These are some brief personal notes designed for a non-scientific readership on an excellent full day symposium that was organised by the Northern CFS/ME Clinical Network, the Institute for Ageing and Health, and the Institute of Cellular Medicine at the University of Newcastle.
The symposium highlighted research that is currently taking place in various sites at the University of Newcastle into the role of disabling fatigue, along with autonomic dysfunction and orthostatic symptoms, in a range of chronic conditions. The presentations concentrated on the role of muscle rather than brain as a cause of fatigue.
There was a good attendance from a range of health professionals – who were mainly from the North of England.
Dr Charles Shepherd
Hon Medical Adviser, ME Association
FATIGUE RESEARCH: WHERE ARE WE NOW?
The morning session was chaired by Professor Tom Kirkwood, who observed that we should neither seek nor avoid complexity when it comes to the challenges of unravelling the answers as to what causes chronic disabling fatigue.
INTRODUCTION: Professor David Jones
Professor David Jones set the scene for the morning presentations – which concentrated on how muscle normally functions and what abnormalities in muscle function are being found in people with ME/CFS, along with other diseases such as primary biliary cirrhosis, where disabling fatigue is a significant clinical feature.
Covering familiar ground he pointed out that fatigue in its widest sense is involved in a quarter of all GP consultations and forms the main reason for people seeing a GP in 6% of consultations. Surveys also suggest that around 10% of the UK population have regular fatigue.
There are clearly major problems in how we define fatigue – which is where life starts to get complicated. And the economic costs are enormous – as we know in the case of ME/CFS.
So are there any links between the chronic disabling fatigue that is found in a range of chronic medical conditions that could help us to understand the explanation for the more specific form of exercise-induced fatigue that is so characteristic of ME/CFS? And how could co-operation between researchers working with different discplines help to take this forward?
MUSCLES AND HOW THEY FUNCTION: Professor Patrick Chinnery
Professor Chinnery took us right back to medical school basics by giving a very clear and detailed review of the anatomy (ie the microscopic structure of the muscle cell), physiology and biochemistry of human muscle. He summarised how all the different anatomical and biochemical components of human muscle work together so that when a message comes from a nerve to make the muscle contract, and movement to occur, this is done in a coordinated and effective manner. Numerous small blood vessels, under autonomic nervous system control, also penetrate the tissue to keep muscles supplied with oxygen and glucose, which are needed to make the muscles contract.
Professor Chinnery also explained the complex chain of biochemical events that help to produce energy within muscle. In very simple terms during the onset of exercise, glycogen, the storage form of the carbohydrate product glucose, is utilized within the muscle in a cycle of electrochemical reactions that produce adenosine triphosphate (ATP), a key source of energy within the muscle. This biochemical process also results in the production of a waste product known as lactic acid.
In relation to the mitochondria, a key part of the muscle cell that may be involved in ME/CFS, Professor Chinnery explained that these organelles – the Duracell batteries within muscle – have their own DNA (=genetic material) and that defects in mitochondrial DNA (mtDNA) can be inherited from a person's mother as well as occurring sporadically.
The clinical problem that can sometimes occur in differentiating a rare but specific mitochondrial disease from ME/CFS was illustrated by a case history of a patient who complained of muscle weakness and was originally diagnosed as having ME/CFS because there was no evidence of mitochondrial abnormality being present on a muscle biopsy at the time. She then developed further muscle weakness and wasting and eventually had to use a wheelchair. At this point there was clear evidence from further muscle biopsies of severe loss of mitochondrial function and the diagnosis was changed to a specific mitochondrial myopathy.
Professor Chinnery finished by summarising some of the epidemiological research that is being carried out in the North of England into inherited muscle disease. This is looking at the incidence of mtDNA mutations and mitochondrial disease in the population and posed the question as to whether these mutations may be higher in people with ME/CFS and so act as a risk factor in developing ME/CFS.
MUSCLE BIOENERGETIC FUNCTION AND FATIGUE: Dr Kieren Hollingsworth
Dr Kieran Hollingsworth, from the MRC Physics Group at Newcastle, studies muscle function using a scanning technique called 31p magnetic resonance spectroscopy. This type of scanning allows researchers to follow what is happening to complex muscle biochemistry at rest, during exercise, and after exercise.
In very simple terms this means that muscle function in people with ME/CFS can be compared to that of normal healthy controls from the point at which they start using glycogen as an energy source right through to the production of lactic acid as the waste product of energy production.
The different chemical processes taking place during rest, exercise and recovery can be seen as spikes on a computer recording. This information also provides a guide to mitochondrial performance.
Dr Hollingsworth referred to work that has already been published which compared people with ME/CFS and a group with primary biliary cirrhosis (PBC). This is a liver condition where patients often report chronic disabling fatigue and is characterised by an autoantibody (= an antibody that can harm normal human tissue) response which is directed against the mitochondrial antigen pyruvate dehydrogenase complex (PDC) – see also the afternoon presentation from Dr Phil Manning. People with PBC have a significant prolongation of muscle pH recovery time after exercise, which correlates with clinical fatigue.
An abstract describing this research in more detail by clicking here.
An abstract from another new research paper from this group, which relates to an investigation into cardiac (heart) and skeletal muscle can be found on the MEA website by clicking here.
On a personal level it is interesting to note that it is now just over 25 years since the work I did with Professor George Radda at Oxford, using 31p nuclear magnetic resonance to demonstrate excessive intracellular acidosis in skeletal muscle in my own muscle, was published in The Lancet. Even so, the medical profession is still being told that muscle fatigue in ME/CFS has nothing to do with muscle abnormalities and that it is simply the result of inactivity and deconditioning. Ref: Excessive intracellular acidosis of skeletal muscle on exercise in a patient with a post-viral exhaustion fatigue syndrome. Lancet 1984, 1, 1367 – 1368.
FATIGUE AND AUTONOMIC FUNCTION: Professor Julia Newton
Professor Julia Newton started off by describing the physiological changes that take place in heart rate and blood pressure when we change posture, especially from lying to standing, in order to maintain a good supply of blood to the brain. This activity, which helps to compensate for the fact that about 750 mls of blood heads downwards to pool in the legs on standing, is controlled by the brain through what is called the autonomic nervous system.
Autonomic dysfunction is the term that doctors use when this control mechanism fails goes wrong and results in symptoms such as dizziness, sweating, feeling faint, and even fainting. The situation where symptoms and problems occur in relation to standing is known as orthostatic intolerance and orthostatic hypotension (when this involves a fall in blood pressure on standing).
Professor Newton summarised the ways in which autonomic dysfunction can be assessed using fairly simple questionnaires (eg the Orthostatic Grading Scale and the COMPASS/composite autonomic symptom score scale) along with dynamic tests of heart rate and blood pressure which involve continual monitoring over a period of time (ie tilt table testing)
From the research point of view Professor Newton also referred to the interesting overlap between ME/CFS and primary biliary cirrhosis (PBC). Orthostatic intolerance (symptoms related to standing up) are common in both conditions (90% in ME/CFS; 69% in PBC) and fatigue levels appeared to be related to the degree of orthostatic intolerance.
Professor Newton also reviewed the treatment options for people with significant orthostatic intolerance, including the possible use of drugs such as fludrocortisone and midrodine and discussed some of the group's new research which is looking at whether fatigue levels in PBC are related to life expectancy in this condition.
A new paper from the Newcastle group on orthostatic symptoms, and the way in which they predict functional capacity in ME/CFS, has been epublished ahead of print in the Quarterly Journal of Medicine. Abstract available at: http://www.ncbi.nlm.nih.gov/pubmed/20534655 :A. Costigan, C. Elliott, C. McDonald and J.L. Newton From the NIHR Biomedical Research Centre in Ageing-Cardiovascular Theme, Newcastle University, Newcastle, UK
Objectives: To establish the relationship between the functional impairment
experienced by Chronic fatigue syndrome (CFS) patients and the symptoms
frequently experienced by those with CFS; specifically cognitive impairment,
fatigue and orthostatic symptoms.
Design: Cross sectional questionnaire survey.
Setting: Specialist CFS Clinical Service.
Subjects: Ninety-nine Fukuda diagnosed CFS and 64-matched controls.
Main outcome measures: Symptom and functional assessment tools completed and
returned by post included; PROMIS HAQ (Patient-Reported Outcomes Measurement
Information System, Health Assessment Questionnaire), CFQ (Cognitive
Failures Questionnaire), FIS (Fatigue Impact Scale) and OGS (Orthostatic
Grading Scale) assessment tools.
Results: CFS patients experience greater functional impairment than controls
[mean (95% CI) PROMIS HAQ scores CFS 36 (31-42) vs. controls 6 (2-10); P <
0.0001], especially in the functional domains of activities and reach.
Poorer functional ability impairment is significantly associated with
greater cognitive impairment (P = 0.0002, r = 0.4), fatigue (P < 0.0001, r =
0.5) and orthostatic symptoms (P < 0.0001, r = 0.6). However, only
orthostatic symptoms (OGS) independently associated with functional
impairment (β = 0.4, P = 0.01).
Conclusions: Treatment of orthostatic symptoms in CFS has the potential to
improve functional capacity and so improve quality of life.
Professor Newton's group has already had several other papers published in this area. References can be found in the section on autonomic dysfunction in ME/CFS/PVFS – An Exploration of the Key Clinical Issues.
A fairly straightforward description of how the antonomic nervous system functions, and way in which it helps to control activity in the heart, blood vessels – including those that supply skeletal muscle – bowel, bladder etc can be found here: http://en.wikipedia.org/wiki/Autonomic_nervous_system
EXERCISE INTOLERANCE IN CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA – WORK IN PROGRESS: Professor Jo Nijs
Professor Jo Nijs started off by looking at the most recent American College of Rheumatology diagnostic criteria for fibromyalgia and the issues of exercise intolerance and post-exertional malaise in ME/CFS, where there is a significant exacerbation in symptoms in the 24 hours following exercise.
From the research angle, he considered some of the possible explanations for exercise intolerance in ME/CFS. These include having an ‘exhausted hypothalamic-pituitary-adrenal axis' (which accounts for the blunted cortisol response), changes in brain chemical activity – serotonin and endorphin (the ‘feel good' chemicals) in particular; and the way in which exercise can cause immune system activation through the complement system.. He also considered abnormalities in the processing of information relating to pain within the central nervous system.
Professor Nijs concluded by looking at how this information might help in deciding on what were safe and appropriate levels of activity and exercise for people with ME/CFS.
FATIGUE RESEARCH: WHERE WE WANT TO GO
The afternoon session was chaired by Dr Gavin Spickett and started off by looking at how chronic disabling fatigue is an important, but sometimes unrecognised feature, of many chronic illnesses. Chronic fatigue seen in other conditions can have important similarities and differences to that seen in ME/CFS. So if we are going to gain a better understanding of the mechanisms involved, and possible forms of treatment, then it is important to also learn from the research that is being carried out elsewhere into the subject of physical and mental fatigue.
THE MRC SJOGREN's SYNDROME REGISTRY: Dr Fai Ng
Dr Ng pointed out that 70% of patients with Sjogren's Syndrome – an autoimmune rheumatic disorder with some interesting clinical and pathological overlaps with ME/CFS – experience fatigue, And when asked about their symptoms, fatigue are dryness (involving eyes and mouth) are the most important symptoms that they require help with. A significant proportion of people with SS also have autonomic dysfunction.
The explanation for chronic disabling fatigue in SS remains uncertain but this may involve immune activation and dysregulation of the hypothalamic-pituitary-adrenal axis, both of which are implicated in ME/CFS.
The MRC funded biobank at Newcastle is currently recruiting well characterised patients with SS and the register now holds around 500 people who can be used for research purposes.
During the discussion session, CS raised the issue of dorsal root ganglionitis being found in post-mortem cases of ME/CFS and the fact this abnormality has also been found in SS patients who have a sensory neuropathy and autonomic dysfunction.
More information on the overlap between SS and ME/CFS, and dorsal root ganglionitis, can be found in ME/CFS/PVFS – An Exploration of the Key Clinical Issues
HIV AND MUSCLE – ASSOCIATIONS WITH FATIGUE: Dr Brendan Payne
Dr Payne explained that fatigue is a common problem in patients with HIV and AIDS. It does not appear to be linked to demographics (= age, sex and other population variables) or immune system cell markers. It does appear to be linked to lipodystrophy (= changes in body fat distribution caused by antiretroviral drug treatment), orthostatic intolerance, depression and sleep disturbance.
Of particular interest is the fact that patients who are treated with antiretroviral drugs such as AZT, which almost completely suppresses HIV replication, find that this has very little effect on fatigue levels. In other words, removing the HIV infection does not remove the fatigue. So, as with ME/CFS, the question is raised as to whether fatigue is being caused by immune activation that is triggered by an infection.
The session on HIV and fatigue also briefly covered the very important issue of muscle mitochondrial damage following antiretroviral therapy (AZT) – which is related to the lipodystropy and appears to be permanent in some cases. This observation is obviously going to be very relevant if it turns out that XMRV is a causative factor in ME/CFS and clinical trials involving antiretroviral therapy take place.
There was a short discussion on the Science paper reporting XMRV in patients with ME/CFS and results of the four validation studies which have failed to find XMRV in other cohorts of people with ME/CFS.
MITOCHONDRIAL MYOPATHY: Dr Grianne Gorman
Dr Gorman started off with a further explanation about the role of mitochondria in the body. All our cells have mitochondria with the exception of red blood cells. They have their own genetic material – mitochondrial DNA/ mtDNA – which is inherited from the mother. Their function is to act as Duracell batteries within the cell – producing energy in the form of a molecule called ATP (adenosine triphosphate).
Problems with mitochondrial function lead to muscle fatigue, weakness and wasting. But because mitochondria are present in all body tissues, helping them to function efficiently, mitochondrial diseases can also produce other types of symptoms involving the brain and heart etc.
As far as the overlap with ME/CFS is concerned, most people with a mitochondrial disorder experience mild to moderate fatigue which may fluctuate in severity, some have autonomic dysfunction (which may involve bowel function as well) and significant sleep disturbance is common.
Treatment of these rather rare mitochondrial disorders is symptomatic – there is no drug or supplement at present that can improve mitochondrial function or reverse the damage.
RESPIRATORY DISEASE AND FATIGUE – Dr Tony De Souza
Dr De Souza spoke about the type of chronic fatigue that is often reported by patients with chronic lung disease – bronchiectasis (infective damage to the lungs ) and COPD (chronic obstructive pulmonary disease ) in particular.
Once again the issue as to whether chronic inflammation in the lungs could be producing an abnormal immune response and causing fatigue was questioned. As with HIV/AIDS-induced fatigue, an effective form of treatment (ie replacing the diseased lung with a transplant) may not reduce fatigue and improve exercise tolerance.
FATIGUE, AUTONOMIC DYSFUNCTION AND EARLY RENAL DISEASE: Professor Neil Sheerin
Professor Sheerin explained that while fatigue was seen in patients with renal disease it was not directly related to disease severity. So people with a severe loss of kidney function can have little or no fatigue whereas those with only a mild loss of renal function may complain of severe fatigue. There also appears to be no direct link between chemical markers of renal disease (eg calcium and phosphate balance) and fatigue levels. Fatigue in renal disease does, however, appear to be linked to sleep disturbance and orthostatic intolerance. In common with other speakers, Professor Sheerin hypothesised that an element of on-going immune activation may be a factor.
EXERCISE AS AN INTERVENTION IN FATIGUE ASSOCIATED DISEASES: Dr Mike Trenell
This was a more general talk on the role of exercise and not specifically related to activity management in ME/CFS.
NANOSENSOR TECHNOLOGY IN INVESTIGATING MUSCLE FUNCTION IN ME/CFS: Dr Phil Manning
Dr Manning explained how this new and very complex item of medical technology could be used for intracellular chemical analysis – one example being the evaluation of intracellular ph (= acidity levels) in myoblasts (= a cell that develops into a muscle cell).
Research carried out within Dr Manning's group has demonstrated that a significant subgroup of ME/CFS patients exhibit impaired energy generation in muscle and overproduction of lactic acid.
At a biochemical level, pyruvate dehydrogenase complex (PDC) plays a key role in the regulation of cellular energetics. Decreased function of PDC results in increased metabolism of pyruvate via the lactate dehydrogenase pathway, with subsequent overproduction of lactic acid. Impaired energy generation by muscle, an increase in the lactate/pyruvate ratio in ME/CFS, and a propensity towards excess intra-muscular acidosis following limited exercise suggests PDC dysfunction in muscles of ME/CFS patients, with implications for the mechanism of expression of fatigue.
The group have postulated that patients with ME/CFS have a significant abnormality in acid control within their muscles related to both acid generation and its clearance from tissue which, they believe, results in generation of a centrally-perceived exercise “stop” signal.
SYSTEMS MEDICINE: UNDERSTANDING THE COMPLEXITY OF FATIGUE: Professor David Jones
Professor Jones brought the meeting to a close by talking about his longstanding interest in the liver disease known as primary biliary cirrhosis (PBC) – a condition that affects around 20,000 people in the UK and has some interesting overlapping features with ME/CFS. Professor Jones and his colleagues now run the largest UK clinical service for people with PBC.
Professor Jones traced the history of PBC – a condition which before 1990 was often described as consisting of serious liver symptoms such as jaundice, ascites and varices. Thanks to the work carried out in Newcastle we now know that this is not the true picture – because many patients with PBC present with fatigue, cognitive dysfunction and pruritis (= skin itching) whereas others are asymptomatic. As with ME/CFS, these symptoms can become chronic and severe. It also appears that fatigue levels in PBC are linked to both autonomic dysfunction and cognitive dysfunction.
Professor Jones also spoke about the research being carried out into long term prognosis in PBC and the role of the MRC (Medical Research Council) in funding good quality research in this area.
FUTURE RESEARCH OPPORTUNITIES: Professor Stephen Holgate
A major disappointment was the fact that Professor Stephen Holgate, who chairs the MRC Expert Group on ME/CFS, had to send in his apologies as he had to take part in an important interview panel at the University of Southampton.
Overall, this was a very useful meeting on the wider subject of fatigue and I believe there are several key conclusions.
Firstly, there is strong evidence for a peripheral (ie muscular) component to fatigue in ME/CFS, certainly in a sub-group of patients. So muscle fatigue cannot simply be explained by the popular and very flawed cause and treatment model involving inactivity and deconditioning.
Secondly, there are important similarities and differences between the type of exercise-induced fatigue found in ME/CFS and the chronic fatigue which is found in a number of other medical conditions.
Thirdly, by examining factors such as autonomic dysfunction and immune activation, which appear to be playing a role in a variety of conditions where fatigue is a significant clinical feature, we should be able to find more effective forms of treatment aimed at the fatigue that affects both brain and muscle function.
It is also very encouraging to find that a multidisciplinary centre of excellence in relation to ME/CFS research is steadily emerging at the University of Newcastle.
The MEA Ramsay Research Fund is very pleased to be financing some of this muscle research that is being carried out there by Professor Julia Newton and her colleagues.
Dr Charles Shepherd
Hon Medical Adviser, MEA
22 June 2010