Written Submission on Research Evidence
to
The Gibson Inquiry
by
BRAME
B R A M E
Blue Ribbon for the Awareness of Myalgic Encephalomyelitis
30 Winmer Avenue, Winterton-On-Sea, Great Yarmouth, Norfolk, NR29 4BA
Telephone/Fax: 01493 – 393717
www.brame.org brame@brame.org
17 January 2006
Dr Ian Gibson
MP for Norwich
c/o Ian Woodcroft
House of Commons
Westminster
LONDON
SW1A 0AA
Dear Dr Gibson
here is a covering letter to go alongside the papers and review of papers we are also sending you – just highlighting some points we feel are important.
What’s in a name?
This illness has been referred to as “the Disease of A Thousand Names” – this could be due to the heterogeneity of the sufferers currently created by the use of inappropriate research diagnostic criteria.
Illnesses fitting the symptoms of ME/CFS have been recorded as far back as 1900BC, the first British epidemic is thought to have occurred in the time of Henry VIII when it became known as “The English Sweats” – it later became known as “The English Disease” or “muscular Rheumatism”. The illness also impacted on soldiers fighting throughout the centuries with many people returning at the end of the Battle of Agincourt with an ME-like illness, after the American Civil War it was known in America as the “Soldier’s Disease” and most famously Florence Nightingale became ill with what is thought to be this illness during her time as a nurse in the Crimean War.
It was not until the full-blown poliomyeltitis epidemic swept California, and a specific outbreak in Los Angeles in the summer of 1934, described by Gilliam, that ME was actually recognised as a separate illness, it was referred to as atypical poliomyelitis – many people having the symptoms of polio-myelitis without being paralysed. In Britain the next major epidemic occurred in July 1955, at the Royal Free Hospital in London, when it became known as the Royal Free Disease – later being given the name Benign Myalgic Encephalomyelitis by Prof Ramsey – which is also when the illness’ links to poliomyelitis became distanced with polio being reduced by the polio vaccines, and ME continuing to become a problem. Since 1934 over 50 similar clusters have documented. Despite the accurately recorded clinical data from these events, and their characteristic similarities, more than 70 years on, there is still controversy over this most debilitating and complex illness, which has also been called the ‘disease of a thousand names’.
The main problem that people with ME have faced is that doctors believe that because there has been no definitive aetiology and pathogenesis of the illness shown by research, then the illness must be psychosomatic, we must remember that they also thought this of Polio, and that MS was known as “hysterical paralysis” – just because something is unknown, does not mean that it does not exist merely that science, is at present, unable to prove anything – as research techniques improve so the wealth of data of the biological discoveries about the illness grows. The stigma attached to this illness by the scientific community, and the media, has led to people with this illness being victimised at their time of greatest need. Even the CMO report acknowledged that this illness is not just fatigue and should not be reduced to one symptom saying that it is akin to Alzheimers being called Chronic Forgetfulness Syndrome – for Alzheimers is so much more than forgetfulness.
The WHO ICD listing of ME has been that of a neurological Illness for many decades now, it is now listed in WHO ICD-10 G93.3. Chronic Fatigue Syndrome was coined in America by Holmes et al in 1988 the groups there did not like the term and so adapted it to Chronic Fatigue Immune Dysfunction Syndrome (CFIDS). Many patients do not like the term CFS because they feel that it belittles there illness – defining it as just fatigue – whereas for many sufferers, in particular the severely affected – this is just not the case, fatigue is not their main problem symptom – yes they all have it but often find that the symptom of pain is more difficult to deal with.
The patient group do not like the term CFS as they feel it is derogatory to their condition, however if this name must be kept at present then it must be recognised as an umbrella illness of which Myalgic Encephalomyelitis is one of the illnesses, as is Post Viral Fatigue Syndrome.
What is ME/CFS?
ME/CFS can be both sporadic and epidemic in form, and has no known specific diagnostic test, (although current biomedical research is encouraging) and as yet there is still no known cure, nor is there a treatment which is helpful for everyone. Unfortunately for ME patients, and their carers and families, the illness is still very misunderstood and met with scepticism by some in the medical profession, and other professional bodies.
ME/CFS is characterised by persistent and relapsing debilitating mental and physical fatigue, and this post exertional malaise is characteristically delayed. Patients typically experience an array of symptoms including:- myalgia; arthralgia; cognitive impairment; low-grade fever and flu-like symptoms; swollen lymph nodes; headaches – often severe, and non-refreshing sleep, along with neurological, endocrine and immune dysfunction. For the severely affected ME becomes a multi-system, mutli-organ illness.
ME/CFS is recognised and listed by WHO as a neurological illness – WHO (ICD10:G93.3)
ME/CFS affects all socio-economic groups, and all ages, with the peak incidence being 20-40, with a secondary peak at puberty. There appears to be a female predominance possibly linked to hormone levels. There is evidence to believe it is increasing in all ages. The CMO Report on ME/CFDS (2002) estimated numbers up to 240,000 (0.4% of the population) with an estimated 25% of sufferers being severely affected, although many believe the total numbers are greater than this. The Dowsett/Colby (1996) study also showed that school absence due to ME/CFS showed a rate of 70/100,000 in pupils and 500/100,000 in staff – the largest number for any one illness..
The complexity of this illness means that prognosis is equally difficult to predict. Those who receive an early diagnosis, subsequent understanding, support and appropriate individually tailored management, in partnership with their doctor, tend to be the ones which make the most significant progress. However for many the progress will be slow and gradual over several years. The majority will make variable progress, with relapses, but some may reach 70-80% of normal function, whilst others may continue to deteriorate, and will remain severely affected and house/bedbound for years/decades/lifetime. Many research papers acknowledge, as did the CMO report, that those who have been severely affected for more than 5 years are unlikely to make any significant recovery. The severely affected are a group of patients who will need appropriate health and social care for some years, and maybe a lifetime.
The need for funding and acknowledgement of the biomedical research into the aetiology and pathogenesis of this most complex, debilitating and life-changing disease is urgently needed to help alleviate the pain and suffering of this group of chronically ill and misunderstood patients.
Severely affected
The severely affected are severely overlooked within the realms of research. The very nature of the severity of the illness means that patients are bed/house-bound – going out of the house very rarely. This group make up at least 25% of the ME population. Much ME research requires that the patients are able to travel to the place of research – which the majority are unable to do, they also have to have the ability to withstand the testing of many of the research studies – which they are usually unable to do – particularly as far as treatment is concerned.
This means that the severely affected are not included in the research. Due to the chronic and complex nature of their illness, their hypersensitivity, and multitude of symptoms this means that extrapolating research findings and applying them to the severely affected, is dangerous and irresponsible – particularly as many papers use the Oxford criteria of CFS for which you only need to suffer from unexplainable fatigue.
The severely affected are sometimes used within research papers but they are then lost within the results, this is due to many research papers not putting the patients into sub-groups – meaning that the results relating directly to the severely affected are not extrapolated and are therefore lost. Researchers say that it takes too much time and money to create sub-groups within their results and examine the meaning of the results and as such valuable information is being lost. Where researchers have taken the time to compare the severely affected with those less severely affected they have found differences – showing that this is a worthwhile exercise.
Treatments
The majority of research into treatments such as CBT and GET do not include the severely affected and yet these are the treatments advised for this group – despite research from the patients who show that these treatments do not help and a lot of the time harm the patients – with over 50% of patients who had undertaken GET being made worse by the treatment – some of these severely affected patients were only moderately affected before the treatment. Patient evidence cannot continually be swept under the carpet because they do not like the results.
There also needs to be awareness made that there are discrepancies in the way that treatments are used in the real world – the treatment protocol followed in the research lab is often not followed in the field – leading to people becoming both physically and psychologically damaged as a result of inappropriate GET and CBT treatment.
Sub-groups
Sub-groups need to be looked at, including severity and co-morbidity of other illnesses for the results will then give clearer information. The Karnoffsky scale of severity is a very good indicator for use within research, and allowing the results to at least be split into those mildly, moderately and severely affected will allow researchers to greater understand the impact severity has on their findings.
We, and many researchers, believe that CFS is an umbrella term for many unknown illnesses, for which debilitating fatigue, and post-exertional malaise are core symptoms – subgroups including ME and PVFS. The CDC Fukuda 1994 research criteria creates a too heterogeneous group which does not help patients or researchers – for it encompasses too wide a spectrum, and picks up too many illnesses for which other causes could be identified. The only clinical diagnostic criteria is that of the Canadian Guidelines – research papers have found that this criteria creates a more homogeneous group, also picking up those that are more severely affected – this criteria also allows for those who do not fit the full criteria of CFS to be provisionally diagnosed and treated under the illness “Idiopathic CFS” – this would allow clinics to treat these patients, but the treatments offered to them would be different to those offered for ME/CFS/PVFS.
Jason et al (2005) in their paper on the need for subtypes says “Individuals with CFS have been found to differ with respect to characteristics such as the case definition utilised, psychiatric comorbidity, method of case ascertainment, functional disability, and viral, immunologic, neuroendocrine, neurology, autonomic, and genetic biomarkers (jason et al., 2003a). As a result of this heterogeneity, findings emerging from studies in a number of areas are, at best, discrepant, and at worst, contradictory.” He also said, and this particularly refers to the Oxford, and possibly the Fukuda diagnostic criteria; “ if there is limited reliability of the diagnostic groups studied, because of failure to attend to subtype differences, the results of any study using such diagnostic categories are likely to be unreliable and /or invalid” This is saying that you cannot extrapolate the findings from many studies because of the heterogeneity of the groups used for the studies, especially when using the Oxford criteria, means that often these results cannot be used, due to lack of reliability of application to sufferers.
Research
Since the illness has been known as ME it did not originally bear the brunt of the stigma it now has within the medical and rest of the world. This has been down to a group of psychiatrists from Britain who hijacked the illness for their own psychiatric explanations – their view being that because there is now proof of another explanation it must be a psychosomatic illness. This is now being seen in America where up until the last year or so, the illness has been recognised, including its severity and physical nature of the illness with the CDC listing it as a priority one illness along with AIDS – yet recently the psychiatrists have begun changing the views of the doctors and researchers in the US, patients are now reporting that where doctors were supportive and understanding of the organic and biological nature of their illness, that they were now doubting this, and suggesting the CBT and GET route. Despite the tide now turning in America for the worst they still hold the illness in greater stead than the UK.
There are some Wessley/Cleare papers that are showing the physical changes in the body but then, Wessley does another paper which says it is a psychological illness, which is just plain contradictory and where he simply chooses to ignore the physical results he himself has discovered! – they state that we don’t get better because we hold the belief that we have a physical illness, and if we stop believing in the biological nature of the illness then we will get well – would they say the same to a cancer sufferer – just stop believing that you have cancer and you will get better!!
There appears to be a bias in the research into this illness, especially in the UK with any funding into the aetiology and pathogenesis of this illness primarily coming from patient groups and organisations set up to specifically research into the illness such as MERGE and the CFSRF. This is shown by the funding by the MRC of the PACE and FINE trials – both into treatments which the patients are mainly against and the majority don’t find helpful, and both take the psychiatric point of view – with the MRC having all this funding why are they not funding the wonderful genetic research that is happening in this country. Organisations which do represent the views of the patients feel that this is just throwing good money after bad. Research is desperately needed into subgroups, the aetiology and pathogenesis of this illness. The country also needs to start using the Canadian Diagnostic Criteria so that a more homogeneous group could be used within research and proper diagnosis can be made –there still seems to be a feel that because this is an illness diagnosed by exclusion that all unexplained illnesses which contain fatigue are just diagnosed as CFS.
Further research: if you go on the website: http://ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed then you will be able to search of abstracts and links to the full articles of many published medical papers.
Good luck with the Inquiry. We will be in London next week for a NICE meeting if you need us any further.
Best wishes
Tanya Harrison
Chairperson - BRAME
SUMMARY OF RESEARCH EVIDENCE ON ME/CFS
COMPILED BY BRAME FOR
PARLIAMENTARY RESEARCH INQUIRY ON ME/CFS
All research papers highlighted here have numerous references to other relevant papers
As there are so many papers that could have been presented, we have tried to concentrate on those that highlight the pathogenesis of this illness.
There are papers which we feel are essential that you read in full to give you a broad understanding of the main areas of this illness, along with references to other literature which has already been presented to the Parliamentary libraries by BRAME, following the BRAME meeting in Parliament on 14 May 1998. We strongly suggest reading/referring to the book referred to as the ‘ME Bible’ – “the Clinical and Scientific Basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome” by Byron Hyde – which you should find in the Parliamentary library. The book “Enteroviral and Toxin Mediated Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome and Other Organ Pathologies” by Dr John Richardson is another must read as this gives a good UK background to the illness as well as being based on the study of the illness for fifty years. The other document which you should read is “The Canadian Guidelines” by Carruthers et al1 (which we are sending you) – although this is not a perfect document it is a consensus created review of research and formulation of the only Clinical Diagnostic Criteria and contains advice on diagnosis and treatment – this is also the paper which the ME groups around the world support as being, at present, the best available.
Subgrouping
CFS:The Need for Subtyping
Researchers: Jason et al (2005)2 – USA
Please read this paper
This article provides information concerning the need for the appropriate diagnosis of CFS subtypes and an overview of research papers into this illness concerning the aetiology, pathogenesis, diagnosis and treatment of ME/CFS.
With particular regard to treatment we must also be highly aware of sub groups. Jason et al has shown that there are distinct sub-groups and it is remiss of doctors to treat CFS/ME as one illness, but rather as a number of illnesses clustered under the heading of CFS. His research shows that:
“It is clear that the current cohort of individuals diagnosed with CFS is a diverse group with varying disease course and disability patterns”
“Similar to disorders such as cancer, it is highly likely that a number of distinct types of CFS exist and that the current method of grouping all individuals who meet diagnostic criteria together is complicating the identification of biological markers of the subgroups.”
“Inevitably, there is some risk that samples of individuals with chronic fatigue and somatic symptoms include those with solely psychiatric diagnoses, with solely CFS diagnoses, and with some CFS and psychiatric comorbidity. Therefore, these three groups need to be differentiated and analyzed separately as opposed to being collapsed into one category.”
“When the HPA axis and sympathetic nervous system become upregulated, possibly due to heightened central nervous system sensitivity to stimuli such as cytokines, secretions of glucocorticoids and catecholamines (adrenalin and noradrenalin) are raised. This could result in a Th1 to Th2 immune response shift, which could impair the body’s defense against viral or intracellular bacterial infections. Once adrenal insufficiency stimulates immune activation, this process can contribute to brain dysfunction (Komaroff, 2000b). Further, the process might occur in different intensities and stages for different patients, thereby necessitating the need to subtype individuals on this dimension. For some individuals, cortisol levels are within normal ranges, whereas it is not for others. This might represent a critical dimension to understand the pathophysiology of this illness. Although no virus has been identified as the primary cause of CFS, the immune system seems to be fighting a virus in some patients, as evidenced by the RNase-L pathway. Evidence also points to neurological findings including hyperintense signals on MRI scans (Lange et al., 1998) and autonomic dysfunction (primarily neurally mediated hypotension; Schondorf and Freeman, 1999). In this review, we have only covered several of the subtypes that have been more extensively studied. There are other more recent subtypes, for example, the finding of chronic phase lipids in the majority of patients with CFS (Hokama et al., 2003), increased DNA fragmentation in muscle tissues of patients with FM (Sprott et al., 2004), or a deficiency in the expression of STAT1 proteins in about 30% of patients with CFS (Knox et al., 2004). Many of the dimensions reviewed are worthy of efforts at subtyping in future studies. As stated by Glaser et al. (2005), inconsistent patterns of immune markers may be due to our present knowledge base in fields such as virology and immunology, and as we learn more about the immune system and new types of immune cells and cytokines are discovered, there may be other links to CFS that will help us better understand the aetiology of pathophysiology of subtypes.”
“The identification of clinically significant subgroups is the logical next step in furthering CFS research. Some individuals might be at higher risk of developing this chronic activation due to genetic vulnerabilities or to constitutional or psychological factors. There might be multiple pathways leading to the cause and maintenance of the neurobiologic disregulations and other symptoms experienced by individuals with CFS. Depending upon the individual and subtype, these may include unique biological, genetic, neurological, psychological, and socioenvironmental contributions. Subgrouping is the key to understanding how CFS begins, how it is maintained, how medical and psychological variables influence its course, and in the best case, how it can be prevented, treated, and cured.”
This review suggests that there is a need for a greater diagnostic clarity and this might be accomplished by sub-groups. Fukuda et al (1994) when creating there research criteria, which is used world-wide as the CDC 1994 Criteria for CFS, also called for subgrouping within the identified group of individuals with CFS – thus suggesting an awareness that they were creating a criteria which would identify a heterogeneous group of patients, this was highlighted by Jason et al (1999d)3 and paraphrased by Jason et al (2004) showing that “the US case definition for CFS (Fukuda 1994)4 is characterised by vaguely worded criteria that lack operational definitions and guidelines to assist healthcare professionals in their interpretation and application of the diagnostic tool.” The Canadian Clinical Diagnostic Criteria in comparison with the Fukuda criteria (Jason et al 2004)5 however creates a more homogeneous group selecting “cases with less psychiatric comorbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurology symptoms.” (neuropsychiatric referring to cognitive dysfunction) “The Canadian case definition does include these critical symptoms (post-exertional malaise, memory and concentration problems) and use of such types of case definitions might aid in the selection of more homogeneous samples.”
As Jason shows sub-grouping is vital, not just levels of severity – which is not based on how long you have the illness, although this does create an impacting effect, but more on the levels of disability. Until we start trying to find the sub-groups of patients and stop creating such heterogeneous diagnostic research criteria, and using such to complete research, then we are not going to get such helpful results. The importance of the need for proper diagnostic criteria to be used within both clinical diagnosis and research cannot be reduced. The constant use of Oxford criteria within research leads to misleading research data as the only symptom needed to fulfil the Oxford criteria is fatigue. Fatigue on its own is not indicative of this illness, that is just Chronic Fatigue – this is Chronic Fatigue Syndrome, one of the subgroups of which is ME, and by definition a syndrome must compose of many symptoms, this is shown in this paper by the comment “the results of any study using such diagnostic categories are likely to be unreliable and/or invalid” – see also covering letter.
CARDIOVASCULAR DYSFUNCTION IN PATIENTS WITH ME/CFS
This is an important section for the Group to be aware of, as the sudden death, particularly of young people with severe ME in their 20’s and early 30’s, is often heart failure. They either collapse, or are found dead in their beds by their carers.
Abnormal Impedance Cardiography Predicts Symptom Severity in CFS
Researchers: Arnold Peckerman, Ben Natelson et al (2003 – USA)6
This is an important research paper that needs to be read. It may well provide some real answers to, if not the majority of ME sufferers, a sub-group of patients. We are also submitting 2 summaries of this paper, which may make it easier to understand the implications of this research. One ‘CFS is Heart Failure Secondary to Mitochondrial Malfunction’ by Dr Sarah Myhill who treats patients in the UK, and one ‘The Heart of the Matter: CFS and Cardiac Issues’ an interview with Dr Paul Cheney7, who has treated patients in the USA for more than 20 years.
This research at the New Jersey Medical Centre was funded by a multi-million dollar grant from the National Institute of Health (NIH). The US Government had wanted the research to try and find a physiological parameter that could be objectively measured and would correlate with the level of disability of the patient.
The researchers identified accumulating evidence to a possible problem with circulation in CFS. The reported findings included autonomic dysfunction, lower plasma volume and/or red cell mass, and abnormalities in neurohormonal systems of circulatory control. Although on their own abnormalities would be insufficient to cause a circulatory dysfunction, cumulatively they could produce significant deficiencies in organ blood flow and symptoms. Previous studies showed reduced blood flow to muscles using magnetic resonance spectroscopy, and nuclear imaging found evidence of post-exercise reduction in brain blood flow in CFS.
The researchers hypothesised that CFS patients have a reduced cardiac output, and they would measure this, using noninvasive impedance cardiography. Early analyses however indicated that reduction in cardiac output was characteristic of the patients most severely affected with CFS, rather than all patients with CFS. To meet the criteria for severe CFS, patients had to meet the more stringent 1988 CDC case definition, which requires >50% reduction in activities and 7 or more of the symptoms listed in the case definition, and at least 7 of those symptoms had to be substantial, or worse in severity, in the previous month. The patients were divided into severe and less severe for this study. The study also wanted to identify whether there are relationships between low cardiac output and specific CFS symptoms, which would be useful for further research.
Patients were tested in a temperature controlled room between 11 am and 1 pm. The study consisted of a 10 minute period of supine rest (laying down) followed by a 5 minute period of quiet standing. Impedance cardiograms were computer scored and edited without the subject group status to provide measures of stroke volume and pre-ejection period. Heart rate was measured from the electrocardiograph. Mean arterial pressure was recorded in synchrony with impedance cardiography.
Statistical analysis of the effects of illness were examined in analysis of variance for the severe, less severe and control groups on measurements taken in supine and standing positions. Symptom patterns descriptive of the severe CFS and their relationships with cardiac output were explored, respectively, with stepwise logistic and multiple regression analyses, using P<0.05 criteria for entry or removal. P<0.05 means there is a possibility that the association between the factor and the outcome is due to chance – so 0.01 means a 1% chance, and 0.0001 a 1 in 10,000 chance.
They found:
• Patients with severe CFS had lower supine stroke volume (P<0.03)
• Cardiac output (Q) was significantly lower in group with severe CFS, both in supine and standing positions (P0.03). From the graph, controls and less severe CFS patients showed a cardiac output of about 7 litres per minute when supine and about 4.8 on standing. For the severely affected the Q values of cardiac output are just over 5 litres supine and drops to about 3.5 litres standing. (this level is thought to be borderline for organ failure)
Looking at comparisons of reported symptoms of severe and less severe – post-exertional malaise and sore throats emerged as significant differences between the groups – providing correct identification for 88..5% of patients (P0.05 and 0.005)
• Lower cardiac output (the mean of supine and standing values) was associated with greater severity ratings for post-exertional fatigue and fever/chills, and lower ratings for a problem with memory and concentration (P<0.0001, 0.008, and 0.006 respectively).
• Comparison within the study illustrated the degree to which low levels of cardiac output in CFS patients were specifically related to the symptoms characteristic of severe CFS
• As a specific example of the relationship between post-exertional fatigue and cardiac output, increases in tiredness, after the testing, as measured by changes in the AD ACL energy scores, tended to be greater in patients with lower cardiac output (P<0.006)
Conclusions
• The correlation coefficient of 0.46 with P value of 0.0002 suggests that the disability level of those that were disabled was exactly proportional to the severity of their Q defect (Q stands for cardiac output in litres per minute)
• Results provide initial evidence of reduced cardiac output
• Suggests that in some CFS patients, blood pressure is maintained at the cost of restricted flow, possibly resulting in low circulatory state
• Therefore at times daily activities and demands for blood flow are not adequately met, compromising metabolic processes, in at least some vascular compartments.
• This finding would signify that some cases of CFS might be explained and potentially treated as low circulation problems.
• Several deficiencies capable of affecting cardiac output have been reported in CFS, including lower blood volume, impaired venous regulation and changes in autonomic, endocrine and cardiac function
• A percentage of patients with symptoms of CFS may in fact have covert heart disease
• Abnormalities causing a reduction in cardiac output in CFS may be dispersed over multiple body systems and changes in any of them may be subtle and difficult to detect
• This study does suggest interpretations regarding the causes of reduced cardiac output in severe CFS. The reduction in stroke volume was more clearly seen in the supine position and tended to improve during standing, indicating worsened cardiac performance under conditions of augmented preload.
• Contractility or diastolic function could affect stroke volume. Although this pattern is consistent with cardiac dysfunction, it could also be due to circulatory, neurogenic and endocrinologic abnormalities.
• Lack of heart rate differences does not preclude the possibility patients are moderately hypovolemic
• Reduction in cardiac output in CFS patients is unlikely to be due to deconditioning
• Secondary analyses, relating cardiac output to specific symptoms, found that post-exertional fatigue and symptoms in the infectious category, were the most characteristic in patients with severe CFS, and severity of these symptoms was associated with lower cardiac output
• Ratings of cognitive impairment were not predictive of reduced cardiac output. This suggests that problems outside of circulation produce cognitive deficits in CFS
• Reduction in cardiac output in CFS is not likely to fall within abnormal range, but this should not detract from the physiological significance. Even marginal reduction in cardiac output can result in selective under-perfusion of various organs and systems of the body, eg autoregulation, digestion in the gut etc
(Please also read Dr Myhill’s and Dr Cheney’s analysis of this paper)
CFS is Heart Failure Secondary to Mitochondrial Malfunction
Paper by Dr Sarah Myhill – UK8
Dr Myhill has written this paper and interpreted Dr Peckerman’s paper on Abnormal Impedance Cardiography very eloquently. She explains the impact of reduced cardiac output on all of the organs of the body. However she has taken the evidence a step further to mitchondrial malfunction.
Poor blood supply:
• Effects on skin – shut down of blood supply to the skin has 2 main effects – (1) patients become intolerant of heat – cannot lose heat through the skin so core temperature increases – to compensate body switches off the thyroid gland – giving a compensatory underactive thyroid – worsening the problem of fatigue. (2) Body cannot sweat – unable to help remove toxins from body
• Muscles – with impaired blood supply, muscles quickly run out of oxygen on exercise – they go into anaerobic metabolism – producing lactic acid – making muscles ache
• Liver and Gut – results in inefficient digestion in the gut, poor production of digestive juices and leaky gut syndrome (LGS). LGS cause other problems such as allergies, autoimmunity, malabsorption etc. Poor circulation in the liver results in poor detoxification eg heavy metals, pesticides, volatile compounds and toxins form gut fermentation
• Brain – Seeing scans of CFS patients Dr Myhill would have diagnosed strokes as blood supply to some areas of the brain was so impaired. This default is temporary and with rest, blood supply recovers. This however explains the multiplicity of brain symptoms, also brain cells are not well stocked with mitochondria, so run out of energy quickly.
• Heart – 2 effects – the first effect of poor micro-circulation to the heart is disturbance of the electrical conductivity causing dysrhythmias. Many CFS patients complain of palpitations, missed heart beats. The second is poor exercise tolerance. Heart muscle fatigues causing chest pain and fatigue. Long term it can cause heart valve defects because muscles holding the mitral valve open also fatigue. The difference between this type of heart failure and medically recognised congestive heart failure is that CFS patients protect themselves from organ failure because of their fatigue symptoms.
• Lung and Kidney – these organs are relatively protected from poor micro-circulation, because they have the largest renin angiotensin system, which keeps blood pressure up in these organs, so less likely to see CFS patients with kidney failure or pulmonary hypoperfusion.
Mitochondrial Malfunction – explanation of fatigue problems in CFS patients
Energy to the body is supplied by mitochondria, which produce Nicotinamide Adenosine Diphosphate (NAD) and Adenosine Triphosphate (ATP). Almost all energy requiring processes in the body uses NAD and ATP, but largely ATP. The reserves of ATP in a cell are very small eg a heart muscle cell has only enough ATP to last about 10 contractions. Therefore mitochondria have to be extremely good at recycling ATP to keep the cell constantly supplied with energy. If not this causes symptoms of weakness and poor stamina. The cell literally has to ‘hibernate’ and wait until more ATP is manufactured.
In producing energy, ATP (3 phosphates) is converted into ADP (2 phosphates). ADP is recycled back through mitochondria to produce ATP. But if the cell is pushed for more energy it will use ADP instead. The body can create energy from ADP to AMP (1 phosphate) – but AMP cannot be recycled. The only way that ADP can be regenerated is by making it from fresh ingredients, and this can take days to do. This explains the delayed fatigue seen in CFS. When patients ‘hit a brick wall’ this is because they have no ATP or ADP to function at all. This series of reactions is known as the Kreb’s Citric Acid Cycle and a process of oxidative phosphorylation. For ATP to cross the mitochondrial membrane it needs acetyl-L-carnitine and for ADP to cross back through the membrane it needs L-carnitine. Need a healthy diet and/or supplements to support this process.
Dr Myhill goes on in her paper to say how these problems might be addressed and possibly treated.
Prevalence of Abnormal Cardiac Wall Motion in the Cardiomyopathy Associated with Incomplete Multiplication of Epstein-Barr Virus and/or Cytomegalovirus in Patients with CFS
Researchers: Lerner et al (2004 – USA)9 -Abstract
The researchers reported unique incomplete herpes virus Epstein-Barr Virus (EBV) and/or non-structural (HCMV) cytomegalovirus multiplication in 2 distinct subsets of CFS patients. The CFS subsets were identified by:
• Presence of IgM serum antibodies to HCMV nonstructural gene products p52 and CM2 (UL44 and UL57 and/or
• IgM serum antibodies to EBV viral capsid antigen (EBV, VCA IgM)
• Diagnostic IgM serum antibodies were found in 2 independent blinded studies involving 49 CFS patients, but the same antibodies were absent in 170 controls (P<0.05)
• Abnormal 24 hour electrocardiographic monitoring, tachycardias at rest and, in severe chronic cases, abnormal cardiac wall motion (ACWM) were seen in these same CFS patients
The Group now report a prospective consecutive case control study form 1987-1999 of cardiac dynamics as measured by radionuclide ventriculography in 98 CFS aptients from 1987-1999. Controls were patients with various malignancies who were evaluated in protocols requiring radionuclide ventriculography before intitiation of cardiotoxic chemotherapeutic agents.
• The prevalence of abnormal cardiac wall motion (ACWM) at rest in CFS patients was 10 out of 87 patients (11.5%).
• With stress exercise, 21 patients (24.1%) demonstrated ACWM
• Cardiac biopsies in 3 of these CFS patietns with ACWM showed a cardiomyopathy
• Among the controls, ACWM at rest was present in 4 out of 191 patients (2%) – (P=0.0018)
The researchers conclude that a progressive cardiomyopathy, caused by incomplete virus multiplication of EBV and/or HCMV in CFS patients is present.
NB: Dr Betty Dowsett and Dr John Richardson (now deceased) worked with ME patients for over 50
Years. Both felt enteroviruses were highly implicated in the disease process of ME, and they also felt the enterovirus ended up in the heart. Excellent information can be found in Dr John Richardson’s book on Enteroviruses, and a documented history of his patients over 50 years.
Cardiac Involvement in Patients with CFS as Documented with Holter and Biopsy Data in Birmingham, Michigan 1991-1993
Researchers: Martin Lerner, James Goldstein et al (1997 – USA)10
Excellent paper that needs to be read
The researchers have observed that abnormal oscillating T-waves (eg falttening and/or inversions) in one or both pre-cordial leads (modified lead 1 or V5) at Holter monitoring are integral to CFS. In CFS patients, oscillating abnormal T-waves were regularly seen with the onset of sinus tachycardia, and the abnormal T-waves then resolved with reappearance of normal sinus rhythms.
Despite an absence of any known associated diseases in CFS patients, every CFS patient, but only 22.4% of the non-CFS patients, showed abnormal oscillating T-wave flattenings or inversions at Holter monitoring (P<0.01)
Mention is given here of another study by Rowe et al who reported abnormal tilt-table testing in a high proportion of CFS patients. They suspected an abnormal neural reflex or another unknown cause for their findings. (this is now a well recognised characteristic with many CFS patients.
A previous study by Lerner et al (pub 1994) showed 24% of 87 nonselected CFS patients from a recent consecutive case series exhibited left ventricular dysfunction, by stress radioisotopic multiple gated acquisition (blood pool image) (MUGA) method. They found abnormal left ventricular dynamics in patients in Birmingham 1987-94. Abnormal cardiac wall motion at rest and stress, dilation of left ventricle, and segmental wall motion abnormalities. Left ventricular ejection fractions at rest and with exercise, of as low as 30% were seen in CFS patients.
This study compares the prevalence of the abnormal T-wave oscillations at Holter monitoring in a new consecutive case series of CFS patients, with a similar case series in non-CFS patients from a cardiology practice. Also report on light and electron microscopic findings from right ventricular endomyocardial biopsies in 9 CFS patients. Abnormal T-wave oscillations (T-wave flattenings or T-wave inversions) of at least 25 normally conducted beats were necessary to be considered abnormal. These T-waves varied in frequency and depth, frequently appearing only with the advent of sinus tachycardias. Usually reverted to normal upright T-waves when the cardiac rate decreased to <100 bpm, often with sinus tachycardias >120 bpm T-wave inversions deepened further.
Sensitivity and specificity of T-wave inversions and T-wave flattenings in the diagnosis of CFS were calculated. Sensitivity was defined as the percentage of patients with CFS who met abnormal Holter monitoring findings, whereas specificity was measured by the percentage of non-CFS patients without these abnormalities. The predictive accuracy of T-wave inversions and flattenings for determining the presence or absence of CFS was calculated.
• 49 of 51 CFS patients exhibited oscillating abnormal T-wave flattenings – being a sensitive indicator of CFS, but this Holter monitoring abnormality is not specific.
• T-wave inversions are a less sensitive indicator of CFS, but they are a more specific finding
• Analysis of the combination of T-wave inversions and T-wave flattenings did not enhance the predictive value of these tests.
Light and Electron Microscopy of Cardiac Biopsies:
9 CFS patients underwent right ventricular endomyocardial biopsies. Specimens were taken from the right ventricular septum. 2 specimens were examined by light, and the other 7 by light and electron microscopy.
• One of the biopsies showed lymphocytic myocarditis
• 6 patients showed myocardial fibre hypertrophy
• 5 patients showed myofibre disarray
• 3 patients showed focal interstitial fibrosis
• 5 patients showed perimysial fat infiltration
• 6 patients showed increased mitochondria
• 5 patients showed increased fat droplets and increased lipofuscin granules in myofibres
• No patient showed myofibre necrosis, however one muscle fibre, in patient 4, under electron microscopy showed focal myofibre necrosis. These changes describe an early cardiomyopathy.
Conclusion:
8 of the 9 patients had a cardiomyopathic changes, and one had an inflammatory myocarditis. (This is an important study as sudden deaths in ME/CFS sufferers, especially in their 20’s and 30’s is due to cardiomyopathy – usually severe sufferers - who are found in their beds.
The abnormal oscillating T-wave flattenings and T-wave inversions at Holter monitoring, appear to be an essential element to the pathological physiology of the cardiomyopathy of CFS, and was an accurate indicator of the possible presence of CFS.
Circulating Blood Volume in CFS
Researchers: David Streeton and David Bell (1998 – USA)11
These are two very well respected researchers in the cardiovascular field relating to CFS.
They acknowledge that observations have linked CFS with neurally mediated hypotension and delayed orthostatic intolerance. Previous studies of the pathogenesis of both hyperadrenergic and hypoadrenergic orthostatic hypotension have shown that, in addition to the most invariable finding of excessive orthostatic blood pooling in the lower limbs attributable to subnormal venous constriction of the legs, reduction of red blood cell (RBC) mass is frequently present.
RBC mass and plasma volume were determined with standard methods, using 51Cr-labelled autologous red blood cells and 125I-labelled human serum albumin, respectively, in 5 university radiology departments.
A subnormal RBC mass and/or decreased circulating blood volume may well result in diminished cerebral blood flow with subnormal oxygen-carrying capacity. 3 patients in this study had normal RBC mass and plasma volume, but had similar symptomology. (? Sub-group)
The high prevalence of reduced RBC mass in these patients with severe CFS suggests that this abnormality may well be important to the pathogenesis of their persisting symptoms. Post polio fatigue bears striking resemblance to CFS. Hereditary factors may also play a role, perhaps through effects on autonomic nervous system function. Whatever its initiating cause, CFS may be perpetuated, at least in part, by low RBC mass in many patients.
Acetlycholine Mediated Vasodilation in the Microcirculation of Patients with CFS
Researchers: Vance Spence, Neil Abbot et al (2003 – UK) – funded by MERGE12
This will be a brief synopsis as MERGE will be presenting their research findings independently.
Research into this illness is hindered by the considerable heterogeneity (eg ME, CFS, PVFS, CFIDS) seen across patients, but several reports have highlighted disturbances in cholinergic mechanisms in terms of the central nervous system (CNS) activity neuromuscular function and auto-antibodies to muscarinic receptors. Apart from its neurotransmitter functions, acetylcholine is a well established and prominent vasodilator, whose action is dependent upon an intact layer of functioning endothelial cells that line the lumen of all blood vessels. This study looks at acetylcholine, and its role as generalised vasodilator.
A common test of endothelial integrity is the response of blood vessels to both endothelial-dependent vasodilators like acetycholine and endothelial-independent vasodilators like Nitric Oxide (NO) via an NO donor like sodium nitroprusside.
In most medical conditions associated with cardiovascular disease there is a blunted response to acetylcholine. However in MERGE's studies they have reported increased responses to a cumulative dose regime of Acetylcholine (Ach) delivered by iontophoresis into the microcirculation of CFS patients when compared to controls.
In 3 separate studies by these researchers they have demonstrated:
• Abnormalities of the ACH endothelium-dependent vasodilator pathway in CFS patients
• Sensitivity to Ach seems to be restricted to those patients within the CFS construct who fit descriptions for ME, PVFS, but not Gulf War Syndrome, Fibromyalgia, or Organophosphate exposure
• Increased sensitivity to ACh is normally associated with trained athletes, while CFS patients are characterised by having a substantial reduction in previous levels of activities
• Results are important in terms of vascular control mechanisms in this patient group and may be relevant to some of the unusual vascular symptoms, such as hypotension and the problems of orthostatic stability that is evident in most CFS patients.
• These findings are specific to endothelial cholinergic activity and may or may not be applicable to other more widespread neurotransmitter functions of Ach.
Recent evidence in a very small group of patients suggested that CFS might be the consequnece of cholinergic dysautonomia and that treatment with cholinesterase inhibiting agents might well be therapeutic. Such a hypothesis is in direct contrast with the findings of these studies so great CAUTION is needed in treating an illness with such heterogenity. It is important that the mechanisms underlying the pattern of abnormal peripheral endothelial cholinergic activity that this study has described in CFS patients is unravelled and that significance of altered cholinesterase activity, the prostanoid pathway and the role of endothelium-derived hyperpolarising factor (EDHF) is determined.
Two other papers from this group of scientists at MERGE with similar studies:
‘Enhanced Sensitivity of the Peripheral Cholinergic Vascular Response ion Patients with CFS’
‘Prolonged Acetylcholine-induced Vasodilation in the Peripheral Microcirculation of Patients with CFS’
Myalgic Encepahlomyelitis (ME) a Haemorheological Disorder Manifested as Impaired Capillary Blood Flow
Researcher: Dr Leslie Simpson (mid 1990’s – New Zealand) – Please read this paper
Dr Les Simpson was one of 3 amazing doctors, who despite being in their 80’s, had worked so hard to understand this complex and debilitating illness and most of all to help their patients. The other two are Dr Betty Dowsett, who worked with Dr Melvin Ramsey in the 1950’s and Dr John Richardson, sadly now passed away, both of whom continued with seeing and helping patients, and with their research into this illness.
Dr Les Simpson travelled the world to meet with ME patients and give talks to groups. Despite collecting thousands of blood samples from ME sufferers around the world and testing them, he, like many researchers into the pathophysiology of ME, had great difficulty in getting his research published. Now cardiovascualr problems are being more acknowledged in ME his work is being recognised.
BRAME published his paper in our newsletter ME TODAY issue 7 in March 1998, a copy of which has been sent for inquiry, please do try to read this paper.
• In his research over the past decade, Dr Simpson has found that more than 80% of ME patients have changed red blood cell shape population
• His earlier published work with ME patients showed altered blood rheology and subsequent tests using scanning electron microscopy of immediately fixed blood samples, which provided a basis for understanding the poor blood filterability.
• The blood of ME patients contains higher than usual proportions of one or other of the different cell shapes, notably increased percentages of cup transformed cells (stomatocytes), which are considered as a ‘marker’ for ‘acute ‘ ME, however these may persist for some years.
• Data presented at the Cambridge Symposium in 1990 also showed that increased cup forms was the most common change, but it also showed that a smaller number of both sexes had increased cells with altered margins. Increase percentages of these cells, or of flat cells or cells with surface changes are markers for ‘chronic’ ME.
• Impaired capillary blood flow results in inadequate rates of delivery of oxygen and nutrient substrates, having the greatest adverse effect on the tissues with great metabolic activity and high demand for substrates, eg muscles and glands
• Nervous tissue is particularly sensitive to oxygen deprivation – the brain has no capacity to store oxygen and can store only a minuscule amount of glucose. Normal brain function is dependent on normal rates of capillary blood flow to deliver these metabolites.
• Such observations imply that when reduced cerebral blood flow can be demonstrated brain function must be impaired commensurately.
• While it is claimed that psychological, psychiatric and cognitive problems are features of ME, it seems more likely that such morbidity is due to impaired cerebral blood flow.
• The different cell shapes, and an associated reduction in cell flexibility reduces their capacity to pass through capillaries smaller in diameter than the cell. This slows the flow of blood and increases it viscosity. As a result the oxygen, nutrients and hormones transported in the blood are delivered at a reduced rate and cell exhaustion may occur.
• A percentage of the population has unusually small capillaries that leaves them at risk of developing ME-like symptoms if their red cells become less flexible.
• The most severe symptoms will be associated with tissues and organs containing the smallest capillaries. This could account for different ME patients having a slightly different cluster of symptoms.
• The hypothalamus has an extremely dense capillary bed. Decreased blood flow to this part of the brain would account for the cognitive problems, sleep disturbances and emotional lability experiences by people with ME.
• The changes in red blood cell shapes correlate to physical and emotional stresses experienced by the patient, and patients who have improved can relapse following over-exertion.
• Capillary size cannot be changed. The solution is to try to improve the shape and flexibility of the red blood cells so they will flow more easily through the capillaries.
Dr Simpson suggests some possible treatments (not cures) to help patients improve.
• For those with cup-transformed cells – B12 injections help 50% (why the other 50% do not respond is not known)
• For those with other types of red cell shape change – 70% or more of cases respond to evening primrose oil. The effects of the oil are to increase the blood levels of prostaglandin E1. This hormone has been shown to increase red cell flexibility. Those who do not respond to evening primrose oil should explore the effects of fish oil rich in omega-3 fatty acids. These fatty acids improve red cell flexibility by a different mechanism to that of evening primrose oil. The suggested dose is 2 x 1000 mg capsules with food 3 times daily
NB: There has recently been a study published by Dr Basant Puri, who works at a London Hospital, that omega-3 fish oils are helpful for patients with ME/CFS. He wishes to extend these studies but has been unable to secure further funding.
Central Nervous System – Brain
Gray Matter – Volume Reduction in CFS
Research (Floris P de Lange et al - Netherlands 2004)13 mapping structural cerebral morphology and volume, by using high-resolution structural magnetic resonance images, using voxel-based morphometry. Additionally they also recorded physical activity levels to explore the relation between severity of symptoms and cerebral abnormalities. This research has shown that there is:-
• Significant global gray matter volume reduction in the CFS patients compared to controls.
• This decline in gray matter volume appeared to be more prominent in those patients who were more severely affected.
• This is an important and significant find as it is showing a possible link between the reduction of gray matter and the severity of illness.
• Found a significant 8% reduction of gray matter volume compared with healthy controls.
• This research shows that the Central Nervous System (CNS) plays a key role in the aetiology and pathophysiology of CFS.
• It points to a new objective and quantitative tool for clinical diagnosis of this disabling disorder.
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Mechanisms underlying fatigue: a voxel-based morphometric study of CFS
Research by Tomohisa Okada et al – Japan 200414 – MRI using voxel-based morphometry. This research has shown:-
• A significant reduction in gray-matter volume/atrophy in the bilateral prefrontal cortex areas of CFS patients
• The affected areas extended from BA8 to 9 in the right cerebral hemisphere and from BA9 to 11 in the left.
• In the study, right dorsolateral prefrontal-cortex atrophy was significantly correlated with the severity of fatigue.
• Study felt similar clinical manifestations of CFS and MS suggests a common pathogenesis underlying the symptoms of fatigue in both illnesses. This speculation is supported by the fact L-carnitine has been found to improve fatigue in both sets of patients.
• Found large decrease in acetyl-L-carnitine. This could be due to hypofunction of the frontal sub-cortical circuits, or the decrease could be due to the remote effects of the pathology in the dorsolateral prefrontoal cortex.
• This relates to the model by Chaudhuri and Behan (Fatigue and Basal Ganglia 2000) hypofunction of the dorsolateral prefrontal cortex might interrupt the associate striato-thalamo-corticol loop, resulting in enhanced fatigability.
• These results are consistent with previous reports of an abnormal distribution of acetyl-L-carnitine uptake, which is one of the biochemical markers of CFS, in the prefrontal cortex.
• Therefore the prefrontal cortex might be an important element of the neural system that regulates sensations of fatigue.
• The gray matter volume was reduced on average 11.8% in CFS patients, and in some areas up to 16.9% compared to healthy controls.
MERGE has an appraisal paper on these 2 research papers, which is easy to read, and highlights some of the main points. It also discusses whether the reduction in gray matter is the ‘cause’ or the ‘consequence’ of the illness. Important that 2 separate research groups have found correlations between loss of gray matter and patients symptoms/severity.
MERGE has also being doing research with oxidative stress and feel that it is possible that this could involved as gray matter of the brain appears more susceptible to oxidative stress than white matter, and is the likely primary target of oxidative stress at all ages. There are a number of reports now linking raised levels of oxidative stress in the tissues with ME/CFS.
Brain Magnetic Resonance (MR) in CFS
Research by Greco, Tannock, Brostoff, Costa (1997)15 to determine the prevalence of MR white matter abnormalities in patients with CFS. Studies found:-
• Although abnormalities were found in some patients, this was not specific to CFS.
• However there was a trend toward more abnormalities in the CFS subgroup of patients with no depression or associated other psychiatric disorders than in the control group.
• Some showed fronto-parietal subcortical white matter foci of high T2 signal.
Brainstem Perfusion is Impaired in CFS
Research by Costa, Tannock, Brostoff (1995)16. Research showed:-
• Widespread reduction of regional brain perfusion in 24 ME/CFS patients compared to 24 normal controls.
• Hypoperfusion of the brainstem was marked and constant
• A larger study of 146 subjects – including with depression, psychiatric disorders and epilepsy. Brain perfusion ratios were calculated using Tc-HMPAO and SPET with GE Neurocam
• Brainstem hypoperfusion was confirmed in all ME/CFS patients
• The ME/CFS patients with no psychiatric disorders showed significantly lower brainstem hypoperfusion than depressed patients.
• Patients with ME/CFS have a generalised reduction of brain perfusion, with a particular pattern of hypoperfusion of the brainstem.
Altered CNS signal during motor performance in CFS
Research by Vlodek Siemionow et al (2004 – USA)17
Objective: The purpose of the study was to determine whether brain activity of CFS patients during voluntary motor actions differs from that of healthy individuals.
8 CFS patients and 8 matched controls performed isometric handgrip contractions at 50% maximal voluntary contraction level. They first performed 50 contractions with a 10 sec rest between adjacent trial – Non-Fatigue Task (NFT).Subsequently the same number of contractions was performed with only a 5 sec rest between trials – Fatigue Task (FT). 58 channels of surface EEG were recorded simultaneously from the scalp. Spectrum analysis was performed to estimate power of EEG frequency in different tasks. Motor activity-related corticol potential (MRCP) was derived by triggered averaging of EEG signals associated with the muscle contractions
Results of study:
• Motor performance of the CFS patients was poorer than the controls
• Relative power of EEG theta frequency band (4-8Hz) during performing the NFT and FT tasks was significantly greater in the CFS than control group
• The amplitude of MRCP negative potential (NP) for the combined NFT and FT tasks was higher in the CFS than control group
• Within the CFS group the NP was greater for the FT than NFT task, whereas there was no difference in the control group
Conclusion: These results clearly show that CFS involves altered central nervous system signals in controlling voluntary muscle activities, especially when the activities induce fatigue. Physical activity-induced EEG signal changes may serve as physiological markers for more objective diagnosis of CFS.
A Chronic Fatigue Syndrome – related proteome in human cerebrospinal fluid
Research by Baranuick et al – 2005 –USA18 – This paper needs to be read as there are many significant findings. Some findings are:-
• Independently tested cohort 1 pooled group, and then a separate individually tested cohort 2 group.
• SF-36 Scores: The pooled CFS group (cohort1) and CFS individuals (cohort 2) had equivalent scores for each domain. The CFS scores for most domains were significantly different from the respective healthy control scores (domains listed in the paper). Their presence in the CFS-associated proteome suggested a potential pathophysiological link.
• Proteomics of Cohort 1 - The 20 proteins detected in CFS patients, but not in the healthy controls, were defined as the ‘cohort 1 pooled CFS proteome’, The most pertinent of these matched proteins had probable origins in plasma or the central nervous system (see paper for more details)
• Proteomics of Cohort 2 – there were 16 proteins found only in the CFS patients of the second individualised study, identified as the ‘cohort 2 CFS-related proteome’.
• These 2 independent assessments identified 10 of these 16 proteins shared by the cohort 1 and cohort 2 CFS proteomes – and not detectable in healthy samples.
• This degree of protein matching between 2 independent populations of CFS patients was highly unlikely to be a random event.
• Some proteins identified were significantly associated with CFS status and gender. It suggests that other gender-related factors may be found in future surveys given the female predominance.
• Predictive statistical model for CFS from cohort 2 – Multilogistic analysis demonstrated that a smaller set of 5 proteins could identify all of the cohort 2 CFS subjects. They were α-2-mac, APLP1, K16, OMD2, and PEDF. Subjects who had detectable levels of at least 1 out of these 5 proteins had an odds ratio of 34.5 in favour of having CFS regardless of gender. This new ‘biosignature’ variable of having ≥ 1 out of 5 proteins present in the cerebrospinal fluid was defined as B1/5
• This was used in a logistical model to predict CFS status for the subjects in cohort 2 –
CFS status = gender + B1/5
• The model was significant (converged asymptotically) and had a concordance rate of 80%. To the researchers knowledge this is the first model to predict CFS status based solely on objective data.
• The CFS-associated proteome and B1/5 were consistent with the researchers’ hypothesis that a common pathological mechanism was shared by the CFS spectrum of illnesses, and was independent of the set of symptoms expressed by each individual.
• This research showed a differential protein expression in this syndrome
• Further studies could possibly refine the CFS-related proteome and the terms of the biosignature variable for predicting CFS status and related syndromes, from other fatigue and chronic pain states, and inflammatory central nervous system disorders.
• Antiproteases, antioxidant, pro- and anti-inflammatory proteins suggested activation of the cerebrospinal innate immune system.
• Significantly more frequent detection of heme scavengers in CFS (55%) compared to healthy controls (15%). Number of CNS conditions may lead to localized bleeding with haemoglobin release with the induction of heme sequestering proteins. One large group meeting these characteristics are the cerebral amyloid angiopathies (CAA) (cerebrovascular amyloidosis). CAA syndromes are defined by protien misfolding, perivascular amyloid deposition, weakening of vessel walls, micorhaemorrhages to severe cerebral infarction, and dementia or sudden death in 3rd to 5th decades. The CFS spectrum of illnesses do not show higher than normal rates of death in this way so felt unlikely to be due to a currently identified CAA syndrome. However the researchers hypothesise that a mild, focally transient or reversible form that does not lead to either permanently damaging or lethal haemorrhage or dementia may occur in CFS. This hypothesis would explain many of the parallels between the proteins associated with CAA syndromes and the CFS-related proteome.
• Other components of CFS-related proteome promote amyloid deposition – these become activated in amyloidosis and Alzheimer’s disease
• Hypothesize that the presence of keratin 16 in CFS-associated proteome was an indication of epithelial cell activation within the CNS in CFS
• The ‘protein swapping’ mechanism detected is analogous to a DNA recombination-like process
• An alternative to the CAA hypothesis is glial cell activation with the release of innate immune and regulatory factors. Activation of leptomeningeal cells with the secretion of several of the proteins listed. CFS syndromes may be initiated by unknown factors that activate these cells, or they may activate anti-inflammatory and innate immune defences as a result of the original insult. These possibilities may be addressed in future studies and by comparison of the proteomes from CFS subjects with different durations and patterns of illness.
• This research developed an objective model to predict CFS status based only on the proteomic detection of the 5 proteins, keratin 16, ∝-2-macroglobulin, orosomucoid 2, autotaxin, and pigment epithelium-derived factor. This is the first predictive model of CFS to be based on objective data and legitimise the hypothesis that a common CNS pathophysiology was present in the CFS spectrum of illnesses. Individual proteins or their patterns of detection may prove valuable biomarkers in diagnostic assays. These assays may gauge disease severity, dynamic variations in symptomology, and longitudinal alterations with age or treatments.
• From these results the researchers propose the hypothesis that CFS may be a nonlethal, protein-misfolding, cerbrovascular amyloidosis-like syndrome.
• Given the continued controversy over whether CFS and its allied syndromes are legitimate medical conditions, the researchers’ state that their proteomic model provides initial objective evidence for the legitimacy of CFS as a distinct neurological disease.
Spinal Fluid Abnormalities in Patients with CFS
Research by Ben Natelson et al (2005 – USA)19
In parallel work these researchers have reported data suggesting that some patients with CFS have neurological dysfunction. Specifically those patients with a sudden illness onset, as well as those with no history of psychiatric diagnosis had more evidence of cognitive dysfunction than other CFS groups. Also showed that CFS patients with no history of psychiatric diagnosis had more abnormalities on brain magnetic resonance imaging (MRI) and that those patients with MRI abnormalities had poorer physical function. Relevant linked papers to these observations can be found in this paper.
• Outcome measures in this research were the white blood cell count, protein concentration in spinal fluid, and cytokines detectable in spinal fluid.
• The study found significantly more CFS patients had elevations in either protein levels, or number of cells, than healthy controls (30 versus 0%)
• Patients with abnormal fluid had a lower rate of having co-morbid depression.
• 11 cytokines were detectable in the spinal fluid
• Cytokine – levels of granulocyte-macrophage colony stimulating factor were lower in patients than controls
• Levels of interleukin-8 (IL-8) were higher in patients with sudden, flu-like onset, than gradual onset or in controls
• IL-10 levels were higher in patients with abnormal spinal fluids than normal fluids or controls
• The researchers feel the results support 2 hypotheses
• 1 – That some CFS patients have a neurological abnormality that may contribute to the clinical picture of the illness and
• 2 – Immune dysregulation within the central nervous system may be involved in this process.
• A recent study showing elevations of IL-8 and IL-10 levels during chemotherapy-induced symptoms resembling some of those seen in CFS provides additional evidence for this hypothesis. (see ref in this paper)
Objective evidence of cognitive complaints in CFS: A BOLD fMRI study of verbal working memory
Research by Lange et al (2005 – USA)20
Using a series of 2 Blood Oxygen Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) to compare BOLD signal changes between controls and individuals with CFS who had difficulties in complex auditory information processing (study 1) and those who did not (study 2) in response to performance on a simple auditory monitoring and a complex auditory information processing task (mPASAT).
Researchers hypothesised that under conditions of cognitive challenge individuals with CFS with this problem will utilise frontal and parietal brain regions to a greater extent than controls. Blocked design fMRI paradigms was used in both studies and statistical parametric mapping (SPM99).
Findings showed that individuals with CFS are able to process challenging auditory information as accurately as controls but that they utilise more extensive regions of the network associated with the verbal WM system. They appear to have to exert greater effort to process auditory information as effectively as similar healthy adults. These findings provide objective evidence for the subjective experience of cognitive difficulties in individuals with CFS.
Research in Function of Hypothalmic-Adrenal-Pituitary Axis
This has long been felt to play a major part in ME/CFS - to date research has found some changes in this area, but further research is needed.
HPA Axis Reactivity in CFS and Health under Psychological, Physiological and Pharmacological Stimulation
Research by: Gaab et al (2002 – USA)21 This study found:-
• Significantly lower adrenocorticotrophin hormone (ACTH) responses in the psycho-social stress test and the exercise test
• Significantly lower ACTH responses in the Insulin Tolerance Test (ITT), with no differences in plasma total cortisol responses.
• Salivary-free cortisol responses did not differ between the groups in the psycho-social stress test and the exercise test BUT were significantly higher for the CFS patients in the ITT.
• In all tests CFS patients had significantly reduced baseline ACTH levels
The researchers concluded that these results suggested that CFS patients are capable of mounting a sufficient cortisol response under different types of stress, but that on a central level subtle dysregulations of the HPA axis exist.
24-hour Pituitary and Adrenal Hormone Profiles in CFS
Research by: A Di Giorgio, Tony Cleare et al (2005 – Italy)22
Disturbances of neuroendocrine function particularly the HPA axis have been implicated in the pathophysiology of CFS. This study aimed to measure the blood levels of pituitary and adrenal hormones over a whole 24-hour period, to assess 24-hour pituitary and adrenal function.
15 medication-free CFS patients, without co-morbid psychiatric disorder, and 10 healthy controls were tested. Blood samples were collected over a 24-hour period – on an hourly basis during daytime hours (10am-10pm) and every 15 minutes thereafter (10pm-10am). The blood samples were assayed for cortisol, corticotropin (ACTH), growth hormone (GH) and prolactin (PRL).
Results: There was a reduced mean ACTH secretion in patients with CFS over the whole monitoring period, and a group-by-time interaction, suggesting a differential pattern of ACTH release. Analysis showed reduced ACTH levels in CFS during the 8am to 10 am period. No differences were found in the cortisol circadian rhythm parameters, but the ACTH rhythm did differ, patients with CFS showing an earlier acrophase. There were no significant abnormalities in the levels of cortisol, GH and PRL.
Conclusion: Patients with CFS demonstrated subtle alterations in HPA axis activity characterised by reduced ACTH over a full circadian cycle and reduced levels during the usual morning physiological peak ACTH secretion. This provides further evidence of subtle dysregulation of the HPA axis in CFS. Whether this dysregulation is a primary feature of the illness or instead represents a biological effect secondary to having the illness itself remains unclear.
Diurnal Patterns of Salivary Cortisol and Cortisone Output in CFS
Research: Tony Cleare, Simon Wessley et al (2005 –UK)23
Study to obtain a naturalistic measure of diurnal HPA axis output unaffected by medication of comorbid psychiatric disorder. Cortisol and Cortisone levels were measured in saliva samples collected from 0600 to 2100 in 3 hourly intervals in patients and controls.
The study showed mean cortisol and cortisone concentrations were significantly lower in CFS patients than controls across the whole day, as were levels at each individual time point except 2100. Significant diurnal rhythm of cortisol and cortisone that was not phase-shifted in CFS compared to controls. Conclusion:
• This study provides further evidence for reduced basal HPA axis function in at least some patients with CFS
• Shows for the first time that salivary cortisone is also reduced in CFS and has a diurnal rhythm similar to that of cortisol.
• Also demonstrated cortisol/cortisone ratio remains unchanged in CFS, suggesting that increased conversion of cortisol to cortisone cannot account for the observed lowering of salivary cortisol.
Disturbed Adrenal Function in Adolescents with CFS
Researchers; Segal, Hindmarsh & Viner (2005 – UCL London)24
This study tested adrenal function in children and adolescents by testing serum cortisol concentrations at 5 minute intervals from 10-45 minutes. Low dose (500ng/m2) synacthen tests (LDST).
• Patients with CFS had significantly lower mean cortisol levels during the LDST, lower peak cortisol, reduced cortisol area under curve (AUC) and longer time to peak cortisol.
• Abnormalities were seen in both sexes but were more pronounced in females.
• Unstimulated adrenal androgen and 17 hydroxyprogesterone concentrations were normal.
Conclusion: Adolescents with CFS have subtle alterations in adrenal function suggesting a reduction in central stimulation of the adrenal glands. The more pronounced effects in females may reflect differential central effects of stress on HPA axis regulation between the sexes.
Brain 5-HT1A Receptor Binding in CFS measured using Positron Emission Tomography (PET) and (11C)WAY-100635
Researchers: Tony Cleare et al (2005 – London)25
This study assessed brain 5-HT1A receptor binding potential directly using PET and specific redioligand (11C)WAY-100635. 10 patients and 10 controls – medication free and did not have comorbid psychiatric illness.
There was a widespread reduction in 5-HT1A receptor binding potential in CFS relative to controls. This was particularly marked in the hippocampus bilaterally, where a 23% reduction was observed. Researchers concluded that there is evidence of decreased 5-HT1A receptor number or affinity in CFS, this may be a primary feature of CFS, related to underlying pathophysiology, or a finding secondary to other processes.
Pituitary-Adrenal Function in People with Fatiguing Illness - At present an eminent and well-respected US researcher Ben Natelson has an ongoing study to evaluate and compare the function of the HPA axis between Gulf War Veterans and CFS patients.
Adrenal Function - The Adrenal Stress Profile Test (ASP) looks at cortisol and DHEA levels over 24 hours by sampling salivary samples. Cleare et al – Lancet 1999 - Low cortisol levels were found and a course of low dose hydrocortisone was prescribed. This resulted in ‘significant reduction in self-rated fatigue and disability in patients with CFS’. Researchers felt this shed interesting light on the possible role of low cortisol levels in the disease processes involved in CFS. But CAUTION is required as participants’ baseline cortisol levels could not predict their response to hydrocortisone treatment and participants appeared to have baseline cortisol levels within the normal reference range. McKenzie et al - 1998 – USA – followed a similar research study, giving small daily doses of hydrocortisone (20-30 mg at 8am and 5 mg at 2 pm for 12 weeks). This induced mild suppression of the HPA axis and resulted in only slight symptomatic improvement, the authors appropriately concluded that their regimen, or comparable doses of other glucocorticoids, should not be used for prolonged treatment of CFS.
GENE EXPRESSION IN ME/CFS PATIENTS
Association between CFS and the Corticosteroid-Binding Gene ALA SER224 Polymorphism
Researchers: Torpy et al (2004 – Queensland Australia) – Abstract26
CFS is characterised by idiopathic fatigue with post-exertional exacerbation and many other symptoms. A trend to relative hypocortilism is described in CFS. Twin and family studies indicate a substantial genetic aetiological component to CFS Recently severe corticosteroid-binding globulin (CBG) gene mutations have been associated with CFS in isolated kindreds. Human leukocyte elastase, an enzyme important in CBG catabolism at inflammatory sites, is reported to be elevated in CFS.
The researchers hypothesised that CBG gene polymorphisms may act as a genetic risk factor for CFS. 248 patients and controls were recruited. Sequencing and restriction enzyme testing of the CBG gene coding region allowed detection of severe CBG gene mutations and a common exon 3 polymorphism. Plasma CBG levels were measured by radioimmunoassay. Total and free cortisol levels were ascertained in single samples between 8-10 am. A trend toward a preponderance of serine224 homozygosity among the CFS patients was noted.
Homozygosity for the serine allele of the CBG gene may predispose to CFS, perhaps due to an effect on HPA axis function related to altered CBG-cortisol transport function or immune-cortisol interactions.
Gene Expression in Peripheral Blood Mononuclear Cells from Patients with CFS
Research by Jonathan Kerr et al (2005 – UK).27
The objective of the research was to test the hypothesis that there are reproducible abnormalities of gene expression in patients with CFS compared to normal healthy controls and to enable them to gain further insight into the pathogenesis of this disease.
Researchers selected 25 patients with CFS – these included those, whose disease was severe and necessitated bed rest for much of the day, and those whose disease was of a milder nature, and 25 blood donors for healthy controls. Researchers studied gene expression in peripheral blood mononuclear cells (PBMC) using a microarray, and using Taqman real time Polymerase Chain Reaction (PCR) to confirm those genes being differentially expressed between the groups.
Researchers found:-
• Microarray analysis – this analysis identified 35 genes that showed significantly different expression in patients with CFS compared to normal controls
• The degree of expression of these 35 genes revealed a cluster of 18 subjects, 17 CFS patients and 1 control
• Taqman real time PCR – was used to confirm the importance of genes identified using microarray analysis
• Significantly different expression was confirmed for 16 of 33 genes.
• This method revealed upregulation of 15 genes and downregulation of one gene
• In general the standard deviation of these 16 genes in normal persons is very much lower than in patients with CFS, except for IL-10RA. A full list of the 16 genes can be found in the paper.
• Although these genes do not fit neatly into known metabolic pathways, several broad themes are apparent – T-cell activation and neuronal and mitochondrial function.
• T-cell activation is suggested by upregulation of CD2BP2 and downregulation of IL-10RA – in addition PRKCL1 plays a role in immune response.
• Genes that are active in the immune response have been found to be differentially expressed in all studies of gene expression in CFS, as have genes that are crucial for T-cell activation.
• These findings are consistent with previous studies (see paper) showing that patients with CFS have evidence of immune activation, such as increased numbers of activated T cells and cytotoxic T cells, and raised circulating cytokine concentrations.
• The upregulation of EIF4G1 identified in this study may represent a common host response to persistent infection with several different viruses. The vulnerability of this gene may have particular importance in the development of CFS after an acute virus infection.
The researchers concluded that there was a differential expression of 16 genes in CFS patients compared to normal controls. The involvement of genes from several disparate pathways suggests a complex pathogenesis involving T-cell activation and abnormalities of neuronal and mitochondrial function, and suggests possible molecular bases for the recognised contributions of organophosphate exposure and virus infection.
This research was funded by the CFS Research Foundation.
NB: This research is currently being extended to a much larger population (involving 1000 patients) and results are looking very similar to the initial smaller study. This study is reaching its conclusion and should be reported shortly.
Association of CFS with human leucocyte antigen class II alleles
Research by Jonathon Kerr, Tony Cleare, Simon Wessley et al (2005 – UK)28
This research studied the role of HLA class II antigens in CFS. 49 patients diagnosed with CFS at Kings College, London and 102 normal individuals were studied. 25 of the 49 CFS patients were not depressed and 24 were depressed. Patients and controls were typed for HLA class II alleles by PCR using sequence specific primers, with DNA extracted from whole blood. Research found:-
• There were no HLA class II associations with depression versus non-depression within the CFS group
• Results suggest that HLA-DQA1*O1 may be the primary association with CFS. This allele has been associated with few disease conditions, although associations have been found with tubulointerstitial nephritis and uveitis syndrome, and hyper-response to measles vaccine.
• There was also a marginal increase in the expression of HLA-DQB1*O6
• Additional sub-typing of both of these alleles will be necessary to identify which particular sub-types are important.
• These results suggest an association between CFS and the HLA class II region, primarily the HLA-DQA1*O1 allele.
• Because of the strong linkage disequilibrium between genes in this region, an association with other genes within the HLA locus cannot be ruled out. Further studies are needed.
In conclusion, the current available data on immune cell and cytokine deregulation in CFS are consistent with an immunomodulatory role for the HLA system in this disease.
Dr John Gow and colleagues at the University Department of Neurology in Glasgow has been doing a similar study to seek a ‘biomarker’ for the illness ME/CFS using novel microarray technology and researching the gene expression of ME/CFS patients against healthy controls. Dr Gow’s team has suggested alterations to genes controlling the metabolism of prostaglandin and those regulation-specific immune cells. This could lead to a specific ‘gene signature’ for particular proteins being revealed. It is felt once the microarray test has been developed and in regular use, the cost for patients being tested could be as little as £50.
This work has been supported by MERGE who will present the full report. But it further reinforces the work of Dr Jonathon Kerr et al.
Integration of Gene Expression, Clinical, and Epidemiological Data to Characterise CFS
Research by Suzanne Vernon, Toni Whistler et al (2003 – USA)29
This study used the integration of peripheral blood gene expression results with epidemiological and clinical data to determine whether CFS is a single or heterogenous illness. Results of such research they feel may help to identify CFS sub-groups. Deciphering the physiological basis for CFS would go far in accessing the heterogenity of the illness and would advance diagnosis and treatment.
Research found:-
• CFS patients were grouped with respect to variables and the mean difference between their gene expression values then compared
• This approach identified 117 genes that were differentially expressed when they were grouped by on-set type (gradual or sudden).
• For this reason only 117 genes identified by two-class analysis were examined further.
• The majority of subjects clustered according to onset type and the genes fell into two distinct clusters.
• Expression of 19 of the 117 genes was increased, in the gradual compared to the sudden onset group, while the expression of the remaining 98 genes was decreased.
• Fig 3 in the paper summarises the functional classification of all 117 differentially expressed genes with respect to cluster group
• 24 genes are associated with metabolism – 20 of which were down-regulated in the gradual onset cluster – mainly involved with regulation of glycolysis, glucose and disaccharide metabolism, oxidative phosphorylation, amino acid biosynthesis, and purine or pyrimidine metabolism.
• Oxidative phosphorylation and the ATP generated by this process are the major source of energy for the normal function of most cells in the body.
• Of the 19 up-regulated genes, some were involved in metabolism, but were not statistically significant.
• The 7 genes involved in RNA processing were, however, statistically significant in this group
• Many RNA processing proteins are central to the effective action of the antiviral interferon
• Alterations in effective anti-microbial responses may also explain the chronic fatigue state
• The researchers identify that physiological stressors such as infection, trauma and toxins can trigger the development of CFS in susceptible individuals.
• In most studies subjects have been ill for many years, making it difficult to detect initial disease triggers, as causal factors may be difficult to detect or no longer present. In addition, in many diseases, factors associated with disability are distinct from causative factors. Biomarkers have the potential to give clues to disease aetiology as well as mode of action.
• Different gene expression profiles among those who describe a difference in illness onset imply distinct aetiological or triggering events, and shows that these differences are maintained well into the disease process.
In conclusion this research should advance the cause for defining CFS at a molecular level, resulting in diagnosing and possible identification of causative agents, and the genes may serve as a platform to further explore relevant mechanisms of pathogenesis and improve the understanding of the molecular basis of CFS.
Exercise Responsive Genes Measured in Peripheral Blood of Women with CFS and Matched Control Subjects
Researchers Suzanne Vernon, Toni Whistler et al (2005 – USA)30
Aim: To search for markers of CFS-associated post-exertional fatigue, measuring peripheral blood gene expression profiles of women with CFS and matched controls before and after exercise.
Research found:
• Exercise response genes were evaluated before and after exercise and 21 genes were identified as being differentially expressed
• 16 of the 21 genes could be categorised in the Gene Ontology (GO) of biological process and 15 in molecular function.
• 5 of the 21 genes were involved in the biological process of transport (both vesicle-mediated and protein transport)
• Since these 21 genes reflect a healthy subject’s peripheral blood gene expression response to exercise challenge, this could be compared to the CFS subjects.
• The response of 10 of the 21 genes was similar in both groups
• For the other 11 genes the magnitude of exercise change was considerably smaller in CFS subjects
• With regard to the GO categories of the 21 genes, 10 genes were associated with binding and 8 with metabolism
• Healthy Controls: Exercise in healthy untrained people induces changes in homeostasis in 1 to 4 hours and a return to basal levels in 24 hours as measured in muscle. Analysis of peripheral blood gene expression confirmed this observation since the majority of the gene expression levels were the same before and 24 hours after the exercise challenge. Many of the 21 exercise-induced, differentially expressed genes in control subjects were characterised by GOs that reflect a diverse set of molecular functions necessary for cell function and viability.
• CFS Patients: In comparison, 11 of the genes were unchanged in CFS subjects before and after exercise, with 5 being classified in a transport-related ontology. Because this difference in gene expression is so dramatic, it implicates a fundamental perturbation in the biochemical activity of lymphocyte and monocyte peripheral blood fractions from CFS subjects compared with the controls that does not affect classical immunological markers (ie CD45) that have been shown to be unaffected in CFS patients. Rather, low expression of these genes may have subtle effects on immune function. Immune dysfunction has been inconsistently implicated in CFS pathogenesis.
• The GO categories with significant difference after exercise were those pertaining to ion transporter activity (87 genes applied to this category in comparison of CFS and controls following exercise) and ATPase activity coupled to transmembrane movement (42 genes).
• It is evident that ion transport and ion channel activity segregate cases from controls and that exercise seems to intensify these differences.
• Several other illnesses with fluctuating fatigue have abnormal ion channels. These include genetically determined channelopathies and acquired conditions such as neuromyotonia, myasthenic syndromes, multiple sclerosis, and polyneuropathies.
• The other transmembrane function difference between CFS patients and controls, include transducer activity through receptor binding/activity. Signal transduction of transmembrane receptors occurs by a number of mechanisms, including structural changes, ion channels, and changes of transmembrane potentials. The G-protein-coupled receptors play an important role in the membrane trafficking machinery.
The most obvious exercise-induced changes in CFS cases pertain to gene regulation at the point of chromatin structure – whether these changes reflect the differences seen in the mRNA transcripts relating to membrane trafficking differences between cases and controls has not yet been determined. One interesting correlate of this study was the finding that the complement pathway, and complement activation was identified as an ontology, showing significant differences between CFS and controls subjects after exercise.
Differential-display PCR of Peripheral Blood for Biomarker Discovery in CFS
Researchers: Steinau, Unger, Vernon et al (2004 – CDC – USA) – Abstract31
Used differential-display PCR of peripheral blood mononuclear cells (PBMCs) to search for candidate biomarkers for CFS. PBMCs were collected from patients and controls before and 24 hours after exercise. RNA expression profiles were generated using 46 primer combinations, and the similarity between individuals was striking. Differentially expressed bands were excised, reamplified, and sequenced, yielding 95 nonredundant sequences.
• Of these 38 matched to genes of unknown function
• 7 had no similarity to any database entry
• 86% of the differences between the 2 subjects were present at baseline
• Differential expression of 10 genes was verified by real-time reverse transcription PCR
• 5 genes – cystatin F, MHC class II, platelet factor 4, fetal brain expressed tag, and perforin – were down-regulated in CFS patients
• The remaining 5 genes – cathepsin B, DNA polymerase epsilon4, novel EST PBMC191MSt, heparanase precursor, and ORF2/L1 element – were up-regulated in CFS patients
• Many of these genes have known functions in defence and immunity, thus supporting prior suggestions of immune dysregulation in the pathogenesis of CFS
PCR is a powerful tool for identification of candidate biomarkers and the real-time reverse-transcript PCR assays developed for assay of these biomarkers will facilitate high-throughput testing.
Identification of Novel Expressed Sequences, Up-regulated in the Leucocytes of CFS Patients
Researhers: Powell et al (2003 – UK) – Abstract32
12 short expressed sequence tags were identified that were over-expressed in lymphocytes from CFS patients -–2 of these correspond to cathepsin C and MAIL 1 – genes known to be up-regulated in activated lymphocytes. The researchers conclude their research adds weight to the idea that CFS is a disease characterised by subtle changes in the immune system.
Association between Serotonin Transporter Gene Polymorphism and CFS
Researchers: Narita et al (2003 – Japan) Abstract33
Interaction between HPA axis and serotonergic system is thought to be disrupted in CFS patients. Examined a serotonin transporter (5-HTT) gene promoter polymorphism, which affects the transcriptional efficiency of 5-HTT by using PCR amplification of the blood genomic DNA.
A significant increase of longer (L and XL) alleic variants was found in CFS patients compared to controls, both by genotype-wise and allele-wise analyses. Attenuated concentration of extracellular serotonin due to longer variants may cause higher susceptibility to CFS.
A Twin Study of the Etiology of Prolonged Fatigue and Immune Activation
Researchers: Hickie, Lloyd et al (2001 – Australia)34
NB: this is a paper which may be presented to the Group, and whilst it may highlight some points, as we will here, it must be remembered that this is a paper looking into Prolonged Fatigue States (PFS), of which they think CFS may be related in some way, because of the fatigue element of the illness. Being psychiatrists they are looking more at the activation of the immune state in relation to the psychological state,
They looked at 79 pairs of monozygotic twins (MZ) and 45 pairs of dizygotic twins (DZ). Multivariate genetic and environmental models were fitted to explore the patterns of covariation between aetiological factors. They found:
• For fatigue, the MZ correlation was more than double the DZ correlation, indicating strong genetic control of familial aggregation
• By contrast, for in vitro immune activation measures MZ and DZ were simialr, indicating the aetiological role of shared environments
• Relevant aetiological factors included:
• (1) A common genetic factor accounting for 48% of the variance for fatigue, which also accounted for 4%, 6% and 8% reductions in immune activation;
• (2) specific genetic factors for each of the in vitro immune measures; a shared environment factor influencing the 3 immune activation measures;
• (3) Most interestingly environmental influences which increased fatigue but also increased markers of immune activation;
They conclude that PFS that are associated with in vitro measures of immune activation are most likely to be the consequence of current environmental factors rather than genetic factors. Environmental factors could include physical agents such as infection and/or psychological stress.
However they end the paper ‘the actual clinical pheno-type will ultimately depend on the interplay between these various specific environmental and genetic factors. Prospective studies of specific infective agents provide an important methodology for further clarification of the aetiological contribution of each agent, while alternative genetic methods may lead to clarification of the specific genetic factors involved in the genesis of some other types of prolonged fatigue states, notably CFS.
Non-responder gene
Been unable to get a research paper on this. It was in the Guardian newspaper on 14 January 2006 – Wellbeing section. Research by Pennington Biomedical Research Centre at Louisiana State University suggests that some people simply do not respond to exercise. More than 700 people were put through a challenging 20 week endurance training programme and, while markers of aerobic fitness improved by 17% on average, some people showed no improvement at all, while others improved by as much as 40%. ‘The inheritability of responsiveness to exercise is at least as great as body weight, blood pressure and cholesterol levels’ says Claude Bouchard, on eof the researchers. He estimates that about 10% of the population will never get any fitter through exercise – neither losing weight, nor improving strength, speed or stamina.
This may be totally irrelevant, but it may be there is such a gene, and this is one of a number of genes, which is further compromised and affecting the wellbeing of people with ME/CFS.
OXIDATIVE STRESS
Oxidative stress has been defined as a disturbance to the equilibrium status of prooxidant and antioxidant systems in favour of prooxidation. The term oxidative stress is used to describe a number of chemical reactions involved in the production of free radicals and other reactive molecules that are potentially able to induce cellular injury.
Plasma Isoprostanes and Other Markers of Oxidative Stress in CFS
Researchers: Dr Gwen Kennedy (2003 – Dundee) – MERGE35
This study investigated lipid peroxidation in CFS examining isoprostanes. The following markers of oxidative stress were determined from a blood sample oxidised low-density lipoproteins (oxLDL) and high density lipoprotein (HDL) levels, plasma isoprostanes, in conjunction with a measure of red blood cell GSH
The study found that people with CFS had:
• Significantly increased levels of isoprostanes (p<0.005) and oxLDL (p=0.02), indicating a direct measure of lipid peroxidation and oxidative stress.
• People with CFS also had lower levels of the antioxidant GSH (p=0.05) and lower levels of ‘good cholesterol’ HDL (p<0.001).
In conclusion the researchers state this new data provides further evidence of dysfunction to oxidative pathways in CFS. The finding of high levels of isoprostanes in people with CFS is particularly important given this measure’s sensitivity, reliability and correlation with other measures of lipid peroxidation in vivo. Furthermore, isoprostanes may not only be markers of oxidative injury, but may in fact mediate the effects of free radicals and reactive oxygen species.
Oxidative Stress Levels are Raised in CFS and are Associated with Clinical Symptoms
Researchers: Gwen Kennedy, Vance Spence et al (2005 – Dundee) MERGE36
Please read this paper
This study investigated for the first time levels of 8-iso-prostaglandin-F2a-isoprostanes alongside other plasma markers of oxidative stress and antioxidant status in well-defined CFS patients and controls, and to relate these levels to reported clinical symptoms of CFS. The CFS patients were divided into 2 groups – Group 1 had previously defined cardiovascular (CV) risk factors of obesity and hypertension and Group2 were normotensive and non-obese.
While free radicals may generate tissue oxidative injury it is also evident that other oxidative by-products, especially peroxidised lipids such as 8-iso-prostaglandin F2∝ may be even more pivotal in the pathological process, and is a member of the F2-isoprostane family and can exert potent biological activity, such as platelet activation, and act as a powerful vasoconstrictor of the peripheral vasculature. Such biological effects may be instrumental in the development of some of the vascular features that characterise patients with CFS.
A further indication of the in vivo consequences of increased lipid peroxidation would be;
• higher levels of oxidised low-density lipoproteins (oxLDL), which is toxic to the endothelium
• accompanied by low levels of high density lipoproteins (HDL) which are associated with the development of atherosclerosis
• The antiviral properties of HDL, low levels may reflect impaired antiviral defence pathways that are characteristic of this patient population.
• OxLDL: has the ability to stimulate genes associated with antioxidant responses such as the gene transcription factor nuclear factor-kappa B (NF-kB).
• Free radicals, certain viruses, and inflammatory cytokines can also activate NF-kB and there is recent evidence pointing to an upregulation of this in CFS patients.
• Antioxidant capacity, represented by Glutathione levels, is significantly reduced in Group1 patients
Results:
• CFS patients had significantly increased levels of isoprostanes (Group1 – P = 0.007 and Group2 – P = 0.03) and oxidised low-density lipoproteins (Group2 P = 0.02) indicative of a free readical attack on lipids.
• CFS patients also had significantly lower high-density lipoproteins (Group1 P = 0.011 and Group2 P = 0.005)
• CFS symptoms correlated with isoprostanes levels, but only in Group2 – low cardiovascular risk CFS patients.
• Isoprostanes correlated with: total symptom score P = 0.005; joint pain P = 0.002; post-exertional malaise P = 0.027
It could be suggested that CFS is an inflammatory condition with many patients in a prooxidant state and this could explain many of the pathological manifestations that underlie the illness. On balance CFS patients have a lipid profile and oxidant biology that is consistent with cardiovascular risk and the presence of high levels of F2 isoprostanes may explain some of the symptoms of the disease. Supplementation with specific antioxidant medications might help to ameliorate symptoms and any potential cardiovascular complications of the illness.
CFS: Assessment of Increased Oxidative Stress and Altered Muscle Excitability in Response to Incremental Exercise
Researchers: Jammes et al (2005 – France)37
Patients and controls performed an incremental cycling exercise until exhaustion. Researchers measured oxygen uptake (VO2), heart rate (HR), systemic blood pressure, percutaneous O2 saturation (SpO2), M-wave recording from vastus lateralis and venous blood sampling allowing measurements of pH (pHv), PO2 (PvO2), lactic acid (LA) and 3 markers of the oxidative stress – thiobarbituric acid-reactive substances(TBARS), reduced glutathione, GSH, and ascorbic acid (RAA). They found:
• Resting PvO2 level, before exercise, was higher in resting CFS patients, suggesting a reduced baseline oxygen uptake by tissues.
• In CFS patients the exercise-induced oxidative stress occurred sooner, that is at the maximal work-rate, lasted more, and there was a significant enhanced maximal post-exercise decrease in RAA level.
• This accentuated post-exercise oxidative stress was associated with marked alterations in muscle excitability (lengthened M-wave duration) – these M-wave changes were totally absent in the control subjects.
• Changes in PCr and intramuscular pH occurred more rapidly in CFS patients suggesting an acceleration of glycolysis.
• Oxidative stress is highly expressed in skeletal muscles because their antioxidant defences are poor.
• Early changes in blood redox status in CFS patients during the exercise bout have a real significance. These differences prevail for the changes in plasma RAA concentration.
• In humans RAA is the only endogenous antioxidant that completely protects the plasma lipids from any detectable damage induced by the formation of hydroperoxide radicals (HRad), trapping all HRad in the aqueous phase before they can reach the plasma lipids.
• In CFS patients the accentuated and prolonged post-exercise oxidative stress may be responsible for muscle membrane alterations eg the formation of lipid hydroperoxides, with the consequence of the impaired membrane excitability.
An increased level of free radical damage in CFS may be a contributor to the underlying functional defects and symptom presentation.
Biochemical Evidence for a Novel Low Molecular Weight 2-5A-Dependent RNase L in CFS
Researchers: Robert Suhadolnik, Daniel Perterson et al (1997 –USA)38
The full paper for this research can be found in the BRAME newsletter ME TODAY – ISSUE 6 – December 1997.
This research identified a possible biological marker for CFS. The study shows a defective RNase L enzyme in CFS patients. This newly discovered enzyme, which has a lower molecular weight than the normal enzyme found in the viral pathway in which this protein is active, may explain common observations in patients with CFS.
• An inability to control common viruses; like Epstein-Barr (EBV) and Human Herpes Virus 6 (HHV6)
• An inability to maintain cellular energy
• The viral pathway known as the 2-5A synthestase/RNase L antiviral pathway may control both of these processes.
• When all components of this viral pathway are working normally, the body can effectively control virus infection. This research has shown that several components of this antiviral pathway are not functioning properly in CFS patients.
• Specifically, the antiviral pathway is upregulated (or overactive) in people with CFS
• While all CFS patients tested positive for the low molecular weight enzyme, some also had the normal RNase L. However extracts from the most severely disabled CFS patients in this study contained only the low molecular weight enzyme
Researchers feel that this new enzyme may not function as well as the normal RNase L found in healthy people, and it may explain why CFS patients’ bodies have a hard time maintaining the energy necessary for cellular growth.
It is interesting to note that the researchers found that RNase L was overactive, unlike anything seen before in studies on RNase L activity in other people with AIDS, MS, lupus, human T-cell leukaemia and kidney cancer.
To determine why RNase L in CFS patients is overactive, a new two part technology was developed, using ultra-violet light and an antibody to human RNase L . Measuring the activity of RNase L, the researchers were surprised to discover a new smaller form of RNase L in all people with CFS. They also felt their research suggested that the presence and activity of the new form RNase L correlates with the severity of clinical symptoms in people with CFS.
Chronic Fatigue syndrome: a risk factor for osteopenia?39
Researchers: Nijs J, De Meirleir K, Englebienne P, McGregor N.
Department of Human Physiology, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussel, Belgium. Jo.Nijs@vub.ac.be
No data documenting a possible depletion of bone mineral density in patients with chronic fatigue syndrome (CFS) are currently available. However, recent pathophysiological observations in CFS patients may have deleterious consequences on bone density. Firstly, the deregulation of the 2,5A synthetase RNase L antiviral pathway and its associated channelopathy, implicates increased demands for calcium and consequent increased calcium-re-absorption from the skeletal system. Secondly, Mycoplasma fermentans which has been frequently associated with CFS, produces a lipopeptide, named 2-kDa macrophage-activating lipopeptide (MALP-2), which stimulates macrophages. MALP-2 has been shown to enhance bone resorption in a dose-dependent manner, at least in part by stimulating the formation of prostaglandins. Thirdly, decreased levels of insulin-like growth factor I (IGF-I) have been reported in CFS-patients. IGF-I is critical to the proliferation of osteoblasts. Consequently, depleted levels of IGF-I may shift the balance between osteoclastic and osteoblastic activity towards bone resorption.
INFECTIOUS AGENTS
Dr Betty Dowsett and Dr John Richardson did a great deal of work regarding enteroviruses, and they may well play a great part in the disease process of ME/CFS. Dr Garth Nicholson with Mycoplasma. Viruses such as Epstein-Barr, Cytomegalovirus, HHV6, Parvovirus are all felt to implicated in underlying or triggering the initial infection in the body.
A severe flu-like illness that occurs in most cases of CFS followed by persistent illness and fatigue suggests an infectious aetiolgy that triggers and possibly perpetuates this syndrome.
In small sub-sets of patients Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), Parvovirus B19 (PB19), brucella, toxoplasma, Coxiella burnetti,and Chalmydia pneumoniae have been reported to cause prolonged fatigue, fevers and many other symptoms of CFS.
Other viruses have been investigated as the causative agents of CFS: Human Herpes Virus 6 (HHV6), Group B Coxsackieviruses (CVB), Human T-Cell Leukaemia virus II-like virus, Spumavirus, Hepatitis C virus , Human Lentivirus and Herpes Virus 7, although consistent and supportive evidence is still lacking.
Kormaroff et al view CFS as an immunological disturbance that allows the reactivation of latent and persistent infectious agents, particularly viruses in the host. Levy believes that although no viral agents have been found consistently in patients with CFS, an infectious organism may be the cause fo this condition and may continue to be present in the individual.
Recent data suggests that CFS is a heterogenous disease, and can have several potentially treatable infectious aetiologies.
The Role of Enteroviruses in CFS
Researcher: JKS Chia (2005 –USA)40 This is a paper that should be read in full
Several investigators have used DNA/RNA hybridisation or polymerase chain reaction (PCR) to detect the presence of enteroviral RNA in tissues of patients with CFS.
• The results of antiviral treatment provided supportive evidence for the pathogenic role of RNA in patients with CFS
• To date 8 of 14 severely ill patients with detectable enteroviral RNA in their peripheral blood leucocytes have responded to the combination of interferon α and δ. But relapse still occurred after heavy exertion a few months later.
• Patients with CFS and the presence of viral RNA in peripheral blood leucocytes or in tissues, but without true viraemia, have debilitating symptoms, the severity of the symptoms correlated with the frequency of finding enteroviral RNA in the peripheral blood leucocytes
• In most patients with CFS, the cyclic nature of low grade febrile illness and severe exacerbations after physical activity would be consistent with a cyclical pattern in the viral replicative activity.
• It is possible that viral RNA found inside cells, in a stable double stranded form, can dissociate and replicate using viral RNA replicase; some of the positive strands, although restricted in replication, are translated to viral proteins during active metabolic states (for instance, exercise) which perpetuates the immunological response, including but not limited to synthesis of specific neutralising antibody.
• Among other immunostimulatory effects, double stranded RNA is a potent inducer of interferon synthesis, which activates intracellular RNase L with resultant degradation of excessive single stranded RNA. The finding of a higher level of RNase L activity in mononuclear cells of CFS patients is consistent with this paradigm.
• Ironically the continuing inflammatory response towards persistently infected cells/tissues to halt viral infection may be partially responsible for the difficulty in finding viral genomes in these patients, and may also be responsible for the symptoms.
• Despite an ongoing immune response, these viral RNA infected cells are not eradicated. It is possible that viruses hide in long living, immunologically privileged cells, including but not limited to macrophages, muscles, myocardial cells and neurones.
• Persistent infection of B cells and monocytes/macrophages, the cells initially responsible for the uptake and transport of virus has been well described for other intracellular pathogens.
• Recently the researchers have found enteroviral RNA in the bone marrow samples of 2 patietns with CFS and cyclic neutropaenia, suggesting that stem cells in the bone marrow could be a source of ongoing viral infection.
Enterovirus Related Metabolic Myopathy: a Postviral Fatigue Syndrome
Researchers: Lane et al (2002 –London)41 - Read this paper
This research was to detect and characterise enterovirus RNA in skeletal from patients with CFS and compared efficiency of muscle energy metabolism in enterovirus positive and negative CFS patients.
Enteroviruses have been implicated in the pathogenesis of chronic myocarditis and dilated cardiomyopathy. Recent application of the reverse transcription, nested polymerase chain reaction (RT-NPCR), including nucleotide sequencing of PCR products, has unequivocally demonstrated coxsackie B3-like RNA in endomyocardial biopsies from such cases. Although PCR studies on CFS patients have been conflicting.
• Some CFS patients have been shown to have abnormal lactate responses to exercise in the subanaerobic threshold exercise test (SATET). This could not be explained on the basis of deconditioning of muscle tissue, and subsequently these researchers, and others, showed that some CFS patients have abnormal muscle energy metabolism on phosphorous NMR spectroscopy.
• Fulcher and White compared exercise characteristics and muscle strength in CFS patients, and patients with clinical depression. CFS patients were weaker in tests on quadriceps strength.
• This study describes the detection and characterisation of enteroviral RNA in muscle from CFS patients and examine the relation between the presence of enterovirus and lactate responses to exercise.
• This research showed that the presence of enterovirus sequences in muscle is not typical of the normal population.
• An abnormal lactate response toe exercise was present 9 times more commonly in CFS patients with enterovirus sequences in muscle than in enterovrius negative cases
• Mutations at other sites in the viral RNA might determine viral persistence and effects on mitochondrial function.
This research shows that some CFS patients have abnormal muscle energy metabolism which is related statistically to the presence of enterovirus sequences in muscle, and that the viruses involved are predominantly coxsackie B-like. The data here supports the concept of a true post viral fatigue syndrome following enterovirus infection.
Pathogenesis of Parvovirus B19 Infection: Host Gene Variability, and Possible Means and Effects of Virus Persistence.
Researcher: Jonathan Kerr42
Department of Cellular and Molecular Medicine, St George's University of London, Cranmer Terrace, London SW17 0RE, UK. jkerr@sgul.ac.uk
Since conducting follow-up studies of patients with acute symptomatic parvovirus B19 infection which showed that a significant proportion of patients develop prolonged arthritis and chronic fatigue syndrome (CFS), the researchers have become interested in the mechanisms of this phenomenon. Showed that these cases have:
• High levels of pro-inflammatory cytokines in their circulation and that this correlates with the symptoms. However, the underlying mechanisms were not apparent, and various approaches to begin studying this phenomenon have been used.
• DNA polymorphisms were looked for and several were shown to be more common in these subjects compared with controls; these occur within genes of both the immune response [human leucocyte antigen (HLA)-DRB1, HLA-B, transforming growth factor (TGF)-beta1] and those involved in several other cellular functions (predominantly the cytoskeleton and cell adhesion).
• Interestingly, one particular single-nucleotide polymorphism (SNP) which is associated with symptomatic B19 infection occurs in the Ku80 gene which has recently been shown to be a B19 co-receptor. B19 persistence is probably the key to this phenomenon, and some new data are presented on short regions of sequence homology (17-26 bp) between human, mouse and rat parvoviruses and their respective hosts which occur in many host genes. This homology may provide a foothold for virus persistence and may also play a role in the genesis of disease through gene disruption.
• Finally, microarrays and TaqMan real-time polymerase chain reaction were used in 108 normal persons to study human gene expression in persons who are B19-seropositive versus B19-seronegative (age- and sex-matched) to examine the hypothesis that gene regulation may be altered in subjects harbouring the B19 virus DNA.
• Six genes were found to be differentially expressed with roles in the cytoskeleton (SKIP, MACF1, SPAG7, FLOT1), integrin signalling (FLOT1, RASSF5), HLA class III (c6orf48), and tumour suppression (RASSF5).
These results have implications not only for B19 but also for other persistent viruses as well and confirmation is required. In conclusion, these disparate findings contribute to our understanding of the pathogenesis of B19 disease. We are using these studies as a starting point to study the phenomenon of chronic immune activation following B19 infection.
Cytokines in Parvovirus B19 infection as an aid to understanding CFS
Researchers: Kerr JR, Tyrrell DA.43
Department of Microbiology, Royal Brompton Hospital, National Heart & Lung Institute, Imperial College London, UK. j.kerr@imperial.ac.uk
Human parvovirus B19 infection has been associated with various clinical manifestations of a rheumatic nature such as arthritis, fatigue, and chronic fatigue syndrome (CFS), which can persist for years after the acute phase. The authors have demonstrated recently that acute B19 infection is accompanied by raised circulating levels of IL-1b, IL-6, TNF-a, and IFN-g and that raised circulating levels of TNF-a and IFN-g persist and are accompanied by MCP-1 in those patients who develop CFS. A resolution of clinical symptoms and cytokine dysregulation after intravenous immunoglobulin (IVIG) therapy, which is the only specific treatment for parvovirus B19 infection, also has been reported. Although CFS may be caused by various microbial and other triggers, that triggered by B19 virus is clinically indistinguishable from idiopathic CFS and exhibits similar cytokine abnormalities and may represent an accessible model for the study of CFS.
Multiple Co-infections (Mycoplasma, Chlamydia, Human Herpes Virus-6) in Blood of CFS patients: Association with Signs and Symptoms.
Researchers: Nicolson GL, Gan R, Haier J.44
The Institute for Molecular Medicine, Huntington Beach, California 92649, USA. gnicolson@immed.org
Previously found that a majority of chronic fatigue syndrome (CFS) patients showed evidence of systemic mycoplasmal infections, and their blood tested positive using a polymerase chain reaction assay for at least one of the four following Mycoplasma species: M. fermentans, M. hominis, M. pneumoniae or M. penetrans.
Consistent with previous results, patients in the current study (n=200) showed a high prevalence (overall 52%) of mycoplasmal infections. Using forensic polymerase chain reaction they also examined whether these same patients showed evidence of infections with Chlamydia pneumoniae (overall 7.5% positive) and/or active human herpes virus-6 (HHV-6, overall 30.5% positive). Since the presence of one or more infections may predispose patients to other infections, we examined the prevalence of C. pneumoniae and HHV-6 active infections in mycoplasma-positive and -negative patients. Unexpectedly, we found that the incidence of C. pneumoniae or HHV-6 was similar in Mycoplasma-positive and -negative patients, and the converse was also found in active HHV-6-positive and -negative patients. Control subjects (n=100) had low rates of mycoplasmal (6%), active HHV-6 (9%) or chlamydial (1%) infections, and there were no co-infections in control subjects. Differences in bacterial and/or viral infections in CFS patients compared to control subjects were significant.
Severity and incidence of patients' signs and symptoms were compared within the above groups. Although there was a tendency for patients with multiple infections to have more severe signs and symptoms (p<0.01), the only significant differences found were in the incidence and severity of certain signs and symptoms in patients with multiple co-infections of any type compared to the other groups (p<0.01). There was no correlation between the type of co-infection and severity of signs and symptoms. The results indicate that a large subset of CFS patients show evidence of bacterial and/or viral infection(s), and these infections may contribute to the severity of signs and symptoms found in these patients.
High Prevalence of Mycoplasma Infections Among European CFS patients. Examination of Four Mycoplasma Species in Blood of CFS patients.
Researchers: Nijs J, Nicolson GL, De Becker P, Coomans D, De Meirleir K.45
Department of Human Physiology, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, KRO Gebouw-1, Laarbeeklaan 101, 1090 Brussel, Belgium. jo.nijs@vub.ac.be
Prevalence of Mycoplasma species infections in chronic fatigue syndrome (CFS) has been extensively reported in the scientific literature. However, all previous reports highlighted the presence of Mycoplasmas in American patients. In this prospective study, the presence of Mycoplasma fermentans, M. penetrans, M. pneumoniae and M. hominis in the blood of 261 European CFS patients and 36 healthy volunteers was examined using forensic polymerase chain reaction. One hundred and seventy-nine (68.6%) patients were infected by at least one species of Mycoplasma, compared to two out of 36 (5.6%) in the control sample (P<0.001). Among Mycoplasma-infected patients, M. hominis was the most frequently observed infection (n=96; 36.8% of the overall sample), followed by M. pneumoniae and M. fermentans infections (equal frequencies; n=67; 25.7%). M. penetrans infections were not found. Multiple mycoplasmal infections were detected in 45 patients (17.2%).
Compared to American CFS patients (M. pneumoniae>M. hominis>M. penetrans), a slightly different pattern of mycoplasmal infections was found in European CFS patients (M. hominis>M. pneumoniae, M. fermentansz.Gt;M. penetrans).
CFS is Associated with Diminished Intracellular Perforin.
Researchers: Maher KJ, Klimas NG, Fletcher MA.46
Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33176, USA.
Chronic fatigue syndrome (CFS) is an illness characterized by unexplained and prolonged fatigue that is often accompanied by abnormalities of immune, endocrine and cognitive functions. Diminished natural killer cell cytotoxicity (NKCC) is a frequently reported finding. However, the molecular basis of this defect of in vitro cytotoxicy has not been described. Perforin is a protein found within intracellular granules of NK and cytotoxic T cells and is a key factor in the lytic processes mediated by these cells. Quantitative fluorescence flow cytometry was used to the intracellular perforin content in CFS subjects and healthy controls.
A significant reduction in the NK cell associated perforin levels in samples from CFS patients, compared to healthy controls, was observed. There was also an indication of a reduced perforin level within the cytotoxic T cells of CFS subjects, providing the first evidence, to our knowledge, to suggest a T cell associated cytotoxic deficit in CFS. Because perforin is important in immune surveillance and homeostasis of the immune system, its deficiency may prove to be an important factor in the pathogenesis of CFS and its analysis may prove useful as a biomarker in the study of CFS.
Stress-Associated Changes in the Steady-State Expression of Latent Epstein-Barr Virus: Implications for chronic fatigue syndrome and cancer.
Researchers: Glaser R, Padgett DA, Litsky ML, Baiocchi RA, Yang EV, Chen M, Yeh PE, Klimas NG, Marshall GD, Whiteside T, Herberman R, Kiecolt-Glaser J, Williams MV.47
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Medical Center, 333 W. 10th Avenue, Columbus, OH 43210, USA. glaser.1@osu.edu
Antibodies to several Epstein-Barr virus (EBV)-encoded enzymes are observed in patients with different EBV-associated diseases. The reason for these antibody patterns and the role these proteins might play in the pathophysiology of disease, separate from their role in virus replication, is unknown. In this series of studies, we found that:
• Purified EBV deoxyuridine triphosphate nucleotidohydrolase (dUTPase) can inhibit the replication of human peripheral blood mononuclear cells in vitro and upregulate the production of TNF-alpha, IL-1beta, IL-6, IL-8, and IL-10.
• It also enhanced the ability of natural killer cells to lyse target cells.
• The EBV dUTPase also significantly inhibited the replication of mitogen-stimulated lymphocytes and the synthesis of IFN-gamma by cells isolated from lymph nodes and spleens obtained from mice inoculated with the protein.
• It also produced sickness behaviours known to be induced by some of the cytokines that were studied in the in vitro experiments. These symptoms include an increase in body temperature, a decrease in body mass and in physical activity.
The data provide a new perspective on how an early nonstructural EBV-encoded protein can cause immune dysregulation and produce clinical symptoms observed in patients with chronic fatigue syndrome (CFS) separate from its role in virus replication and may serve as a new approach to help identify one of the etiological agents for CFS. The data also provide additional insight into the pathophysiology of EBV infection, inflammation, and cancer.
Dysregulated Expression of Tumour Necrosis Factor in CFS: Interrelations with Cellular Sources and Patterns of Soluble Immune Mediator Expression.
Researchers: Patarca R, Klimas NG, Lugtendorf S, Antoni M, Fletcher MA.48
E. M. Papper Laboratory of Clinical Immunology, University of Miami School of Medicine, Florida.
Among a group of 70 individuals who met the criteria established by the Centers for Disease Control and Prevention (Atlanta) for chronic fatigue syndrome (CFS), 12%-28% had serum levels exceeding 95% of control values for tumour necrosis factor (TNF) alpha, TNF-beta, interleukin (IL) 1 alpha, IL-2, soluble IL-2 receptor (sIL-2R), or neopterin; overall, 60% of patients had elevated levels of one or more of the nine soluble immune mediators tested. Nevertheless, only the distributions for circulating levels of TNF-alpha and TNF-beta differed significantly in the two populations. In patients with CFS--but not in controls--serum levels of TNF-alpha, IL-1 alpha, IL-4, and sIL-2R correlated significantly with one another and (in the 10 cases analyzed) with relative amounts (as compared to beta-globin or beta-actin) of the only mRNAs detectable by reverse transcriptase-coupled polymerase chain reaction in peripheral-blood mononuclear cells: TNF-beta, unspliced and spliced; IL-1 beta, lymphocyte fraction; and IL-6 (in order of appearance). These findings point to polycellular activation and may be relevant to the aetiology and nosology of CFS.
CHRISTINE AND TANYA HARRISON
Secretary and Chairperson BRAME
Encs
References:
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7. Sieverling, Carol/Cheney April 2005. The Heart of the Matter: CFS & Cardiac Issues. http://www.cfids-cab.org/MESA/Cheney.pdf
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12. Spence, V.A et al. Acetylcholine Mediated Vasodilation in the Microcirculation of Patients with Chronic Fatigue Syndrome. Prostaglandins, Leukotrienes and Essential Fatty Acids. 70 2004: 403-407.
13. F.P. De Lange et al 2005. Gray Matter Volume reduction in the Chronic Fatigue Syndrome. Neuroimage. 26 2005:777-781
14. Okada et al 2004. Mechanisms Underlying Fatigue: A Voxel-Based Morphometric Study of Chronic Fatigue Syndrome. BMC Neurology. 4:14 2004
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16. Costa et al. 1995. Brainstem Perfusion is Impaired in Chronic Fatigue Syndrome. Quarterly Journal of Medicine (OUP). Vol. 88:11 November 1995:767-773.
17. Siemionow et al. 2004. Altered Central Nervous System Signal During Motor Performance in Chronic Fatigue Syndrome. Clinical Neurophysiology. Vol.115:10, October 2004:2372-2381.
18. Baraniuk et al. 2005. A Chronic Fatigue Syndrome – Related Proteome in Human Cerebrospinal Fluid. BMC Neurology. 5:22 2005
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20. Lange, Natelson et al. 2005. Objective Evidence of Cognitive Complaints in Chronic Fatigue Syndrome: A BOLD fMRI Study of Verbal Working Memory. Neuroimage. Vol.26:2, June 2005:513-524
21. Gaab et al. 2002. Hypothalamic-Pituitary-Adrenal Axis Reactivity in chronic Fatigue Syndrome and Health Under Psychological, Physiological, and Pharmacological Stimulation. Psychosomatic Medicine. 64:2002, 951-962
22. Di Giorgio, Cleare et al. 2005. 24-Hour Pituitary and Adrenal Hormone Profiles in Chronic Fatigue Syndrome. Psychosomatic Medicine. May-June 2005;67(3):433-440.
23. Jerjes, Cleare, Wessely et al. 2005. Diurnal Patterns of Salivary Cortisol and Cortisone Output in Chronic Fatigue Syndrome. Journal of Affective Disorders. Aug 2005:87(2-3):299-304.
24. Segal et al. 2005. Disturbed Adrenal Function in Adolescents with Chronic Fatigue Syndrome. Journal of Pediatric Endocrinol. Metab. Mar 2005;18(3):295-301.
25. Cleare et al. 2005. Brain 5-HT1A Receptor Binding in Chronic Fatigue Syndrome Measured Using Positron Emission Tomography and [11c]WAY-100635. Biol Psychiatry. Feb 2005 1;57(3):239-246.
26. Torpy et al. 2004. Association Between Chronic Fatigue Syndrome and the Corticosteroid-Binding Globulin Gene ALA SER224 Polymorphism. Endocr Res. Aug 2003;30(3):417-429.
27. Kerr et al. 2005. Gene Expression in Peripheral Blood Mononuclear Cells From Patients with Chronic Fatigue Syndrome. Journal Clinical Pathology. 2005;58:826-832
28. Smith, Kerr, Cleare, Wessely et al. 2005. Association of Chronic Fatigue Syndrome with Human Leucocyte Antigen Class II Alleles. Journal of Clinical Pathology. 2005;58:860-863
29. Vernon, Whistler et al. 2003. Integration of Gene Expression, Clinical, and Epidemiologic Data to Characterize Chronic Fatigue Syndrome. Journal of Translational Medicine. 2003;1:10
30. Vernon, Whistler et al. 2005. Exercise Responsive Genes Measured in Peripheral Blood of women with CFS and Matched Control Subjects. BMC Physiol. 2005 Mar 24;5(1):5.
31. Vernon, Steinau et al 2004. Differential-display PCR of Peripheral Blood for Biomarker Discovery in CFS. J Mol Med. 2004 Nov;82(11):750-5
32. Powell et al 2003, Identification of Novel Expressed Sequences, Up-regulated in the Leucocytes of CFS Patients. Clin Exp Allergy. 2003 Oct;33(10):1450-6
33. Narita et al 2003. Association between Serotonin Transporter Gene Polymorphism and CFS. Biochem Biophys Res Commun. 2003 Nov 14;311(2):264-6.
34. Hickie, Lloyd et al 2001. A Twin Study of the Etiology of Prolonged Fatigue and Immune Activation. Twin Res. 2001 Apr;4(2):94-102
35. Gwen Kennedy 2003. Plasma Isoprostanes and Other Markers of Oxidative Stress in CFS
36. G Kennedy, V Spence et al 2005. Oxidative stress Levels are Raised in CFS and are Associated with Clinical Symptoms. Free Radical Biology & Medicine. 39 2005:584-589
37. Jammes et al 2005. CFS: Assessment of Increased Oxidative Stress and Altered Muscle Excitability in Response to Incremental Exercise. Journal of Internal Medicine. 2005; 257: 299–310
38. Suhadolnik et al 1997. Biochemical Evidence for a Novel Low Molecular Weight 2-5A-Dependent Rnase L in CFS. J Interferon Cytokine Res. 1997 Jul;17(7):377-85.
39. Nijs, De Meirleir et al 2003. Chronic Fatigue Syndrome: A Risk Factor For Osteopenia. Medical Hypotheses. Jan 2003;60(1):65-68
40. Chia, JKS 2005. The Role of Enterovirus in Chronic Fatigue Syndrome. Journal Clinical Pathology. 2005;58:1126-1132
41. Lane et al 2002. Enterovirus Related Metabolic Myopathy: a Postviral Fatigue Syndrome. Journal of Neurology, Neurosurgery, Psychiatry. 2003;74:1382-1386
42. Kerr, JR 2005. Pathogenesis of Parvovirus B19 Infection: Host Gene Variability, and Possible Means And Effects of Virus Persistence. J Vet Med B Infect Dis Vet Public Health. Sep-Oct 2005;52(7-8):335-339.
43. Kerr, JR & Tyrell DA 2003. Cytokines in Parvovirus B19 Infection as an Aid to Understanding Chronic Fatigue Sydrome. Curr Pain Headache Rep. Oct 2003;7(5):333-341
44. Nicolson et al 2003. Multiple Co-Infections (Mycoplasma, Chlamydia, Human Herpes Virus-6) in Blood of Chronic Fatigue Syndrome Patients: Association With Signs And Symptoms. APMIS. May 2003;111(5):557-566.
45. Nijs, Nicolson et al 2002. High prevalence of Mycoplasma infections among European chronic fatigue syndrome patients. Examination of four Mycoplasma species in blood of chronic fatigue syndrome patients. FEMS Immunology and Medical Microbiology. 2002 Nov 15;34(3):209-214
46. Maher, Klimas, Fletcher 2005. Chronic Fatigue Syndrome is Associated with Diminished Intracellular Perforin. Clinical and Experimental Immunology. Dec 2005;142(3):505-511.
47. Glaser et al 2005. Stress-Associated Changes in the Steady-State Expression of Latent Epstein-Barr Virus: Implications For Chronic Fatigue Syndrome and Cancer. Brain Behav Immun. Mar 2005;19(2):91-103.
48. Patarca, Klimas et al 1994. Dysregulated Expression of Tumor Necrosis Factor in Chronic Fatigue Syndrome: Interrelations with Cellular Sources and Patterns of Soluble Immune Mediator Expression. Clinical Infectious Diseases. Jan 1994;18 Suppl 1:S147-153
49.
Abstracts and links to their full papers, used in this document can be found at: http://ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed.
BRAME, 30 Winmer Avenue, Winterton-on-Sea, Great Yarmouth, Norfolk, NR29 4BA
Tel/Fax: 01493 393717 Web: www.brame.org E-Mail: info@brame.org
Oral Presentations
to
The Gibson Inquiry
by
Tanya Harrison
(Long-Term Severe ME Sufferer & Chairperson – BRAME)
and
Christine Harrison
(24 Hour Carer & Secretary – BRAME)
on
18 April 2006
Tanya Harrison – Chairperson BRAME
Parliamentary Research Inquiry into ME – Oral Hearing
Thank you for inviting us to speak to you today. It is impossible for me to get across to you in 4 minutes just how debilitating and life-changing this illness is for me, my family and fellow sufferers, as the only way you could possibly understand it is to live it.
Imagine being completely exhausted but unable to sleep, when you do manage to get to sleep it is not a deep sleep, it is snatched, restless, often the sleep pattern is reversed, and you are constantly being woken up by the pain. Then you wake up feeling like you have had no sleep at all, that you have the worst flu you have ever had, you are in excruciating and relentless pain, feeling as if you have just run a marathon, you ache everywhere, your throat is always sore and ulcerated, you are constantly nauseous and dizzy, unable to control your body temperature, have hyperacuity and photophobia, your brain is in a fog, and even having a hug is painful – this is the life of a person with ME, not just on the odd day, but every hour of every day, year after year, and for me, decade after decade
I would like to tell you some of my story. I am 30 and ME has taken, or rather stolen, two thirds of my life away. I have been bedridden for half my life. My ill health started at the age of ten when I got query glandular fever, the test was negative but the blood picture was unusual, around the same time I also suffered a gastro-intestinal infection. I am a Type-A personality, so I wasn’t going to stop a little thing like being ill keep me from my education and extra-curricular activities, which were numerous, so I insisted on returning to my normal life before I had recovered, but my body did not like this. I had constant recurring throat infections which the antibiotics weren’t clearing, in the end I had my tonsils removed but I reacted very badly to the anaesthetic. I developed asthma. Then aged 11 I had query meningitis, which is when the unrelenting severe head pain and photophobia started, and has never left me. The doctor didn’t understand what was happening and so I still did not heed my body and returned to school. Aged 12 the illness stepped up a gear and it started attacking my back and legs, leading to repeated spells using crutches, as it caused such pain to try and walk. Then the pain in my head and spine became so severe and debilitating, and the amount of time I was having to take off school became so frequent that I was unable to leave my bed. My doctor, finally, referred me to my local hospital, I was fifteen, It had been five years since I first became ill, with my GP constantly commenting that he “didn’t like the look of this, but didn’t know what is wrong or what to do about it”, so just left it. I truly believe that if my post-viral fatigue syndrome had been identified when it first appeared, as that is what I believe I originally had, had appropriate advice then been given, then I would probably not have developed ME, and not gone on to become severely affected, which is what happened by leaving me for five years.
When I reached the hospital I had become so desperately ill that I had reached collapsing point. I could barely stand, was in extreme pain, had a multitude of seemingly random but debilitating symptoms, and felt constantly as if I had a very bad bout of the flu. At the local hospital, I was put under a rheumatologist, he was brilliant, from the first time he saw me he told me that “he believed that I was very ill and that he wouldn’t stop until he had found out what was wrong”, sadly that is something that most people with this illness never have the fortune to hear. After seeing me weekly in his clinic, which was a trial in itself, leaving my bed to lay on the backseat of the car for the sheer agony of the journey, he could see that I was continuing to deteriorate and finally conceded that I was too ill to be at home and admitted me. By this point my illness, although undiagnosed, had already become multi-system/multi-organ, within three days I was seen by five specialists, as they feared for my life. Whilst in the hospital they thought I had suffered a mini stroke as I suffered from facial paralysis down one side, and since that time I have had limited or no reflex responses. Eventually I was diagnosed with a terminal illness. I was put on a heavy treatment regime of drugs and Graded Exercise (GET), which turned out to be totally inappropriate, and led me to deteriorate further, recognising this the consultant stopped everything and differential diagnoses were looked at. Eventually Dr Terry Mitchell, who although a consultant haematologist had started taking an interest in cases like mine, was brought in and I was diagnosed with severe and chronic ME.
In case you are wondering my symptoms have never left, only increased, they do go in cycles of severity, depending on what part of my body is particularly affected at the time, the core symptoms however have never gone away, or become easier. I am often too ill to even sit up, or even communicate and my Mum says that I am not really there, I have been swamped by the illness and am neither coherent, or very aware of what is happening around me. She says it is like watching me tread water, but when the illness consumes me, I have gone under and only the illness is left.
A lot is supposedly made of the fact that many results come back normal. This does mean that there are not abnormal results, I consistently have a high ESR level, and a high fibrinogen and platelet level, and low mean cell volume, other results fluctuate between normal and abnormal, for example my iron has just dropped again, last year it dropped to 2, this year to 4. For the iron deficient anaemia, this would be easy to handle for other people, but being an ME sufferer I have adverse reactions to medication, I can’t take iron tablets, and the doctor’s feel that a blood transfusion is more likely to kill me than help me, this leaves my health difficult to manage. My body does seem to have trouble absorbing vitamins and minerals and I find supplements difficult to tolerate, for example when my B12 level had dropped, The consultant gave me an injection of an 1/8th of a normal dose of B12, in hospital in case of side effects, but my body interpreted the injection wrongly and sent my body into spasms. I also had a bad reaction to oxygen, with the hypothesis of, and the research showing, low oxygen in the blood, particularly to the brain, the thought was to try extra oxygen to see if there was any improvement, so I was given 4% oxygen above the level we breathe, my body went into spasms, and the pain in my head became excruciating, this should not have happened, especially at that level, again showing the body’s hypersensitivity. My body has now become so compromised by the severe ME, that I have been told by two consultants that they felt unable to operate on me as they feared that my hypersensitivity would prove fatal, even trying to decide which is the safest local anaesthetic for urgent dental work has prompted a nine month consultation between specialists. This is the reality for the severely affected, the simple becomes complex and life-threatening.
Aside from the relentless pain, one of the hardest things for me, has been the impaired cognitive functions, going from being an avid reader to having trouble following even a page in a book, not recognising the words, as if it is written in ancient Greek, not remembering the sentence, or paragraph, I have just read. I also went from being a straight A student, to not being able to follow the simplest lessons, my brain having difficulty processing the information, as if I am having to translate it. I also started having trouble communicating, mid sentence forgetting my words, going blank, becoming muddled. These problems affected my education in that I was treated abominably by my school, who believed I was malingering – this is not unusual, resulting in children and young people with this illness, not being afforded the same assistance given to those with other chronic illnesses.
Everyday life is affected, siblings can’t play music or have friends round because of the sufferer’s sensitivity to sound, everyone lives in darkness, as the person with ME has photophobia. Everyone’s diet changes as the sufferer becomes unable to tolerate different types of food, or even the smell of food being cooked. Even something as simple as sleeping is difficult for the family, as the sufferer may be one of two types, either a hypersomniac or an insomniac, and even then, they will probably have sleep reversal, meaning a normal daily routine goes out of the window, and nothing can be planned, as it depends on the sufferer’s sleep pattern at the time. Cleaning is also difficult as they are often unable to tolerate the smells of the chemicals used to, for example, bleaching toilets or polish. Holidays, seeing family and friends, and special occasions are foregone, even sitting at the table and having a family meal is virtually impossible. In short ME is a drastic, and life-changing experience, for all those who are affected by it, not just the sufferer.
With ME family life is affected, financial problems are increased, for us personally, my mother had to give up a very well paid job 15 years ago in order to care for me 24/7, and with help being given to pensioners and children, there is very little help given to families, when a dependent disabled child becomes an adult, but still a dependent. There are particular problems being allocated benefits – particularly DLA, with over 50% initially being turned down, and then 80% of those being awarded the benefits on appeal. We also fear for increased problems with the proposed changes to Incapacity Benefit, especially given the unpredictable nature of this illness, fearing that people will be forced back into work before they are fit enough to do so, inducing a relapse, for fear of losing their benefits. Most of these problems originate from the Medical Policy Unit of the DWP taking the psychiatric viewpoint of this illness. As many here today are aware, we are currently challenging and redrafting their proposed new Clinical Guidelines for ME/CFS.
Help for people with this illness is few and far between, with patients and their carers still being met with disbelief and stigmatism by the medical profession, and in some cases treatment tantamount to abuse. There are a few good doctors, but most other doctors either refuse to accept or treat the illness, or they prescribe inappropriate management regimes. The forcing of patients into GET and CBT programmes is widespread in this country –one survey showed that 80% of people who had gone through GET had been made worse by the experience, much research has shown the bodies of people with ME react differently, and adversely, to exercise. The CBT which is widespreadly used is also inappropriate, as it perpetuates the psychiatric model. Instead of teaching coping mechanisms, as with other chronic illnesses, they instead focus on illness beliefs, aiming to convince sufferers that they remain ill, because they believe they have an organic illness, and if they change that belief they will get better. I don’t mean to be rude but this is complete and utter rubbish, the use of CBT and GET is shameful treatment of extremely ill people.
I was a member of the Key Group for the CMO Report on ME/CFS and worked hard to try and represent the patient’s voice, unfortunately I wasn’t able to sign up to the document because of the recommendations of CBT and GET. In relation to this Inquiry the report recommended 4 years ago that research was urgently needed in six areas. In reality, of these six, the only research that has been done is on the last recommendation, which would relate to the controversial PACE and FINE trials, which is putting millions more pounds into the psychiatric school of thought, into CBT and GET – the treatments the patients find the most harmful or unhelpful. Where is the promised money into research into the organic aetiology and pathogenesis of this illness, as called for by the report?
I know that my prognosis of remission, to any semblance of a normal life, is only 2%, this does not however stop me from being hopeful that I am in that 2%, or, that with appropriate research into the organic aetiology and pathogenesis of this illness, that in the near future, hope of a cure, or treatment, to improve my quality of life will be renewed.
ME, and its continuing mismanagement, is destroying the lives of all those affected by this illness, and we beg the group to become the starting point for the change and advances that are so desperately needed.
• Calling for the adoption of the Canadian Clinical Guidelines by both the clinical and research communities, and the end of the use of the Oxford Criteria.
• Calling for better treatment and services for patients with ME.
• Calling for research into the aetiology and pathogenesis of this chronic illness and
• Calling for the money to be provided to do this.
We no longer need empty promises that things will change, we need urgent action.
Tanya Harrison
Chairperson BRAME 18/4/06
BRAME
30 Winmer Avenue, Winterton-on-Sea,
Great Yarmouth, Norfolk, NR29 4BA
Tel/Fax: 01493 393717 E-mail: info@brame.org
www.brame.org
B R A M E
Blue Ribbon for the Awareness of Myalgic Encephalomyelitis
30 Winmer Avenue, Winterton-On-Sea, Great Yarmouth,
Norfolk, NR29 4BA
Telephone/Fax: 01493 – 393717
Website: www.brame.org e-mail: info@brame.org
18 APRIL 2006
BRAME PRESENTATION – PART 1
TO PARLIAMENTARY RESEARCH INQUIRY INTO ME/CFS
Before I start we would like to thank you for inviting us to speak today and we welcome the initiative and support for ME/CFS patients by Dr Gibson in setting up this long awaited inquiry into the research evidence of this devastating disease.
After two hours of hearing all the presentations, I’m sure that most of you are beginning to possibly have some insight into the physical and cognitive fatigue, that people with ME experience after just 5 mins. We would hope that we can possibly put in the odd punchline that may lighten the mood, but sadly the reality of living with this illness, and the impact it has on people’s lives, is so overwhelmingly dramatic that it is not possible to add any levity to our presentation.
ME/CFS has been classified as a neurological disease by the World Health Organisation since 1969, this is acknowledged by the Dept of Health, who state that ICD10:G93.3 is the only listing for this illness. ME/CFS is also listed by the CDC in America as a priority one illness alongside TB and AIDS. We urgently need to give this illness the same high priority in the UK, as sadly both the illness and the patients are still faced with disbelief and stigmatism.
ME/CFS is an acquired organic, pathophysiological illness that occurs in both sporadic and epidemic forms, affecting all socio-economic groups and all ages. In most cases ME/CFS is probably caused by a viral trigger, in conjunction with a compromised immune system, a genetic predisposition and environmental factors. The illness becomes for many a multi-organ, multi-system, illness.
ME patients will characteristically become symptomatically ill post-exertion, showing evidence of clinical neurocognitive, neuroendocrine, dysautonomic (eg orthostatic intolerance) cardiovascular and immune malfunction. Some researchers have shown neurological abnormalities, including reduction in grey matter, postural cardiac output abnormalities which correlate with symptom severity and reactive exhaustion, and many patients have lower blood volume and lower blood cell mass, highlighting what a disabling illness this is.
The latest advances in genetics with the human genome has helped advance research into the gene expression in ME/CFS patients, with one study finding up-regulation in 15 genes and down-regulation in one gene. These genes were found to be implicated with immune activation, neuronal and mitochondrial function. This is perhaps the most promising research to find a diagnostic test for ME/CFS, however funding is greatly needed, and at present is funded by small donations by charities and individuals – government funding is vital.
As with any other chronic diseases, ME/CFS patients experience varying levels of severity of their illness. But for the majority of patients, ME/CFS is a complex, debilitating and individualistic illness that can cause life-long disability, and in some cases, sadly, premature death. Studies have shown that less than 6% of adults return to their pre-illness level of functioning, whilst relapses can be on-going, or occur several years after remission.
The prognosis for the long-term severely affected is very poor, less than 2%, where ME can become a multi-system, multi-organ illness, and for some, there can be a progressive degeneration of organs, leading particularly to cardiac or pancreatic failure. There have been a number of cases now of severely affected young adults in their 20’s and early 30’s who have suddenly died of undiagnosed cardiomyopathy. It is vital that this group of severely affected patients are given the high-level of care and monitoring of their condition, as is afforded to those with other chronic illnesses, and the development of any complications or co-morbid conditions should be identified and monitored. However, at present, the severely affected have become lost in the system, a non-statistic, as they have been ignored and neglected, not just in research, but by the medical profession.
Just because something is unknown, does not mean that it does not exist, merely that science, is at present, unable to prove anything – as research techniques improve so the wealth of data of the biological discoveries about the illness grows. The main problem that people with ME have faced, is that doctors believe that because there has been no definitive aetiology and pathogenesis of this illness shown by research, then the illness must be psychosomatic, and so they treat patients with scepticism and disbelief, we must remember that they also thought this of Polio, and that MS was known as “Hysterical Paralysis”. The result of such attitudes can be traumatising, as they at best challenge the patient’s belief in an organic origin of their illness, and at worst can lead to patients being wrongly sectioned.
On 14 May 1998, at the BRAME meeting in Parliament, we highlighted the plight of a 15 year old boy, who was at that time forcibly removed from his home and locked away in a psychiatric unit, as he insisted he had an organic illness. Until the fight through the courts enabled him to go home again, he was held in that psychiatric unit for almost a year, obviously very unwell, unable to speak, or see, and forced to endure CBT and GET. He was so traumatised it took him 5 years before he spoke and recognised his mother again, and he still has an enormous fear of any medical professionals, or social workers, to this day.
8 years on nothing has improved, for we have just heard of more cases, one of another young man, in his early 20’s, with similar symptomology, locked away, and the mother of a young woman who continues to battle with the court system in a similar manner.
This style of patient care is wholly unacceptable and the evidence is disturbing enough, but recently a young woman has died, largely due to the consequences of being forcibly sectioned and locked away in a psychiatric unit. As the mother fought on behalf of her daughter, she too was threatened with being sectioned. This case is shortly to go to inquest, however the mother has given us permission to disclose to the Group that research on her daughter’s spinal cord showed that ‘there was unequivocal inflammatory changes affecting the dorsal root ganglia, which are the gateways for all sensations going to the brain through the spinal cord. The changes of dorsal root ganglionitis, seen in 75% of the spinal cord were very similar to that seen during active infection by herpes virus (such as shingles)’. A research paper is shortly to be published on this.
(NB: For any members of the Group, who read this statement, please keep the information about the research on the spinal cord confidential within the Group, until after the inquest on 13 June. The mother wanted the Group to hear this evidence)
The problem is that most research papers, although often published in leading medical journals, are not picked up in evidence based reviews, and so many of these papers are not included for debate, and there does appear to be a psychiatric bias, whilst patient evidence is completely ignored and is said to be invalid to their criteria.
Sub-grouping
There is an urgent need for sub-grouping as we believe that there is a spectrum of disorders, which share similar symptomology eg ME, CFS, PVFS, FM, MCS. At present these illnesses are all grouped together to form an unmanageable heterogenous group. It is clear that the current cohort of individuals diagnosed with ME/CFS is a diverse group, with varying disease course and disability patterns, offering limited understanding of the aetiology or pathology of the illness and its components when considered together. This makes any research difficult as it is complicating the identification of biological markers of the sub-groups and the results cannot be extrapolated for the wider ME population. Fukuda, who wrote the CDC criteria, had intended for his research criteria to incorporate sub-groups, but this has been ignored. The more specific Canadian Clinical Guidelines is the only Clinical Criteria, and is much more concise, and identifies a more homogenous group, permitting a clearer diagnosis of ME/CFS for patients.
Sub-grouping is the key to understanding how ME/CFS begins, how it is maintained, how medical and psychological variables influence its course, and in the best case, how it can be prevented, treated and cured.
As we have said many times, we feel the term CFS is an inappropriate and derogatory name for this illness, as the illness is so much more than fatigue. Our analogy was used in the CMO Report on ME/CFS, that it would be wholly and equally inappropriate to call Alzheimers – CFS – Chronic Forgetfulness Syndrome, as Alzheimers is a chronic and devastating illness, which is so much more than being forgetful
It is essential that ME/CFS is not confused with ‘chronic fatigue’, as with some research criteria such as the Oxford criteria, this opens up a large remit, and then includes all patients with fatigue as a symptom. For patients with ME, fatigue is not usually their main symptom, but one of many core symptoms, and although debilitating, is caused by pathophysiological exhaustion, involving immune system activation, channelopathy with oxidative stress, nitric oxide toxicity and orthostatic intolerance. Use of the Oxford Criteria in research must be stopped as it creates a too heterogeneous group, and incorporates a multitude of alternative diagnoses.
Subgrouping must be looked at, even if to start with there are only three categories; those without co-morbid conditions, those with co-morbid physical conditions and those with co-morbid psychiatric conditions.
If members of the Group have time to read only two papers fully from those we submitted, then we recommend the Canadian Clinical Guidelines on ME/CFS, and CFS the Need for Subtypes by Jason et al (2005). We feel that these are two of the best documents produced to date, giving an accurate an overall view of this illness.
We hope that the Group, in their concluding statements from this inquiry, will feel able to acknowledge the importance of the Canadian Clinical Guidelines on ME/CFS, to help medical professionals understand the complexity and chronicity of ME/CFS, and how best to manage their patients, and recommend its use within the NHS generally and PCTs, which would hopefully lead to the medical profession having a greater understanding of ME/CFS, and the impact this overwhelming, and complex illness, has on the patient, and their families.
NHS Services
Since Jacqui Smith MP, the then Minister at the Department of Health, on 12 May 2003 announced £8.5 million for new ME/CFS services within the NHS, we have written to her, and her successors, for this money to be allocated appropriately, and to support what ME/CFS sufferers have found to be good practice of management of ME/CFS. Unfortunately of the 12 new Clinical Network Co-ordinating Centres (CNCC) for ME/CFS, many of these are run by psychiatrists, who use CBT and GET as management of their patients.
Most ME sufferers feel that there are no real services for them and still seek support and information from the local and national ME groups. We often get calls from patients, even after attending the specialised clinics, who have felt they have still been met with disbelief in their illness, been seen by a psychiatrist, and just offered coping skills.
Most patients have already learnt to listen to their bodies, and pace themselves, or welcome help from specially trained OT’s, who understand the debilitating, complex and individualistic nature of the illness.
As we say in our literature the doctor’s role should be to ‘heal sometimes, relieve often, comfort always’. Even those who do acknowledge ME/CFS are often at a complete loss as to how to manage their patient’s symptoms, but saying to a patient with ME, as they would with patients with other chronic illnesses, for which there is no cure or effective treatment, that they believe in their illness, understand how ill they are, offer their support, and say that together they will work through this, would make living with this illness so much better.
ME patients have been met with so much injustice and inequality within the NHS over the years, they just want to be accepted, believed, and offered the same NHS services as is afforded to other patients with chronic disease. They need, especially the severely affected, a consultant lead to assess and manage their complex medical condition, not to have 12 clinics in England, some of which are run by psychiatrists, or a GP, with Occupational Therapists to help. There would be an outcry if this was the service offered to other chronic neurological diseases.
Conclusion
Patients urgently want and need research into the aetiology and pathogenesis of the illness, to try and understand what is going wrong in their bodies, and to hopefully find an answer to their illness, or a means of helping to control their multiple symptoms. To date any research into this area is funded by donations from ME groups and individuals and not by Government. ME is responsible for the longest absence from school, and possibly in the workplace. There is a real cost to the Government for benefits and medical services, and urgent funding is needed, from the Government, into biomedical research, to try and find an answer to this illness. But the very real cost is the extent of the suffering of ME patients, and the loss of years of their life to this life-changing, debilitating illness.
We sincerely hope that once you have heard all the evidence that you will appreciate the injustice and inequality within the NHS, social services and DWP that people with this illness face, and feel able to recognise and acknowledge the extent of the suffering of ME patients over so many years, and make relevant and helpful guidelines for urgent and quality research into the aetiology and pathogenesis of ME/CFS.
Those living with ME need the group to recommend
• The adoption of Canadian Clinical Guidelines for the diagnosis and management of ME/CFS throughout the NHS.
• Improved education and awareness of medical professionals on ME/CFS
• These two things combined would hopefully lead to improvement in the diagnosis, care and management of ME patients.
• Implementation of the CMO Report Research Recommendations from 2002, that stated research was urgently needed and
• Provision of the necessary funds for quality and appropriate research into the organic aetiology and pathogenesis of this illness.
It is time that this illness was recognised and acknowledged for the chronic, disabling and life-changing illness we all know it to be, and that the care and medical needs of the sufferers are urgently addressed. Hopefully the written and oral evidence presented to the Group, by ourselves and others, will help to make a very significant move forward in addressing the inequalities in biomedical research, and the care and medical services offered to patients with ME.
NB: CMO Research Recommendations four years ago in 2002 were:
• Elucidate the aetiology and pathogenesis of CFS/ME
• Clarify its epidemiology and natural history
• Characterise its spectrum and or/sub-groups (including age-related groups)
• Assess a wide range of potential therapeutic interventions including symptom control measures
• Define appropriate outcome measures for clinical and research purposes
• Investigate the effectiveness and cost-effectiveness of different models of care
The research programme should include a mix of commissioned or directed research alongside sufficient resource allocation for investigator-generated studies on the condition.
Christine Harrison
