPECT scans from his practice, and observed that they showed evidence of brain injuries. As regards the question of the triggers or causes of ME, he discussed epidemics, particularly the 1984–1992 Ontario ME epidemic period during which enterovirus seemed to have an important role, concluding that it would be scientifically inexcusable not to consider that the enterovirus group was responsible for the diffuse brain damage noted in acute onset ME patients. As regards ME patients across the board, Dr Hyde’s view is that the cause of the illness could be anything (virus, immunisation, physical trauma) that can cause a chronic diffuse injury of the CNS, hence the need for brain SPECT and brain PET imaging in evaluation.

He highlighted sleep dysfunction as a prominent part of the illness. Indeed, when his Nightingale clinic in Ottawa studied 53 consecutive patients, only one had normal sleep; most patients had insufficient sleep or were blocked in stage 1 and 2 non-restorative sleep, 31 had no stage 3 sleep, and 43 had insufficient or no stage 4 sleep. In a significant minority of these patients, mean oxygen saturation fell to low levels during the night. A copy of Dr Hyde’s presentation to the conference can be found at the Nightingale Clinic website.

Dr Derek Enlander (Mount Sinai Medical School, New York; and New York ME/CFS Center, New York, USA) gave the next presentation which described his treatment of ME/CFS patients with a complex intramuscular injection, oral l-cystine, glutathione, methylcobalalmin, follinic acid and electrolytes. Based on treatment of approximately 800 patients over 15 years, he explained that he has developed a protocol which has helped 65% of patients, based on SF36 and other test criteria. Although the protocol originally started with weekly intramuscular kutapressin, results indicated that only approx 30% of patients were helped, so Dr Enlander has persisted over the past decade to better these results, adding (in stages) intramuscular magnesium sulphate, calphosan, methylcobalamin, folic acid, glutathione, trace zinc and molybdenum. This protocol seemed to be in line with a theory of a methylation cycle defect in ME/CFS. Although glutathione is poorly absorbed, Dr Enlander surmised that if glutathione was given by intramuscular and oral routes, a certain percentage will enter the circulation, so the protocol was extended to include daily oral capsules of glutathione and l-cystine, and daily oral capsules containing a range of vitamins. The addition of a potassium, sodium, magnesium and calcium combination seems to help muscle weakness and pain.

The role of the ME/CFS Clinic in the UK as regards clinical assessment and service delivery was described in a presentation by Dr Gavin Spickett (Consultant Clinical Immunologist, Royal Victoria Infirmary, Newcastle upon Tyne). There are now 13 Clinical Network Co-ordinating Centres (CNCC in the UK — see the CFS/ME Service Investment Programme 2004–2006 Programme Report — and Dr Spickett is Clinical Champion for Northern ME/CFS CNCC in Newcastle.

His presentation discussed the care pathways adopted in clinical practice in the North of England — recently described in the Nice Guideline 2007 — including the key role of medical assessment which aims to undertake a detailed clinical evaluation (after GPs have already performed routine tests, including pre-screening bloods) to identify alternative diagnoses that may present with fatigue to ensure that patients receive appropriate treatment for these. Evidence from studies in the clinics has shown that experienced clinicians are able to make alternative diagnoses in a significant percentage of patients referred from primary care with suspected ME/CFS, and that education programmes directed at primary care, as well as strict referral guidelines, do not seem to have reduced the prevalence of alternative diagnoses. For example, an audit of the Newcastle clinic in 1998 showed that 17% of patients referred could be given alternative diagnoses, and a recent re-audit in 2007 showed that in the first three years of the new service ME/CFS was confirmed in only 56% of referrals, with the remainder consisting of alternative diagnoses (28%), sleep apnoea (9%), and depression and anxiety (7%). He explained that with the advent of the NICE Guideline 2007 and its encouragement of earlier diagnosis, the proportion of alternative diagnoses might be expected to rise.

Gavin Spickett and Malcolm Hooper
Gavin Spickett and Malcolm Hooper

Dr Spickett (pictured left, with Prof. Malcolm Hooper) emphasised that it is essential both for the subsequent therapeutic intervention and for the development of research cohorts that, in the absence of specific confirmatory tests, a clear diagnosis, according to International Criteria can be made for each patient. For those with a diagnosis of ME/CFS, the NICE-based management approaches consist of interventions based around models used for the chronic pain team (biopsychosocial model) including activity-based approaches (pacing, graded exercise, sleep hygiene), lifestyle management, CBT, and physio and occupational therapy. An important aspect of the work of the clinical service is the provision of help with benefits, and the provision of letters to the Department of Work and Pensions to support the maintenance of benefits for patients attending the clinic.

Dr Spickett presented preliminary data on outcomes of the management approach above for a small number of patients (n=7 or 8) using the Minimum Dataset; these showed mixed results on the Chalder fatigue score (42%/42%/14% improved/unchanged/worsened, respectively), pain score (28%/28%/28%, respectively), and SF36 quality of life score (0/28%/57%). As he explained, the numbers available for analysis are very small as yet, but in the future there will be a need to identify those patients not benefiting from the interventions on offer, who might need to be offered a different therapeutic approach.

The morning session was brought to a close by Prof. Julia Newton (Senior Lecturer, Institute of Cellular Medicine, Newcastle University) who spoke of her work on the autonomic nervous system and its dysfunction in ME/CFS. Prof. Newton explained how the autonomic nervous system is responsible for subconscious activities that occur in the human body, such as respiration, bladder and bowel function. It is also integral to the maintenance of cardiovascular functions such as maintenance of heart rate and blood pressure. Autonomic dysfunction and particularly low blood pressure (hypotension) are a frequent finding in people with the symptom of ‘fatigue’ generally, and her programme of research is directed towards understanding the role of autonomic dysfunction and developing interventions that target autonomic nervous system abnormalities.

Julia Newton and Bob McRae
Julia Newton and Bob McRae

She explained to a rapt audience that her research group has recently shown that 89% of those with ME/CFS experience symptoms on standing (orthostatic intolerance) and autonomic nervous system symptoms are frequently present in those with ME/CFS, the degree of which correlates with fatigue severity and is comparable to the symptom burden seen in a range of fatigue-associated chronic diseases (click here for a more exhaustive discussion of this work). Again, her studies examining haemodynamic responses to standing have shown that 27% (n=63) of ME/CFS patients have Positional Orthostatic Tachycardia Syndrome, and that cardiovascular parameters correlate with increasing fatigue. Recent preliminary results from a series of MRI scans in her unit have shown impaired proton removal from muscle during exercise in 16 patients with ME/CFS compared with matched controls, leading to the hypothesis that fatigue arises due to impaired pH run off from muscle during exercise, which is influenced either entirely or at least in part by the degree of autonomic dysfunction. As Julia explained in questions chaired by Bob McRae (pictured), research is now focusing on techniques to help patients with their autonomic symptoms, and one of these — orthostatic (tilt) training — is to be further assessed for ME/CFS patients; it might be that a (self-managed) tilt training program could be helpful symptomatically. Prof. Newton has recently received a large grant from ME Research UK to continue her important investigations on ME/CFS patients from the Newcastle clinic over the next two years.