From edmesh newsletter 78, Autumn 2011

Introduction

edmesh extended another warm welcome to Dr Vance Spence, (Chairman) and Dr Neil Abbot (Operations Director), from the Perth based charity, ME Research UK (MERUK). Their return to the Lammermuir Hall, St Cuthbert’s Church, Edinburgh on 15th October 2011, was much anticipated. After a few words, Dr. Spence  addressed the meeting of around 70 people.

He began his talk with a brief outline of how the charity evolved, its aims, the challenges they face and the key problems in ME research today. He explained that MERUK’s mission is to “Energise ME Research” by funding high calibre research into the causes of ME, which will lead to effective treatment and ultimately, discovery of a cure.

The charity, which relies totally on donations, also wants to raise awareness of the need for world class research, so that the information gained from these studies can be circulated not just to other scientists but to other health professionals giving them a better understanding of this illness. MERUK also acts in an advisory role to Government agencies and public bodies both in Scotland and the UK.

Any research is expensive by its nature and there is little funding for biomedical research. It costs around £300,000 to run a medium sized clinical trial. MERUK’s intention is to support new biomedical or clinical studies in established research institutions. This fundamental research lays the groundwork for bigger trials or studies. Once a study is finished the research group aims to submit their findings for “peer review” by a group of scientists or doctors (who do not have an ME background) and get their work published in a journal with the highest possible “impact factor”. If accepted by a high ranking journal such as British Medical Journal or Lancet, more people will read about the work and it’s this that drives forward the understanding of ME. It would be hoped that this might stimulate more academic interest than there has been up till now. The mainstream media are poor at reporting on ME related topics. As there is a lack of information, public perception of the illness is poor.

Confusion

There is still NO agreement on nomenclature. Is it ME, CFS, ME-CFS or CFS-ME.? There is NO specific diagnostic test for ME and NO agreement on which set of criteria should be used for diagnosis. Myalgic encephalomyelitis (ME) is NOT a diagnosis recognised by doctors or scientists neither is it taught in medical schools. Most doctors use the term Chronic Fatigue Syndrome (CFS) as they see fatigue as the main symptom.

The most widely used set of diagnostic criteria used is the US Centre for Disease Control (CDC) -1994 (Fukuda). The principal diagnostic symptom being fatigue along with 4 out 8 other symptoms. Dr Melvin Ramsay was one of the first to describe the symptoms of ME after the Royal Free Hospital outbreak in 1955 and these were reported around the same time in The Lancet by Dr Acheson: muscle fatigue after exercise, neurological disturbance, cardiac problems, variability of symptoms and chronicity. ME has been shown to occur in sporadic and epidemic forms. Between 1934 and 1990, there have been roughly 63 documented epidemics, 16 in the UK.

There is still a wide spread misdiagnosis of ME. In 2008-09, 260 patients diagnosed by a GP, were referred to The Newcastle NHS Chronic Fatigue Syndrome Service, a unit that specialises in fatigue-related illnesses. It found that 40% of these referrals had been given the wrong diagnosis: 47% had other chronic disease, 20% sleep disorder, 15% psychological disorder, 13 % idiopathic fatigue, 4% cardiovascular, 1% other. As Vance pointed out, fatigue is a part of every illness. Most illnesses with fatigue as a symptom can be medically explained, and in fact 2 – 4% of the population can be classed as having Medically Unexplained Fatigue. This doesn’t equate to having ME. There is a clear need for a specialised ME centre to be set up which would allow for proper diagnosis and treatment. Establishing such a centre would allow researchers access to a valuable and well-defined resource.

Once the researchers have established that their study patients have ME it’s then possible to divide them into subgroups depending on their symptoms. This classification on the basis of symptoms is called “phenotyping”. Such classification of patient types, particularly in ME, is being undertaken in Newcastle with some success. Vance continued his talk by giving a roundup of some research projects that MERUK have funded.

On Going ME Research; Muscle, Brain and Autonomic Nervous System (ANS)

HEART

“Impaired Cardiac Function in CFS Measured Using Magnetic Resonance Cardiac Tagging”
Hollingsworth KG, Hodgson T, MacGowan GA, Blamire AM, Newton JL; University of Newcastle

Some previous research has found that ME patients have a low circulating blood volume. And because of this, some doctors in the USA give their ME patients an intravenous infusion of saline, three times a week. It increases the amount of fluid circulating in the body, which seems to help alleviate symptoms. Vance recalled a report that one woman had had good results with this treatment, though one downside could be problems with the regulation of sodium and potassium levels.

Recently, Prof Julia Newton’s group in Newcastle reported finding that ME patients had substantially reduced left ventricular mass (reduced by 23%) and reduced cardiac output (25%) compared with healthy people, results which are in accord with previous findings.

“Impaired Cardiovascular Response to Standing in CFS patients”
Hollingsworth KG, Jones DE, Taylor R, Blamire AM, Newton JL : University of Newcastle.

As Prof Newton had already shown in previous Magnetic Resonance studies, some ME patients had impairment in their skeletal muscles ability to produce energy at a cellular level. This study was able to demonstrate that cardiac muscle has a similar problem. They showed that the impairment is associated with an increase in cardiac contractility i.e. the hearts of ME patients have to work harder, something which might explain the more severe symptoms patients have on standing. This study allows for a way to define a bioenergetics phenotype in ME patients.

MUSCLE

“Loss of Capacity to Recover from Acidosis on Repeat Exercise in CFS Patients”
Jones D, Hollingsworth K,. Jakovljevic D, Fattakhova G, Pairman J, Blamire A, Trenell M, Newton JL; University of Newcastle.

The Newcastle team wanted to explore the possible causes of these reported difficulties. The study group performed 3 bouts of exercises and
were assessed by Magnetic Resonance (MR) spectroscopy along with a cardiovascular fitness test, to determine at what point their muscles switched from producing energy with oxygen, to producing energy without it i.e anaerobic threshold. A consequence of energy made this way is muscles feel sore and blood becomes acidic.

Interestingly, the results showed that the ME patients fell in to 2 groups, one group who exercised to their capacity and the other group who under-exercised despite thinking they had reached their maximum exercise capacity. This outcome is unique in the research group’s experience. No comparable “exercise avoiding” group is seen in Primary Biliary Cirrhosis (PBC) patients, who have a similar level of muscle fatigue. This suggests that there’s something specific about a sub group of ME patients. They concluded that using MR-directed stratification would be a useful tool in future studies of exercise and exercise therapy.

All the ME patients showed that they had reduced anaerobic threshold, heart rate, and reduced capacity to transport and use oxygen during exercise compared to the control group. Some of this group also showed that it took much longer to get rid of the build up of acid in their muscles and that it took four times longer for pH levels to return to normal.

Autonomic Nervous System

“The Effects of Oral Vitamin D Supplementation on Cardiovascular Disease Risk in Patients with ME-CFS”
Dr Faisel Khan & Prof Jill Belch, Dr Gwen Kennedy & Dr Miles Witham. The University of Dundee

Dr Khan and colleagues are investigating the theory that large doses of Vitamin D improves cardiovascular function in ME patients. Building on previous work that has been done on arterial stiffness (arterial stiffness is one indicator of damage to large blood vessels) – which is an indicator of early cardiovascular disease. They have found some evidence that there’s a link between low levels of Vitamin D and increased arterial stiffness. They are currently carrying out a clinical trial to see if giving large doses of Vitamin D would lead to improvement in cardiovascular functions and improve symptoms in ME patients The trial participants are given a dose of 100,000 unit of cholecalciferol or matching placebo (dummy oil) on 3 occasions. If there are improvements in cardiovascular function then this could prove to be a relatively simple, cheap and effective way of reducing the risk of cardiovascular disease in this group of patients.

ME Research UK has also funded research on young people with ME-CFS……

“Physical and functional impact of chronic fatigue syndrome/myalgic encephalomyelitis in childhood”
Dr Gwen Kennedy, Dr Christine Underwood, Prof Jill Belch, University of Dundee

Little is known about the experience of children who have ME-CFS.despite ongoing attempts to improve the diagnosis and management of the illness. In one study, the group showed quality of life of children with ME-CFS, to be significantly impaired compared to their healthy peer group, and with children affected by other chronic illnesses e.g. type 1 diabetes, asthma. The study also showed that there was a close correlation between the child and parent’s perception of the illness.

In another study, Dr Kennedy measured levels of isoprostanes and antioxidant plasma levels of Vitamin C and E in children’s blood samples. She showed that the ME-CFS paediatric group had increased oxidative stress compared with healthy children and there was also an increased in white blood cell apoptosis (early cell death), showing that neutrophils and lymphocytes were less viable than compared to healthy children.

These biomedical anomalies seen in child ME – increased oxidative stress and increased white blood cell apoptosis – also are seen in adults with clinically diagnosed ME compared with matched controls. Unlike in their adult counterparts, however, arterial stiffness remained within the normal range in these paediatric patients.

The researchers believe that ME patients have an underlying, detectable abnormality that points towards an activated inflammatory response which is consistent with a reactivating or persistent viral infection.

XMRV UPDATE

In autumn 2009, the prestigious scientific journal Science published findings from the University of Nevada, USA, suggesting a link between Xenotropic Murine Leukaemia virus-related virus (XMRV) and ME. Remarkably, the retrovirus could be detected in the peripheral blood mononuclear cells of 67% of the patients but in only 3.7% of control subjects. The researchers also reported data suggesting that infected white blood cells could pass the virus on to uninfected cells – an appealing suggestion at first glance, since it could account for some of the known neurological and immune features of the chronic illness.

Because of uncertainty whether the blood borne virus caused ME, several governments including the UK banned blood donations from anyone who had or has ME.

However, since then 17 distinct studies have been published by other researchers across the world keen to test their own populations of patients, but they have not been able to find significant levels of the retrovirus in their patient groups. There have been some suggestions that laboratory contamination might underlie XMRV-positive findings, but at the moment the jury is still out, though the future looks bleak for the notion that XMRV-infection is the cause of ME around the world.

In September 2011 it was reported that Dr Judy Mikovits, who published the first report, had now left the Whittemore Peterson Institute (WPI) “by mutual agreement”.

MERUK funded a joint study with Prof Blomberg, a leading Swedish Virologist, to try and replicate the WPI study. However, his team could not find XMRV or related viruses in the blood samples of ME patients in Sweden.

Vance posed the question as to whether these events damaged public/ scientific perception of ME. He concluded that he didn’t think so, far from being damaging, it had in fact kindled more interest and it has shown the scientists how sick sufferers are and the wide range of symptoms affecting multiple organs in the body.

UK ME-CFS Biobank

In a joint venture, MERUK, Action for ME, The ME Association and an anonymous donor are sponsoring the establishment of a Biobank at London’s Royal Free Hospital where it will be able to link in with the extensive research facilities at University College London. This facility will collect blood samples from people who are already on the ME-CFS Disease Register and healthy volunteers. This cohort, complete with biological and samples and clinical data, provides the groundwork for other research groups to take forward and investigate the many unanswered questions about ME.

Funding for this work will only be for 18 months to 2 years. It’s hoped that when the time comes the MRC or a similar body will take over the cost of running the Biobank.

RECENT NEW PROJECTS

ME Research UK has undertaken three new projects:

• a) Comparison of various criteria for ME and ME/CFS: Focus on Neurocognitive Performance, Physical Recovery, Physical Activity and Autonomic Manifestations (Belgium)
• b) Search for the aetiology of ME/CFS patients: Development of diagnostic microbiological biomarkers (Sweden)
• c) Quantitative and objective determination of the nature and extent of the visual symptoms experienced by ME/CFS patients (UK)

Round up

Vance believes that only biomedical research is the key to finding a cause for ME. He reiterated that there is an overwhelming need for a research centre to be set up in this country. MERUK has been funding research since 2000. To date they have invested £750,000 in biomedical research. This has resulted in 37 published scientific papers, with 3 more in the pipeline. All of this has been achieved through the generosity of charitable donations. There is no Government or central funding, – though the recent invitation by the MRC for researchers to compete for £1.5 million worth of funding is hopeful and to continue with the expensive business of biomedical research, MERUK needs the support of patients and their families and friends.

Q&A

After a break for refreshments, it was the audience’s chance to quiz Vance, on a number of far- ranging ME topics, in the excellent Q&A session that followed.

A question came from the back of the room asking if the work being done in the Pacific Labs, USA could have been done here. Vance reckoned that it could have but cost was the prohibiting factor – gene work is a very expensive business. He thought that the work referred to, is being done by Dr Alan Light, on gene transcription before and after exercise, and guesses that it would cost in the region of $1 million dollars. He added that it was probably becoming less expensive now as the price of consumables gets cheaper. He also mentioned that this work was related to that of Dr Jonathan Kerr, who was able to genetically subgroup ME-CFS patients.

Then followed another intriguing question as to whether Vance thought there was a link between the Royal Free Hospital Outbreak in 1955 and Sick Building Syndrome (SBS)? Vance thought there was no connection. His reasoning was that SBS is a modern phenomenon which came to the fore in the 1990s. Numbers affected were small. In the 1955 outbreak of ME at the Royal Free Hospital almost 300 members of staff were affected. Most recovered, and it was only a small group who did not. Vance recalled that when he worked at Ninewells Hospital, Dundee, 6 members of staff were taken ill at the same time. 3 recovered, 3 became chronically ill – but he couldn’t ascribe this to SBS. Earlier in the talk he commented on the sporadic and endemic nature of ME-CFS occurrences, which is not the case in SBS.

The next question put to Vance asked if there was any point in taking Vitamin D supplements. Vance replied that the Vitamin D study at Ninewells Hospital, Dundee was looking at cardiovascular parameters. Vitamin D levels were found in a pilot study to be linked with increases in arterial stiffness, risking further cardiovascular illness. He continued to explain that Vitamin D is multifunctional in that it plays a role in many other body systems. Low levels may also affect other ways the body works. The level of Vitamin D taken in the study is much greater than over the counter supplements. A normal supplemental dose is 500 UI compared to 100,000 IU study dose, albeit that the higher dose is slow-release over time.

He then moved on to discuss what the present state of play was in setting up an ME-CFS clinic in Scotland. This is an ongoing issue since Vance “crossed swords” with Dr Mac Armstrong, the ex-CMO, back in 2002. Vance came up with a plan, setting out what was needed. It didn’t have to be an institution; a small room would suffice. Ancillary services such as physios and Occupational Therapists are already in place so ME patients could be easily slotted in. Unfortunately, no funding was attached to the plan, so it went nowhere. As ME patients have multiple referrals to various medical services during the course of their illness, it would make economic sense, for them to be seen at a specialist clinic. But the NHS Health Boards would have had to redirect money for a service, and none would be willing to do so. In 2010, Health Care Needs Assessment was published with 26 recommendations. As yet, there has been no progress in putting these recommendations into practice. Vance thought that the Cross Party Group (CPG) on ME-CFS should focus its efforts on this and push for a ME clinical service to be set up. Another benefit of this service would allow patients to obtain supporting documentation of their illness for benefit claims and pension applications as there would be a recognised expertise to back up their claims. Prof Newton already offers this for patients referred to her clinic in Newcastle.

One lady wondered if there was any other illness that was marginalised as much as ME was. Vance gave the examples of Fibromyalgia or Irritable Bowel Syndrome (IBS) where people aren’t really classified as physically ill with a recognised condition. They’re seen as “functional illnesses” -something’s wrong but there’s no reason for it. Stomach ulcers were viewed that way until the bacterium Helicobacter pylori was discovered, and a cure soon followed. People with Multiple Sclerosis (MS) took a long time to be believed but thanks to improved MR, that all changed. So the hope is that soon there will be a diagnostic test for ME-CFS and the perceptions towards this illness will change.

Someone asked if Scottish patients will be able to use the Biobank? Simple answer is yes as it’s a UK wide facility, and there are plans behind the scenes to have a system through which people can volunteer for the Biobank. Initially patients will be assessed on the Fukuda and Canadian criteria, but all will need to be clinically assessed and this might complicate recruitment initially. This adds weight to having a centre like Newcastle. If finance had been available, a clinic could have been set up in Dundee run by Prof Belch. She had already seen around 400 patients but she could not see anymore. When Vance was the Chairman of Fife ME Steering Group, he along with the other Trustees wrote 438 letters to Fife Health Board asking for support for a clinic. The correspondence was ignored. They did however manage to set up a minimal service of a specialist ME-CFS nurse who remains the only one in Scotland.

The last question put to Vance wondered if the reason scientists were withdrawing from ME research was down to hype? He replied that this could be the case and the furore surrounding the hate mail received by Dr Crawley has not helped. It is more likely that the lack of funding is to blame; as neurological illnesses are poorly funded, there is little interest or incentive for research scientists into this area. Cancer Research UK is way ahead with an annual income of around £530 million. This far outstrips funding into cardiovascular illness which causes more deaths.

As usual, there were many more questions than there was time and reluctantly, the meeting had to come to a close.

Note: Since this talk there have been some changes in the ME world. The Science paper on XMRV was retracted, and XMRV has been largely discredited as a cause of ME. The Scottish Cross Party Group on ME disbanded in 2012.  Also, A Lothian ME-CFS service has been set up at the Astley Ainslie Hospital in Edinburgh.

You can read about the latest ME Research at MERUK’s page here: http://www.meresearch.org.uk/research/studies/index.html