(WHO ICD-10 G93.3)


Professor Malcolm Hooper

February 2010


Extracts from:


Background to, consideration of, and quotations from the Manuals for the

Medical Research Council’s PACE Trial of behavioural interventions for

Chronic Fatigue Syndrome / Myalgic Encephalomyelitis,

together with evidence that such interventions are unlikely to be effective

and may even be contra-indicated

Professor Malcolm Hooper; with contributions from members of the ME Community; Researched by Margaret Williams; February 2010.

Contact details:

Malcolm Hooper

Emeritus Professor of Medicinal Chemistry

Department of Life Sciences

University of Sunderland

SR2 7EE, UK.

the belief that ME/CFS is a psychological illness is the error of our time”. (The Complexities of Diagnosis. Byron Hyde. In: Handbook of Chronic Fatigue Syndrome. Ed: Leonard A Jason et al. John Wiley & Sons Inc. 2003

“…to assign someone to the wrong category on the basis of a false understanding of the nature of the illness and its context is an example of a well-known phenomenon which psychologists term 'fundamental attribution error’ “ (Dr Derek Pheby: InterAction 2009:69:16-17)

“…there are now overv 4,000 published studies that show underlying biomedical abnormalities in patients with this illness. It’s not an illness that people can simply imagine that they have and its not a psychological illness. In my view, that debate, which has waged for 20 years, should be over” (Professor Anthony Komaroff, Harvard Medical School, CDC press conference, 3 November 2006)

I hope you are not saying that (ME)CFS patients are not as ill as HIV patients. I split my clinical time between the two illnesses, and I can tell you that if I had to choose between the two illnesses (in 2009) I would rather have HIV” (Nancy Klimas, one of the world’s foremost AIDS and ME/CFS physicians; Professor of Medicine and Immunology, University of Miami; New York Times, 15th October 2009)


Section 1: Summary of documented organic pathology

The difference between ME/CFS and "CFS/ME"

ME/CFS causes death

Section 2: The biomedical basis of ME/CFS

ME/CFS is not "medically unexplained fatigue"

Evidence that the [MRC PACE Trial] Principal Investigators chose to ignore

Documented pathology in ME/CFS that contra-indicates the use of GET

Documented muscle abnormalities in ME/CFS

Documented cardiovascular abnormalities in ME/CFS

Documented neurological abnormalities in ME/CFS

Documented abnormalities shown on neuroimaging in ME/CFS

Documented neuroendocrine abnormalities in ME/CFS

Documented evidence of inflammation in ME/CFS

Note on inflammation

Documented immune system abnormalities in ME/CFS

Documented hair loss in ME/CFS

Documented gastro-intestinal abnormalities in ME/CFS

Documented liver and spleen problems in ME/CFS

Documented respiratory abnormalities in ME/CFS

Documented abnormal gene expression in ME/CFS

Documented ocular abnormalities in ME/CFS

Documented involvement of viruses in ME/CFS

The role of viruses in ME/CFS

XMRV (retrovirus associated with ME/CFS)

Objective signs in ME/CFS

Documented signs and symptoms in ME/CFS

Documented international concerns about CBT/GET for patients with ME/CFS



A review of biomedical clinical and research literature 1955-2006

(Substantial extracts from Prof. Malcolm Hooper’s submission to UK Parliamentary Inquiry, 2005)

ME/CFS Society of Western Australia


Myalgic Encephalomyelitis (ME) has been classified as a disorder of the central nervous system since 1969 – (World Health Organization International Classification of Diseases) WHO ICD 10 G 93.3

The renaming of ME to Chronic Fatigue Syndrome (CFS) in 1988, giving misplaced emphasis to “fatigue”, trivializes the substantial disability of the disease 1 – which can extend to the wheelchair or bed-bound requiring 24 hour care

ME/CFS is characterized by neurological, immunological, gastrointestinal, cardiovascular and musculoskeletal features – severe forms can present with paresis, seizures, intractable savage headaches and life threatening complications

Amorphous definitions and diagnostic symptom criteria have contaminated study cohorts and corrupted research data 2-10 – researchers and clinicians participating in the 2005 Adelaide ME/CFS Research Forum unanimously endorsed the adoption of the acclaimed 2003 Canadian Clinical Criteria

ME/CFS may include clinical syndromes linked to infectious agents and toxic exposures 11-15 – incl. Epstein Barr virus, ciguatoxin 13, organophosphates and organochlorines 12,14

Prevalence estimates are 235-700 per 100,000 affecting all socio-economic and ethnic groups, and men and women of all ages 16-21 – more prevalent than AIDS, lung or breast cancer 19

Disease impact 22-26 – quality of life equivalent to late stage AIDS 17,27, chronic obstructive lung 25,28 and heart disease and end stage renal failure 29

Some experience recovery (average 7yrs17), some partially recover and a significant proportion (25% 20) are permanently incapacitated 17-20,22-23

Biomedical Abnormalities:

Immune System, including:

chronic immune activation and dysfunction 24,30-32 evidence of persistent viral infection 33 (enteroviral 34-41, EBV 42-47 and HHV-6/7 43,45-50), activation of the 2-5A anti-viral pathway 47,51-56, low natural killer cells and cytotoxicity 33,47,54,57-63, T-cell abnormalities 59,61-62,64-66, pro-inflammatory cytokines and inflammation 66-72, increased cell apoptosis (death) 73-74 and allergy 54,75-77

abnormal immuno-genetic expression 61,66,78-81

Brain/Central Nervous System, including:

objective measurement of dysfunction 54,82-86 –deficits in working memory, concentration, information processing 87-95, autonomic function 96-98 (incl. neurally mediated hypotension and orthostatic intolerance)

abnormalities –regional brain hypoperfusion 99-106 by SPECT, white and gray matter abnormalities 106-112 by MRI, inflammation 66,106-107,113-114, hypomyelination 83,113-114, neurotransmitter 115-116,119 and metabolic dysfunction 117-121 by MRS/PET and abnormal spinal fluid proteins 122-123

abnormal neuro-genetic expression 114

Endocrine System: impaired activation of the hypothalamic-pituitary-adrenal (HPA) axis 124-131 and abnormalities of neuroendocrine-genetic expression 78

Heart and Circulatory System: hypoperfusion 54,83,99-106,132-136, impaired vascular control 27,134-137 (incl. abnormal response to acetylcholine), low blood volume 134-135, vasculitis 136-137 (incl. raised oxidative stress, inflammation and arterial stiffness 138-139) and heart dysfunction 132,135,140-141

Muscular: structural and biochemical abnormalities 38,68,89,142-148 including impaired muscle recovery after exercise 149-154 (exercise responsive gene expression abnormal, worsening after exercise 155)

Others: gastrointestinal dysfunction 156-158 including food intolerance 159-160 and IBS 156,161, mitochondrial dysfunction 38,82,125,162-163 including abnormal mitochondrial associated gene expression 164 and ion transport channelopathy 155,165-166

The difference between ME/CFS and “CFS/ME”

What the Wessely School refers to “CFS/ME” is, according to them, a condition of “medically unexplained” fatigue that is perpetuated by inappropriate illness beliefs, pervasive inactivity, current membership of a self-help group and being in receipt of disability benefits (PACE Trial Identifier, section 3.9) and it should be managed by behavioural interventions (CBT and GET). Simon Wessely believes that it is the same as neurasthenia: “Neurasthenia would readily suffice for ME” (Lancet 1993:342:1247-1248) and that attribution by patients to a virus is somatisation “par excellence” (J Psychosom Res 1994:38:2:89-98). The Wessely School believes that there are no physical signs of disease and assert that there is no pathology causing the patients’ symptoms, simply that patients are “hypervigilant” to “normal bodily sensations” (see below).

Seemingly because of the Wessely School’s beliefs, children with ME/CFS have been diagnosed as having “pervasive refusal syndrome” and many have been forcibly removed from their distraught parents (see below), who themselves have been labelled as having Munchausen’s Syndrome by Proxy, a damaging label that is never deleted from their medical records.

Whilst Wessely School psychiatrists continue to believe and teach (and advise Government agencies) that “CFS/ME” is a behavioural disorder that must be managed by behavioural interventions and incremental aerobic exercise (and which two of the PIs assert can be “cured” by those interventions), in reality true ME/CFS affects every system in the body and many physiological abnormalities have been documented.

At the Press Briefing held on 3rd November 2006 by the US Centres for Disease Control to announce its ME/CFS awareness campaign, two eminent professors who specialise in ME/CFS spoke on public record about the nature of ME/CFS. Anthony Komaroff, Professor of Medicine, Harvard Medical School, said:

It’s a pleasure to be here today with several people who have dedicated successfully a big part of their lives to trying to understand and get recognition for this terrible illness.

It’s not an illness that people can simply imagine that they have and it’s not a psychological illness. In my view, that debate, which was waged for 20 years, should now be over.

Brain imaging studies…have shown inflammation, reduced blood flow and impaired cellular function in different locations of the brain…(and) they change a person’s life.

Today we have powerful new research technologies and tools we didn’t have even 20 years ago, and they are being put to good use by laboratories all over the world”.

Nancy Klimas, Professor of Medicine and Immunology at the University of Miami (who at the time was President of the International Association for Chronic Fatigue Syndrome, an organisation of medical professionals and research scientists), said:

I’ve been waiting for this day for a long time. Over the past 20 years, I’ve treated more than 2,000 (ME)CFS patients.

Whilst attitudes have improved in recent years, the launch of this national awareness campaign is so important to increasing understanding of this illness.

Historically, it’s been the lack of credibility in this illness that has been one of our major stumbling blocks to making progress.

Today there is evidence of the biological underpinnings. And there’s evidence that the patients with this illness experience a level of disability that’s equal to that of patients with late-stage AIDS, patients undergoing chemotherapy, patients with multiple sclerosis.

And that has certainly given it a level of credibility that should be easily understood.

We need to educate physicians and other health care workers about this illness so that every single doctor…knows the diagnostic criteria.

There are diagnostic criteria that enable clinicians to diagnose (ME)CFS in the primary care setting.

The CFS toolkit should be in the hands of every doctor…in the country, because this is the key to moving forward” (

Referenced illustrations from the medical literature are provided in Section 2, but an introductory overview of documented abnormalities in ME/CFS include the following:

  • abnormalities of the central nervous system include abnormalities of brain cognition, brain perfusion, brain metabolism and brain chemistry; there is evidence of low blood flow in multiple areas of the brain; neuro-imaging has revealed lesions in the brain of approximately 80% of those tested and according to the researchers, these lesions are probably caused by inflammation: there is a correlation between the areas involved and the symptoms experienced; abnormalities on SPECT scans provide objective evidence of central nervous system (CNS) dysfunction; there is evidence of a chronic inflammatory process of the CNS, with oedema or demyelination in 78% of patients tested; there is evidence of a significant and irreversible reduction in grey matter volume (especially in Brodmann’s area 9) which is related to physical impairment and may indicate major trauma to the brain (which could also explain the low recovery rate); there is evidence of seizures; a positive Romberg is frequently seen in authentic ME/CFS patients

  • abnormalities of the autonomic and peripheral nervous systems: there is evidence of dysautonomia in ME/CFS patients

  • cardiovascular dysfunction: there is evidence of haemodynamic instability and aberrations of cardiovascular reactivity (an expression of autonomic function); there is evidence of diastolic cardiomyopathy; there is evidence of endothelial dysfunction; there is evidence of peripheral vascular dysfunction with low oxygenation levels and poor perfusion and pulsatilities; there is evidence of abnormal heart rate variability and evidence of abnormal orthostasis; there is evidence of abnormally inverted T-waves and of a shortened QT interval, with electrophysiological aberrancy; there is evidence of abnormal oscillating T-waves and of abnormal cardiac wall motion (at rest and on stress); there are indications of dilatation of the left ventricle and of segmental wall motion abnormalities; there is evidence that the left ventricle ejection fraction – at rest and with exercise – is as low as 30%; there is evidence of reduced stroke volume

  • respiratory system dysfunction: there is evidence of significant reduction in many lung function parameters including a significant decrease in vital capacity; there is evidence of bronchial hyper-responsiveness

  • a disrupted immune system: there is evidence of an unusual and inappropriate immune response: there is evidence of very low levels of NK cell cytotoxicity; there is evidence of low levels of autoantibodies (especially antinuclear and smooth muscle); there is evidence of abnormalities of immunoglobulins, especially sIgA and IgG3, (the latter having a known linkage with gastrointestinal tract disorders); there is evidence of circulating immune complexes; there is evidence of a Th1 to Th2 cytokine shift; there is evidence of abnormally diminished levels of intracellular perforin; there is evidence of abnormal levels of interferons and interleukins; there is evidence of increased white blood cell apoptosis, and there is evidence of the indisputable existence of allergies and hypersensitivities and positive mast cells, among many other anomalies, with an adverse reaction to pharmacological substances being virtually pathognomonic

  • virological abnormalities: there is evidence of persistent enterovirus RNA in ME/CFS patients; there is evidence of abnormalities in the 2-5 synthetase / RNase L antiviral pathway, with novel evidence of a 37 kDa binding protein not reported in healthy subjects or in other diseases; there is evidence of reverse transcriptase, an enzyme produced by retrovirus activity, with retroviruses being the most powerful producers of interferon; there is evidence of the presence of HHV-6, HHV-8, EBV, CMV, Mycoplasma species, Chlamydia species and Coxsackie virus in the spinal fluid of some ME/CFS patients, the authors commenting that it was surprising to find such a high yield of infectious agents on cell free specimens of spinal fluid that had not been centrifuged; recently a direct link between a gammaretrovirus (XMRV, which is the same family as the AIDS virus) and ME/CFS has been demonstrated.

  • evidence of muscle pathology: this includes laboratory evidence of delayed muscle recovery from fatiguing exercise and evidence of damage to muscle tissue; there is evidence of impaired aerobic muscle metabolism; there is evidence of impaired oxygen delivery to muscle, with recovery rates for oxygen saturation being 60% lower than in normal controls; there is evidence of prolonged EMG jitter in 80% of ME/CFS patients tested; there is evidence of greater utilisation of energy stores; there is evidence that total body potassium (TBK) is significantly lower in ME/CFS patients (and abnormal potassium handling by muscle in the context of low overall body potassium may contribute to muscle fatigue in ME/CFS); there is evidence that creatine (a sensitive marker of muscle inflammation) is excreted in significant amounts in the urine of ME/CFS patients, as well as choline and glycine; there is evidence of type II fibre predominance, of scattered muscle fibre necrosis and of mitochondrial abnormalities

  • neuroendocrine abnormalities: there is evidence of HPA axis dysfunction, with all the concomitant implications; there is evidence of abnormality of adrenal function, with the size of the glands being reduced by 50% in some cases; there is evidence of low pancreatic exocrine function; there is evidence of an abnormal response to buspirone challenge, with a significant increase in prolactin release that is not found in healthy controls or in depressives; there is evidence of abnormal arginine – vasopressin release during standard water-loading test; there is evidence of a profound loss of growth hormone; even when the patient is euthyroid on basic screening, there may be thyroid antibodies and evidence of failure to convert T4 (thyroxine) to T3 (tri-iodothyronine), which in turn is dependant upon the liver enzymes glutathione peroxidase and iodothyronine deiodinase, which are dependant upon adequate selenium in the form of selenocysteine (which may be inactivated by environmental toxins)

  • defects in gene expression profiling: there is evidence of reproducible alterations in gene regulation, with an expression profile grouped according to immune, neuronal, mitochondrial and other functions, the neuronal component being associated with CNS hypomyelination

  • abnormalities in HLA antigen expression: Teraski from UCLA found evidence that 46% of ME/CFS patients tested were HLA-DR4 positive, suggesting an antigen presentation

  • disturbances in oxidative stress levels: there is mounting evidence that oxidative stress and lipid peroxidation contribute to the disease process in ME/CFS: circulating in the bloodstream are free radicals which if not neutralised can cause damage to the cells of the body, a process called oxidative stress: in ME/CFS there is evidence of increased oxidative stress and of a novel finding of increased isoprostanes not seen in any other disorder; these raised levels of isoprostanes precisely correlate with patients’ symptoms (isoprostanes being abnormal prostaglandin metabolites that are highly noxious by-products of the abnormal cell membrane metabolism); there is evidence that incremental exercise challenge (as in graded exercise regimes) induces a prolonged and accentuated oxidative stress; there is evidence of low GSH-PX (glutathione peroxidase, an enzyme that is part of the antioxidant pathway: if defective, it causes leakage of magnesium and potassium from cells)

  • gastro-intestinal dysfunction: there is evidence of objective changes, with delays in gastric emptying and abnormalities of gut motility; there is evidence of swallowing difficulties and nocturnal diarrhoea; there is evidence going back to 1977 of hepatomegaly, with fatty infiltrates: on administration of the copper response test, there is evidence of post-viral liver impairment -- an increase of at least 200 in the copper level is the expected response, but in some severely affected ME/CFS patients the response is zero; there is evidence of infiltration of splenic sinuses by atypical lymphoid cells, with reduction in white pulp, suggesting a chronic inflammatory process; there is evidence that abdominal pain is due to unilateral segmental neuropathy; there is significant evidence that people with ME/CFS have increased serum levels of IgA and IgM against the LPS of gram-negative enterobacteria, indicating the presence of an increased gut permeability resulting in the autoimmunity seen in many ME/CFS patients; this indicates that the symptoms of irritable bowel seen in ME/CFS reflect a disorder of gut permeability rather than psychological stress as most psychiatrists believe (gastro-intestinal problems are a serious concern in ME/CFS, and 70% of the body’s immune cells are located in the GI tract)

  • reproductive system: there is clinical evidence that some female patients have an autoimmune oophoritis; there is evidence of endometriosis; there is evidence of polycystic ovary syndrome; in men with ME/CFS, prostatitis is not uncommon

  • visual dysfunction: there is evidence of latency in accommodation, of reduced range of accommodation and of decreased range of duction (ME patients being down to 60% of the full range of eye mobility); there is evidence of nystagmus; there is evidence of reduced tracking; there is evidence of problems with peripheral vision; there is evidence that the ocular system is very much affected by, and in turn affects, this systemic condition.

The above list is by no means comprehensive but merely gives an overview of documented abnormalities seen in ME/CFS that can be accessed in the literature, all of which is available to the Wessely School.

ME/CFS has been defined in the Canadian Guidelines (2003), which have been adopted internationally and are the best aid to the diagnosis of ME/CFS but which the Chief Investigator Peter White insists should not be used in the UK (see below), perhaps because they are unambiguous:

The question arises whether a formal CBT or GET programme adds anything to what is available in the ordinary medical setting. A well-informed physician empowers the patients by respecting their experiences, counsels the patients in coping strategies, and helps them achieve optimal exercise and activity levels within their limits in a common-sense, non-ideological manner, which is not tied to deadlines or other hidden agenda”.

In its 2007 Clinical Guideline 53 on “CFS/ME”, the National Institute for Health and Clinical Excellence (NICE) specifically recommended that the Canadian case definition of ME/CFS should not be used in the UK. NICE based its decision on a small number of mildly positive clinical trials by the Wessely School, while devaluing evidence from scientific studies and patients’ own evidence. ME/CFS is the only physical condition for which behavioural modification is the primary (indeed only) management approach in a NICE Guideline. The MRC declines to fund biomedical studies, yet the cost of implementing the Wessely School regime in the UK is £3.75 million annually, in addition to non-recurrent costs of £26.45 million (Breakthrough, MEResearch UK, Spring 2008).

ME/CFS causes death

People die from ME/CFS, but not from states of chronic “fatigue” or “CFS/ME” as defined by the Wessely School.

On 13th December 1988 Brynmor John MP died from ME/CFS. His experience of the illness was all too familiar: ‘Though there is only a slight gradient from our house to the main road, it could have been the North face of the Eiger. I just could not get up it’. He found himself unable to dress; the slightest exertion exhausted him and it took days to regain his strength. He was irritated by the profusion of psychiatric comment and was trying to ensure better understanding of ME/CFS (Perspectives, Summer 1991:28-30). Brynmor John suddenly collapsed and died as he was leaving the House of Commons gym after having been advised to exercise back to fitness.

In 1992, Professor Hugh Fudenberg from South Carolina (a pioneer of clinical immunology and one of the most distinguished minds in the field, being awarded The Medal of the Institut Pasteur at the age of 32; he was also a Nobel Prize nominee) stated that there is “a greater death rate than normals in the same age range” (The Clinical and Scientific Basis of Myalgic Encephalomyelitis Chronic Fatigue Syndrome: ed. BM Hyde, published by The Nightingale Research Foundation, Ottawa, Canada, 1992: page 644).

This was corroborated 14 years later by Professor Leonard Jason et al, who found that the three most prevalent causes of death in ME/CFS patients were heart failure, suicide and cancer and that the age of death is considerably younger than in the general population (Health Care Women Int 2006:27(2):615-626).

Perhaps the most tragic and well-known death from ME/CFS is that of Alison Hunter from Australia, who died in 1996 and whose death certificate stated the cause of death as “Severe progressive ME”. She was just 19 years old. The pathologist’s report confirmed that she had severe oedema of the heart, liver and brain. She had also suffered severe ulceration to her throat, seizures, paralysis, other neurological symptoms, and gastrointestinal paresis with failure of the gut and bowel. James Ibister, Head of Haematology at Royal North Shore Hospital, Sydney, said: “To be honest, I felt helpless towards the end. On many occasions I was extremely embarrassed about the way she was treated by the system. A lot of terrible things Alison went through were doctors projecting their own fears and inadequacies. How anyone could not think she had a major medical illness was beyond me”. Alison, he said, suffered “terrible physical distress compounded by insults and inhumanity” (

In 1998, an ME/CFS sufferer wrote: “I’ve had ME for nearly five years, 18 months of which were a living hell. The physical suffering (inability to walk unaided, chew, swallow, breathe properly, hold my head up, hands which became spastic) was bad enough, but the brain symptoms were at times unbearable – my brain exploding with stimulus until I thought I’d gone mad (and) the room spun like I was drunk, making me feel physically sick. The bed felt like it was moving. I had explosions of light before my eyes. Worst of all were the ‘seizures’, which felt like I was having a stroke – pins and needles on my head and face, drooping muscles around my mouth, my head would start to tip backwards, absolutely terrifying. I live alone, yet have been refused home care, disability living allowance or any form of medical advice. The public need to be shocked by seeing the severely affected, those being tube fed, shaking, uncontrollable, paralysis, unable to hold up their head, speak, see, control bowel movements. The myth that ME is never fatal must be dismissed. I know of several people who have died of the complications ME can bring(Perspectives, September 1998:26).

UK Coroners are now providing incontrovertible evidence that ME/CFS can lead to death. This is something that the ME/CFS community has known for many years. The UK authorities keep no statistics, so the actual number of deaths from ME/CFS remains unknown.

In 1992, a 30 year old woman in the UK who had suffered from ME/CFS for five years committed suicide; the post-mortem study (using polymerase chain reaction) showed enteroviral sequences in samples from her muscle, heart, the hypothalamus and the brain stem. No enteroviral sequences were detected in any of the control tissues. The researchers stated: “The findings further support the possibility that hypothalamic dysfunction exists in the pathogenesis of (ME)CFS (and) they suggest that the chronic fatigue syndrome may be mediated by enterovirus infection and that persistent symptoms may reflect persistence in affected organs” (McGarry et al. Ann Intern Med: 1994:120:11: 972-3).

On 18th June 1995, Consultant Radiologist Dr Eric Booth died from ME/CFS aged 48 years, having had ME/CFS for 16 years. Four years before he died, Booth wrote: “I have been very seriously ill for the last five years, being totally bedridden (but) am unable to convey this to my medical colleagues. I have come to believe that physicians suffer from compassion fatigue” (BMJ 28 October 1995:311). The autopsy findings were disturbing but were suppressed; Booth’s next of kin was warned by the Official Solicitor that action would be taken against her if she divulged the post-mortem findings, to the extent that she was reduced to a state of chronic fear.

In 1998, there was the well-reported case of Joanna Butler, a young woman aged 24 from Leamington Spa, Warwickshire, who was severely affected by and died from ME/CFS. She was nursed at home by her parents and was bed-bound for the last two years of her life and required tube-feeding. Although she died of ME/CFS, her parents were suspected of having caused her death by administering too high a dose of a medically-prescribed morphine-related compound, and the local paper (Courier) reported that the Warwickshire County Coroner (Michael Coker) ordered a police investigation. This investigation cleared them of blame but they were hounded to such an extent that they were forced to move away from the area (see the press reports in The Observer, 19th March 1998: “Tragic death of young ME victim” and the reports in the local paper, including the Courier, which carried a report on the ‘many who die each year’ of ME).

In January 2003 the wife of Richard Senior died of ME/CFS; the North Wales Coroner entered CFS as the cause of death on the death certificate.

On 4th July 2005 Casey Fero died of ME/CFS at the age of 23 in the US. The autopsy showed viral infection of the heart muscle. The pathologist was shocked at the state of Casey’s heart, which showed fibrosis indicating the presence of a long-standing infection.

In November 2005 Sophia Mirza died of ME/CFS in the UK and the death certificate of 19th June 2006 gives CFS as the cause of death, with acute renal failure.

Another UK death from ME/CFS occurred in May 2008 when a severely affected and courageous woman died in the North of England; her death certificate gives “Myalgic encephalomyelitis” as the cause of death.

Evidence from autopsies of people who have died from ME/CFS is chilling. In Sophia Mirza’s case (a 32 year old woman sectioned by psychiatrists who alleged that she was suffering from a mental disorder so she was kept in a locked ward and, according to her mother’s evidence, denied basic care), there was evidence of severe inflammation throughout 75% of her spinal cord. This was one of three such autopsies spoken about by Dr Abhijit Chaudhuri at the Royal Society of Medicine meeting on 11th July 2009 (see below).

A 2005 autopsy in the US showed oedema of the lower limbs; the alveolar spaces of the lungs were filled with inflammatory cells and there were small emboli scattered throughout the arteries; there was marked congestion of the liver and spleen; the bowel was ischaemic; there was mild inflammation of the kidneys; there was also evidence of rhabdomyolysis (the breakdown of muscle fibres resulting in the release of muscle fibre contents into the circulation, some of which are toxic to the kidney); the bladder showed a hyperplastic epithelium; the thyroid showed colloid filled follicles, with scattered dystrophic calcifications and calcification of the small arterial walls; the right occipital lobe of the brain showed areas of degeneration and degenerated astrocytes, and the white matter surrounding this defect appeared puckered.

The Medical Director of The National CFIDS Foundation (chronic fatigue immune dysfunction, a commonly-used US term for ME/CFS), Dr Alan Cocchetto, commented: Every time you look closely at someone with this disease, you see immense suffering. There appears to be no limit as to the human toll that this disease is capable of exerting on patients(

The Wessely School, however, including the three PACE Trial Principal Investigators and the Director of the Clinical Trial Unit, continue to believe that ME/CFS is an “aberrant illness belief” and they assume that all patients – including those with ME/CFS -- suffering from what they deem to be “medically unexplained symptoms” (which they refer to as MUS) or from “medically unexplained physical symptoms” (which they refer to as MUPS) are really suffering from the same mental illness, ie. somatisation, and as such their symptoms will never be medically explained, therefore there is no point in wasting health service resources in seeking a biomedical explanation.

The Wessely School claim that they are reacting against Cartesian dualism – the long-held belief in Western medicine that an illness is either “organic” or “psychiatric”. However, as Dr Mary Schweitzer (a US ME/CFS sufferer and patient advocate) points out, the Wessely School has simply turned Cartesian dualism on its head. Disorders such as schizophrenia used to be regarded as “mental”, but advances in understanding now show that the psychiatric disturbances that present in schizophrenia are manifestations of underlying organic pathology. In their own interpretation, the Wessely School has reversed this in relation to ME/CFS, claiming that the physical is psychological which hardly accords with 21st century medicine

( ).



Despite the absence of a definitive test, ME/CFS is clinically recognisable: “Once one is familiar with the concept of (ME/CFS), such patients are in practice not too difficult to differentiate from those with true psychiatric illnesses…The physical symptoms should be an aid to diagnosis, although they may be wrongly attributed to primary psychiatric illness unless care is taken in eliciting them” (Professor Rachel Jenkins; BMB 1991:47:4:241-246).

Fifteen years later, Professor Nancy Klimas said: “There are diagnostic criteria that enable clinicians to diagnose (ME)CFS in the primary care setting” (CDC Press Conference to launch the (ME)CFS Toolkit, November 2006) which enable all conscientious clinicians to feel confident in making the diagnosis.

Although there is as yet no definitive test, there are numerous accredited biomarkers of pathology in ME/CFS (see below), all of which lend support to the diagnosis.

As stated by Dr Suzanne Vernon (see Section 1 above), there are now over 5,000 worldwide peer-reviewed scientific papers (and numerous textbooks) showing that ME/CFS is a complex multi-system disorder involving demonstrable pathology not only of the central and autonomic nervous systems but also of the immune, cardiovascular and endocrine systems, and that on-going inflammation is a significant feature, with damage to skeletal and cardiac muscle as well as to other end organs including the pancreas and liver.

In his presentation at the Royal Society of Medicine meeting on ME and CFS held on 11th July 2009, consultant neurologist Dr Abhijit Chaudhuri demonstrated evidence from three autopsies of people who had died from ME/CFS, all of which showed inflammatory changes in the dorsal root of the spinal cord. His abstract states that all three autopsies provide “evidence of neuroinflammation in the dorsal root ganglia, which are the gatekeepers of peripheral sensory information travelling to the brain. This finding may help explain the high level of fatigue and pain”.

For many years research has shown evidence of enterovirus (Coxsackie B) in the tissues of people with ME/CFS, which was roundly dismissed by Wessely School psychiatrists. More recent work of Douche-Aourik F et al (Journal of Medical Virology 2003:71:540-547) confirmed earlier work: “Enterovirus RNA has been found previously in specimens of muscle biopsy from patients with…(ME)CFS. These results suggest that skeletal muscle may host persistent enteroviral infection. The presence of viral RNA…is in favour of a persistent infection involving defective viral replication”.

Research has continued to provide evidence of long-term enteroviral persistence in the face of the adaptive immune response: “This previously unknown and unsuspected aspect of enterovirus replication provides an explanation for previous reports of enteroviral RNA detected in diseased tissue in the apparent absence of infectious viral particles” (Human Enterovirus and Chronic Infectious Disease. Steven Tracy and Nora M Chapman. Journal of IiME 2009: 3:1).

A recent paper reported that biopsy of muscle fibres in ME/CFS showed that fibre-type proportion was “significantly altered in (ME)CFS samples” and concluded: Taken together, these results support the view that muscle tissue is directly involved in the pathogenesis of (ME)CFS” (Int J Immunopathol Pharmacol 2009:22(2):427-436).

Another recent paper demonstrated that a large percentage (95%) of patients clinically diagnosed with (ME)CFS have elevated levels of the IgM isotope to CL (cardiolipin), suggesting that acute phase lipids may be part of disease pathogenesis in patients with (ME)CFS. These lipids may be analogous to acute phase proteins triggered by cytokines involved in the inflammatory processes in the liver, such as C-reactive protein and serum amyloid A (which have been reported in ME/CFS and other diseases attributed to toxic chemicals). The authors note that a survey of the literature reports ACAs (anticardiolipin antibodies) as common serological markers in many diseases, including diseases resulting from viruses and chemical exposure, as well as autoimmune diseases such as multiple sclerosis and lupus erythematosus. The authors conclude that (ME)CFS may be an autoimmune disease, and that classification of it as such may serve to increase the availability options for patients suffering from the disease. They confirm that experiments are under way to elucidate why ACAs are produced in (ME)CFS, and that these studies are investigating the effects of specific chemical agents on mitochondrial metabolic pathways that are indicative of blocked energy production as occurs in (ME)CFS (Yoshitsugi Hokama et al. J Clin Lab Anal 2009:23:210-212).

Yet more research has shown that (ME)CFS is an autoimmune disorder: Ortega-Hernandez et al looked at the influence of autoantibodies, polymorphisms in the serotonin pathway, and HLA Class II genes in relation to (ME)CFS, and tested autoantibodies to different components of the central nervous system. They conclude: “Our results reveal that in (ME)CFS, like other autoimmune diseases, different genetic features are related to age at onset and symptoms” (Ann N Y Acad Sci 2009:1173:589-599).

Blaney et al looked at a number of chronic and autoimmune conditions (including multiple sclerosis, lupus, fibromyalgia and (ME)CFS) and demonstrated the use of 1,25-D (1,25-dihydroxyvitamin D3) as a clinical marker in autoimmune conditions, with results that “showed a strong positive association between these autoimmune conditions and levels of 1,25- D greater than 110 pmol/L”, noting that high levels of 1,25-D may result when dysregulation of the vitamin D receptor prevents it from expressing enzymes necessary to keep 1,25-D in a normal range (Ann N Y Acad Sci 2009: 1173:384-390).

It has long been known that the resting energy expenditure (REE) in ME/CFS patients is abnormally high (see, for example: J Neurol Sci 1997:150:S225; JCFS 1998:4:4:3-14; Medical Hypotheses 2000:54: (1):59-63). When individual resting energy expenditure (REE) was predicted on the basis of total body potassium values, 45.5% of the (ME)CFS patients tested had resting energy expenditure above the upper limit of normal, suggesting that there is upregulation of the sodium-potassium pump in (ME)CFS. There was no evidence that the results were due to lack of activity (which would have affected total body water estimates).

Given that the energy expended at rest by the ME/CFS patient is significantly elevated when compared with controls, it is not difficult to understand what may be the result when the ME/CFS patient is subjected to even minimal exercise.

ME/CFS is not “medically unexplained”

The seminal work of Martin Pall, Professor Emeritus of Biochemistry and Basic Medical Sciences, Washington State University, is thought to have unravelled the mechanisms that underlie what the Wessely School regard as “functional somatic syndromes”, including ME/CFS, fibromyalgia, irritable bowel syndrome and multiple chemical sensitivity (MCS).

Professor Pall’s work is quoted with his specific permission (from his paper “Multiple Chemical Sensitivity: Toxicological and Sensitivity Mechanisms” on his new website ); see also his book “Explaining ‘Unexplained Illnesses’: Disease Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia, Post-Traumatic Stress Disorder, Gulf War Syndrome and Others”. Harrington Park (Haworth) Press, New York, 2007 and “The NO/ONOO-Cycle as the Cause of Fibromyalgia and Related Illnesses”; In: New Research in Fibromyalgia, Ed. John A. Pederson, pp 39-61; Nova Science Publishers, Inc 2006.

Pall’s ME/CFS Review, a requested paper on ME/CFS in a Nova Biomedical volume on ME/CFS was due to be published towards the end of 2009, and chapter XX in the prestigious toxicology reference book “General and Applied Toxicology”, 3rd Edition, Eds. Ballantyne, Marrs and Syversen was published by John Wiley & Sons on 23rd October 2009. The press release for this book says: “1. MCS is a stunningly common disease, even more common than diabetes. 2. MCS is caused by toxic chemical exposure. 3. The role of chemicals acting as toxicants in MCS has been confirmed by genetic studies. 4. We have a detailed and generally well supported mechanism for MCS. 5. For over 20 years, some have falsely argued that MCS is a psychogenic disease. This view is completely incompatible with all the evidence. It is clear now that MCS is a physiological disease initiated by toxic chemical exposure”.

Given that MCS in the form of intolerance to everyday household chemicals and foods, and to medicinal drugs -- especially those acting on the central nervous system -- is a well-documented feature of ME/CFS (a feature that in May 1994 at the Dublin International Symposium on the disorder held under the auspices of The Ramsay Society and The World Federation of Neurology, the internationally renowned neurologist Professor Charles Poser of Harvard described as pathognomonic of the disorder), Pall’s work cannot be separated from the body of knowledge that now exists about ME/CFS.

For a resume of Pall’s significant paper “Exquisite Chemical Sensitivity Mechanisms in MCS” (FASEB 2002:16:1407-1417), see

Pall provides compelling evidence that none of these overlapping disorders is a somatoform disorder and that the Wessely School paradigm is deeply flawed.

Pall posits that these multi-system chronic disorders are initiated and maintained by chemicals that produce a toxic response in the body, characterised by NMDA activity.

NMDA is N-methyl-D-aspartate, an amino acid derivative acting at the NMDA receptor, mimicking the actions of the neurotransmitter glutamate on that receptor. Glutamate is the most important excitatory transmitter in the brain. Activation of NMDA receptors results in the opening of an ion channel. A unique property of the NMDA receptor is that it allows changes in the flow of sodium, calcium and potassium into and out of the cell.

The main classes of chemicals that initiate multi-system disorders such as ME/CFS are the very large class of organic solvents and related compounds, and three classes of pesticides: (i) organophosphorus and carbamate pesticides, (ii) the organochlorine pesticides and (iii) the pyrethroid pesticides, all of which are known to produce a common toxic response in the body (ie. increased activity of the NMDA receptors).

Increased NMDA activity is known to produce increased calcium influx into cells, leading to increased activity of two calcium-dependent nitric oxide synthases, nNOS and eNOS, which in turn produce increased nitric oxide. Nitric oxide reacts with superoxide to form peroxynitrite, a potent oxidant. Peroxynitrite leads to a partial breakdown of the blood-brain barrier, leading to increased chemical access to the brain. This cycle is known as the NO/ONOO- cycle.

Cases of ME/CFS are also commonly initiated by viral or bacterial infection, including Coxsackie, Epstein-Barr, rubella, varicella, parvovirus, Borna and Ross River viruses; such viral initiating stressors also act to increase nitric oxide levels, which is the common feature. Physical trauma also increases nitric oxide levels.

Once the cycle is initiated, it becomes the cause of the chronic illness, with the initiating chemical, viral or traumatic stressor often long gone.

Pall notes that the most characteristic symptom in ME/CFS is the inability to deal effectively with exercise, and that it has been observed that the difference in ME/CFS patients in response to exercise is their cortisol response, in that ME/CFS patients’ cortisol level fails to rise but stays the same (or even drops) after exercise.

It is known that HPA axis dysfunction occurs not only in ME/CFS but also in other NO/ONOO-cycle diseases including fibromyalgia and multiple chemical sensitivity, as well as in many other chronic inflammatory diseases, so changes in cortisol control are not specific to ME/CFS.

However, there is published evidence that ME/CFS patients may have a specific change in cortisol regulation (Demitrack MA, Crofford LJ. Ann N Y Acad Sci 1998:840:684-697; Crofford LJ et al. Brain Behav Immun 2004:18:314-325; Adler GK et al. The Endocrinologist 2002:12:513-522), indicating that the post-exertional increase in symptoms may be explained by the hypocortisol responses.

Significantly, Jammes et al reported that markers of oxidative stress increased more in ME/CFS patients after exercise (J Intern Med 2005:257:299-310), a finding that is entirely consistent with a NO/ONOO-cycle elevation.

Pall notes that there is evidence that lowered cortisol levels can produce cardiac dysfunction, a common finding in ME/CFS and that the need for cortisol may be particularly important during and immediately following exercise due to the stress placed on the heart by exercise, suggesting that the cardiac dysfunction seen in many ME/CFS patients may be caused by their lowered cortisol production during and following exercise. (

For the avoidance of doubt, the MRC PACE Trial Principal Investigators did not consider it necessary to measure participants’ cortisol levels; furthermore, Baschetti et al noted that many people diagnosed on the Wessely School’s Oxford criteria do not have the hypocortisol response to exercise and therefore may not have true ME/CFS (J Intern Med 2005:258:292-292).

Pall provides evidence supporting each of the following in ME/CFS and related multi-system disorders:

  • excessive NMDA activity

  • elevated levels of nitric oxide

  • elevated peroxynitrite

  • oxidative stress

  • breakdown of the blood/brain barrier

  • inflammatory biochemistry

  • elevated levels of inflammatory cytokines

  • elevated TRPV1 activity (the vanilloid receptor opens calcium channels, allowing too much calcium into cells, resulting in cellular dysfunction in a whole range of cells, for example, muscle cells contract, causing spasm, and there is increased secretion from secretory cells, ie. it is a multi-system stimulus)

  • mitochondrial / energy metabolism dysfunction

  • neural sensitisation

  • neurogenic inflammation.

The Wessely School’s claims that ME/CFS and related multi-system disorders are psychogenic are clearly flawed because none of the psychogenic advocates has considered how chemicals can act as toxicants in the body, yet they have dismissed this model as a “belief” without providing any evidence to support their own beliefs.

As Pall says: “Clearly one cannot claim to be doing science whilst simultaneously ignoring most of the relevant scientific literature. Wherever data exists clearly contradicting their views, they simply pretend it does not exist”.

When in 2002 Stanley, Salmon and Peters from the UK wrote an editorial for the British Journal of General Practice (referred to above) arguing that “CFS/ME” is a “social epidemic” in which symptoms are generated by psychogenic mechanisms and asserting that these issues “must be interpreted within a rigorous scientific framework” (Br J Gen Pract 2002:52:355-356), Pall wrote to the Editor listing eight different objectively measurable physiological changes that had been repeatedly found in ME/CFS patients:

  • immune (NK) cell dysfunction

  • elevated levels of inflammatory cytokines

  • elevated levels of neopterin

  • elevated levels of oxidative damage

  • orthostatic intolerance

  • elevated levels of 37 kD RNase L

  • mitochondrial dysfunction

  • neuroendocrine dysfunction.

Pall challenged Stanley, Salmon and Peters to show that each of these eight abnormalities was consistent with their interpretation of a “rigorous scientific framework”.

Their response was astonishing: they accused Pall of “a naïve form of reductionism” and asserted that there was no need for them to question the validity of the physiological findings, as the findings could be “secondary consequences” that are “entirely consistent with the social origins of persistent unexplained physical symptoms (PUPS)” (Br J Gen Pract 2002:52:763-764).

As Pall notes in his book “Explaining ‘Unexplained Illnesses’”:

One of the great puzzles about the psychogenic literature regarding these multisystem illnesses is how do so many bad papers get published? How do so many papers dominated by emotion laden phrases, by transparent falsehoods, by logical flaws, by overstated claims and by unsupported or poorly supported opinion get published in what appear to be respectable, peer-reviewed journals? These papers consistently ignore massive amounts of contrary data and opinion and cannot, therefore, lay claim to objective assessment of the literature.

This is by far the largest failure of the peer-review system that I am aware of. I am almost tempted to call this failure inexplicable.

I can’t help speculate on…the abject failure of the psychogenic advocates to uphold even the minimum of scientific standards”.

The Wessely School persistently fail to assess the scientific evidence and continue to base their beliefs on ignorance rather than current knowledge, an ideology that, according to Pall, is intellectually bankrupt.

Mindful that multiple chemical sensitivity is a well-recognised component of ME/CFS for many sufferers, to quote again from Pall’s book:

It is difficult to encompass the damage created by the psychogenic advocates. They have made it difficult to obtain research funding on the physiological basis of these multisystem illnesses. This difficulty has been particularly profound for MCS, where not coincidentally the fear of massive liability has created major vested interests among industries who have a legitimate fear of law suits that may parallel the liability of the cigarette companies. What is not legitimate is to use their economic and political influence to stifle the scientific and health needs. And what is not legitimate, is to continue the fiction that MCS is unrelated to chemical exposure, such that millions of additional people inevitably become chemically sensitive due to what should be avoidable chemical exposures. Responsibility for these millions of additional new cases of MCS should be placed squarely on the door of the psychogenic advocates and their financial supporters.

" Those who fear illegitimate claims of liability, whether they are insurance companies concerned about disability claims or claims for health benefits or companies using or producing synthetic chemicals, such companies have an obvious route to minimize such claims. They should be using their influence with the media, with political organizations and with scientists to push for research leading to the development of specific biomarkers of these illnesses such that any illegitimate claims can be falsified. Their failure to do this is sufficient evidence to infer that these powerful and very canny organizations have a different goal entirely: it is to deny legitimate claims and therefore deny any culpability on their part. To the extent that psychogenic advocates act to encourage such behaviour, they have a lot to answer for. To the extent that they make it difficult to develop truly effective therapies for these illnesses, they have still more”.


For the avoidance of doubt, the American Medical Association 2008 Annual Meeting Highlights for the AMA House of Delegates Reference Committee on Amendments to the Constitution and Bylaws states: “The AMA will encourage the training of medical students, physicians and other health professionals on the human health effects of toxic chemical exposure”; clearly -- unlike the Wessely School -- the AMA does not regard MCS as a non-existent disorder

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Despite the Wessely School’s perpetual denial, much is now known about ME/CFS


On 18th February 1993, Professor Paul Cheney from Capital University, USA, testified before the US FDA Scientific Advisory Committee:

I have evaluated over 2,500 cases. At best, it is a prolonged post-viral syndrome with slow recovery. At worst, it is a nightmare of increasing disability with both physical and neurocognitive components. The worst cases have both an MS-like and an AIDS-like clinical appearance. We have lost five cases in the last six months. The most difficult thing to treat is the severe pain. Half have abnormal MRI scans. 80% have abnormal SPECT scans. 95% have abnormal cognitive-evoked EEG brain maps. Most have abnormal neurological examination. 40% have impaired cutaneous skin test responses to multiple antigens. Most have evidence of T-cell activation. 80% have evidence of an up-regulated 2-5A antiviral pathway. 80% of cases are unable to work or attend school. We admit regularly to hospital with an inability to care for self”.

In 1994, one of the world’s most renowned ME/CFS clinicians, Dr Daniel L Peterson from the US, powerfully expressed the severity of ME: “In my experience, it is one of the most disabling diseases that I care for, far exceeding HIV disease except for the terminal stages (Introduction to Research and Clinical Conference, Fort Lauderdale, Florida, October 1994; published in JCFS 1995:1:3-4:123-125).

In 1995, Professor Mark Loveless, Head of the AIDS and ME/CFS Clinic at Oregon Health Sciences University said in his Congressional Briefing that an ME/CFS patient:

feels effectively the same every day as an AIDS patient feels two weeks before death; the only difference is that the symptoms can go on for never-ending decades.

In 2004, Dr William Reeves, Chief of the ME/CFS research programme at the US Centres for Disease Control, (CDC) reported that ME/CFS patients “are more sick and have greater disability than patients with chronic obstructive lung or cardiac disease, and that psychological factors played no role (Press Release, AACFS, 7th October 2004).

Also in 2004, a randomised clinical trial found “In comparison with other chronic illnesses such as multiple sclerosis, end-stage renal disease and heart disease, patients with (ME)CFS show markedly higher levels of disability (Am J Occup Ther 2004:58:35-43).

In 2005, Nancy Klimas, Professor of Medicine, Division of Immunology, University of Miami; Co-Director, E.M. Papper Laboratory of Clinical Immunology; Professor of Microbiology and Immunology, University of Miami, and Director of AIDS Research and Co-Director of the AIDS Clinical Research Unit, Miami VA Medical Centre, said in her American Association for CFS In-coming Presidential Address: Our patients are terribly ill, misunderstood, and suffer at the hands of a poorly informed medical establishment and society”.

In a Keynote Lecture on 27th May 2007 at the ME Research UK International Conference held at the University of Edinburgh, Nancy Klimas listed the three main categories of diagnostic symptoms as being autonomic, inflammatory and endocrine, all of which indicate serious underlying pathology. Klimas, a world expert in ME/CFS, was one of the authors of “Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols” (JCFS 2003:11(1):7-115), which is usually known as “the Canadian Definition”. An Overview of that document (“ME/CFS: A Clinical Case Definition and Guidelines for Medical Practitioners”) states:

ME/CFS is an acquired organic, pathophysiological, multisystemic illness that occurs in both sporadic and epidemic forms. Myalgic Encephalomyelitis (ICD 10 G93.3), which includes CFS, is classified as a neurological disease in the World Health Organization’s International Classification of Diseases (ICD). Chronic fatigue must not be confused with ME/CFS because the “fatigue” of ME/CFS represents pathophysiological exhaustion and is only one of many symptoms. Compelling research evidence of physiological and biochemical abnormalities identifies ME/CFS as a distinct, biological, clinical disorder” (

Long-time clinician and researcher Professor Paul Cheney has stated that the cardiac index of ME/CFS patients is so severe that it falls between the value of patients with myocardial infarction (heart attack) and those in shock. Cheney, a world expert on heart problems in ME/CFS, is on record as stating that all patients with the cardinal symptomatology of ME/CFS are in a form of heart failure ( For over 25 years, Cheney has pioneered clinical research into ME/CFS. He has lectured around the world on ME/CFS and is an internationally recognised authority; he has authored or co-authored over 35 articles in peer-reviewed medical journals, including three landmark studies (PNAS 1991; Ann Int Med 1992; Clin Inf Dis 1994); his pre-medical background as a physicist (PhD, Duke University) and as research associate in the Division of Tumour Immunology at the Centres for Disease Control informed his efforts to understand complex medical diseases such as ME/CFS (Cheney Press Release, Co-Cure RES; NOT: 8th October 2009).

A DePaul University (US) study found that patients diagnosed according to the Canadian criteria had more variables that significantly differentiated them statistically from the psychiatric comparison group, and that the Canadian criteria selected cases with less psychiatric co-morbidity and more physical impairment (JCFS 2004:12(1):37-52) but in its Clinical Guideline CG53 on “CFS/ME”, NICE recommended that the Canadian Criteria should not be used in the UK.

For Wessely School psychiatrists so persistently to disregard this evidence-base and to assume and assert that those severely affected by ME/CFS are merely somatising is held by many to amount to professional negligence, because the Wessely School’s beliefs are contrary to the available biomedical evidence.

In stark contrast to the Wessely School’s apparent intellectual dishonesty, in his “Forward” to the book “Lost Voices from a hidden illness” by Natalie Boulton (Invest in ME, 2008), Professor Leonard Jason, Vice-President of the International Association for CFS/ME, wrote:

In telling their stories so poignantly, ‘Lost Voices’ sheds new light on the urgent needs of people who are very ill. It is hard to imagine or understand the shattered world experienced by patients in this book. Patients with extreme illnesses like ME are often sequestered in their homes (and) there are hundreds of thousands of people who live in this underworld inhabited by a devastating illness. Even though ME is a debilitating medical condition, many physicians continue to believe that most patients with this disease are suffering from a psychiatric illness (and) these biases have infiltrated the media. The traditional healthcare system often refuses to treat people with ME. When treatment is offered, all too frequently social service personnel will refer people with ME to psychiatric services. The patients of ‘Lost Voices’ and their carers are heroes in the best sense of the term”.

Fourteen years earlier, in his Eliot Slater Memorial Lecture in May 1994 referred to above, Simon Wessely said: “Organic diseases lose their credibility as their psychological causes are recognised”. Despite Wessely’s confident assertion, it has not been possible to find an example of an organic disorder losing its organic status when its psychological cause was recognised.

The Wessely School has ensured that virtually no biomedical research has been allowed to challenge their steadfast belief that ME is a primary psychiatric disorder, and the result is the harrowing human suffering revealed in ‘Lost Voices’.

Wessely did not mention that psychiatrists have a long track record of medical misattribution: the literature is replete with examples of diseases with (then) “unexplained” symptoms that psychiatrists claimed – with absolute certainty – as psychosomatic. These diseases include diabetes mellitus; epilepsy; multiple sclerosis, Graves’ disease; pernicious anaemia; myasthenia gravis; Parkinson’s Disease; gastric ulcer; migraine; Dupuytren’s contracture; gout; glaucoma; asthma; angina; ulcerative colitis and hay fever (Case Histories in Psychosomatic Medicine. Miles HHW, Cobb S and Shands HC (eds); 1959; WW Norton & Co Inc., New York).

As noted by George Davey-Smith, Professor of Clinical Epidemiology at Bristol, a further example is that in 1948 – long before H-Pylori was discovered in 1989-- doctors in Mount Sinai Hospital advocated antibiotics for peptic ulcers, a treatment they knew was successful. A patent for an antibiotic formulation was issued in 1961, but the “stress model” served to block people from building on this and moving towards an answer that would have led to a treatment that could have dramatically improved the quality of life for millions of people. Various psychological interventions for peptic ulcer were advocated and large numbers of people were subjected to them. The usual claims for dramatic success were made, but properly conducted randomised controlled trials demonstrated no benefit. The conclusion of one well-conducted trial was that “our study demonstrates a need for humility about the degree to which psychological interventions can effect powerful biological processes”. Sick people were directed away from a treatment for peptic ulcers that really worked – antibiotics – to ones that did not work, and the answer that could have led to an effective treatment was missed because of a particular model --- essentially the BPS (biopsychosocial) model --- and the mindset that it generated (Biopsychosocial Medicine, OUP 2005; ed. Peter White).

Davey-Smith is the one dissenting voice in Biopsychosocial Medicine: his contribution (“The biopsychosocial approach: a note of caution”) carries the torch for intellectual integrity.

Davey-Smith showed that bias can generate spurious findings and that when interventional studies to examine the efficacy of a psychosocial approach have been used, the results have been disappointing. To quote from Davey Smith’s contribution: “Over the past 50 years many psychosocial factors have been proposed and accepted as important aetiological agents for particular diseases and then they have quietly been dropped from consideration and discussion”. The illustrations he cited included cholera, pellagra, asthma and peptic ulcer.

Davey-Smith went on to quote Susan Sontag’s well-known dictum: “Theories that diseases are caused by mental state and can be cured by willpower are always an index of how much is not understood about the physical basis of the disease” (Illness as a metaphor. Random House; New York. 1978).

In his book “The Greatest Benefit to Mankind” (Harper Collins, London, 1997) the late Roy Porter noted that it was the biomedical model (not the psychosocial model) that has provided advances in the understanding -- and thus in the treatment and prevention -- of disease processes.

Evidence that the PACE Trial Investigators chose to ignore


In 1996, US neurologist Dr Benjamin Natelson et al evaluated patients with ME/CFS for a placebo effect in a randomised, double blind, controlled trial and found no evidence that ME/CFS is an illness due to patients being overly suggestible or that ME/CFS is a psychogenic illness, and that: “No clear effect of any treatment has ever been demonstrated in this devastating illness (Psychopharmacology 1996:124:226-230).


In 1996, Natelson et al examined the rates of somatisation disorder (SD) in ME/CFS relative to other fatiguing illnesses and found that the diagnosis of SD is extremely problematic in terms of its validity because it involves a series of judgments that can be arbitrary and subjective: “(ME)CFS can be viewed as an organic disease involving many organ systems or as an undifferentiated somatoform disorder. A diagnosis of somatoform disorder may be so arbitrary as to be rendered meaningless in illnesses such as (ME)CFS(Psychosom Med 1996:58(1):50-57).

In 1997, a Review article by Jason et al found that flaws in the case definition and in the design of early epidemiological studies have led to “inaccurate and biased characterisations of (ME)CFS” which incorrectly favour a psychiatric view of the disorder. The authors were clear: “The erroneous inclusion of people with primary psychiatric conditions in (ME)CFS samples will have detrimental consequences for the interpretation of both epidemiologic and treatment efficacy findings. Until more differentiated subgroups are developed, it will be exceedingly difficult to identify characteristics that are common for all people with the diagnosis of (ME)CFS” (American Psychologist 1997:52(9):973-983).

In 1998, a report of an Australian international conference on ME/CFS held in Sydney on 12th –13th February noted the recommendation for “‘fully informing the medical profession….. to increase competence in diagnosis (and to include ME/CFS) in the medical student / training curriculum’.. The guidelines are also intended to 'redress the harm and distress caused by inappropriate psychiatric referral, placing such misdiagnosis in the context of malpractice in terms of duty of care’ (Lancet 1998:351:574).

In 1999, Jason et al noted: “Chronic fatigue syndrome is one of the most debilitating medical conditions when quality of life indicators such as those measuring quality of relationships, financial security, and health status are used. Many physicians believe that most patients with this disease are suffering from a psychiatric illness. These biases have been filtered to the media, which has portrayed chronic fatigue syndrome in simplistic and stereotypic ways. Due to the controversy surrounding a chronic fatigue syndrome diagnosis, people with this illness are sometimes overwhelmed with disbelieving attitudes from their doctors, family and/or friends, and many experience profound losses in their support systems” (AAOHN J. 1999:47(1):17-21).

Also in 1999, Fred Friedberg, Clinical Assistant Professor, Department of Psychiatry and Behavioural Science, State University of New York, pointed out the differences between CBT trials in England and the US: “Several studies of graded activity-orientated cognitive behavioural treatment for CFS, all conducted in England, have reported dramatic improvements in functioning and substantial reductions in symptomatology. On the other hand, cognitive behavioural intervention studies conducted in Australia and the United States have not found significant improvements in functioning or symptoms. Descriptive studies of CFS patients in England, the US and Australia suggest that the CFS population studied in England shows substantial similarities to depression, somatization or phobia patients, while the US and Australian research samples have been clearly distinguished from primary depression patients and more clearly resemble fatiguing neurological illnesses. Because successful trials have all been conducted in England, a replication of these findings in a well-designed US study would be necessary before a general recommendation for graded activity / CBT could be made” (JCFS 1999:5: 3-4:149-159).

Another key paper in 1999 was by Hill, Tiersky, Natelson et al. This study showed that the prognosis for recovery was extremely poor for the severely affected: the majority showed no symptom improvement and only 4% of the patients recovered: “Not only do patients with severe (ME)CFS not recover to full health, but they remain quite severely ill over many years. These data suggest that in patients who do not have psychiatric diagnoses before (ME)CFS onset, depressed mood is a correlate of illness rather than a risk factor for poor prognosis. The cost of (ME)CFS is great, both to the individual and to our society” (Arch Phys Med Rehabil 1999:80:1090-1094).

In January 2002, psychiatrist Alan Gurwitt who has been seeing patients with ME/CFS since 1986 published “Pseudo-science” in which he summed up the problem in the UK: “I have often been embarrassed by and angry at many of my colleagues who fall in line with self-declared ‘experts’ who see somatisation everywhere. Ever since the mid-1980s there have been ‘researchers’ with an uncanny knack at cornering research funds because of their already-formed biases that are in synch with the biases of the funding government organisations (and who) indicate that CBT and graded exercise will do the therapeutic job, thus implying a major psychological causative factor. I have noticed the following deficits in their work, their thinking, their word choices and their methods:

  • They often fail to distinguish between ‘chronic fatigue’ and CFS

  • They fail to distinguish between pre-illness psychological functioning and post-onset occurrence of reactive symptoms. This error would disappear if they did thorough psychiatric evaluations. Their failure to do proper in-depth psychiatric evaluations in at least some of their studies is a serious error with drastic implications

  • Their studies make use of flawed, inappropriate and superficial tests of psychological state which then lead to flawed, inappropriate and superficial conclusions. Their use of large numbers of study subjects gives the impression that they are scientific; in my view it is pseudo-science

  • They fail to include, or to be aware of, the mounting medical-neurological-immunological evidence demonstrating the medical nature of ME/CFS

  • They demonstrate instead a morbid preoccupation with psychiatric morbidity” (Co-Cure ACT 11th January 2002).

In response to an article in the BMJ 2002:324:1298 that promoted CBT and GET as the only effective treatments for “CFS/ME”, on 9th June 2002 the following was published in the eBMJ:

More naïve research: As a long-term CFS sufferer and retired psychology lecturer who taught CBT and behaviour modification, I can confirm that I have tried CBT and graded exercise and it does not work. CBT cannot do anything for the underlying physical and neurological problems. Hence CBT is a red herring for most of us long-term sufferers. What we need is serious research into the underlying factors” (James Wolsey).

In 2003, US researchers Tiersky and Natelson et al showed that in patients with ME/CFS, co-morbid psychiatric disorder, including anxiety or depression, is not related to physical disability in those who developed psychiatric disorder after becoming ill, in contrast to other diseases wherein co-morbid psychiatric disease does compromise physical functioning. Tiersky et al found that people with ME/CFS suffer from profound physical impairment, with scores below the standard norm for patients with type II diabetes, arthritis, cancer, congestive heart failure, hypertension and myocardial infarction (J Nerv Ment Dis 2003:191:324-331).

Natelson was also part of the research team that found left ventricular failure upon exertion in a subset of ME/CFS patients, which again produced hard scientific data using sophisticated tests that showed the profound disability in this disease. This study argues against the claims by Wessely School psychiatrists that the profound disability of ME/CFS is “in the cognition of those affected”.

In 2004, a US Centres for Disease Control (CDC) Surveillance study found that (ME)CFS subjects did not demonstrate any unique patterns of psychiatric disorders and noted that the CDC places ME/CFS at the top priority of new and re-emerging infectious diseases (EK Axe et al. JCFS 2004:12 (3) ).

In 2005, US researchers Song and Jason investigated whether the psychogenic (behavioural) model of ME/CFS by Vercoulen et al (which characterises patients as having insufficient motivation for physical activity or recovery, lacking self-control, and maintaining a self-defeating preoccupation with symptoms) could be replicated in a community-based sample. The authors noted that for some, ME/CFS was assumed to be a psychologically-determined problem (quoting Wessely and Sharpe), and that while this model has been cited frequently, no critical reviews or replication of the Vercoulen et al study of 1998 (which characterised individuals with ME/CFS as inclined to improperly associate physical activity with a worsening of symptoms) have been published. Song and Jason tested the Vercoulen model six times. The results showed that the Vercoulen model represented those with chronic fatigue secondary to psychiatric conditions, but did not represent those with ME/CFS: “In other words, the present study does not support a psychogenic explanation for (ME)CFS” (Journal of Mental Health 2005:14 (3):277-289).

In 2005, Canadian psychiatrist Eleanor Stein (whose practice specialises in ME/CFS) published “Chronic Fatigue Syndrome: Assessment and Treatment of Patients with ME/CFS: Clinical Guidelines for Psychiatrists” ( ). Stein was clear that the Oxford criteria (created and used by the Wessely School) fail to exclude patients with primary psychiatric diagnoses and are not often used by other researchers. The symptoms of ME/CFS occur in multiple organ systems and no other disorder can account for the symptoms. ME/CFS is not a primary psychiatric disorder; rates of psychiatric disorder in ME/CFS are similar to rates in other chronic medical disorders and studies that reported higher prevalence rates of psychiatric disorder had sampling biases; rates of personality disorder in ME/CFS are not elevated, and illness severity, not psychological factors, predict outcome. Stein was outspoken: “Despite the preponderance of research to the contrary, a group of primarily British psychiatrists continue to publish that ME/CFS is caused and exacerbated by faulty self-perception and avoidance behaviour. The faulty beliefs are described as: ‘the belief that one has a serious disease; the expectation that one’s condition is likely to worsen; (patients with ME/CFS adopt) the sick role; and the alarming portrayal of the condition as catastrophic and disabling’. It should be noted that neither this paper nor any of the others with similar views are evidence-based – they are the personal opinions of the authors. Those who think of ME/CFS as ‘fatigue’ and forget the importance of the other symptoms will be at risk of misdiagnosing patients leading to inappropriate treatment recommendations. CBT to convince a patient that s/he does not have a physical disorder is disrespectful and inappropriate. Grief is a universal issue for people with ME/CFS. The losses are numerous. Patients with ME/CFS cannot manage ordinary stressors. The rationale of using CBT in ME/CFS is that inaccurate beliefs and ineffective coping maintain and perpetuate morbidity (but) it has never been proven that these illness beliefs contribute to morbidity in ME/CFS. It is likely that activity avoidance is necessary for the severely ill. It is important to note that no CBT study has reported that patients have improved enough to return to work, nor have they reported changes in the physical symptoms. Despite the fact that worsening of symptoms after exercise is a compulsory criterion for diagnosis of ME/CFS, graded exercise programmes have often been prescribed for such patients (but) neither exercise tolerance nor fitness has been shown to improve with exercise programmes. The medical literature is clear that ME/CFS is not the same as any psychiatric disorder”.

In 2006, Demitrack encapsulated the problem that the Wessely School, NICE and the MRC decline to address. In his paper “Clinical methodology and its implications for the study of therapeutic interventions for chronic fatigue syndrome: a commentary”, Demitrack was concise: “The role of clinical methodology in the study of therapeutics is not trivial, and may confound our understanding of recommendations for treatment”. Demitrack noted the entanglement of physical symptoms and behavioural symptoms, and the various studies by certain psychiatrists purporting to show that the likelihood of psychiatric disorder increased with the number of physical symptoms.

He noted that: “The most extreme view considers these observations to provide convincing evidence that (ME)CFS is, in essence, embedded in the larger construct of affective disorders”. However, in relation to ME/CFS, he noted that: “The observation of specific protracted fatigue and the absence of substantial psychiatric comorbidity argues convincingly that this is an inappropriate and overly simplistic way of approaching this puzzling condition. A major consideration in the approach to clinical therapeutics in (ME)CFS is the fact that it is, by definition, a chronic illness. The magnitude of disease chronicity is a feature that has an important impact on overall treatment responsiveness. Given these observations, it is notable that the specific methodology used to measure treatment outcome rarely comes under close scrutiny in studies of therapeutic intervention in this condition. I believe it is crucial that the quality and interpretability of past and future therapeutic studies of (ME)CFS be critically appraised to the extent that they have considered the impact of these issues in their design and conclusions”.

Demitrack noted the growing body of central nervous system (CNS) research, especially neuroendrocrine physiology and neuroimaging studies, that have reinforced the view that symptoms may indeed be manifestations of a primary disruption in CNS function. In relation to interventions, Demitrack was unambiguous: “To appropriately design and implement (successful interventions), it becomes critically important to specify the patient population most likely to benefit from the proposed intervention, and exceedingly important to define the specific symptom, or cluster of symptoms, that may be presumed to benefit from the intervention. In the absence of a coherent understanding of disease pathogenesis, it does not seem plausible that any single intervention would be helpful in an undifferentiated majority of patients. It therefore may not be surprising that current treatment options for (ME)CFS appear only modestly effective. Non-response, or partial response is the norm, and more than half of all patients fail to receive any benefit from many interventions”.

Demitrack concluded: “In the face of accumulating evidence, there is an increasing realisation that a unitary disease model for this condition has been a theoretical and practical impediment to real progress towards effective therapeutics for (ME)CFS. Many treatment studies have, unfortunately, neglected to thoroughly consider the significance of patient selection (and) symptom measurement(Pharmacogenomics 2006:7(3):521-528).

In 2006, Jason et al sought to subgroup patients with CFS based on a battery of basic laboratory tests and identified infectious, inflammatory and other subgroups. When compared with controls, all subgroups reported greater physical disability:

CFS can impact any number of bodily systems including neurological, immunological, hormonal, gastrointestinal and musculoskeletal. Researchers have reported various biological abnormalities, including hormonal, immune activation, neuroendocrine changes and neurological abnormalities, among others. However, studies involving basic blood work appear to show no typical pattern of abnormality among individuals with CFS.

Borish et al (1998) found evidence of low level inflammation, similar to that of allergies. Natelson et al (1993) found that those with ongoing inflammatory processes reported greater cognitive and mental disabilities. Buchwald et al (1997) found individuals with CFS to have significant abnormalities in C-reactive protein (an indicator of acute inflammation) and neopterin (an indicator of immune system activation, malignant disease, and viral infections). Buchwald et al (1997) stated that individuals with active low level inflammatory, infectious processes could be identified and that this was evidence of an organic process in these patients with CFS. Cook et al (2001) found that individuals with an abnormal MRI and ongoing inflammatory processes had increased physical disability, suggesting an organic basis for CFS.

Clearly, individuals diagnosed with CFS are heterogeneous.

Grouping all individuals who meet diagnostic criteria together is prohibiting the identification of these distinct biological markers of the individual subgroups. When specific subgroups are identified, even basic blood work may reveal a typical pattern of abnormality on diagnostic tests (DeLuca et al. 1997; Hickie et al. 1995; Jason et al. 2001).

The relationship between psychiatric diagnosis and CFS diagnosis is one that is far from being understood”.

Discussing the subtypes found, Jason et al state: “It is notable that these findings emerged utilising only a basic battery of laboratory screening tests. Many people with CFS exhibit only minimal or subtle abnormalities on these tests, and these abnormalities may not be acknowledged by the primary care physician.

The more commonly reported physiological abnormalities in people with CFS, such as the presence of RNase L (Suhadolnik et al 1997), adrenal insufficiency with subsequent low cortisol levels (Addington 2000), the presence of orthostatic intolerance (Schondorf et al 1999), and immunological abnormalities (Patarca-Montero et al 2000) can only be assessed using highly specialised tests to which people with CFS typically have little access.

This study demonstrates that subgrouping is possible using laboratory tests that are readily available and can easily be ordered by primary care physicians.

The identification of clinically significant subgroups is the next logical step in further CFS research. Previous research examining people with CFS as a homogeneous group may have missed real differences among subgroups of this illness” (“Exploratory Subgrouping in CFS: Infectious, Inflammatory and Other”. In: Advances in Psychology Research 2006:41:115-127. A Columbus (Ed): Nova Science Publishers, Inc).

In 2007 an important article by Jason and Richman reviewed two aspects of ME/CFS: the issues involving the inappropriate name of the illness favoured by some psychiatrists (“chronic fatigue syndrome”, which undoubtedly trivialises the disorder), and the flawed epidemiological approaches, both of which may have contributed to the diagnostic scepticism and the stigma that those with ME/CFS encounter.

The authors suggest that the increases in cases during the past 15 years are due to a broadening of the case definition to include those with primary psychiatric conditions (as the Wessely School have done). The authors note how flawed epidemiology can contribute to inappropriate stereotypes, and stress the need for accurate measurement and classification in disorders that might be labelled as ‘functional somatic syndromes’ (as the Wessely School deems ME/CFS to be).

The authors state: “Accurate measurement and classification of (ME)CFS, fibromyalgia and irritable bowel syndrome is imperative when evaluating the diagnostic validity of controversial disease entities alternatively labelled ‘functional somatic syndromes’. Measurement that fails to capture the unique characteristics of these illnesses might inaccurately conclude that only distress and unwellness characterise these illnesses, thus inappropriately supporting a unitary hypothetical construct called functional somatic syndromes (JCFS 2007:14(4):85-103).

Documented pathology seen in ME/CFS that contra-indicates the use of GET


There is an extensive literature from 1956 to date on the significant pathology that has been repeatedly demonstrated in ME/CFS, but not in “CFS/ME” or “chronic fatigue”; this can be accessed on the ME Research UK website at: .

According to Professor Nancy Klimas, ME/CFS can be as severe as congestive heart failure and the most important symptom of all is post-exertional relapse (presentation at the ME Research UK International Conference held in Cambridge in May 2008).

Unique vascular abnormalities have been demonstrated in ME/CFS, with markers of oxidative stress. Oxidative stress is caused by highly reactive molecules known as free radicals circulating in the bloodstream and results in cell injury. Oxidative stress levels are significantly raised in ME/CFS and are associated with clinical symptoms. (Kennedy G, Spence VA, McLaren M, Hill A, Underwood C, Belch JJF. Free Radical Bio Med. 2005;39:584-589).

Exercising muscle is a prime contender for excessive free radical generation (Niess AM, Simon P. Front Biosci. 2007 Sep 1;12:4826-38).

Research has shown that many patients with ME/CFS may have an inflammatory condition and be in a ‘pro-oxidant’ state (Klimas NG, Koneru AO. Curr Rheumatol Rep. 2007;9(6):482-7).

In 1983, UK researchers documented evidence of a consistent pattern of complexity, including “malaise, exhaustion on physical or mental effort, chest pain, palpitations, tachycardia, polyarthralgia, muscle pains, back pain, true vertigo, dizziness, tinnitus, nausea, diarrhoea, abdominal cramps, epigastric pain, headaches, paraesthesia and dysuria” (Keighley and Bell, JRCP: 1983:339-341).

Documented muscle abnormalities in ME/CFS

In 1984, Arnold et al demonstrated excessive intracellular acidosis of skeletal muscle on exercise in ME/CFS patients, with a significant abnormality in oxidative muscle metabolism and a resultant acceleration in glycolysis (Proceedings of the Third Annual Meeting of the Society for Magnetic Resonance in Medicine, New York: 1984: 12-13).

In 1985, UK researchers demonstrated muscle abnormalities in ME/CFS patients: “The post-viral fatigue syndrome, also known as ME, has been recognised recently as a distinct neurological entity with increasing evidence of the organic nature of the disease. The most important findings were type II fibre predominance, subtle and scattered fibre necrosis and bizarre tubular structures and mitochondrial abnormalities. About 75% of the patients had definitely abnormal single fibre electromyography results” (Goran A Jamal Stig Hansen JNNP 1985:48:691-694).

In compelling the evidence for an hysterical basis may be, there is further, equally compelling, evidence of organic disease. Some patients do have frank neurological signs. Muscle biopsies showed necrosis and type II fibre predominance (JRCGP: 1987:37:212-216).

It was documented as long ago as 1988 that there was “general agreement that (ME’s) distinguishing characteristic is severe muscle fatigability, made worse by exercise. It becomes apparent that any kind of muscle exercise can cause patients to be almost incapacitated (and) the patient is usually confined to bed. What is certain is that it becomes plain that this is an organic illness in which muscle metabolism is severely affected” (Crit Rev Neurobiol: 1988:4:2:157-178).

In 1988, UK researchers Archard and Bowles et al published the results of their research into muscle abnormalities in ME/CFS: “These data show that enterovirus RNA is present in skeletal muscle of some patients with postviral fatigue syndrome up to 20 years after onset of disease and suggest that persistent viral infection has an aetiological role. These results provide further evidence that Coxsackie B virus plays a major role in ME, either directly or by triggering immunological responses which result in abnormal muscle metabolism” (JRSM 1988:81:325-331).

Also in 1988, Teahon et al published a study of skeletal muscle function in ME/CFS; it showed significantly lower levels of intracellular RNA, suggesting that ME/CFS patients have an impaired capacity to synthesise muscle protein, a finding which cannot be explained by disuse (Clinical Science 1988: 75: Suppl 18:45).

In 1989, Professor Tim Peters spoke at a meeting of microbiologists held at the University of Cambridge: “Other muscle abnormalities have been reported, with decreased levels inside the cell of a key enzyme called succinate dehydrogenase, which plays an important role in energy production inside the mitochondria (the power house of the cell)”. A report of this conference was published in the ME Association Newsletter, Autumn 1989, page 16.

In 1990, as mentioned above, a UK researcher pointed out the folly of CBT/GET: “It has been suggested that a new approach to the treatment of patients with postviral fatigue syndrome would be the adoption of a cognitive behavioural model” (Wessely S, David A et al. JRCGP 1989:39:26-29). Those who are chronically ill have recognised the folly of the approach and, far from being maladaptive, their behaviour shows that they have insight into their illness” ( D O Ho-Yen JRCGP 1990:40:37-39).

Also in 1990, the BMJ published an important study: “Patients with the chronic fatigue syndrome have reduced aerobic work capacity compared with normal subjects. We found that patients with the chronic fatigue syndrome have a lower exercise tolerance than normal subjects. Previous studies have shown biochemical and structural abnormalities of muscle in patients with the chronic fatigue syndrome (Aerobic work capacity in patients with chronic fatigue syndrome. MS Riley DR McClusky et al BMJ:1990:301:953-956).

In 1991, evidence of muscle damage in ME/CFS was demonstrated by Professor Wilhelmina Behan from Glasgow: “The pleomorphism of the mitochondria in the patients’ muscle biopsies was in clear contrast to the findings in the normal control biopsies. Diffuse or focal atrophy of type II fibres has been reported, and this does indicate muscle damage and not just muscle disuse”. This study was done on a fairly homogeneous population and 80% of the biopsies showed structural damage to the mitochondria (Acta Neuropathol 1991:83:61-65).

In 1992, US researchers (including Robert Gallo, the co-discoverer of the HIV virus) found that “57% of patients were bed-ridden, shut in or unable to work. Immunologic (lymphocyte phenotyping) studies revealed a significantly increased CD4 / CD8 ratio. Magnetic resonance scans of the brain showed punctate, subcortical areas of high signal intensity consistent with oedema or demyelination in 78% of patients. Neurologic symptoms, MRI findings, and lymphocyte phenotyping studies suggest that the patients may have been experiencing a chronic, immunologically-mediated inflammatory process of the central nervous system” (A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpes Type 6 infection. Dedra Buchwald, Paul Cheney, Robert Gallo, Anthony L Komaroff et al Ann Intern Med 1992:116:2:103-113).

Also in 1992, the US Department of Health and Human Services produced a pamphlet on ME/CFS for the guidance of physicians (NIH Publication No. 92-484) which stated: “ME/CFS symptoms overlap with those of many well-recognised illnesses, for example, lupus erythematosus (SLE) and multiple sclerosis. Psychiatric evaluations fail to identify any psychiatric disorders. Many people with ME/CFS have neurologic symptoms, including paraesthesiae, dysequilibrium and visual blurring. A few patients have more dramatic neurologic events such as seizures, periods of severe visual impairment, and periods of paresis. Evidence suggests that several latent viruses may be actively replicating more often in (ME)CFS patients that in healthy control subjects. Most investigators believe that reactivation of these viruses is probably secondary to some immunologic challenge. It is important to avoid situations that are physically stressful”.

On 18th February 1993, Professor Paul Cheney testified before the US FDA Scientific Advisory Committee as follows: “I have evaluated over 2,500 cases. At best, it is a prolonged post-viral syndrome with slow recovery. At worst, it is a nightmare of increasing disability with both physical and neurocognitive components. The worst cases have both an MS-like and an AIDS-like clinical appearance. We have lost five cases in the last six months. The most difficult thing to treat is the severe pain. Half have abnormal MRI scans. 80% have abnormal SPECT scans. 95% have abnormal cognitive-evoked EEG brain maps. Most have abnormal neurological examination. 40% have impaired cutaneous skin test responses to multiple antigens. Most have evidence of T-cell activation. 80% have evidence of an up-regulated 2-5A antiviral pathway. 80% of cases are unable to work or attend school. We admit regularly to hospital with an inability to care for self”.

Also in 1993, Professor Anthony Komaroff from Harvard published his “Clinical presentation of chronic fatigue syndrome” in which he stated: “ME/CFS can last for years and is associated with marked impairment. (It) is a terribly destructive illness. The tenacity and ferocity of the fatigue can be extraordinary. As for the symptoms that accompany the fatigue, it is striking that these symptoms are experienced not just occasionally but are present virtually all the time. In our experience, 80% of patients with ME/CFS have an exceptional post-exertional malaise. (Physical examination findings) include abnormal Romberg test (and) hepatomegaly (and) splenomegaly. Anyone who has cared for patients with ME/CFS will recognize that (the) description of the patient with lupus eloquently describes many patients with ME/CFS as well” (In: Chronic Fatigue Syndrome. John Wiley & Sons, Chichester. Ciba Foundation Symposium 173:43-61).

In 1993, UK researchers Barnes et al demonstrated that there is a significant abnormality in oxidative muscle metabolism with a resultant acceleration in glycolysis in ME/CFS patients [cf. the work of Arnold in 1984 above] (JNNP:1993:56:679-683).

In 1995, UK researchers Lane and Archard published the article “Exercise response and psychiatric disorder in chronic fatigue syndrome”, which stated: “In previous studies patients with ME/CFS showed exercise intolerance in incremental exercise tests. We examined venous blood lactate responses to exercise at a work rate below the anaerobic threshold in relation to psychiatric disorder. Our results suggest that some patients with ME/CFS have impaired muscle metabolism that is not readily explained by physical inactivity or psychiatric disorder” (BMJ 1995:311:544-545).

That same year (1995), UK researchers Geoffrey Clements et al reported that: “Enteroviral sequences were found in significantly more ME/CFS patients than in the two comparison groups. The presence of the enteroviral sequences in a significant number of patients points to some role in ME/CFS. A variety of immunological disturbances have been reported for ME/CFS patients which may relate in some way to the enteroviral persistence. This study provides evidence for the involvement of enteroviruses in just under half of the patients presenting with ME/CFS and it confirms and extends previous studies using muscle biopsies. We provide evidence for the presence of viral sequences in serum in over 40% of ME/CFS patients” (J Med Virol 1995:45:156-161).

In 1996, Pizzigallo E et al reported:“We performed histochemical and quantitative analysis of enzymatic activities and studies of mitochondrial DNA deletions. All specimens showed hypotrophy, fibres fragmentation, red ragged fibres, and fatty and fibrous degeneration. Electron microscopy confirmed these alterations, showing degenerative changes, and allowed us to detect poly/pleomorphism and cristae thickening of the mitochondria. The histochemical and quantitative determination of the enzymatic activity showed important reduction, in particular of the cytochrome-oxidase and citrate-synthetase. The ‘common deletion’ of 4977 bp of the mitochondrial DNA was increased as high as 3,000 times the normal values in three patients. Our results agree with those of Behan et al 1991 and Gow et al 1994. The alterations are compatible with a myopathy of probable mitochondrial origin (which) could explain the drop in functional capability of the muscle” (JCFS 1996:2:(2/3):76-77)

In 1997, Charles Lapp, Professor of Community Medicine at Duke University, Charlotte, North Carolina, found that a trial allowing ME/CFS patients to reach their maximum oxygen consumption within 8-10 minutes of exercise caused 74% to experience a worsening of fatigue and that none improved. The average relapse lasted 8.82 days. Lapp concluded: “These findings suggest that, pushed to maximal exertion, patients with ME/CFS may relapse” (Am J Med 1997:103:83-84).

In 1998, a study of autonomic function by Rowe and Calkins found that “Virtually all ME/CFS patients (regardless of their haemodynamic response) have their symptoms provoked by standing upright” (Am J Med 1998:105: (3A):15S – 21S).

That same year, (1998) UK researchers Russell Lane and Leonard Archard published their findings of muscle abnormalities in response to exercise in ME/CFS patients: “The object of this study was to examine the proportions of types I and II muscle fibres and the degree of muscle fibre atrophy and hypertrophy in patients with ME/CFS in relation to lactate responses to exercise, and to determine to what extent any abnormalities found might be due to inactivity. Muscle fibre histometry in patients with ME/CFS did not show changes expected as a result of inactivity. The authors note that one of these patients had an inflammatory infiltrate, and it would seem that inflammation and class I MHC expression may occur in biopsies from patients with ME/CFS. The authors note that this is of some interest, as they have argued previously that some forms of ME/CFS may follow a previous virally-mediated inflammatory myopathy”. In general, following exercise, patients with ME/CFS showed more type I muscle fibre predominance and infrequent muscle fibre atrophy, unlike that which would be expected in healthy sedentary people. (JNNP 1998:64:362-367).

In 1999, Paul et al provided irrefutable evidence of delayed muscle recovery after exercise. That paper states: The use of 31 P-nuclear magnetic resonance (31 P-NMR) has now provided positive evidence of defective oxidative capacity in ME/CFS. Patients with ME/CFS reach exhaustion more rapidly than normal subjects, in keeping with an abnormality in oxidative metabolism and a resultant acceleration of glycolysis in the working skeletal muscles. When the rate of resynthesis of phosphocreatine (PCr) following exercise is measured, this abnormality is confirmed. (This) provides a conclusive demonstration that recovery is significantly delayed in patients with ME/CFS. The results demonstrate that patients with ME/CFS fail to recover properly from fatiguing exercise and that this failure is more pronounced 24 hours after exercise(European Journal of Neurology 1999:6:63-69).

In 2000, a Belgian / Australian collaborative study entitled “Exercise Capacity in Chronic Fatigue Syndrome” was unequivocal: “Comparing the exercise capacity in our patients with data from other studies shows a functionality similar to that of individuals with chronic heart failure, patients with chronic obstructive pulmonary disease, and those with skeletal muscle disorder”. Specific findings included (i) the resting heart rate of patients was higher than controls but patients’ maximal heart rate at exhaustion was lower than controls (ii) the maximal workload achieved by patients was almost half that achieved by controls (iii) the maximal oxygen uptake was almost half that achieved by controls. This would affect patients’ physical abilities, leading the authors to comment: “This study clearly shows that patients with ME/CFS are limited in their capabilities”. Taken together, these findings “suggest that alteration in cardiac function is a primary factor associated with the reduction in exercise capacity in ME/CFS(P De Becker et al. Arch Intern Med 2000:160:3270-3277).

In 2001 an Australian study by Sargent, Scroop, Burnett et al from the Adelaide CFS Research Unit found that ME/CFS patients are not de-conditioned and that “There is no physiological basis for recommending graded exercise programmes” (The Alison Hunter Memorial Foundation ME/CFS Clinical and Scientific Meeting, Sydney, Australia, December 2001).

This was later published (Med. Sci. Sports Exerc: 2002:34:1:51-56) and the authors stated: “The fatigue is often present at rest and exacerbated by the simplest of physical tasks. The purpose of the present study was to employ ‘gold standard’ maximal exercise testing methodology. Exercise performance is well recognised to be impaired in ME/CFS patients, with a reduced exercise time to exhaustion being a common finding. The present findings indicate that physical deconditioning (is not) a critical factor in the fatigue that (patients) experience. Although the recommendation or imposition of exercise-training programmes may have benefit in terms of social interaction, such programmes could well be based on a false premise if the intention is to improve well-being by correcting the effects of deconditioning”.

In 2003, Professor Ben Natelson from the US found that “The patients with ME/CFS (indicated) profound physical impairment. These scores tended to be below the published norm for patients with cancer, congestive heart failure and myocardial infarction” (J Nerv Ment Dis 2003:191:324-331).

In 2003 a UK study of skeletal muscle tissue by neurologist Russell Lane et al provided evidence of impaired mitochondrial structure and function in ME/CFS patients, once again demolishing the “de-conditioning” theory (JNNP: 2003:74:1382-1386).

In the Summer of 2004, Professors Christopher Snell and Mark VanNess from the University of the Pacific (specialists in sports medicine and muscle function who have been involved in ME/CFS research since 1998) published an article in The CFIDS Chronicle in which they wrote: “Healthcare professionals often recommend aerobic exercise as a cure-all for the symptoms of ME/CFS without fully understanding the consequences (and) the results can be devastating (and can lead to) symptom exacerbation, post-exertional malaise and even collapse. It is obvious that persons with ME/CFS do not recover well from aerobic activity. This may be because, for them, the activity is not aerobic. The aerobic system depends on a constant supply of oxygen being delivered to active muscles. There is evidence that this process may be impaired in ME/CFS. In the absence of an adequate supply of oxygen, energy production shifts to anaerobic (without oxygen) process, leading to oxygen debt. Oxygen debt equals fatigue and before normalcy can return (that debt) must be repaid. Interest rates on the (oxygen debt) may be significantly high. Exercise therapy for ME/CFS will not work because one size does not fit all”.

In October 2004, at the 7th AACFS International Conference held in Madison, Wisconsin, Susan Levine from Columbia presented evidence of an analysis of metabolic features using MRSI (magnetic resonance spectroscopy imaging) which showed elevated lactate levels in ME/CFS patients, suggesting mitochondrial metabolic dysfunction similar to mitochondrial encephalomyopathy. Elevation of thalamic choline was also demonstrated, suggesting the presence of neuronal damage.

At the same International Conference, Spanish researchers (Garcia-Quintana) presented their work on aerobic exercise, providing evidence of low maximal oxygen uptake in ME/CFS patients. This confirmed previous studies showing that patients with ME/CFS have a markedly reduced aerobic work capacity on bicycle ergometry.

At this Conference, findings were presented by a Belgian team (Nijs) which provided evidence of underlying lung damage through intracellular immune dysregulation, with impairment of cardiopulmonary function – elevated elastase levels could damage lung tissue and impair oxygen diffusion across the alveoli in the lungs, potentially explaining decreased oxygen delivery to tissues that is seen in ME/CFS. (This presentation was singled out as being outstanding).

The “Exercise Workshop” at this same conference highlighted the understanding that people with ME/CFS suffer exercise intolerance and post-exertional malaise unless they stay within prescribed limits, the limit suggested being the anaerobic threshold (AT -- this is the time during exertion that the heart and lungs can no longer provide adequate oxygen to muscles, and muscle metabolism changes from aerobic to anaerobic; it is well known that this change occurs unusually early in people with ME/CFS). If the anaerobic threshold is determined to occur at 4.5 minutes, then the patient is advised to exert no more than 4 to 4.5 minutes before stopping to rest.

(For conference reports, see by Professor Charles Lapp from the US and Co-Cure NOT, RES: 2nd November 2004 by Dr Rosamund Vallings from New Zealand).

In 2005, Black and McCully published their results of an exercise study in patients with ME/CFS: “This analysis suggests that ME/CFS patients may develop exercise intolerance as demonstrated by reduced total activity after 4 – 10 days. The inability to sustain target levels, associated with pronounced worsening of symptomatology, suggests the subjects with ME/CFS had reached their activity limit” (Dyn Med 2005: Oct 24: 4 (1): 10).

Black and McCully’s results concur with those of Bazelmans et al that were published in the same year. That study examined the effects of exercise on symptoms and activity in ME/CFS: “For ME/CFS patients, daily observed fatigue was increased up to two days after the exercise test. For controls, fatigue returned to baseline after two hours. Fatigue in ME/CFS patients increased after exercise” (J Psychosom Res 2005:59:4:201-208).

Also in 2005, Jammes et al assessed increased oxidative stress and altered muscle excitability in response to incremental exercise in ME/CFS patients: “The data reported here were taken from well-rested subjects and research has demonstrated that incremental exercise challenge potentiates a prolonged and accentuated oxidant stress that might well account for post-exercise symptoms in ME/CFS” (J Intern Med 2005: 257 (3):299-310).

In 2006, Belgian researchers Nijs and De Meirleir reported on the observed associations between musculoskeletal pain severity and disability, noting that pain was as important as fatigue to ME/CFS patients: “A few years ago, little was known about the nature of chronic musculoskeletal pain in ME/CFS. Research data gathered around the world enables clinicians to understand, at least in part, musculoskeletal pain in ME/CFS patients. Fear of movement (kinesiophobia) is not related to exercise performance in ME/CFS patients. From a pathophysiologic perspective, the evidence of a high prevalence of opportunistic infections is consistent with the numerous reports of deregulated and suppressed immune functioning in ME/CFS patients. Infection triggers the release of the pro-inflammatory cytokine interleukin-1 which is known to play a major role in inducing cyclooxygenase-2 (COX-2) and prostaglandin E2 expression in the central nervous system. Upregulation of COX-2 and prostaglandin E2 sensitises peripheral nerve terminals. Even peripheral infections activate spinal cord glia (both microglia and astrocytes), which in turn enhance the pain response by releasing nitric oxide (NO) and pro-inflammatory cytokines. These communication pathways can explain the wide variety of physiological symptoms seen in ME/CFS. Experimental evidence has shown that ME/CFS patients respond to incremental exercise with a lengthened and accentuated oxidative stress response, explaining muscle pain and post-exertional malaise as typically seen in ME/CFS. In many of the published studies, graded exercise therapy has been adopted as a component of the CBT programme (i.e. graded exercise was used as a way to diminish avoidance behaviour towards physical activity). Unfortunately, the studies examining the effectiveness of GET/CBT in ME/CFS did not use musculoskeletal pain as an outcome measure (and) none of the studies applied the current diagnostic criteria for ME/CFS. From a large treatment audit amongst British ME/CFS patients, it was concluded that approximately 50% stated that GET worsened their condition. Finally, graded exercise therapy does not comply with our current understanding of ME/CFS exercise physiology. Evidence is now available showing increased oxidative stress in response to (sub)maximal exercise and subsequent increased fatigue and post-exertional malaise (Manual Therapy 2006: Aug. 11(3):187-189).

In 2007, collaborating researchers in Japan and America noted that people with ME/CFS reported substantial symptom worsening after exercise, symptoms being most severe on the fifth day. There was no cognitive or psychological benefit to the exercise, and patients suffered physical decline (Yoshiuchi K, Cook DB, Natelson BH et al. Physiol Behav July 24, 2007).

Also in 2007, Klimas et al reported:“Gene microarray data have led to better understanding of pathogenesis. Research has evaluated genetic signatures (and) described biologic subgroups. Genomic studies demonstrate abnormalities of mitochondrial function” (Curr Rheumatol Rep 2007:9(6):482-487).

In 2007 Nestadt P et al reported neurobiological differences in (ME)CFS: “These results show that a significant proportion of patients diagnosed with (ME)CFS have elevated ventricular lactate levels, suggesting anaerobic energy conversion in the brain and / or mitochondrial dysfunction”. Elevated blood lactate levels after mild exercise are considered to be a sign of mitochondrial damage (IACFS International Research Conference, Florida).

In 2008, a collaborative study involving researchers from Belgium, the UK and Australia (published by J Nijs, L Paul and K Wallman as a Special Report in J Rehabil Med 2008:40:241-247) examined the controversy about exercise for patients with ME/CFS. Although published after the production of the NICE Guideline, the paper contains relevant references showing adverse effects of GET that were published before the Guideline (and so were available to the GDG and also to the PACE Trial Principal Investigators):

ME/CFS describes a disorder of chronic debilitating fatigue that cannot be explained by any known medical or psychological condition. The Cochrane Collaboration advises practitioners to implement graded exercise therapy for patients with ME/CFS, using cognitive behavioural principles. CBT represents a psychological and physical intervention approach aimed at assisting individuals in re-evaluating concepts related to their illness and in adopting thoughts and behaviours designed to promote recovery (the reference for this statement is Chalder, Deale and Wessely et al. Am J Med 1995:98:419-420). This approach to GET advises patients to continue exercising at the same level even when they develop symptoms in response to exercise (two references are provided for this statement, one being Fulcher KY and White PD, BMJ 1997:314:1647-1652 – this being one of the RCTs based on the Oxford criteria that the GDG relied upon for its recommendation of GET. The other reference was Clark LV and White PD (J Mental Health 2005: 14: 237-252), in which Clark and White state that patients with ME/CFS are de-conditioned, and argue that: “Patient education is necessary to inform patients of the positive benefit / risk ratio in order to improve acceptance and adherence”). Nijs et al continue: “Conversely, there is evidence of immune dysfunction in ME/CFS, and research shows further deregulation of the immune system in response to too-vigorous exercise, leading to an increase in fatigue and post-exertional malaise. It has been shown that even a 30% increase in activity frequently triggers a relapse (ref: Black CD, O’Connor, McCully K. Dynamic Medicine 2005:4:3). The severe exacerbation of symptoms following exercise, as seen in patients with ME/CFS, is not present in other disorders where fatigue is a predominant symptom. This post-exertional malaise is a primary characteristic evident in up to 95% of people with ME/CFS. It is possible that exercise at ANY intensity that exceeds an ME/CFS patient’s physical capabilities may result in the worsening of symptoms. Early approaches to GET advised patients to continue exercising at the same level when they developed symptoms in response to the exercise. This led to exacerbation of symptoms and adverse feedback from patients and patient charities”.

In 2008 a paper by Professor Julia Newton et al (Hollingsworth JG, Newton JL et al; Clin Gastroenterol Hepatol 2008:6:(9):1041-1048) compared mitochondrial function in patients with primary biliary cirrhosis (PBC), patients with primary sclerosing cholangitis, patients with ME/CFS and normal controls; the authors stated that PBC is characterised in 95% of patients by autoantibody responses directed against the mitochondrial antigen pyruvate dehydrogenase complex (PDC). To define mitochondrial function in peripheral muscle during exercise, (31)P magnetic resonance spectroscopy was used.

Whilst the paper is chiefly concerned with mitochondrial dysfunction in patients with primary biliary cirrhosis (and the results clearly indicate mitochondrial dysfunction in patients with PBC, who showed excess muscle acidosis at higher levels of exercise), the authors state about ME/CFS patients: “Interestingly, prolonged time to maximum proton efflux was also seen in the (ME)CFS control group, indicating that there are aspects of muscle pH handling that are abnormal in this important clinical group”.

Professor Newton is Lead Clinician in the internationally renowned Cardiovascular Investigations Unit at the University of Newcastle, UK, which is the largest autonomic function testing laboratory in Europe; her work focuses on the role of the autonomic nervous system in the development of fatigue, specifically in primary biliary cirrhosis, but also in the pathogenesis of fatigue in ME/CFS. In her Conference pack for the ME Research UK International Research Conference held at the University of Cambridge on 6th May 2008, Professor Newton said: “Recent results from a series of MR scans have shown impaired proton removal from muscle during exercise in patients with ME/CFS compared to matched controls. This has led us to hypothesise that fatigue arises due to impaired pH run off from muscle during exercise which is influenced by the degree of autonomic dysfunction”.

In 2009, Light et al published evidence demonstrating that after moderate exercise, (ME)CFS and (FM)CFS patients show enhanced gene expression for receptors detecting muscle metabolites and that these were highly correlated with symptoms of both physical and mental fatigue and pain. The marked alterations in gene expression from circulating leucocytes of (ME)CFS patients after exercise suggest that such alterations could be used as objective biomarkers, with ~ 90% of the (ME)CFS patients being distinguishable from controls using four of the genes measured. The authors have shown that 25 minutes of moderate exercise generates large and rapid increases in gene expression in leucocytes of (ME)CFS subjects but not in control subjects, findings which confirm previous suggestions that alterations in all parts of the HPA axis may mediate and sustain symptoms of (ME)CFS (The Journal of Pain 2009: doi:10.1016/j.pain.2009.06.003).

In 2009, a team led by Professor Myra Nimmo (an internationally renowned metabolic physiologist from the Strathclyde Institute of Pharmacy and Biomedical Sciences in Glasgow) found that during an incremental exercise test, the power output at the lactate threshold was 28% lower in ME/CFS patients than in matched controls and in addition, F2-isoprostanes (indicators of oxidative stress) were higher in patients than in controls at rest, as well as after exercise and after 24 hours. These results confirm the earlier work of Kennedy et al from Dundee which showed raised levels of isoprostanes in ME/CFS patients at rest. Not only do Nimmo’s results show that the levels remain high during exercise and in the recovery period, but that the level of isoprostanes in “rested” ME/CFS patients was as great as that reached by the healthy controls after exercise (Scandinavian Journal of Medicine and Science in Sports 2009: doi:10.1111/j.1600-0838.2009.00895.x ).

In 2009, Pietrangelo T and Fulle S et al published a transcription profile analysis of the vastus lateralis muscle in male and female (ME)CFS patients. They used global transcriptome analysis to identify genes that were differently expressed in the vastus lateralis, and their results are significant. They found that the expression of genes that play key roles in mitochondrial function and oxidative balance (including superoxide dismutase) were altered in (ME)CFS patients. Other genes that were altered in these patients include the genes involved in energy production, muscular trophism and fibre phenotype determination. Importantly, the expression of a gene encoding a component of the nicotinic cholinergic receptor binding site was reduced, suggesting impaired neuromuscular transmission. The authors argue that these major biological processes could be involved in and/or responsible for the muscle symptoms of (ME)CFS (Int J Immunopathol Pharmacol 2009:22(3):795-807).

There is a significant literature suggestive of mitochondrial defects (both structural and functional) in ME/CFS from 1984 to date.

Mitochondria are the powerhouses of the cells. They are responsible for generating energy as adenosine triphosphate (ATP) and are involved in the apoptosis signalling pathway (apoptosis being programmed cell death).

Despite the irrefutable evidence of mitochondrial dysfunction and damage in patients with ME/CFS, the NICE Guideline on “CFS/ME” proscribes mitochondrial testing and recommends only behavioural modification in the form of cognitive behavioural therapy, together with incremental aerobic exercise, and refers to “perceived exertion” (52 page version, page 30). It claims that it offers the best practice advice on the care of people with CFS/ME” (52 page version, page 6) and that its advice is “evidence-based”. It is notable that the alleged evidence-base upon which the Guideline Development Group relied specifically states: If patients complained of increased fatigue, they were advised to continue at the same level of exercise (Fulcher and White, BMJ 1997:314:1647-1652).

Given the evidence of mitochondrial damage, such advice cannot conceivably qualify as “best practice advice”.

Medications documented to induce mitochondrial damage include analgesics; anti-inflammatories; anaesthetics; angina medications; antibiotics; antidepressants; anxiolytics; barbiturates; cholesterol-lowering medications (statins); chemotherapy; and the mood-stabiliser lithium, amongst others, including medications for Parkinson’s Disease, diabetes, cancer and HIV/AIDS (Mol Nutr Food Res 2008:52:780-788).

It is a matter of record that Professor Wessely advises the prescription of lithium for patients with ME/CFS: “There is no doubt that at least half of CFS patients have a disorder of mood. The management of affective disorders is an essential part of the treatment of CFS/ME. Numerous trials attest to the efficacy of tricyclic antidepressants in the treatment of fatigue states. Patients who fail to respond should be treated along similar lines to those proposed for treatment-resistant depression. Adding a second antidepressant agent, especially lithium, may be beneficial (The chronic fatigue syndrome – myalgic encephalomyelitis or postviral fatigue. S Wessely PK Thomas. In: Recent Advances in Clinical Neurology (ed): Christopher Kennard. Churchill Livingstone 1990: pp 85-131).

In addition to lithium, specific medications listed that are known to induce mitochondrial damage include aspirin; acetaminophen (paracetamol / Tylenol); fenoprofen (Nalfon); indomethacin (Indocin, Indocid); naproxen (Naprosyn); lidocaine; amiodarone (Cordarone); tetracycline; amitriptyline; citalopram (Cipramil); fluoxetine (Prozac); chlorpromazine (Largactil); diazepam (Valium); galantamine (Reminyl) and the statins, amongst others.

For the Wessely School to subject patients with ME/CFS to graded exercise that will almost certainly induce more pain and thus give rise to ingestion of analgesics that are known to induce further mitochondrial damage cannot be said to be acting in patients’ best interests.

Documented cardiovascular abnormalities in ME/CFS

Illustrations of cardiovascular dysfunction in ME/CFS include the following:


One of the most useful and important descriptions of ME is that of Dr Andrew Wallis as contained in his doctoral thesis (An Investigation into an Unusual Disease seen in Epidemic and Sporadic Form in a General Practice in Cumberland in 1955 and subsequent years. Andrew Lachlan Wallis.  Doctoral Thesis, University of Edinburgh, 1957). For a summary, see .

Wallis particularly noted myocarditis  (heart rate was accelerated during the illness), with dyspnoea on slightest exertion. The post-mortem histopathology report from one (female) case stated:

There are in the entire diencephalon, particularly round the third ventricle, numerous small haemorrhages, which extend into the adjacent parts of the mid-brain.  Similar haemorrhages can be seen in the corpora mamillare. The haemorrhages are mostly around the small vessels but some are also to be seen in the free tissue.  This is a significant finding.”

Comparison of the Wallis findings with other published findings

The post-mortem histopathology report in Wallis’ thesis was particularly interesting, given the subsequent documented evidence of vascular abnormalities and impaired blood flow in ME/CFS. For example, references in one textbook of ME/CFS to vasculopathy include the following:

lymphocytes in the cerebrospinal fluid congregate in the perivascular (Virchow Robin) spaces of the brain…these findings do suggest that the disease may involve the perivascular spaces of the brain

dilatation of the Virchow Robin spaces could also suggest intracranial arterial or periarterial pathology, in particular, one would expect to find a congregation of lymphocytes in the perivascular spaces around the central nervous system arteries…(Wallis) revealed an artefact that is in an anatomical position similar to that suggested by MRI studies re: the Los Angeles 1934 epidemic: “The blood vessels throughout the nervous system were distended with red blood cells…the most characteristic change was infiltration of the blood vessel walls” (The present consensus on MRI in ME/CFS.  Royce J Biddle.  In: The Clinical and Scientific Basis of ME/CFS. ed: BM Hyde; The Nightingale Press, Ottawa, Canada 1992).  Other references to vasculopathy in ME/CFS in the same textbook include:page 42 (Chapter 5 / BM Hyde): "We routinely observe patients with severely cold extremities and a visible line demarcating the cold from the area of normal skin temperature. The fact that the loss of normal blood flow may be persistent has been indicated by Gilliam (1938)"

page 62: "Patients will complain of severe blanching of their extremities, nose, ears, lower arms and hands as well as lower legs and feet. Observation will often reveal a blanched clearly demarcated line separating warm from icy cold tissue. The whitened extremities may persist for hours and can be extremely painful"

page 70: "The haemorrhages are mostly around small vessels, but some are also to be seen in the free tissue"

page 73: Hyde discusses the occurrence of Raynaud's Disease in ME/CFS: “This is common in ME/CFS. These acute Raynaud's Disease changes are visible"

page 89 (Chapter 8 / John Richardson):A liver biopsy showed a vasculitis of the liver"

page 91: "Liver Function Tests are sometimes abnormal and signify a vasculitis of the liver"

page 250 (Chapter 23 / Jay Goldstein): "SPECT scanning may justify vasodilator therapy with calcium channel blockers"

page 286 (Chapter 28 / EG Dowsett): "ME is a multisystem syndrome including nervous, cardiovascular, endocrine and other involvement. Symptoms and Signs (table 2): Vasculitic skin lesions, autonomic dysfunction, especially circulation and thermoregulation"

page 376: (Chapter 42: Hyde and Jain: Cardiac and Cardiovascular Aspects of ME/CFS): reference is made to "frequent vasomotor abnormalities"

page 377: "vasomotor disturbances were almost constant findings, with coldness and cyanosis. It was the impression of most observers that a generalised disturbance of vasomotor control occurred in these patients"

page 377:Findings included sinus tachycardia, abnormal T waves in two or more leads (and) prolongation of Q-T interval”

page 377:Myocarditis in the acute phase: the heart rate was accelerated (and) tachycardia was considered to be a diagnostic feature. In four cases there was a persistent rise in blood pressure (which) slowly lowered over a period of many months”

page 378: “Cardiovascular symptoms: angina-like pain; vascular headache; orthostatic hypertension; oedema; dyspnoea; transient hypertension” (note that on page 42, Hyde states about blood pressure regulation: “Some seem to be unable to adjust blood pressure with body activity, resulting in high blood pressure on modest activity and very low pressure when reclining”)

page 378: referring to Professor Peter Behan’s CIBA lecture in 1988: “using SPECT scan techniques, his team was regularly able to demonstrate micro-capillary perfusion defects in the cardiac muscle of ME patients”

page 380: These chronic ME/CFS patients complain of severe chest pain and shortness of breath as if suddenly stopped by an invisible barrier”

page 381:Arrhythmias are frequently noted in the first few weeks of illness, then decrease in frequency, only to return in a chronic form 20 years later”

page 433 (Chapter 49 / Ismael Mena): referring to the need for SPECT scans in ME/CFS patients, Mena states: "The accuracy and reproducibility of these measurements are justification to evaluate cerebral perfusion abnormalities in patients with ME/CFS. Most probably, temporal lobe perfusion defects may fingerprint primary inflammatory changes or secondary vascular impairment in these patients”

page 437:the diminished uptake of this oxime can be interpreted as due to a) diminished rCBF (regional cerebral blood flow), b) inflammatory regional changes (present in 71% of patients studied)”

page 598 (Chapter 65 / LO Simpson): "if the stasis did not resolve, focal lesions of ischaemic necrosis would develop"

page 673 (Chapter 75 / J Russell): Dr Jon Russell is a world expert on fibromyalgia (which may be a comorbidity with ME/CFS: “Fibromyalgia appears to represent an additional burden of suffering amongst those with ME/CFS”. Buchwald D et al. Rheum Dis Clin N Am 1996:22:2:219-243) and says about the prevalence of vasculitis: "It is apparent that some patients with fibromyalgia also exhibit vasculitis with a frequency that has caught the attention of clinicians".

Since its publication in 1992, this major medical textbook on ME/CFS has been resolutely ignored by the Wessely School and by those Government agencies which they advise.

Other references in the literature to cardiovascular problems in ME/CFS


From the earliest reports of ME/CFS, autonomic vasomotor instability has been noted (AM Ramsay, Update: September 1976:539-541).


There have been many reports of impaired blood flow in the microcirculation (LO Simpson, NZMJ:1984:698-699).


Evidence of cardiac involvement may be seen: palpitations, severe tachycardia with multiple ectopic beats and occasional dyspnoea may occur and are quite distressing. It is of great interest that some patients have evidence of myocarditis” (Behan P. Crit Rev Neurobiol 1988:4:2:157-178). 


 “The data are compatible with latent viral effects on cardiac pacemaker cells, or their autonomic control, and skeletal muscle, that are unmasked by the stress of exercise (Montague TJ et al. Chest 1989:95:779-784).



Persistent viral infections impair the specialised functions of cells. Evidence of persistent enterovirus infection has been found in both dilated cardiomyopathy and in myalgic encephalomyelitis. Immunological and metabolic disturbances in ME may result from chronic infection, usually with enteroviruses, providing the organic basis of the postviral fatigue syndrome. This condition is characterised by recuperation through rest. The myocardium, however, cannot rest – except terminally” (NR Grist. BMJ 1989:299:1219).


A significant group have cardiac symptoms (Professor Peter Behan, Cambridge Conference Report, 17th March 1990; ME Association Medical Update 1990: 2).



There is a high incidence of cardiomyopathy in CFS patients” (Dr Jay Goldstein, Director of the CFS Institutes, Anaheim Hills; member of the Faculty of the Department of Psychiatry, University of California; CFIDS Reporter, Oregon, October 1990).


The patient with Post-viral fatigue syndrome (ME) is referred to a cardiologist almost always because of chest pain. In viral pericarditis, as with ME, there is now abundant evidence that the disease process arises from an abnormal response to a viral infection. Chest pain is variable in character. It is sometimes severe, sharp and stabbing, or it may be dull and aching. It is unrelated to exertion, although the patient frequently feels the pain to be worse after a day of increased physical activity. The pain may last for several hours or even days. It frequently occurs centrally but even in the same patient may recur on a different occasion in the right or left chest or the back. It is commonly aggravated by sudden movement, change of posture, respiration or swallowing. Palpitations are frequent, with sinus tachycardia being a common and troublesome symptom. The diagnosis of the cause of chest pain in ME rests almost entirely on careful clinical evaluation. Pericarditis may continue or recur for many years and, like ME, be a distressing and debilitating illness. There is alas no way of predicting how long the condition will persist, and no reliably successful means of treating it” (Post-viral Fatigue Syndrome and the Cardiologist. RG Gold. In: Post-Viral Fatigue Syndrome. Ed: Rachel Jenkins and James Mowbray. John Wiley & Sons, 1991).



Evidence of repetitively negative to flat T waves on 24-hour ECG monitoring was found in some ME/CFS patients (Lerner AM et al. Chest 1993:104:1417-1421).


Abnormal left ventricular dynamics (i.e. an abnormal pumping mechanism) were demonstrated in ME/CFS patients, including abnormal wall motion at rest; dilatation of the left ventricle, and segmental wall motion abnormalities (Dworkin HJ, Lerner AM et al. Clinical Nuclear Medicine 1994:19:8:675-677).


As with any chronic inflammatory condition affecting the central nervous system, the T2-bright foci on MR (magnetic resonance) in ME/CFS may represent perivascular cellular infiltrate and / or reactive demyelination of the surrounding white matter….these abnormalities may reflect the result of a vasculopathy specifically involving the small vessels of the cerebral white matter; indeed, the distribution of lesions on MR in ME/CFS is similar to that observed in occlusive arteriolar disease of any origin.  The cortical defects measured with SPECT may result from decreased flow through cortical arterioles owing to vasculitis. Specifically, on the basis of our observations, the white matter abnormalities seen on MR images may represent chronic demyelination, which appears to be irreversible  (Detection of Intracranial Abnormalities in Patients with Chronic Fatigue Syndrome: comparison of MR imaging and SPECT.  Schwartz RB, Komaroff AL et al.  Am J Roentgenol 1994:162:935-941).


The use of cardiopulmonary exercise testing is not only valid and reliable, but also serves as an objective indicator for assessing disability. Maximal cardiopulmonary exercise testing provides two objective markers of functional capacity. The first is maximal oxygen consumption. The most important determinant of functional capacity is not maximal oxygen consumption, but anaerobic threshold. Typically ME/CFS patients achieve less than 80% of predicted maximal oxygen consumption with an anaerobic threshold lower than 40% of predicted peak oxygen consumption levels. In ME/CFS patients, we have not found re-conditioning to be possible. In fact, attempts to re-condition patients consistently results in exacerbation of symptomatology. Cardiopulmonary exercise testing can be used to provide ME/CFS patients with another objective marker that will aid them in obtaining disability status” (SR Steven. JCFS 1995:1:3-4:127-129).


At the State of Massachusetts educational workshop given by Professor Paul Cheney, evidence was presented of the complexity of ME/CFS (referred to as “CFIDS”, or Chronic Fatigue and Immune Dysfunction Syndrome). According to Cheney, 80% of ME/CFS patients display medication and environmental sensitivities; there is evidence of lymphatic involvement, with the thoracic duct being tender, and the swollen areas on the neck or upper chest being a back-up of lymphatic fluid.

Cheney biopsied 16 digits of people with ME/CFS and found a vasculitis not uncommon in immune activation and similar to that which is found in SLE / systemic lupus erythematosus (The Massachusetts CFIDS Update).


Myocarditis was a common symptom in an analysis of 1,000 patients of ME/CFS who were seen in Glasgow over the past 20 years. We were struck by the often-occurring association of patients who develop ME/CFS with acute chest pain resembling a coronary thrombosis. On subsequent clinical follow-up, all these patients had a clinical course that was indistinguishable from patients who presented with Syndrome X. Nuclear magnetic resonance spectroscopy studies of skeletal muscle in patients with Syndrome X show abnormalities that are identical to those found in patients with ME/CFS. We, in examining muscle biopsies of patients with ME/CFS, showed an increase in calcium ATPase activity in skeletal muscles. These data strengthen the relationship between ME/CFS and Syndrome X and suggest that an increased energy expenditure, with a consequent reduction of intra-cellular ATP (adenosine triphosphate) and an increase in ATPase activity could account for the abnormalities in these two conditions. Thallium cardiac scans (thallium-210 SPECT scans) in patients with ME/CFS revealed moderate defects in the left ventricle (Arguments for a role of abnormal ionophore function in CFS. A Chaudhuri et al. In: Chronic Fatigue Syndrome. Ed: Yehuda and Mostofsky; Plenum Press, New York, 1997).


We report the prevalence of abnormal oscillating T waves at Holter monitoring in a consecutive case series of ME/CFS patients from an infectious diseases centre. Every ME/CFS patient, but only 22.4% of the non-ME/CFS patients, showed abnormal oscillating T wave flattenings or inversions at Holter monitoring. Abnormal cardiac wall motion at rest and stress, dilatation of the left ventricle, and segmental wall abnormalities were present. Left ventricular ejection fractions, at rest and with exercise, as low as 30% were seen in ME/CFS patients. The abnormal (results) which we confirm here appear to be an essential element to the pathologic physiology of the cardiomyopathy of ME/CFS” (Cardiac Involvement in Patients with CFS as Documented with Holter and Biopsy Data in Michigan, 1991-1993. AM Lerner et al. Infectious Diseases in Clinical Practice 1997:6:327-333).

This research was summarised by Dr PD Corning, having been reviewed and approved by Dr Lerner:

Dr Lerner, an Infectious Diseases specialist at Wayne State University, and his colleagues have found evidence that ME/CFS may be caused by a persistent (virus) infection of the heart. This research is significant and well-documented. In this study, 100% of the ME/CFS patients showed abnormal oscillating T waves at 24-hour Holter monitoring and 24% showed weakened function on the left side of the heart (the side that pumps oxygenated blood to all the body except the lungs). The data showed that patients exhibited evidence of cardiomyopathy, or disease of the heart muscle. This finding is so consistent (and) it distinguishes ME/CFS from those with fatigue of unexplained origin. This work offers hard evidence to back up ME/CFS patients’ much disbelieved claim that exercise is harmful and causes disease progression in ME/CFS. In many cases, the resulting disease process is progressive. (The virus) attacks the heart tissue producing exercise intolerance, the hallmark of ME/CFS. These researchers have backed up their work with biopsies of the cardiac tissue in ME/CFS patients. They found heart muscle disorganisation, muscle fibre disarray, abnormal formation of fibrous tissue in place of heart muscle cells, fat infiltration and increases in mitochondria within heart muscle cells. All these results are indicative of cardiomyopathy. The weakened heart is aggravated by physical activity, accounting for post-exertional sickness so common in this disease. When the heart muscle tissue is infected, overactivity causes death of cardiac tissue and disease progression. This is in direct conflict with conclusions that ME/CFS symptoms are caused by underactivity due to a sedentary lifestyle. Dr Lerner and associates have also documented abnormal fraction ejection in ME/CFS. Normally, over half the blood in the left ventricle is ejected when the left ventricle contracts. In Dr Lerner’s subjects, the ejection fraction is decreased. Some patients had a reduced ejection fraction at rest. Others had an ejection fraction that decreased during exercise from 51% to 36%. In a normal subject, the ejection fraction will rise over 5% during exercise. Declining ejection fractions are not seen in normal persons leading sedentary lives”.

The full summary is at .


At the Fourth International AACFS Research and Clinical Conference held in Massachusetts in October 1998, Arnold Peckerman and Benjamin Natelson et al presented evidence of a disorder of the circulation in ME/CFS: as a group, patients with ME/CFS displayed similar cardiovascular function status on most parameters but the results showed that in ME/CFS patients, a lower stroke volume was highly predictive of illness severity: across three different postures, the most severely affected patients were found to have a lower stroke volume and cardiac output compared with those with more moderate illness. These findings suggest a low flow circulatory rate in the most severe cases of ME/CFS; this may indicate a defect in the higher cortical modulation of cardiovascular autonomic control. In the most severely affected, situations may arise where a demand for blood flow to the brain may exceed the supply, with a possibility of ischaemia and a decrement of function”. (CFS Severity is Related to Reduced Stroke Volume. Peckerman et al. Presented at the Fourth International AACFS Research & Clinical Conference on ME/CFS, Mass. USA).


Watson et al reported that perfusion defects seen in thallium cardiac scans of ME/CFS patients were unlikely to be explained by occlusive coronary vessel disease and that in their studies (as well as in other independent studies), cardiac thallium SPECT scans were shown to be abnormal in the majority of patients with ME/CFS and perfusion defects were common.  Cardiac SPECT scanning is a nuclear medicine technique used to identify regions of under-perfused myocardial tissue  (A Possible Cell Membrane Defect in Chronic Fatigue Syndrome and Syndrome X.  Walter S Watson et al.  In: Kaski JC (Ed). Chest pain with normal coronary angiogram: pathogenesis, diagnosis and treatment. Kluwer Academic Publishers, London 1999: chapter 13:143-149).


This study examined the cardiovascular response to orthostatic challenge. Among subjects who completed the test, those with ME/CFS had higher heart rate and smaller stroke volume than corresponding control subjects. These data show that there are baseline differences in the cardiovascular profiles of ME/CFS patients when compared with control subjects” (La Manca JJ et al. Clinical Physiology 1999:19:2:111-120).


The results of this study show enhanced cholinergic activity in the peripheral microcirculation of patients with ME/CFS. Many of the symptoms of ME/CFS, such as temperature sensitivity, gastrointestinal difficulties, problems with sleep, and orthostatic intolerance, are consistent with altered cholinergic activity. Our findings might have important implications for features of ME/CFS that involve vascular integrity (V Spence et al. Am J Med 2000:108:736-739).


Convincing evidence of cardiovascular impairment can be demonstrated” (Research Update presentation to the Alison Hunter Memorial Foundation Third International Clinical and Scientific Conference on ME/CFS held in Sydney, Professor Mina Behan, University of Glasgow).


According to David Streeten, Professor of Endocrinology at Upstate Medical Centre in Syracuse, NY: Inconsistently excessive increases in heart rate were found in ME/CFS patients, in whom venous compliance was significantly reduced (and in whom) delayed orthostatic hypotension was clearly demonstrable, implying impaired sympathetic innervation. Excessive lower body venous pooling, perhaps by reduced cerebral perfusion, is involved in the orthostatic component in these patients” (Streeten DH. Am J Med Sci 2001:321:3:163-167).


Erich Ryll, Assistant Clinical Professor of Medicine, Division of Infectious and Immunology Diseases, University of California, believes that in ME/CFS there is an infectious venulitis: “Troublingly (in the literature) very few vascular features were mentioned. I have followed these patients since 1975. Because of this, I have learned all the nuances, all the signs and symptoms of the disease. In studying this disease, one must always have an open mind. This disease teaches the physician to be humble. The extremity discomfort is often described as a burning, searing sensation. Numbness and tingling of the extremities is common (and) cases have spontaneous bruises that occur without any injury. The disease is frightening to patients because of its severity and its many unusual features. Physicians are not trained to diagnose an illness that encompasses so many signs and symptoms. Two common statements patients make are: ‘I hurt all over’ and ‘I am going to die’. During relapse, many can be totally helpless and unable to care for themselves. Dizziness often occurs and for some patients, it is constant. They are uncoordinated and lurch about. They state that their legs just give way, causing them to fall. The autonomic nervous system that controls blood vessels is deranged in the disease. Sweating, flushing, icy and blue hands and feet, hot sweaty hands, red and blotchy hands are common. Pain can be the most severe aspect of this disease. There is partial paralysis of the gastrointestinal tract (which) can lead to nausea. Small veins can suddenly rupture. Deep veins can remain inflamed and are not visible on the surface. An electromyogram is frequently abnormal, showing damage to nerves. The MRI brain image often reveals evidence of demyelination. A SPECT scan invariably shows impairment of brain blood circulation. Muscles may be damaged but do not waste away. There is currently no treatment that can cure this disease. Treatments are geared to making life more bearable (



As a group, the ME/CFS patients demonstrated significantly lower cardiovascular as well as ventilatory values compared with the control group. These results indicate either cardiac or peripheral insufficiency embedded in the pathology of ME/CFS (Inbar O et al. Med Sci Sports Exerc 2001:33:9:1463-1470).


The haemodynamic instability score differed significantly between ME/CFS and other groups (Naschitz JE et al. Semin Arthritis Rheum 2001:31:3:199-208).


According to Peter Rowe, Professor of Paediatrics at Johns Hopkins and an ME/CFS specialist: “Several groups have shown that ME/CFS patients have abnormal regulation of heart rate and blood pressure, as well as high rates of allergic disease. About a third of ME/CFS studies have identified low urinary and serum levels of cortisol” (Co-Cure MED: 3rd May 2002; see also Peter C Rowe, Journal of Paediatrics 2002:140:387-388).


The main symptom of the ME/CFS patient, i.e. chronic fatigue that is greatly exacerbated by even minor effort, is similar to that of a patient with left ventricular dysfunction. We performed nuclear ventriculography (MUGA / radioisotopic multiple gated acquisition used to perform a series of dynamic studies of the heart to assess for evidence of abnormalities with myocardial function) stress tests in ME/CFS patients and controls. During maximal exercise, ejection fraction (EF) increased in controls but declined in ME/CFS patients. The decreases tended to be greater in patients with more severe symptoms. These data support the hypothesis that some cases of ME/CFS may be explained and potentially treated as a problem with left ventricular function(A Peckerman B Natelson et al. FASEB 2003:17:5 Suppl: Part 2: A853).

This study was summarised by Donna Krupa, APS Newsroom, 10th April 2003: “Growing evidence points to a possible problem with circulation. Studies have found that ME/CFS patients may have reduced blood flow in exercising muscles. A new study provides indication of reduced cardiac function in some patients with ME/CFS. It raises the possibility that some ME/CFS patients may have cardiac disorders that are subtle enough to escape the current net of clinical cardiological diagnoses, but may be significant enough in some patients to lead to the clinical syndrome of ME/CFS”.


Cardiovascular reactivity is defined as the change on blood pressure, heart rate, or other haemodynamic parameters in response to physical or mental stimuli. 13 variables showed significant differences between ME/CFS patients and controls. The degree of arterial stiffness of the large arteries affects both the cardiovascular reactivity and the pulse wave velocity. The FRAS (Fractal & Recurrence Analysis-based Score) differs between the groups of healthy persons, hypertensives, and ME/CFS patients. The HIS (haemodynamic instability score) distinguished ME/CFS from healthy subjects with 97% sensitivity and 97% specificity. Based on these data, it appears that the HIS can provide objective criteria (in) the assessment of ME/CFS” (JE Naschitz et al. Journal of Human Hypertension 2003:17:111-118).


Accumulating evidence points to a problem with circulation in ME/CFS. Although abnormalities in single systems may be insufficient to cause a circulatory dysfunction, cumulatively they could produce significant deficiencies in organ blood flow and symptoms. We hypothesised that patients with ME/CFS have reduced cardiac output. This present study tested this hypothesis using noninvasive impedence cardiography. These results provide evidence of reduced cardiac output in severe ME/CFS. They suggest that in some patients, blood pressure is maintained at the cost of restricted flow, possibly resulting in a low circulatory state. Thus there may be periods in daily activities when demands for blood flow are not adequately met, compromising metabolic processes in at least some vascular compartments. Some percentage of patients (with) ME/CFS may in fact have covert heart disease. The abnormalities causing a reduction in cardiac output in ME/CFS may be dispersed over multiple systems. Even marginal reductions in cardiac output can result in selective underperfusion during activities that increase demand for blood flow. Inquiries should be directed at conditions that may not be overtly expressed in symptoms of ME/CFS, such as underperfusion in the kidneys and the gut, as the organs in which initial conservation of cardiac output takes place. The patients with severe ME/CFS had significantly lower stroke volume and cardiac output than the controls and less ill patients. This study provides indication of reduced cardiac output in some patients with ME/CFS” (A Peckerman, B Natelson et al. Am J Med Sci 2003:326:2:55-60).

Media coverage of this important paper included the following:

WebMD Medical News: 14th April 2003: “Many people with ME/CFS may have a serious heart problem. When you exercise, your heart pumps out more blood. But these patients’ hearts actually pump less blood. ‘Basically we are talking about heart failure’ Peckerman tells WebMD. ‘ME/CFS is a progressive disease’. Emory University cardiologist Joseph I Miller III MD, says Peckerman’s findings are very interesting (and) he agrees that these patients have serious heart problems”.


ME/CFS is a debilitating condition of unknown aetiology. Recent studies using brain spectroscopy have revealed metabolic disturbances with significantly elevated choline levels in various regions of the central nervous system. In addition, we have recently shown that abnormalities specific to the cholinergic pathway also exist in the peripheral microcirculation of ME/CFS patients (and) our findings might have important implications for vascular integrity in ME/CFS. ME/CFS is commonly associated with viral onset and immunological disturbance sometimes linked to persistent viral infection. The work described here provides new evidence of disruption to ACh pathways specifically within the peripheral circulation of ME/CFS patients(F Khan, V Spence et al. Clin Physiol Funct Imaging 2003:23:282-285).


Aberrations of cardiovascular reactivity (CVR), an expression of autonomic function, occur in a number of clinical conditions. Recently, a CVR pattern particular to ME/CFS was observed. Pathological disturbances may alter cardiovascular reactivity. Our data support the existence of disease-related CVR phenotypes. The importance of recognising disease-specific CVR phenotypes may (offer) supporting data for the diagnosis of certain disorders. Recognising the ME/CFS reactivity phenotype has been found useful in supporting the clinical diagnosis of ME/CFS. Furthermore, CVR phenotype may provide an objective criterion to monitor the course of dysautonomia in ME/CFS” (Naschitz JE et al. QJM 2004:97:3:141-151).


Research into ME/CFS is hindered by considerable heterogeneity. There has been speculation that many of the neurological symptoms might be cholinergically mediated. As well as these neurological findings, there has been a recent report of autoantibodies specifically to muscarinic receptors in many ME/CFS patients, suggesting that there might be subgroups within the ME/CFS construct that are associated with autoimmune abnormalities of cholinergic muscarinic receptors. Apart from its neurotransmitter functions, acetylcholine is a prominent vasodilator whose action is dependent upon an intact layer of endothelial cells that line the lumen of all blood vessels. In most medical conditions associated with cardiovascular disease there is a blunted response to acetylcholine. However, we have reported increased responses to acetylcholine in the cutaneous microcirculation of ME/CFS patients. There was a significantly increased response to substance P in ME/CFS patients and this was often accompanied by a spreading flare and localised oedema, a finding not observed in control subjects. (This may be due to) a heightened sensitivity to substance P in terms of its histamine releasing properties. Indeed, sensitivity to histamine has been implicated in ME/CFS pathogenesis. The data demonstrated that the dynamics of the acetylcholine-stimulated blood flow response is significantly different in ME/CFS patients compared with control subjects, possibly via a viral mechanism. (This) acetylcholine sensitivity is specific to a sub-group of patients within the ME/CFS construct (and) points to a problem on the vascular endothelium of ME/CFS patients. We are confident that the findings of increased sensitivity to acetylcholine in ME/CFS patients are robust and unusual. Our results are important in terms of vascular control mechanisms in this patient group and may be relevant to the problems of orthostatic instability that is so evident in most ME/CFS patients(VA Spence et al. Prostaglandins, Leukotrienes and Essential Fatty Acids 2004:70:403-407).


While the cause of ME/CFS remains to be elucidated, extensive literature exists on the role of a variety of infectious agents; up-regulation of anti-viral pathways; immune abnormalities; disruption to the hypothalamic-pituitary-adrenal (HPA) axis; neuropsychological impairments; dysfunction of the autonomic nervous system; oxidative stress; and lipid peroxidation. Looking at the literature as a whole, there are various strands of evidence suggesting that the vascular system in ME/CFS is compromised. Many ME/CFS patients are unaware that something as simple as being upright can trigger a cluster of symptoms such as dizziness, altered vision, nausea, fatigue, headache, sweating and pallor. Orthostatic intolerance is characteristic of so many of these ME/CFS patients that it could very well serve as a definable subset. It has been suggested by some that orthostatic intolerance in ME/CFS is nothing more than deconditioning associated with bed rest (but) vascular dysfunction appears to be best supported by the data. Some subjects show autonomic dysfunction in their internal organs vasculature (and) evidence points towards enhanced pooling within the internal organs and pelvic circulation. The onset of orthostatic symptoms in many ME/CFS patients is often predated by a viral infection. There is clearly a problem with local vasodilator and vasoconstrictor mechanisms in these patients. There is a significant body of evidence pointing to vascular dysfunction in the peripheral circulation of patients with ME/CFS and this is in addition to blood flow abnormalities within the central nervous system (V Spence & J Stewart. Biologist 2004:51:2:65-70).


Lerner et al demonstrated abnormal cardiac wall motion at rest and in cardiac biopsies: “A progressive cardiomyopathy caused by incomplete virus multiplication in ME/CFS patients is present” (Lerner AM et al. In Vivo 2004:18:4:417-424).


A study of adolescents with ME/CFS looked at blood pressure, arterial stiffness and arterial wall thickness. Arterial stiffness, expressed as common carotid distension, was lower in adolescents with ME/CFS, indicating stiffer arteries. “Pain perception differed considerably between patients and controls (and) this is the first study to confirm this difference. The unexpected finding of stiffer arteries in patients with ME/CFS warrants additional investigation” (EM van de Putte et al. Paediatrics 2005:115:4:415-422).


Orthostatic intolerance certainly causes breathlessness. The cause of the breathlessness is probably a reduction in blood flow through the heart and lungs. Patients with ME/CFS cannot hold their breath as long as healthy people. This was first noted by Dr Paul Cheney” (DS Bell. ).


On 10th April 2005 Carol Sieverling posted on the internet (Co-Cure) “The Heart of the Matter: CFS and Cardiac Issues” – a 41 page exposition of Professor Paul Cheney’s experience and expertise, from which the following notes are taken and to both of whom grateful acknowledgement is made.

Cheney’s focus is based on the paper by Dr Ben Natelson (clinical neurologist and Professor of Neurology) and Dr Arnold Peckerman (cardiopulmonary physiologist) at New Jersey Medical Centre (ref: “Abnormal Impedance Cardiography Predicts Symptom Severity in Chronic Fatigue Syndrome”: Peckerman et al: The American Journal of the Medical Sciences: 2003:326:(2):55-60).

This significant paper says that, without exception, every disabled CFIDS (i.e. ME/CFS) patient is in heart failure.

There are two kinds of heart failure: one that any cardiologist can diagnose in about a minute (which ME/CFS patients do not have); the other is Compensated Idiopathic Cardiomyopathy (CIM). Given that at least 35% of those with CIM will die within 5 years unless they receive a heart transplant, but given that in 20 years’ experience of ME/CFS Cheney has never seen one patient go on to transplant, why aren’t those with ME/CFS-induced CIM not dead? Cheney believes it is because ME/CFS itself is protecting patients from a deeper problem that is often missed because it is so well-hidden.

The problem

The New Jersey team looked at many things in ME/CFS patients and they found something: a “Q” problem. “Q” stands for cardiac output in litres per minute. In ME/CFS patients, Q values correlated -- with great precision – with the level of disability. Q was measured using impedance cardiography, a clinically validated and Government agency-recognised algorithm that is not experimental.

Normal people pump 7 litres per minute through their heart, with very little variance, and when they stand up, that output drops to 5 litres per minute (a full 30% drop, but this is normal). Those two litres are rapidly pooled in the lower extremities and capacitance vessels. Normal people do not sense that 30% drop in cardiac output when they stand up because their blood pressure either stays normal or rises -- the body will defend blood pressure beyond anything else in order to keep the pulse going. This is critical to understanding what happens in ME/CFS patients.

However, what the New Jersey team found in people with ME/CFS was astonishing – when disabled ME/CFS patients stand up, they are on the edge of organ failure due to extremely low cardiac output as their Q drops to 3.7 litres per minute (a 50% drop from the normal of 7 litres per minute).

The disability level was exactly proportional to the severity of their Q defect, without exception and with scientific precision.


The New Jersey team then looked to see if there were any symptoms that were observable in disabled ME/CFS patients but not in others and they found that there was only one such symptom that was seen in patients with a Q problem: post-exertional fatigue. To quote Cheney: “That is, when you push yourself physically, you get worse”.

ME/CFS patients have a big Q problem; to quote Cheney again: “all disabled ME/CFS patients, all of whom have post-exertional fatigue, have low Q and are in heart failure”.

Post-exertional fatigue (long documented as the cardinal feature of ME/CFS but not of non-specific states of chronic fatigue) is the one symptom that correlates with Q. Among disabled ME/CFS patients, 80% had muscle pain; 75% had joint pain; 72% had memory and concentration problems; 70% had unrefreshing sleep; 68% had fever and chills; 62% had generalised weakness; 60% had headaches, but 100% had post-exertional fatigue.

In Cheney’s model, symptoms in ME/CFS reflect the interaction between Q and how the body compensates for too low a Q, so depending on the nature of the compensation (which is individually distinct), there is an array of symptoms that is individually determined and which will arise out of factors unique to each person.

Cheney posits that when faced with a low Q, the body sacrifices tissue perfusion in order to maintain blood pressure: ie. microcirculation to the tissues of the body is sacrificed to maintain blood pressure so that the person does not die in the face of too a low Q. This compensation is what is going on in the ME/CFS patient.

In the Peckerman study, the data on the disabled ME/CFS patients reveals that even when they are lying down, their Q is only 5 litres per minute (not 7 as in normals). When disabled ME/CFS patients stand up, the Q of 5 litres per minute drops to 3.7 litres per minute, so these patients do not have adequate Q to function. The lower the Q, the more time the patient will spend lying down because lying down is the only time they come close to having sufficient cardiac output to survive.

Compensated Idiopathic Cardiomyopathy

Cheney states that it is important to note that the body does not sacrifice tissue perfusion equally across all organ systems: instead, it prioritises the order of sacrifice and one can observe the progression of ME/CFS by noting this prioritisation.

Two organ systems in particular have a protective mechanism (the Renin Angiotensin System, or RAS) against restricted tissue perfusion: the lung and the kidneys. These organs can sustain the greatest degree of Q problems because of this extra protection. Additionally, the heart and the brain also have this extra protection, even in the face of an extremely low Q. Therefore the lung, the brain, the kidneys and the heart are a bit more protected than the liver, the gut, the muscles and the skin from a drop in Q.

In what order is tissue perfusion sacrificed, and what are the consequences? Certainly, Cheney’s submission seems to tally with the experience of long-term ME/CFS sufferers.

The first is the skin: if the microcirculation of the skin is compromised, several problems can arise. One is that without adequate microcirculation to the skin, the body cannot thermoregulate anymore: the patient cannot stand heat or cold and if the core temperature rises, the patient will not be able to sleep and the immune system will be activated. In order to regulate that problem, the body will activate thyroid regulation which will down-regulate in order to keep the body temperature from going too high. The result of this is that the patient develops compensatory hypothyroidism, which means that now the patient will have trouble with feeling cold. Also, the body will not be able to eliminate VOCs (volatile organic compounds), which are shed in the skin’s oil ducts, so VOCs build up in the body’s fat stores and the patient becomes progressively chemically poisoned by whatever is present in the environment -- in other words, the patient develops Multiple Chemical Sensitivity (MCS).

The second effect: if things get worse, the next microcirculation to be sacrificed is that to the muscles and the patient will have exercise intolerance and s/he cannot go upstairs. If things get still worse, the patient begins to get fibromyalgic pain in the muscles. Cheney posits that if microcirculation to the joints becomes compromised, it may precipitate pyrophosphoric acid and uric acid crystals and the patient starts to have arthralgia linked to this circulatory defect.

The next system to be compromised is the liver and gut. One of the first things the patient may notice in this stage of disease progression is that there are fewer and fewer foods s/he will be able to tolerate, partly because microcirculation is necessary for proper digestion. Also the body will not secrete digestive juices so whatever food is tolerated will not be properly digested: if food cannot be digested, there will be peptides that are only partially digested and therefore are highly immune-reactive; they will leak out of the gut into the bloodstream, resulting in food allergies and / or sensitivities. The body will be unable to detoxify the gut ecology, so the gut will begin to poison the patient, who will feel a sense of toxic malaise, with diarrhoea, constipation, flatulence and all kinds of gut problems. If this gets worse, a malabsorption syndrome will develop, resulting in increasing toxicity in which the patient feels “yucky” and which can manifest as a variety of skin disturbances (for instance, a rash), as well as problems in the brain.

The fourth affected system is the brain: Cheney posits that there is a devastating effect in the brain as a result of liver / gut dysfunction, which can quickly toxify the brain, resulting in disturbances of memory and of processing speed. Also, the hypothalamus begins to destabilise the patient from the autonomic nervous system perspective. In all probability, the brain and heart suffer simultaneous compromise, but patients usually notice the brain being affected much earlier than the heart – this is because heart muscle cells have the greatest mitochondrial content of any tissue in the body, so when the mitochondria are impaired, the heart muscle has the greatest reserve. Even if the patient is sedentary with not too much demand on the heart, s/he can still think and make great demands on the brain, and energy is energy, whether it is being used physically or cognitively.

The fifth affected system is the heart: Cheney posits that the effect of compromised microcirculation upon the heart has an “a” part and a “b” part: part “a” is the manifestation of microcirculation impairment and part “b” is “the event horizon”.

Part “a”: manifestation of microcirculation impairment: the initial manifestation of microcirculatory impairment of the heart is arrhythmia with exercise intolerance: when the patient goes upstairs, more cardiac output is needed but the patient cannot sustain it. As it gets worse, there will be mitral valve prolapse (MVP) because of inadequate capillary function. Finally, when there are even more severe microcirculatory problems, the patient starts to get chest pain as the myocardial cells die because they cannot get adequate oxygen.

Part “b”: the event horizon: (once this line is passed, there is no going back): Cheney’s view is that the “event horizon” with respect to the heart is this: when the microcirculation defect within the heart itself begins to impact Q itself, a vicious circle begins – microcirculation impairment reduces the Q, which produces more microcirculation impairment, which produces even more Q problems, so down goes the patient into the next phase of cardiac failure, which is the lung.

The sixth affected system is the lung and kidney: cardiac failure in the lung produces congestive heart failure (CHF) and pulmonary oedema, then the kidney is affected (the kidney is the last to go because it has the RAS back-up system). Combined with liver impairment, this stage is known as hepatorenal failure, which is the requisite cause of death due to Compensated Idiopathic Cardiomyopathy.

Cheney said “How will a patient know if s/he eventually loses the ability to compensate? They will know it if when they lie down, they are short of breath”.

Cheney comments on Professor Martin Pall’s work on the role of peroxynitrite in ME/CFS. Uric acid is a powerful scavenger of peroxynitrite, as is uric acid. Cheney has measured uric acid levels in ME/CFS patients and has found them to be amongst the lowest levels he has ever measured in his entire medical career.

Cheney notes that Dr Les Simpson in New Zealand found that the red blood cells of patients with ME/CFS were deformed and when deformed, they cannot get through the capillary bed and so cause pain. An indication of such deformity is a drop in the sedimentation rate (SED, or ESR) and Cheney has observed that when measured in a laboratory, ME/CFS patients’ sedimentation rate is the lowest he has ever recorded, which confirms to Cheney that ME/CFS patients have an induced haemoglobinopathy. He believes that the ME/CFS patients with the lowest sedimentation rate may have the greatest degree of pain. The more deformed the red blood cells, the more pain may be experienced. Some ME/CFS patients have a problem similar to that of sickle cell anaemia in this regard, and sickle cell patients have unbelievable pain. Cheney emphasises that it is bad enough when patients do not perfuse their muscles and joints (because of poor microcirculation) but it is even worse when red blood cells are so deformed that they can barely get through the capillaries or are blocked entirely.

Cheney notes that in the Laboratory Textbook of Medicine, there are only three diseases that lower the sedimentation rate to that level: one is sickle cell anaemia (a genetic haemoglobinopathy); the second is ME/CFS (an acquired haemoglobinopathy) and the third is idiopathic cardiomyopathy.

Cheney observes that in order to improve cardiac output in ME/CFS, patients need to lie down, as this increases the cardiac output by 2 litres per minute. He notes that some ME/CFS patients need to lie down all the time to augment their blood volume in order to survive. He has found increasing the intake of potassium to be helpful (potassium induces aldosterone, a hormone that significantly increases blood volume), and that magnesium is beneficial as it is a vasodilator and helps reduce the resistance the blood encounters.

Cheney is at pains to emphasise that none of these measures is a cure -- they are simply means to help patients disabled with ME/CFS remain as functional as possible.

(Cheney’s credentials include more than two decades’ experience treating over 5,000 ME/CFS patients in 15 countries; research positions relevant to ME/CFS with the US Centres for Disease Control, Emory University and the University of Pennsylvania, and numerous journal articles. He was a founding director of the International Association of Chronic Fatigue Syndrome, an association of scientists and clinicians).


There is mounting evidence that oxidative stress and lipid peroxidation contribute to the disease process and to some of the symptoms (in ME/CFS). While free radicals may generate tissue injury, it is also evident that other oxidative by-products, especially isoprostanes, can exert potent biological activity 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 ME/CFS. The novel findings of this study are that patients with ME/CFS have significantly elevated levels of F2-isoprostanes alongside other key markers of oxidative stress, and that these correlate with various ME/CFS symptoms. This is the first time that elevated levels of isoprostanes have been reported in patients with ME/CFS. Isoprostanes have potent biological effects associated with increased cell permeability. They have also been shown to be powerfully vasoconstricting and are involved in endothelial injury. Exercising muscle is a prime contender for excessive free radical generation, with recent evidence pointing to good correlations between muscle pain thresholds and fatigue with various blood markers of oxidative injury in ME/CFS patients, and further evidence of viral persistence in muscle tissue in some patients with the illness. Research evidence has demonstrated that incremental exercise challenge potentiates a prolonged and accentuated oxidative stress that might well account for post-exercise symptoms in ME/CFS patients. It could be suggested that ME/CFS is an inflammatory condition with many patients in a pro-oxidant states, and this could explain many of the pathological manifestations that underlie the illness” (G Kennedy, VA Spence et al. Free Radical Biology & Medicine 2005:39:584-589).


Researchers at the US Centres for Disease Control (CDC) reported that patients with ME/CFS exhibited scores on assessment tools that quantify impairment and symptoms occurrence, duration and severity and were able to be identified with precision. The authors reported that the ME/CFS patient exhibited scores similar to patients with congestive heart failure (WC Reeves et al. BioMed Central Medicine, 15th December 2005).


Researchers used serial cardiopulmonary exercise tests to support a diagnosis of ME/CFS. The authors noted: “In the absence of a second exercise test, the lack of any significant differences would appear to suggest no functional impairment in ME/CFS patients. However, the results from the second test indicate the presence of an ME/CFS related post-exertional malaise. It might be concluded that a single exercise test is insufficient to demonstrate functional impairment in ME/CFS patients. A second test may be necessary to document the atypical recovery response and protected malaise unique to ME/CFS” (VanNess MJ et al. Medicine & Science in Sports & Exercise 2006:38:5: Suppl: S85).


In his September 2006 seminar (available on a two-DVD boxed set from ), Professor Paul Cheney again warned that aerobic exercise may kill the patient with ME/CFS. As before, Cheney acknowledges his debt to the work of Peckerman. Cheney noted that there is an objective database in key medical literature that includes evidence of diastolic dysfunction and heart failure in ME/CFS.

There are two types of heart failure: systolic (which is a failure to eject) and diastolic (which is not a failure to eject, but a failure to fill properly). Diastolic heart failure was first described in the 1980s but there was no significant literature until the 1990s, and no significant way to measure it until 2001.

Whilst there has been little recognition of the existence of diastolic dysfunction by some cardiologists (considered a relative rarity in 1986), in 2006 an article entitled “Diastolic heart failure – a common and lethal condition by any name” was published by Gerard Aurigemma, who concluded that: “the development of specific, effective management approaches for diastolic heart failure must become a high priority” (NEJM 2006:355:3:308-310). The NEJM carried a significant paper on more than 4,500 patients studied with diastolic heart failure; this increase is unexplained, but is accelerating, and Cheney wonders if it is in fact an explosion of ME/CFS.

Oxidative stress links ME/CFS to fibromyalgia, multiple chemical sensitivity and Gulf War Syndrome.

Cheney says that on physical examination:

In phase 1: (immune activation) one sees

  • lymphyodynia (seen in 80-90%)

  • crimson crescents bilaterally on soft palate (seen in 80%)

  • sub-normal temperature

In phase 2: one sees


  • evidence of subcortical brain injury

  • vestibular dysfunction (seen in 94%)

  • hyper-reflexia, especially of the knees and ankles (seen in 70%)

In phases 3 and 4: the most interesting are the metabolic disturbances:

  • there is shortened breath-holding capacity (seen in 60%)

  • there is very poor oxygen transport (seen in 90%): pulse oximetry readings measuring saturation of haemoglobin show a significant inhibition to desaturate

  • there is finger-print destruction (seen in 50%): cross-hatching occurs, with degradation of the ridges; punch biopsies found perivascular lymphoid infiltrates ie. an inflammatory cuffing exactly as seen in lupus, which signifies a non-specific immune activation issue (so the finger-print changes could be reflecting much more than just loss of finger-prints and may represent a vasculopathy)

  • there is sub-normal temperature (seen in 80%)

  • there is low systolic blood pressure (in 50% of patients it is less than 100mmHg)

  • there is orthostatic B/P or pulse changes (seen in 70%)

These findings portend significant physiological issues, chief of which is that oxygen is being prevented from getting into the cell, and if there is no oxygen, there is no energy.

On Magnetic Resonance Spectroscopy:

  • 70% of patients show elevated lactate levels in the ventricular system (the lactate elevation is not normal and indicates a defect in energy in the brain: ME/CFS patients have significantly elevated lactate levels and the fatigue correlated significantly with the level of lactate)

  • 10% have evidence of neuronal destruction and elevated choline peaks, typically in the perivascular areas

On Magnetic Resonance Imaging:

  • 78% of patients have punctate lesions which are most consistent with small strokes and there is evidence to support this

Mixed venous blood gas picture:


  • PvO2 is 25 (it should be 40)

  • PvCO2 is 55 (it should be 45)

This is a differential hypoxia with hypercarbia. There are only two diseases where this is seen: one is pulmonary hypertension; the other is ME/CFS.

Cheney asks where does the oxygen go? It is being transported somewhere, but not to the mitochondria. ME/CFS patients have been shown to have increased pooling of extra-cellular fluid in the belly, pelvis and legs which might contain this dissolved oxygen, but it is more likely being consumed by the oxidative pathway to create superoxide in massive amounts. Superoxide is the progenitor of all free radicals. The consequences are increased intra-cellular oxidative stress.

Cheney says there are problems at cell level in energy production, and because of this degraded energy problem, patients suffer a defect in the ability to detoxify toxins, especially in the portal circulation (giving rise to gut toxicity as seen in phase 2). Gene alterations (seen in phase 4) generate a massive disturbance in the development of energy at the cell level. If you lose energy, you lose glutathione, but the more glutathione you give, the more you just create oxidised glutathione, which generates loss of citrate, causing a left shift on oxyhaemoglobin desaturation. Citrate also binds to magnesium, so over time the patient will develop a severe magnesium depletion syndrome. (Cheney says that when that happens: “you’ve had your last good night’s sleep: when you lose magnesium, you can’t sleep any more”).

In ME/CFS, these serious issues are a big problem, especially in the brain, the heart and in muscle. ME/CFS is a compensatory response to down-regulate energy production and oxygen transport in order to reduce tissue damage.

Attempts to push beyond energy limits will cause injury.

Prolonged energy deficits can cause semi-permanent DNA phenotype adaptations and complications can occur, especially within energy-sensitive systems such as the heart, the brain and the muscles.

In ME/CFS, catalase is deficient in the heart, lungs and liver (catalase is the most protective enzyme in the body against the ravages of superoxide), and Cheney noted that electromagnetic fields [EMFs] “screw up” superoxide dismutase (SOD), which is a major anti-oxidant scavenger.

Cheney reports that echocardiograms (sonograms of the heart) indicate that as many as 99% of his ME/CFS patients test positive for some level of diastolic dysfunction.

ME/CFS patients have a high heart rate but a low cardiac output. In ME/CFS there is a cardiac dimension that is independent of (but not excluding) autonomic function or blood volume.

82% of patients have abnormal cardiac impedence.

Cheney says that at least half of patients exhibited atrial cavitation, and that when these patients stood up, in 80% the filling volume collapsed. He tested this with magnesium and the results were significant: magnesium restored 12% of energy in one minute. Magnesium affects the intracellular energetics, proving that patients have a “tremendous” energy problem that is very sensitive to magnesium. (The reason magnesium is so important is that without it, ATP cannot be converted to ADP for the production of energy).

Cheney says that ME/CFS patients “squeeze the hell” out of their left ventricle, resulting in a “whopping” 70% increase in left ventricular wall motion thickness. The reason why patients are squeezing so hard is because they do not have enough energy to fill the chambers of the heart properly so they are trying to compensate by squeezing a lot harder (ie. the way patients are compensating for this loss of cardiac output is by squeezing the left ventricle much harder).

There are significant consequences of this. One consequence is that ME/CFS patients become asynchronised (i.e. the heart can be filling and ejecting at the same time).

If out of synchrony, the ventricle cannot cope, so cardiac output is severely degraded.

A second consequence is that patients develop a strain pattern, which is an indication of ischaemia. Cheney has seen ischaemic changes in the inner ventricular wall because of the increased squeezing.

It is increasingly clear that in ME/CFS, a diminished threshold for oxygen toxicity exists, and that each patient will have a unique threshold. These findings have a significant negative effect on Accident & Emergency and operating theatre uses of oxygen during surgery, because an ME/CFS patient could be given too much oxygen and be killed on the operating table.

There is a difference between diastolic dysfunction and diastolic failure: in diastolic dysfunction there is a filling problem but the body is compensating for it and achieving enough cardiac output to match metabolic demand.

Diastolic failure begins when the body can no longer compensate and there is a reduction in cardiac output. Cheney repeated that this is seen in 80% of ME/CFS patients.


If patients draw down their lifestyle to live within the means of the reduced cardiac output, then progression into congestive cardiac failure (CCF) is slowed down, but if things continue to progress, a point will be reached where there is no adequate cardiac output, and dyspnoea will develop, with ankle oedema and other signs of congestive cardiac failure.

The message from Cheney is clear: in order to stay relatively stable, it is essential for the ME/CFS patient not to create metabolic demand that the low cardiac output cannot match.

According to Cheney, it is difficult to talk about a low cardiac output without talking about the involvement of the brain and the adrenal glands.

If the cardiac output goes down, in order not to die, there is a rise in noradrenergic tone (also involving the adrenal glands) to bring the output back up. In ME/CFS, this is a serious problem, because when the adrenals are exhausted, there will be low cardiac output.

There is no such thing as an ME/CFS patient who is NOT hypothyroid: this has nothing to do with thyroid failure, but everything to do with matching metabolic demand and cardiac output.

A mismatch between metabolic demand and cardiac output, even very briefly, will kill. A major cause of death in ME/CFS is heart failure.


The 8th International Association of Chronic Fatigue Syndrome (IACFS) Conference was held at Fort Lauderdale, Florida, from 10th-14th January 2007. The following extracts are taken from “Facts from Florida” ( ).


  • the conference was attended by over 250 clinicians and researchers from 28 different countries and there was a strong sense that they were all co-operating to build on the science. It is the science that has freed the world from any doubt that ME/CFS is a legitimate disease with an aetiology that is not rooted in the psyche -- Japanese and Swedish research teams collaborated in a comprehensive study of a neuro-molecular mechanism and concluded that ME/CFS is an organic disorder. It was described as “this miserable illness”

  • the latest figures (January 2007) on the economic impact of ME/CFS in the US are between $22 billion and $28.6 billion annually; in Japan, the figure is over $10 billion annually. The Japanese Government recognises ME/CFS as a real threat not only medically but also economically and has initiated a large research programme into causation and treatment


  • one of the most striking elements was the convergence of research findings: the three areas that came up again and again were inflammation, mitochondrial abnormalities, and vascular problems

  • three separate research teams found evidence of microvascular problems in ME/CFS

  • the significant confluence of findings on elastase (a protease enzyme, i.e. it digests and degrades a number of proteins, including elastin, a substance that supports the structural framework of the lungs and other organs); vascular problems; apoptosis (programmed cell death); free radical production (highly damaging to DNA, to cell membranes and to proteins) and inflammation was undeniable

  • in ME/CFS, testing for elastase, RNase-L, C-reactive protein, selected cytokines and NK cell activity are recommended because they are objective markers of pathophysiology and severity. In addition, an exercise test/re-test of cardiopulmonary function is necessary because it is 100% objective and confirms reduced functional capacity as well as post-exertional malaise for disability purposes. Further, lipid abnormalities and evidence of metabolic syndrome should be looked for


  • researchers are developing methods to measure cardiovascular and cardiopulmonary health in ME/CFS patients, which relates to oxygen consumption

  • ME/CFS patients’ ability to work is impaired, as shown by an abnormal exercise stress test. Margaret Ciccolella and Christopher Snell et al from Stockton, CA, demonstrated that patients show extreme abnormalities in a next-day/second session of exercise. They do not recover in 24 hours. In one study, only one patient had recovered to baseline within 48 hours. These changes in serial testing point to a significant and confirmable physical abnormality, verifying the cardinal symptom of post-exertional malaise. This test/retest exercise test is 100% objective and can prove to the disability companies that ME/CFS is neither malingering nor faking. In ME/CFS patients, the measurements declined by about 25%, far more than in other significant diseases such as COPD and even heart failure

  • post-exertional malaise following exercise challenge results in fatigue, light-headedness, vertigo, joint pain, muscle pain, cognitive dysfunction, headache, nausea, trembling, instability, and sore glands

  • in ME/CFS patients, there is cellular hypoxia — oxygen is delivered to the cells of the heart, brain, skeletal muscle and other organs, but the process of turning oxygen into energy is derailed

  • graded exercise therapy is ill-advised — if a patient has abnormal oxygen consumption, muscles will not have enough oxygen and exercise will result in relapse

  • a US NIH-funded trial by Professor Barry Hurwitz, a colleague of Professor Nancy Klimas at the University of Miami, found that 70% of ME/CFS patients have a low red blood cell volume. Treatment to increase blood volume was ineffective in respect of exercise tolerance and fatigue

  • one of the highlights of the conference was the presentation of Dr Vance Spence’s work (University of Dundee) on inflammation and arterial stiffness in patients with ME/CFS – arterial stiffness is rarely found in adolescents, but in ME/CFS these young patients had higher levels of arterial stiffness than diabetic patients. This work looked at inflammatory factors (free radical by-products and C-reactive protein, an inflammatory marker) and found abnormally high levels of free radical by-products and C-reactive protein in patients but not in controls. C-reactive protein levels were significantly correlated with increased arterial stiffness. A likely cause is elastase. Elastase is a central factor in Professor Kenny de Meirleir’s RNase-L paradigm (see below), and Dr Baraniuk’s cerebrospinal fluid proteome study suggests elastase is implicated in blood vessel problems in the brain of ME/CFS patients. The logical consequences of increased arterial stiffness are exercise intolerance and diastolic (cardiac) dysfunction. The circulatory problems seen in ME/CFS may originate in endothelial cells lining all blood vessels. These cells are involved not only in opening and closing blood vessels but in the immune response as well, and they are often attacked by pathogens

  • Professor Paul Cheney presented evidence of diastolic (cardiac) dysfunction in ME/CFS. This results in hypoxia (low oxygen levels relative to metabolic needs)

  • Cheney stated that the cardiac index of ME/CFS patients is so severe that it falls between the value of patients with myocardial infarction (heart attack) and those in shock

  • Professor Mark VanNess from the University of the Pacific found that maximum aerobic capacity (VO2 peak) is reduced in ME/CFS compared with sedentary controls

  • Van Ness found that oxygen capacity at the anaerobic threshold is reduced in ME/CFS

  • Van Ness also found that serum lactate is elevated, suggesting an abnormally early shift to anaerobic metabolism

  • in a subset of patients, Martin Lerner (Wayne State University, Detroit) described persistent EBV and/or CMV in ME/CFS patients: in addition to having high titres, all 37 patients studied had an elevated heart rate at rest, recurrent T-wave inversion on Holter monitoring, cardiac abnormalities and/or biopsy-proven cardiomyopathy. Symptoms included not only tachycardia but chest pain and syncope

  • according to Lerner, all ME/CFS patients have abnormal T waves; inversion is seen in 96%; there is resting tachycardia. Cardiac biopsies show fibrosis, myofibre disarray and fatty infiltrates.

Other key areas of ME/CFS research reported in “Facts from Florida” include Nuclear Medicine (showing some of the abnormalities in functioning that patients with ME/CFS experience on a daily basis); Proteomics (the study of proteins made in the cell, including evidence of unique markers in the cerebrospinal fluid of ME/CFS patients that are completely absent in controls and which were described as “unbelievable”); Virology (showing evidence of viral persistence in ME/CFS patients); Gastrointestinal dysfunction (evidence was presented of enterovirus in stomach biopsies of 80% of ME/CFS patients, compared with none in controls); Sleep disruption (due to a lack of parasympathetic activity during attempted sleep periods); Pain (described as a major feature in many aspects of ME/CFS); Cognitive impairment (evidence was presented suggesting that the central nervous system correlates of cognitive dysfunction in ME/CFS have an inflammatory basis); Immunology (evidence of activated CD8 cells; poorly functioning NK cells; novel findings – seen only in ME/CFS – of abnormalities of the 2-5A pathway [RNase-L ratio]; cytokine abnormalities [pro-inflammatory dysregulation]; increased TGF, and 27 times more circulating immune complexes than in controls); Neuroendocrine dysfunction (evidence of neurobiological distinctions between ‘pure’ ME/CFS and CFS/ME with psychiatric morbidity -- further evidence that ME/CFS is not psychiatric in origin); Genomics (the study of the function and interactions of genetic material, including interactions with environmental factors which play a significant role in ME/CFS) and Paediatrics (with the presentation of new paediatric diagnostic criteria from Professor Leonard Jason et al, which means there is now a science-based instrument to correctly diagnose children and adolescents with ME/CFS).

In summary, this international conference demonstrated the difference between science and psychiatry.


A Scottish team noted that as long ago as 1997, markers of inflammation were demonstrated in some patients with ME/CFS, and that in 2005, vascular stiffness was shown to have an impact on resting and exercise-induced haemodynamics. Aware of the accumulating evidence that the cardiovascular system is compromised in many patients with ME/CFS, this team investigated the relationship between inflammation and arterial stiffness in ME/CFS patients. (If arteries become stiff, the heart has to work harder and, ultimately, blood pressure becomes higher. Stiff arteries have been linked to kidney problems and heart disease, and may contribute to the orthostatic problems (dizziness on standing) experienced by some ME/CFS patients). This study demonstrated that the augmentation index (a measure of arterial stiffness) was significantly greater in patients with ME/CFS than in controls and concluded: “The results of this study have shown that patients with ME/CFS have high serum CRP levels (C-reactive protein, a sensitive biochemical marker of inflammation) indicative of chronic inflammation. The combination of increased arterial wave reflection, inflammation and oxidative stress may result in unfavourable haemodynamics and an increased risk of a future cardiovascular event in these patients” (VA Spence et al. Clinical Science 2008:114:561-566).


At the IACFS International Research Conference held in March 2009 at Reno, Nevada, Drs Allan and Kathleen Light and Dr Lucinda Bateman presented evidence that adrenergic and sensory receptor expression on leucocytes increases after moderate exercise in both (ME)CFS and fibromyalgia. Sensors that monitor muscle health are found on leucocytes (white blood cells) and continually monitor the blood for signs of muscle damage (eg. for increased levels of lactate, for low pH and for purines that are produced during ATP production). Drs Light tested receptor activity at baseline and at varying times after moderate exercise in (ME)CFS patients. At baseline, receptor activity was similar in both (ME)CFS and FM patients, apart from a few receptors suggesting that (ME)CFS patients had increased vascular resistance (suggesting that blood vessels were narrowed). The post-exercise receptor activity was dramatically different in (ME)CFS patients; whereas in controls, the receptor activity barely changed after exercise, in (ME)CFS patients, “they look like Mt Vesuvius. (ME)CFS patients often feel like they’ve run a marathon after mild exercise; these results suggested that at least one part of their body reacted as if they had”. Intense exercise usually caused receptor activity to increase several hours later in healthy people, but even mild exercise caused the receptor activity to increase in just 30 minutes in (ME)CFS patients. Not only did the receptors appear to be over-reacting in (ME)CFS patients, but they also appeared to be responding surprisingly quickly. Beginning at 30 minutes after exercise and continuing at 8, 24 and 48 hours after exercise, (ME)CFS patients showed increases of ion channel receptor activity up to four times the pre-exercise level, while healthy subjects showed no increase at all. The activity of a receptor that is implicated in pain doubled in (ME)CFS patients who also had FM, but showed no increase at all in healthy subjects. Sympathetic nervous system (adrenergic) receptors that detect SNS activity were increased 2 – 6 times. (ME)CFS patients appear to have many times the normal level of these receptors on their white blood cells and remarkably, these receptors were still highly over-reactive 48 hours after mild exercise. The graph of the results was described as “incredible”, and Professor Nancy Klimas commented: “That was a great study” (with grateful acknowledgement to Cort Johnson: Co-Cure MED: 4th October 2009:

Two important questions relating to the PACE Trial remain unanswered: (i) are the West Midlands MREC and the peer reviewers at the MRC who approved the PACE trial protocol certain that the incremental exercise component poses no harm for people with ME/CFS and (ii) have all MRC trial participants been screened for cardiovascular anomalies before starting the trial, or are the Principal Investigators content to rely on the certainty that they themselves can never be held accountable for any harm to any patient, since all participants must sign a compulsory waiver, which means that no participant can ever pursue any claim for medical negligence or damages?

Documented neurological abnormalities in ME/CFS


ME/CFS was included by the distinguished neurologist Lord Brain in his textbook “Diseases of the Nervous System”, Oxford University Press, sixth edition: pp355 “ (ME) is the term applied to a disorder which has been recognised in many parts of the world. Its features are the severity of the symptoms in relation to the slightness of the physical signs. A characteristic feature of the muscular weakness is the intermittency of power of muscular contraction. Changes which are believed to be characteristic have been found on electromyography. A striking feature is the tendency for relapses to occur during the months, and in some cases even years, after the infection”.


Extract from a Press Conference by Professor Paul Cheney held in San Francisco in September 1990 and reported in CFIDS Chronicle, September 1990:

I believe this is a disease that affects the central nervous system (CNS) and I’ll show you some slides to help convince you of that. We are going to (look at) what evidence there is for neurologic disease in these patients. This is a study done by Dr Carolyn Warner from the Dent Neurologic Institute in Buffalo, New York, which specialises in multiple sclerosis. Some people think that (ME)CFS can look like MS and there are clinical features that are overlapping. The most specific neurologic symptom is dysequilibrium. These patients have a balance disturbance and on certain simple neurologic tests they fall over. On more sophisticated neurologic tests of vestibular function they are often grossly abnormal. Nearly every patient had something abnormal within the central nervous system, and also neuromuscular problems, or muscle itself. These patients are cognitively impaired and you can prove it by formalised psychometric tests. Other evidence of CNS involvement can be demonstrated by tests looking directly at the CNS. These are slices of brain created by using magnetic resonance imaging. These inflammatory and/or demyelinating plaques can be seen in the white matter, in the cerebellum and white matter tracts throughout the high cerebral convexities and in the frontal lobes. Over half of (ME)CFS patients will typically show lesions within the central nervous system. Professor Ismael Mena, chairman of the Department of Nuclear Medicine at Harbourview UCLA Medical Centre, found that there were defects in perfusion of temporal lobes primarily. He looked at regional cerebral blood flow and found that in (ME)CFS patients compared to controls, there was a diminishment of cerebral blood flow in the right temporal lobe that was significant. In other words, blood flow to the right temporal lobe was impaired in these patients. The temporal lobe seems to get really hit by this disease. I want to point out that 71% of patients with (ME)CFS are abnormal by this technique”.


Patients with (ME)CFS often complain of dysequilibrium. Data suggests that their symptoms of dysequilibrium can be substantiated with quantitative laboratory testing. The abnormalities are more suggestive of CNS deficits than of peripheral vestibular deficits(JMR Furman. Rev Inf Dis 1991:13: (Suppl 1):S109-111).


In a CME (continuing medical education) credit article, Dr David Bell, an internationally-acclaimed paediatrician specialising in ME/CFS, wrote in Postgraduate Medicine: “Findings now point to CNS involvement: Recent research has yielded remarkable data (and has) provided a steady current of scientific additions to our understanding of (ME)CFS”. Reviewing the immunological abnormalities (and noting that the patients who were the most disabled had the highest levels of interleukin-1), Bell pointed out that a consistent pattern of immune dysfunction is emerging, which helps to characterise and define the illness. He noted the elevated levels of cytokines, particularly those that affect neuronal tissue. He reviewed the evidence for retroviral markers, the pituitary and hypothalamic abnormalities, and the neuroendocrine abnormalities. He reviewed the cerebral perfusion abnormalities and highlighted the importance of elevated serum ACE levels seen in ME/CFS: “Another addition to the bewildering array of laboratory abnormalities found in patients with (ME)CFS is an increased serum concentration of angiotensin-converting enzyme (ACE). This is a marker not only for sarcoidosis but also for diseases involving the blood vessels. This finding is of importance because of the clinical similarities between (ME)CFS and sarcoidosis. Shared symptoms include fatigue, neurologic dysfunction and arthralgia. In patients with an elevated ACE level, attention to the lymph nodes and eyes is called for”. Bell concluded:The symptoms of (ME)CFS have long been viewed as a neurologic pattern, as indicated by other names for the condition such as myalgic encephalomyelitis (and) atypical poliomyelitis. Neurologic involvement is beginning to be confirmed by documentation of abnormalities in cerebral perfusion, hypothalamic function, and neurotransmitter regulation. A link is being forged between the symptoms pattern and objective evidence of CNS dysfunction. A majority, and perhaps all, of the symptoms of (ME)CFS may be neurologic in origin. The view that (ME)CFS is a primary emotional illness has been undermined by research findings(David S Bell. Postgraduate Medicine 1994:96:6:73-81).


Because a complete neurological examination is not emphasised as part of the diagnostic workup, it is possible that less obvious neurological findings may be overlooked. Careful evaluation of neurological features may be one approach to distinguishing subtypes. The neurological symptoms and signs were neuropsychological changes, cutaneous sensory changes, paresis, abnormal muscle movements, abnormal muscle tone, deep tendon reflex changes, cranial nerve signs, posterior column signs, ataxia, and vasomotor instability. Activity or exercise was a precipitant or exacerbation or relapse. Many of the neurological signs and symptoms were not reported on. A complete neurological examination should be an integral part of the diagnostic assessment of illnesses described as CFS” (NC Briggs, Paul Levine. Clin Inf Dis 1994:18: (Suppl 1):S32 –S42).


To assess the clinical impression that patients with (ME)CFS do not walk normally, the gait kinematics of patients with (ME)CFS were studied. Results showed that (ME)CFS patients were significantly slower at running speed than the controls. Further analysis revealed that patients with (ME)CFS took smaller steps than the controls. “The data indicate that (ME)CFS patients have gait abnormalities when compared to sedentary controls. These could be due to balance problems, muscle weakness, or central nervous system dysfunction (Boda WL, Natelson BH et al. Journal of the Neurological Sciences 1995:156-161).


A growing literature exists suggesting that a component of (ME)CFS may include abnormalities in cardiovascular control. Vagal power, a measure of cardiac parasympathetic activity, was computed. In an earlier study, we showed that patients with (ME)CFS had significantly less vagal power than healthy controls during controlled breathing. Our findings suggest that vagal dysregulation may be an additional symptom of (ME)CFS. Moreover, they suggest the presence of a biological link between fatigue and the autonomic nervous system. The (ME)CFS group had less vagal power than the controls at every stage (and also) during the first stage of recovery. These results indicate that vagal power responses in patients with (ME)CFS are different from healthy controls. A common complaint in (ME)CFS is that patients are unable to exert themselves for prolonged periods due to a lack of energy. Our findings might explain this. It is possible that reduced vagal power might interfere with the normal recovery process that follows bouts of exertion. This interference might exacerbate fatigue immediately or for several days following exertion, a common complaint in (ME)CFS. Decreases in vagal power have been identified in several medical conditions, including congestive heart failure. Our data suggest that (ME)CFS may involve a primary neurological abnormality. (ME)CFS patients also show dysfunction in complex auditory processing that is of the same magnitude as that found in patients with multiple sclerosis. Other data show that patients with ME/CFS (sic) had significantly lower brain stem perfusion ratios than either healthy or depressed controls” (DL Cordero, BH Natelson et al. Clinical Autonomic Research 1996:6:329-333).


The aim of this study was to investigate the role of the autonomic nervous system in (ME)CFS. Autonomic signs and symptoms have appeared frequently in reports of CFS, also called myalgic encephalomyelitis. The three criteria used to determine autonomic symptoms eligibility were (1) dizziness upon standing and rapid heart beat; (2) dizziness upon standing and either nausea, diarrhoea, constipation and night sweats and (3) rapid heart beat and either nausea, diarrhoea, constipation or night sweats. Recent reports have documented neurocardiogenic syncope in patients, again suggesting autonomic dysfunction in (ME)CFS. Several autonomic function test results were significantly different in the (ME)CFS group when compared to controls. Our study found that neither depression nor anxiety correlated with any of the measures of autonomic dysfunction. Deconditioning alone did not explain these autonomic abnormalities. 89% of patients in this study reported that the onset of fatigue was preceded by (an infectious illness), a history typical of patients with (ME)CFS. Our results provide evidence for an association between an autonomic neuropathy and (ME)CFS. An exercise programme, alone and in combination, cannot now be generally recommended for patients with (ME)CFS” (R Freeman, AL Komaroff. Am J Med 1997:102:357-364).


Spatial and temporal parameters of gait were collected from (ME)CFS patients by using instrumentation of movement analysis. Interestingly, abnormalities were present from the beginning of the gait, which indicates that they are unlikely to be caused by the rapidly increasing fatigue. This strengthens the hypothesis of a direct involvement of the central nervous system in the onset of the disease(R Saggini et al. Journal of the Neurological Sciences 1998:154:18-25).


A substantial body of clinical evidence now supports an association between various forms of hypotension and (ME)CFS. Features that exacerbated (patients’) fatigue included physical exertion, a hot shower, prolonged standing (such as waiting in line at the grocery store) and a warm environment. Importantly, all (ME)CFS patients but none of the controls developed orthostatic symptoms (during testing), suggesting that orthostatic intolerance may be a defining feature of the illness. Virtually all (ME)CFS patients have their symptoms provoked by the simple process of assuming an upright posture. There is a high prevalence of allergic disease among those with (ME)CFS (and) one would expect to find a mechanism by which allergic disease increases the activation of the NMH reflex pathway. Undem et al have shown that both viral infection and allergic reactions to food antigens enhance the excitability of mechanically sensitive vagal afferents in the airway (which provides a link between these clinical situations). Investigations into the high prevalence of neurally mediated hypotension and other forms of autonomic dysfunction among those with (ME)CFS should improve our understanding of this disorder(Peter C Rowe and Hugh Calkins. Am J Med 1998:105:3A:15S-21S).


The fatigue in (ME)CFS is similar to that found in disorders of the central nervous system such as multiple sclerosis, Parkinson’s disease and multiple system atrophy. It is now clear that (ME)CFS patients differ from patients with major depression in their symptoms (and) biologic markers such as steroid metabolism. We propose dysfunctional ion channels in the cell membranes as the key abnormality in (ME)CFS which may also be responsible for the altered neuroendocrine functions reported in this condition. Associated symptoms that are common in (ME)CFS include paroxysmal attacks of angina-like chest pain (Syndrome X), nocturnal attacks of sweating and palpitations, irritable bowel syndrome, vertigo or dysequilibrium, photophobia (and) daily migraine-like headaches. Autonomic dysfunction in (ME)CFS is well-recognised. One of the most characteristic features of the illness is the fluctuation in symptoms which can be induced by physical and/or mental stress. Acquired ion channel abnormalities in myocardium could explain the pathogenesis of Syndrome X. Acquired mutations of a similar nature may form the basis of the cardiac dysfunction seen in Syndrome X and (ME)CFS. The role of abnormal ionophores governing both Syndrome X and (ME)CFS assume importance in the light of the fact that a highly significant proportion of (ME)CFS patients have cardiomyopathy. (ME)CFS is an episodic neurological disorder with a basic mechanism of disease involving abnormal ion channel functions” (Abhijit Chaudhuri et al. Hum Psychopharmacol Clin Exp 1999:14:7-17).


In 2000, the CFIDS Association of America produced a 24 page document entitled “Neurological Findings in (ME)CFS: A Survey of the Research” containing 175 references. It is available from the CFIDS Association of America, email:


A quantitative assessment of cerebral ventricular volumes in (ME)CFS patients found that volumes were larger than in the control groups. “The results of this study provide further evidence of pathophysiological changes in the brains of participants with (ME)CFS” (Lange G, Natelson BH et al. Appl Neuropsychol 2001:8(1):23-30).


Byron Hyde, medical adviser on ME/CFS to the Canadian Government, pointed out that “ME in adults is associated with measurable changes in the central nervous system and autonomic function and injury to the cardiovascular, endocrine and other organs and systems. The patient with the diagnosis of ME/CFS is chronically and potentially seriously ill. These ME/CFS patients require a total investigation and essentially a total body mapping to understand the pathophysiology of their illness and to discover what other physicians may have missed. A patient with ME is a patient whose primary disease is central nervous system change, and this is measurable. The belief that ME/CFS is a psychological illness is the error of our time”. (The Complexities of Diagnosis. Byron Hyde. In: Handbook of Chronic Fatigue Syndrome Leonard A Jason et al. John Wiley & Sons, Inc. 2003).


Research at the Salk Institute, La Jolla, California, identified a gene that may link certain pesticides and chemical weaponry to a number of neurological disorders. The finding, published in the 17 March online version of Nature Genetics, was the first to demonstrate a clear genetic link between neurological disorders and exposure to organophosphate (OP) chemicals. OPs include household pesticides as well as the nerve gas sarin. The research showed that OPs inhibit the activity of a gene called neuropathy target esterase (NTE). Some of the neurological problems echoed many of the symptoms of Gulf War Syndrome.

This is important because the Proceedings of The National Academy of Science (PNAS) published evidence that NTE is inhibited by several OP pesticides, chemical warfare agents, lubricants and plasticisers, leading to OP-induced delayed neuropathy in more than 30,000 human cases (PNAS 2003:100:13:7983-7987).

(This is highly significant in ME/CFS, because subsequent gene expression research demonstrated 16 genes as having an expression profile associated with (ME)CFS. These genes can be grouped according to immune, neuronal and mitochondrial functions. A neuronal component was identified that is associated with central nervous system hypomyelination, and the researchers specifically noted the association of organophosphates and chemical warfare agents: “A neuronal component is suggested by up-regulation of NTE. NTE is a target for organophosphates and chemical warfare agents, both of which may precipitate (ME)CFS” (N Kaushik, ST Holgate, JR Kerr et al. J Clin Pathol 2005:58:826-832). Stephen Holgate is MRC Clinical Professor of Immunopharmacology at the University of Southampton and this is top-rank research, not mere hypothesis).


The purpose of this study was to determine whether brain activity of (ME)CFS patients during voluntary motor actions differs from that of healthy controls. Fifty-eight channels of surface EEG were recorded simultaneously from the scalp. Major findings include (1) Motor performance of the (ME)CFS patients was poorer than the controls (2) Relative power of EEG theta frequency band during performance of tasks was significantly greater in (ME)CFS than in the control group (3) The amplitude of MRCP (motor activity-related cortical potential) negative potential for tasks was higher in (ME)CFS than the control group. These results clearly show that (ME)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 (ME)CFS” (Siemionow V et al. Clin Neurophysiol 2004:115(10:2372-2381).


The Lancet published a Review entitled “Fatigue in neurological disorders” by Abhijit Chaudhuri et al (Lancet 2004:363:978-988). It included (ME)CFS as a neurological disease and it contained 94 references.


In a study looking at grey matter volume reduction in (ME)CFS, researchers found significant reductions in global grey matter volume in (ME)CFS patients compared with matched controls: “Moreover, the decline in gray matter volume was linked to the reduction in physical activity, a core aspect of (ME)CFS. These findings suggest that the central nervous system plays a key role in the pathophysiology of (ME)CFS and point to an objective and quantitative tool for clinical diagnosis of this disabling disorder” (FP de Langea et al. NeuroImage 2005:26:3:777-781).


A News Release from Georgetown University Medical Centre highlighted objective, physiological evidence that (ME)CFS “can be considered a legitimate medical condition. James Baraniuk, Assistant Professor of Medicine (said) ‘Our research provides initial evidence that that (ME)CFS and its family of illnesses may be legitimate neurological diseases and that at least part of the pathology involves the central nervous system’ ”. The researchers stated: “CFS, Persian Gulf War Illness and fibromyalgia are overlapping symptom complexes. Neurological dysfunction is common. We assessed cerebrospinal fluid to find proteins that were differentially expressed in this CFS-spectrum of illnesses compared to controls. Pooled CFS and (Gulf War Syndrome) samples shared 20 proteins that were not detectable in the control sample. 62 of 115 proteins were newly described. This pilot study detected an identical set of central nervous system, innate immune and amyloidogenic proteins in the cerebrospinal fluids from two independent cohorts of subjects with overlapping (ME)CFS, (Gulf War Syndrome) and fibromyalgia” (BMC Neurology 2005:5:22).


Professor Julia Newton et al studied the prevalence of autonomic dysfunction in (ME)CFS; she found that symptoms of autonomic dysfunction were strongly and reproducibly associated with the presence of (ME)CFS and correlated with severity of fatigue. A particularly strong association was seen with symptoms of orthostatic intolerance, suggesting that abnormality of dynamic blood pressure regulation is particularly associated with fatigue severity in ME/CFS, confirming the conclusions of a previous review, and it made clear that ME/CFS patients are not deconditioned (Q J Med 2007:100:519-526).


Hoad A and Newton J et al described the prevalence of POTS (postural orthostatic tachycardia syndrome) in a cohort of patients with ME/CFS and suggest that prevalence may be even higher than shown in the study results because observations of haemodynamics were limited to just two minutes (some patients were unable to stand without support and were too unwell to be tested). The authors state: “Studies suggest that POTS is accompanied with a range of autonomic nervous system abnormalities including vagal withdrawal and enhanced sympathetic modulation, associated with findings consistent with pooling in the lower limbs. It is important that (in ME/CFS patients) appropriate investigations are performed. We suggest that at the very minimum this includes haemodynamic assessment in response to standing of patients attending CFS/ME clinical services” (Q J Med September 2008:doi:10.1093/qjmed/hcn123).


Newton et al demonstrated that lower blood pressure and abnormal diurnal blood pressure regulation occur in patients with ME/CFS and considered the links between hypotention and fatigue. The authors concluded: “Compared with the control population, the (ME)CFS group had significantly lower systolic blood pressure and mean arterial blood pressure and exaggerated diurnal variation. There was a signficant inverse relationship between increasing fatigue and diurnal variation of blood pressure in the (ME)CFS group. This study has further consolidated the evidence that lower blood pressure occurs in (ME)CFS and that…lower night-time blood pressure seems to be a significant problem that may lead to enhanced diurnal variation in blood pressure that associates with fatigue. We and others have previously demonstrated that autonomic nervous system function is significantly impaired in (ME)CFS. We would suggest that…one mechanism whereby abnormalities in autonomic function may be manifest clinically is through blood pressure dysregulation” (Psychsom Med 2009:71: doi:10.1097/PSY.0b013e31819ccd2a).

Documented abnormalities shown on neuroimaging in ME/CFS

As reported by Dr John Breward as long ago as 2001 in the Newsletter of The 25% ME Group, Issue 11: “The cumulative evidence is now incontestable: there are measurable physical abnormalities in the brain in ME”.


(ME)CFS is a severely disabling illness. Compared to the normal control group, the (ME)CFS group showed significantly lower cortical / cerebellar rCBF (regional cerebral blood flow) ratios throughout multiple brain regions. SPECT provided objective evidence for functional impairment of the brain in the majority of the (ME)CFS subjects. The central nervous system dysfunction in (ME)CFS may be a primary phenomenon or it may be secondary to undefined systemic factors. The majority of (ME)CFS subjects studied showed SPECT scan abnormalities providing objective evidence of central nervous system dysfunction in (ME)CFS” (M Ichise et al; Nuclear Medicine Communications 1992:13:767-772).


We compared SPECT scans of patients with (ME)CFS with those of patients with ADC (AIDS dementia complex) and unipolar depression. The MCUI (midcerebral uptake index) was signficantly different across all groups. This study demonstrates that (ME)CFS shares some similarities on SPECT imaging with both ADC and unipolar depression. The MCUI was significantly lower in patients with (ME)CFS and ADC than in patients with major unipolar depression or the healthy comparison group. By this objective standard, the pathophysiologic process in the central nervous system of patients with (ME)CFS would seem to be more similar to that in patients with ADC than to patients with unipolar depression. Moreover the MCUI values correlated with the regional defect count in the (ME)CFS and ADC groups, but not in the depressed patients or control subjects” (Schwartz RB et al; American Journal of Reontgenology 1994:162:943-951).


We looked for brain perfusion abnormalities in patients with ME/CFS. Hypoperfusion of the brainstem was marked and constant. Brainstem hypoperfusion was confirmed in all ME/CFS patients. Patients with ME/CFS have a generalised reduction of brain perfusion, with a particular pattern of hypoperfusion of the brainstem. Brainstem hypoperfusion appears to be the differentiating factor between our ME/CFS patients and those with major depression. The hypothalamus of ME/CFS patients shows functional abnormalities different from those in depressed patients. Our data suggest that brainstem hypoperfusion in ME/CFS patients could be due to an organic abnormality” (DC Costa et al; Q J Med 1995:88:767-773).


Many neurological diseases produce symptoms of intense fatigue and muscle pain. Abnormalities in cerebral perfusion were seen on visual reporting of the SPECT images in more than half of the patients with (ME)CFS. Perfusion defects were not consistently localised to any one region of the brain, being found in the frontal, temporal, occipital and parietal regions, nor were the defects always unilateral. (ME)CFS is an established, severe and debilitating illness. We have found visual evidence of cerebral perfusion defects in all regions of the brain. This is confirmed by the objective quantitative analysis which demonstrates that there is a greater variability in perfusion pattern of patients with (ME)CFS compared to normal subjects” (J Patterson et al; EOS- J Immunol Immunopharmacol 1995:XV:1-2:53-58).


D Di Giuda, G Racciatti et al found that “(ME)CFS is a severely disabling illness. Regional brain perfusion impairment (mainly hypoperfusion) was found in 83.9% of (ME)CFS patients. This study confirmed previous reports of brain perfusion impairment in (ME)CFS, providing objective evidence of central nervous system dysfunction”. (“Brain SPET in Chronic Fatigue Syndrome”: Fourth AACFS International Research & Clinical Conference, Mass: USA).


Cook DB, Natelson BH et al from the Department of Neurosciences, New Jersey Medical School, reported: “Some have suggested that (ME)CFS is a ‘functional somatic syndrome’ in which symptoms are inappropriately attributed to a serious illness. However, brain magnetic resonance imaging (MRI) data suggest that there may be an organic abnormality associated with (ME)CFS. (Our) results demonstrate that the presence of brain abnormalities in (ME)CFS are significantly related to subjective reports of physical function and that (ME)CFS subjects with MRI brain abnormalities report being more physically impaired than those without brain abnormalities” (Int J Neurosci 2001:107(1-2):1-6).


A study by Puri et al tested the hypothesis that (ME)CFS is associated with altered cerebral metabolite in the frontal and occipital cortices and concluded: “Our results suggest that there may be an abnormality of phospholipid metabolism in the brain in (ME)CFS” (Acta Psychiatr Scand 2002:106(3):224-226). As Dr Charles Shepherd, Medical Advisor to the ME Association, commented: “These results add further weight to recently reported perfusion studies which suggest that there may be pathophysiological abnormalities in the cerebral cortex of ME/CFS patients” (Co-Cure MED: 30th August 2002).


Researchers in Japan (Kuratsune et al) reported that their findings “suggest that the levels of biosynthesis of neurotransmitters through acetylcarnitine might be reduced in some brain regions of (ME)CFS patients” (NeuroImage 2002:17(3):1256-1265).


Using proton magnetic resonance spectroscopy to study the metabolic functions of the basal ganglia in (ME)CFS patients, Chaudhuri et al reported: “A highly significant increase in the spectra from choline-containing compounds was seen in the (ME)CFS patient group” (Neuroreport 2003:14(2):225-228).


German researchers Siessmeier et al used 18-fluorodeoxyglucose positron emission tomography (FDG-PET) to evaluate cerebral glucose metabolism in (ME)CFS and concluded: “PET may provide valuable information in helping to separate CFS patients into subpopulations with and without apparent alterations in the central nervous system” (JNNP 2003:74(7):922-928).


Lange and Natelson et al from New Jersey Medical School studied attentional processes (cognitive difficulties) in patients with (ME)CFS: “Our results provide objective evidence in support of the subjective report of cognitive difficulties in individuals with (ME)CFS and demonstrate an important role for functional neuroimaging in understanding the pathophysiology of (ME)CFS symptoms. The evidence supporting a central nervous system pathophysiological process for some individuals with (ME)CFS is mounting. Findings showed that individuals with (ME)CFS utilise more extensive (brain) regions. Individuals with (ME)CFS appear to have to exert greater effort to process auditory information as effectively as similar healthy adults. Our studies do not support the notion that difficulties in cognitive function in individuals with (ME)CFS are related to poor motivation” (NeuroImage 2005:26(2):513-524).


Further to their 2005 study, DB Cook et al from New Jersey Medical School used functional MRI (fMRI) to determine the association between feelings of mental fatigue and blood oxygen level dependent (BOLD) brain responses during a mentally fatiguing cognitive task in (ME)CFS patients. “Our results demonstrated significant associations between mental fatigue and brain activity during a fatiguing cognitive task (and are) generally consistent with prior research. Brain regions that were significantly related to mental fatigue included the parietal, cingulated, inferior frontal and superior temporal cortices, cerebellum and cerebellar vermis – regions that have been demonstrated as important for several aspects of cognitive function. Chronically fatigued participants exhibited greater brain activity in multiple brain regions during the fatiguing task compared to controls. The results suggest that the phenomenon of mental fatigue can exert demands on the neural processes necessary for efficient information processing” (NeuroImage 2007: doi:10.1016/j.neuroimage.2007.02.033).


In this paper, Japanese researchers summarised neuroimaging findings in patients with (ME)CFS from 1992, including reduced brain blood flow, decreased brain volume and symptom-related neuroimaging changes. They reported: “An increasing amount of neuroimaging evidence supports the hypothesis that (ME)CFS patients have structural or functional abnormalities within the brain. Available neuroimaging data not only show differences between fatigued patients and normal controls, but also indicate the brain’s response to mental fatigue and other complex symptoms of (ME)CFS. Evidence of abnormal perfusion has led to research on brain metabolism (that) found significant hypometabolism in the right mediofrontal cortex and brainstem in (ME)CFS patients. Patients with (ME)CFS have been found to have significantly abnormal brain volume compared with healthy controls and these abnormalities occur not only in white matter but also in grey matter. It is well known that cytokines produced in the brain exert various central actions, including activation of the sympathetic nervous system and HPA axis, impairment of learning memory etc; this points to the possibility that brain cytokines may play a role in the pathogenesis of (ME)CFS. We suggest that the focal point of (ME)CFS research should be transferred to the central nervous system(J Int Med Res 2008:36:867-874).

Given the now-substantial evidence of abnormalities in ME/CFS patients which have been demonstrated on neuroimaging, it is disturbing that the Wessely School apparently continues to dismiss them as of no consequence. Wessely’s colleague at the IoP, Anthony David, long ago went on record as being dismissive of neuroimaging in ME/CFS, asserting that the clinical significance of such testing “has yet to be determined” (Helen Cope, Anthony David et al; Br J. Psychiat 1995:167:86-94) and that “It is premature …to claim unique neuroimaging abnormalities in the chronic fatigue syndrome” (JNNP 1996:60:471-473), a dismissive stance further propounded by the Wessely School’s Joint Royal Colleges’ Report on CFS (CR54; 1996) which was categoric that neuroimaging “may reveal ’abnormalities’ of little consequence (whose) significance remains to be determined”.

This advice has seemingly ensured that, for non-private patients in the UK, it is virtually impossible for people with ME/CFS to be referred for neuroimaging.

Documented neuroendocrine abnormalities




Several lines of evidence suggest that the various components of the hypothalamic-pituitary-adrenal (HPA) axis merit further study in these patients. Debilitating fatigue, an abrupt onset precipitated by a stressor, feverishness, arthralgias, myalgias, adenopathy, postexertional fatigue, exacerbation of allergic responses are all characteristic of glucocorticoid insufficiency. Compared to controls, patients with (ME)CFS showed a significant reduction in basal total plasma cortisol (and) a proportionately higher response to the amount of ACTH released during stimulation with oCRH. We suggest that the hyper-responsiveness of the adrenal cortex to ACTH in patients with (ME)CFS reflects a secondary adrenal insufficiency in which adrenal receptors have become hyper-responsive to inadequate levels of ACTH. In the light of the post-infectious presentation of (ME)CFS in the majority of patients, it should be noted that viral infections can alter neurotransmitter and / or neuroendocrine regulation” (Mark A Demitrack et al. Journal of Clinical Endocrinology and Metabolism 1991:73:6:1224-1234).



The syndrome of (ME)CFS has a lengthy history in the medical literature. The clinical presentation, with evidence of persistent immune stimulation, lends support to the idea that (ME)CFS represents a clinical entity with potential biological specificity. We showed that patients with (ME)CFS demonstrate a significant hypocortisolism (Mark A Demitrack et al. Biol Psychiatry 1992:32:1065-1077).


Patients with (ME)CFS lose muscle protein synthetic potential, but not muscle bulk. These perturbations may contribute to the feature of muscle weakness associated with persistent viral infection in the muscles themselves. 80% of patients had serological indications of current or on-going VP1 positive enterovirus infection. There has to be persistent enterovirus infection to produce the response; it does not rely on the body’s development of antibody. Furthermore, skeletal muscle RNA was significantly reduced. This reflects a reduced capacity to synthesise proteins. Our results imply that there is a subgroup of patients with (ME)CFS in which symptoms of skeletal muscle weakness may be related to proximal myopathy. Direct evidence has been obtained for a subcellular metabolic defect in the muscle per se. These studies indicate that up to 80% of patients with (ME)CFS have identifiable mitochondrial abnormalities” (VR Preedy TJ Peters et al. J Clin Pathol 1993:46:722-726).



The baseline AVP values were significantly lower in patients with (ME)CFS when compared to healthy controls. The mean total body potassium (TBK) was 9% lower than predicted. This study also showed that some patients with (ME)CFS appear to have an increased total body water content when compared with healthy controls. Abnormalities of water metabolism in patients with (ME)CFS have previously been reported. This interference with hypothalamic function may be due to the presence of persistent virus, most likely enterovirus. In such a chronic infection, Oldstone has shown that the agent may persist in cells without producing any evidence of damage but effecting a profound disturbance of hormones and neurotransmitters (AMO Bakheit et al. Acta Neurol Scand 1993:87:234-238).




One of the characteristic complaints of patients with (ME)CFS is the skeletal muscle-related symptom. We show that patients had a deficiency of serum acylcarnitine. This deficiency might induce an energy deficit and/or abnormality of the intramitochondrial condition in the skeletal muscle, resulting in general fatigue, myalgia, muscle weakness and postexertional malaise in patients with (ME)CFS. The measurement of acylcarnitine would be a useful tool for the diagnosis and assessment of (ME)CFS” (H Kuratsune et al. Clin Inf Dis 1994:18: (Suppl 1):S62-S67).



The role of steroids in growth hormone production was determined in patients with (ME)CFS. There were abnormal responses of growth hormone production to administered steroids in patients with (ME)CFS. These data suggest an abnormality in the glucocorticoid receptor bearing neurones that control growth hormone responses in affected patients. These data clearly pointed to an abnormality in neuroendocrine control. Another condition that bears striking similarities to (ME)CFS is post-polio syndrome(T Majeed et al. Journal of the Irish Colleges of Physicians and Surgeons 1995:24:1:20-24).


In a study examining abnormality of adrenal function, Japanese researchers found that these abnormalities are quite different from those found in patients with mental or physical diseases reported previously (Yamaguti K et al. JCFS 1996:2:2/3:124-125).



In reviewing stress-response systems, it is important to keep in mind that activity of stress-response systems is determined by genetic and environmental factors. In (ME)CFS we have demonstrated a significant increase in plasma levels of the serotonin metabolite 5-hydroxyindoleacetic acid. Patients with a longer duration of disease do tend to have more severe basal abnormalities in cortisol levels” (LJ Crofford et al. Rheum Dis Clin N Am 1996:22:2:267-284).



There is an increasing volume of evidence to support the view that patients with (ME)CFS have unique endocrinology patterns. The cardinal findings include attenuated ACTH responses to CRH and low 24-hour urinary cortisol. These are compatible with a mild central adrenal insufficiency. It is well-documented that infectious diseases are often accompanied by various forms of neuroendocrine disturbances with acute viral infections activating the HPA axis. An increase in peripheral turnover of 5-HT may explain the heightened allergic responsiveness as well as the musculoskeletal pain seen in (ME)CFS” (LV Scott TG Dinan. JCFS 1996:2:4:49-59).




It is notable that the pattern of alteration in the stress response suggests a sustained inactivation of central nervous system components of this system. It has not escaped the view of clinical authors that (ME)CFS and its historical antecedents shares many of the characteristics with endocrine disease states (in which there is) functional interdependence of the endocrine system and the nervous system. It is only recently that clinical researchers have clearly documented that neuroendocrine disturbances are evident in patients with (ME)CFS (which) have brought into view a broader understanding of the variety of physiologic accompaniments of this condition. (ME)CFS appears to wax and wane with periods of increased stress. Results of this work provide confirmatory support for an impairment (of) the HPA axis (and) is consistent with the view that adrenocortical function is impaired (MA Demitrack. J psychiat Res 1997:31:1:69-82).



Our group has established that impaired activation of the HPA axis is an essential neuroendocrine feature of (ME)CFS. It is now recognised that (ME)CFS leads to significant physical and psychological debility in a large segment of the population. We have suggested that the findings of reduced adrenal glucocorticoid function in (ME)CFS are most consistent with a central nervous system defect in the activation of this axis. (We found) a basal hypocortisolism. On its own, this observation is a striking finding. These observations provide an important clue to the development of more effective treatment for this disabling condition (MA Demitrack, LJ Crofford. Ann N.Y. Acad Sci 1998:840:684-697).




The right and left adrenal gland bodies were reduced by over 50% in the (ME)CFS subjects, indicative of significant adrenal atrophy in a group of (ME)CFS with abnormal endocrine parameters (Scott LV et al. Psychoneuroendocrinology 1999:24:7:759-768).



Baseline adrenaline levels were significantly higher in (ME)CFS patients. We conclude that (ME)CFS is accompanied by a resistance of the immune system to regulation by the neuroendocrine system. Based on these data, we suggest (ME)CFS should be viewed as a disease of deficient neuroendocrine-immune communication(Kavelaars A et al. J Clin Endocrinol Metab 2000:85:2:692-696).


In the investigation of (ME)CFS, fine needle aspiration (FNA) cytology has been tested in addition to conventional biochemical thyroid function tests. Of 219 patients, 40% were diagnosed with definite cytological lymphocytic thyroiditis. We strongly advocate FNA cytologic assessment of the thyroid in patients with (ME)CFS (B Wikland et al. Lancet 2001:357:956-957).

In a subsequent letter, Wikland stated: “In a letter published in The Lancet (24th March 2001) we report on fine needle aspiration cytology of the thyroid in (ME)CFS. No less than 40% of our patients showed definite autoimmune thyroiditis. Less than half of these patients fulfilled conventional biochemical criteria of hypothyroidism. In our opinion, this aspect merits wider recognition (Bo Wikland. eBMJ 9 January 2002).


One of the most consistent findings in (ME)CFS is a decrease in Th1-mediated immune responses. (ME)CFS patients have been shown to display a disturbed HPA axis and have low levels of cortisol. We speculate that in these patients IL-10 and IL-12 are differently affected by glucocorticoids. The present study shows that, in particular, IL-10 secretion (and its sensitivity to GC) differs from that in healthy controls (J Visser et al. Journal of Neuroimmunology 2001:119:2:343-349).




Endocrinologists were not included in the working groups that prepared two recent reports on (ME)CFS, despite its clinical overlap with Addison’s disease, which is a classic endocrine disease. The failure to include at least one endocrinologist in those panels may explain why in their reports there is not a single word about the 42 clinical features that (ME)CFS shares with Addison’s disease. The failure of both the English and Australian reports to mention other important endocrine abnormalities of (ME)CFS represents a serious omission. Cognitive behaviour therapy may have benefited depressed subjects (but) not patients with (ME)CFS. (ME)CFS and Addison’s disease also share reduced cardiac dimensions, increased heart rate, postural hypotension, orthostatic tachycardia, dizziness upon standing, dehydration, anorexia, nausea (and) diarrhoea. Moreover (they) also share leucocytosis, lymphocytosis, elevations of transaminase values, enhanced TSH secretion, respiratory muscle dysfunction, reduction in exercise capacity and increased sensitivity to chemical exposures. Reason suggests that the clinical overlap of (ME)CFS with Addison’s disease reflects the endocrine and adrenal abnormalities found in (both disorders) and omitted unjustifiably in both the English and Australian reports, namely hypocortisolism, impaired adrenal cortical function, reduced adrenal gland size, antibodies against the adrenal gland, and impaired production of DHEA. Richard Horton, editor of The Lancet, has recently written (JAMA 2002:287:2843-2847): ‘Failure to recognise the critical footprint of primary research weakens the validity of guidelines and distorts clinical knowledge’ ” (R Baschetti. Eur J Clin Invest 2003:33:1029-1031).


(Baschetti was referring to the 2002 UK Report of the CMO’s Working Group and the Australian Report in the Medical Journal of Australia 2002:176:S17-S56).




Patients with (ME)CFS typically present a normal thyroid function. From (our) observations, we raise the hypothesis that molecular mechanisms could explain the development of a clinical hypothyroid state in the presence of a normal thyroid function. Whilst biochemically euthyroid, (ME)CFS patients are clinically hypothyroid. Signal transduction mechanisms could account for a peripheral T3 resistance syndrome leading to a clinically hypothyroid but biochemically euthyroid state, as observed in diseases characterised by dysregulations in the antiviral pathway or during the therapeutic use of INF / ” (P Englebienne et al. Med Hypotheses 2003:60:2:175-180).




The following article is in Serbian and comes from the Institute of Endocrinology, Belgrade; no author is listed:

Similarities between the signs and symptoms of (ME)CFS and adrenal insufficiency prompted the research of the HPA axis derangement in the pathogenesis of (ME)CFS. We compared cortisol response in the (ME)CFS subjects with the response in control subjects and in those with secondary adrenal insufficiency. We have shown that cortisol increment at 15 and 30 minutes is significantly lower in the (ME)CFS group than in controls. However, there was no difference between the (ME)CFS group and those with secondary adrenal insufficiency in any of the parameters. Consequently, reduced adrenal responsiveness to ACTH exists in (ME)CFS (Srp Arh Celok Lek 2003:131:9-10:370374).


It should be noted that Wessely School psychiatrists have carried out several endocrinological studies on “CFS” patients and have had varying results, possibly because of their chosen case definition. Despite the compelling evidence of international researchers, the Wessely School psychiatrists found no evidence of endocrine abnormality in some of their studies, whilst in others they did find evidence of such abnormalities but concluded that even though a distinct abnormality was found (low cortisol), it was likely to be “an epiphenomenon caused by the behavioural changes typical of CFS” (GJ Rubin, M Hotopf, A Cleare et al. Psychosom Med 2005:67:3:490-499).

Documented evidence of inflammation in ME/CFS

A few illustrations of published evidence of inflammation of the central nervous system of ME/CFS patients include the following:




In this outbreak of ME in Adelaide, Australia, an agent was repeatedly transmitted to monkeys; when the monkeys were killed, microscopically, infiltration of nerve roots with lymphocytes and mononuclear cells was seen and some of the nerve fibres showed patchy damage in the myelin sheaths and axon swellings consistent with neurological involvement. In these monkeys, there were widespread changes involving the dorsal root ganglia, cervical and lumbar nerve roots and peripheral nerves. Perivascular collars of lymphocytes and plasma cells were in the cerebral cortex, brainstem and cerebellum, spinal cord and around blood vessels to nerve roots (Pellew RAA, Miles JAR; Med J Aust:1955:2:13:480-482, cited by J Gordon Parish; Postgraduate Medical Journal 1978:54:711-717).


This is particularly significant, given the recent autopsy evidence presented at the Royal Society of Medicine meeting in the series “Medicine and me” on 11th July 2009 by Dr Abhijit Chaudhuri, where he showed slides of inflammation of the dorsal root ganglia in three ME/CFS patients.



Innes reported isolation of Coxsackie B2 virus from the cerebrospinal fluid: “The isolation of an enterovirus from the cerebrospinal fluid in the fourth month is in itself remarkable” (Innes SGB; Lancet:1970:969-971).




Neurologic symptoms, MRI findings, and lymphocyte phenotyping studies suggest that the patients may have been experiencing a chronic, immunologically mediated inflammatory process of the central nervous system” (Buchwald, Cheney, Peterson D, Komaroff, Gallo et al; Ann Int Med: 1992:116:103-113).




As with any chronic inflammatory condition affecting the central nervous system, the T2-bright foci on MRI in (ME)CFS may represent a perivascular cellular infiltrate and/or reactive demyelination of the surrounding white matter. Alternatively, these abnormalities may reflect the results of a vasculopathy specifically involving the small vessels of the cerebral white matter. Specifically, on the basis of our observations, the white matter abnormalities seen on MRI images may represent foci of gliosis or chronic demyelination, which appear to be irreversible” (Schwartz RE et al; Am J Roentgenology:1994:162:935-941).




It is now evident that this illness is not simply an imaginary one, nor the result of anxiously amplifying normal bodily sensations. Substantial objective evidence of abnormalities in the central nervous system is now available. Magnetic resonance imaging has revealed punctate areas of high signal in the white matter more often in patients with (ME)CFS than in healthy controls. They may represent areas of inflammation or demyelination” (Komaroff AL (JAMA:1997:278:14:1179-1184).




These findings are consistent with an activated inflammatory response. Shockingly, the mean QOL (quality of life) scores as regards limitations on physical functioning were very, very low, similar to those found in people with AIDS and multiple sclerosis” (Advances in biomedical understanding of ME. Neil Abbot. Vance Spence. InterAction May 2004).




(ME)CFS is a poorly defined medical condition which involves inflammatory and immune activation. The Type I interferon antiviral pathway has been repeatedly shown to be activated in the most afflicted patients. An abnormal truncated form of ribonuclease L (37-kDa RNase L) is also found in (ME)CFS patients and this protein has been proposed as a biological marker for (ME)CFS. The levels of this abnormal protein have been significantly correlated to the extent of inflammatory symptoms displayed by (ME)CFS patients. (Our) results suggest that chronic inflammation due to excess nitric oxide plays a role in (ME)CFS and that the normal resolution of the inflammatory process is impaired (M Fremont, K De Meirleir et al. JCFS 2006:13(4):17-28).




Our expanded understanding of the genomics of (ME)CFS has reinforced the evidence that the illness is rooted in a biologic pathogenesis that involves cellular dysfunction and interactions between the physiologic stress response and inflammation. These patients displayed increased anti-inflammatory cytokines” (Klimas NG et al; Curr Rheumatol Rep 2007:9:6:482-487).




In a personal communication, Nancy Klimas, Professor of Medicine at the University of Miami, world-renowned immunologist and expert on ME/CFS, said that 80% of all ME/CFS patients (both severely and not so severely ill) do have evidence of inflammation if the correct scans are employed, and she believes that 100% of ME/CFS patients actually have inflammation.



On 17th December 2008 Emory University School of Medicine issued a press release by Kathi Baker: “A new study conducted by researchers from Emory University and the Centres for Disease Control and Prevention (CDC) shows that individuals with (ME)CFS have increased blood levels of the inflammatory chemicals known to increase risk for developing illnesses ranging from cardiovascular disease and dementia to diabetes and cancer. ‘We don’t know where the increased inflammation is coming from in patients with (ME)CFS symptoms in our study, and although depression has been associated with increased inflammation, in our study it did not account for the increased inflammation in individuals with (ME)CFS’ (explained Dr Charles L Raison). The researchers found that subjects with (ME)CFS had higher levels of CRP (c-reactive protein) than did well individuals and also had higher scores on an inflammatory factor that included both CRP and white blood cell levels”



In the study to which the above press release relates, the authors stated: “The current study examined plasma concentrations of high-sensitivity c-reactive protein (hs-CRP), white blood cell count (WBC) and a combined inflammation factor in a large (457) population-based sample. Log-transformed mean plasma concentrations of hs-CRP were increased in subjects with (ME)CFS when compared to subjects who were well” (Charles L Raison et al; Brain, Behaviour and Immunity 2009:23:3:327-337).



Professor M Maes from Belgium reviewed recent findings on inflammatory and oxidative and nitrosative stress pathways and reported: “The ‘psychosomatic’ symptoms experienced by (ME/CFS patients are caused by intracellular inflammation. Symptoms occurring in (ME)CFS have a genuine organic cause, that is activation of peripheral and central IO and NS pathways and gut-derived inflammation” (Curr Opin Psychiatry 2009:22(1):75-83).

Note on inflammation

Following an international meeting on inflammation held in Bordeaux, France, Robert Dantzer et al published a Review entitled “Identification and treatment of symptoms associated with inflammation in medically ill patients” (Psychoneuroendocrinology 2008:33:18-29). Given the documented evidence of inflammation in ME/CFS, this Review has important implications for people with the disorder. It recommends testing with a standard battery of inflammatory markers in medically ill patients. Quotations that might be relevant for people with ME/CFS include the following:

This meeting brought together clinicians and basic scientists with a common interest in understanding inflammation and associated symptoms in medically ill patients (and it) focused on: (a) predominant symptoms associated with inflammation, (b) markers of inflammation at the periphery, (c) possible markers of brain inflammation associated with low-grade peripheral inflammation in humans, (d) animal models of inflammation-associated symptoms, and (e) domains of intervention for controlling inflammation-associated symptoms”.

The diagnostic tools that are favoured by psychiatrists are clearly not the best ones. As pointed out by Joel Dimsdale (San Diego, CA), the concept of somatisation that is used for characterising symptoms in the absence of any detectable disease is of little operational value, if not misleading”.

For instance, the enduring fatigue experienced by the vast majority of breast cancer survivors could easily be labelled as somatisation disorder according to the 4th Edition of the Diagnostic and Statistical Manual of Mental Disorders”.

Making fatigue a somatisation disorder overlooks the fact that fatigue has both mental and physical components, thereby denying a possible organic aetiology to explain such fatigue”.

Furthermore, this emphasis on the lack of an organic basis favours missed diagnoses (e.g. fatigue and thyroid abnormalities, or fatigue and inflammation)”.

Inflammation is not a stable condition. In a given individual it can fluctuate rapidly according to a number of environmental factors (e.g. stressors) and internal variables (e.g. diurnal variation of cortisol)”.

Basic aspects of diagnosis of behavioural disorders remain controversial and lack solid scientific foundations”.

In order to provide consistency, all studies examining the potential impact of inflammatory pathways should include a standard set of inflammatory biomarkers (which should include) the acute phase proteins, CRP, sialic acid and haptoglobin; the inflammatory mediators, prostaglandins E2 and C3A and the innate immune cytokine IL-6 as measured by the high sensitivity (hs)-enzyme-linked immunosorbent assay (ELISA) in plasma. These biomarkers, especially hs-CRP and IL-6, have been found to reproducibly identify the presence of an activated immune response in a number of disorders. Most of these assessments can be run in certified commercial or hospital laboratories”.

Proinflammatory cytokines induce the production of several downstream inflammatory mediators, such as prostaglandins and nitric oxide. Proinflammatory cytokines and other inflammatory mediators are produced by accessory immune cells, such as macrophages and monocytes in the periphery, and microglia within the central nervous system”.

Peripheral infections can sensitise or exaggerate existing brain inflammatory processes (and) elevated cytokine levels in blood have the potential to reverberate and activate central nervous inflammatory systems”.

 The Conclusions of the Review note the intense discussion at the meeting that resulted in a series of recommendations for improving understanding of the relationship between inflammation and subjective health complaints.

These recommendations note that because inflammation-associated sickness symptoms are a major impediment to human health, research on the mechanisms and treatment of such symptom burden in physically ill patients should be strongly encouraged; that clinical tools for assessing inflammation-associated symptoms should be standardised; that there should be a minimum set of inflammatory biomarkers; that brain neuroimaging techniques should be used for revealing the brain structures that are influenced by peripheral inflammatory processes and whose ability to process information is impaired by excessive amounts of interoceptive stimuli (caused, it seems, not – as asserted by Wessely School psychiatrists -- by aberrant focusing on normal bodily sensations or by “remembered illness” but by inflammatory processes), and that the high presence of inflammation-associated symptoms in physically ill patients provides a background against which it is possible to test alleviating effects of therapies targeting immune-to-brain communication pathways.

Documented immune system abnormalities in ME/CFS




Eighty percent of patients demonstrate clinically significant IgE mediated allergic disease, including food and drug reactions. The data indicate that patients have a high association with hypersensitivity states. Percent positive responsiveness to allergens is consistent with the high degree of allergy observed in these patients” (George B Olsen, James F Jones et al. J All Clin Immunol 1986:78:308-314).



Irving Salit, Associate Professor of Medicine and Microbiology at the University of Toronto and Head of the Division of Infectious Diseases at Toronto General Hospital, noted: “Findings include mild immunodeficiency, slightly low complement, anti-DNA antibodies and elevated synthetase, which is an interferon-associated enzyme commonly increased in infections. This illness is of major importance because it is so prevalent and because it has such devastating consequences: afflicted patients are frequently unable to work or carry on with usual social activities. We have found that a wide variety of infections may precipitate this illness (including Coxsackie B and mycoplasma). Some patients have mild elevations of IgM or IgG (and) low levels of anti-nuclear antibody. Patients tend to tolerate medications very poorly and many have a history of drug allergies. Most patients do not improve on anti-depressants and are usually exquisitely sensitive to the side effects. It is important for the physician to understand their suffering. There are enough abnormalities of organic disease to suggest that (it) is not purely a psychological ailment” (Clin Ecol 1987/8:V:3:103-107).



US clinicians and researchers who became world leaders in ME/CFS (including Paul Cheney, Daniel Peterson and Anthony Komaroff) noted: “These studies demonstrated that a majority of patients with (ME)CFS have low numbers of NKH1+T3- lymphocytes, a population that represents the great majority of NK cells in normal individuals. (ME)CFS patients had normal numbers of NKH1+T3+ lymphocytes, a population that represents a relatively small fraction of NK cells in normal individuals. When tested for cytotoxicity against a variety of different target cells, patients with (ME)CFS consistently demonstrated low levels of killing. In humans, studies suggest a correlation between low NK activity and serious viral infections in immunocompromised hosts. We have carried out extensive phenotypic and functional characterisation of NK cells in patients with this syndrome (and have) found that the majority had abnormally low numbers of NKH1+ cells. Further characterisation of such cellular subset abnormalities and the resulting alteration in quantitative and qualitative NK cytotoxic function will hopefully improve our understanding of the immunopathogenesis of this illness” (M Caliguri et al. The Journal of Immunology 1987:139:10: 3306-3313).


Allergies are a common feature of patients with the chronic fatigue syndrome. Among the features of this syndrome is a high prevalence of allergy, an allergy that appears to be substantial” (Stephen E Straus et al: National Institutes for Allergy and Infectious Diseases. J Allergy Clin Immunol 1988:81:791-795).


We report patients (who) had a specific deficiency of IgG1 subclass. The finding of IgG1 subclass deficiency in these patients is novel, as lone deficiency of this subclass is rare and affected patients appear to have common variable hypogammaglobulinaemia. Further scrutiny of cases (of ME/CFS) may reveal a range of subtle immunological abnormalities” (Robert Read, Gavin Spickett et al. Lancet, January 30 1988:241-242).



Our investigations suggest that (ME)CFS is characterized by objective laboratory abnormalities. A more appropriate name for this syndrome would be chronic fatigue-immune dysfunction syndrome (CFIDS), since immune dysfunction appears to be the hallmark of the disease process” (Nancy Eby et al. In: Natural Killer Cells and Host Defense. Ed: Ades EW and Lopez C. 5th International Natural Killer Cell Workshop. Pub: Karger, Basel, 1989:141-145).




"Many of the immunological and physical features of ME/CFS cannot be explained by mental illness” (Stephen E Straus of the National Institutes for Allergy and Infectious Diseases, USA, “USA Today”, 13th April, 1989: reported in CFIDS Chronicle, Spring 1989, pp77-78).


(ME)CFS has been associated with abnormal T cell function. These patients have diminished phytohaemagglutinin-induced lymphocyte transformation and decreased synthesis of interleukin. We studied the display of CD3, CD5, CD2, CD4, CD8 and Leu-M3-defined antigen in peripheral blood mononuclear cells in (ME)CFS who fulfilled the (1988 Holmes et al) criteria. Patients had reduced expression of CD3. These data indicate that in (ME)CFS, some patients have T lymphocytes (CD2- and CD5- positive cells) without immunoreactive CD3” (ML Subira et al. The Journal of Infectious Disease 1989:160:1:165-166).



Disordered immunity may be central to the pathogenesis of (ME)CFS. Reduced IgG levels were common (56% of patients), with the levels of serum IgG3 and IgG1 subclasses particularly affected. The finding of significantly increased numbers of peripheral blood mononuclear cells that express Class-II histocompatibility antigens (HLA-DR) in our patients implies immunological activation of these cells. Once activated, these cells may continue to produce cytokines which may mediate the symptoms of (ME)CFS” (AR Lloyd et al. The Medical Journal of Australia 1989:151:122-124).




The subgroup of patients with immunological abnormalities may have a prolonged illness” (DO Ho-Yen JRCGP 1990:40:37-39).




In order to characterise in a comprehensive manner the status of laboratory markers associated with cellular immune function in patients with this syndrome, patients with clinically defined (ME)CFS were studied. All the subjects were found to have multiple abnormalities in these markers. The pattern of immune marker abnormalities observed was compatible with a chronic viral reactivation syndrome. A substantial difference in the distribution of lymphocyte subsets of patients with (ME)CFS was found when compared with normal controls. Lymphocyte proliferation after PHA and PWM stimulation was significantly decreased in patients (by 47% and 67% respectively) compared with normal controls. Depression of cell-mediated immunity was noted in our study population, with over 80% of patients having values below the normal mean. The present report confirms that a qualitative defect is present in these patients’ NK cells (which) might represent cellular exhaustion as a consequence of persistent viral stimulus. Results from the present study indicate that there is an elevation in activated T cells. A strikingly similar elevation in CD2+ CDw26+ cells has been reported in patients with multiple sclerosis. In summary, the results of the present study suggest that (ME)CFS is a form of acquired immunodeficiency. This deficiency of cellular immune function was present in all the subjects we studied” (Nancy G Klimas et al. Journal of Clinical Microbiology 1990:28:6:1403-1410).




(A) subnormal number of CD8 lymphocytes, a raised serum IgE level and a positive VP1 antigen are sufficiently frequent to suggest that they should become part of the routine screening of such patients. In the present ME study, patients show a 40% incidence of both clinical and laboratory evidence of atopy. It has been shown that T cell deficiency, particularly of the suppressor subset, can predispose to atopy without a genetic family history. We have undertaken extensive T cell subset measurements in normal subjects subjected to psychological stress and would point out in none of these did we see CD8 levels as low as in some 40% of our ME patients (JR Hobbs, JA Mowbray et al. Protides of Biological Fluids 1990:36:391-398).


Compared with controls, (ME)CFS patients showed an increase in CD38 and HLA-DR expression. These data point to a high probability (90%) of having active (ME)CFS if an individual has two or more of the CD8 cell subset alterations. Laboratory findings among (ME)CFS patients have shown low level autoantibodies, which may reflect an underlying autoimmune disorder. A persistent hyperimmune response of the remaining CD8 cells might lead to an outpouring of cellular products and cytokines (eg. interferon, tumour necrosis factor, interleukin-1) that are characteristically associated with myalgia, fatigue, (and) neurological signs and symptoms associated with acute viral infections. Unless the immune system is brought back into balance, this chronic activation affects the individual further and might eventually lead to other clinical illnesses (Alan L Landay et al. Lancet 1991:338:707-712).



Various abnormalities revealed by laboratory studies have been reported in adults with (ME)CFS. Those most consistently reported include depressed natural killer cell function and reduced numbers of natural killer cells; low levels of circulating immune complexes; low levels of several autoantibodies, particularly antinuclear and antithyroid antibodies; altered levels of immunoglobulins (and) abnormalities in number and function of lymphocytes” (Buchwald and Komaroff et al; Reviews of Infectious Diseases 1991:13 (Suppl 1): S12- S28).


The NK (natural killer) cell is a very critical cell in (ME)CFS because it is clearly negatively impacted. The most compelling finding was that the NK cell cytotoxicity in (ME)CFS was as low as we have ever seen it in any disease. This is very, very significant data. In (ME)CFS the actual function was very, very low --- 9% cytotoxicity: the mean for the controls was 25. In early HIV and even well into ARC (AIDS related complex, which often precedes the fully developed condition), NK cytotoxicity might be around 13 or 14 percent. (ME)CFS patients represent the lowest cytotoxicity of all populations we’ve studied” (Nancy Klimas, Professor of Medicine, University of Miami School of Medicine; Director of Immunology; Director of AIDS Research and Director of the Allergy Clinic at Miami. Presentation: Immunological Markers in (ME)CFS. The CFIDS Association Research Conference, November 1990, Charlotte, North Carolina. Reported in CFIDS Chronicle, Spring 1991; pp 47-50).


Despite the broad divergence of opinion in the medical community, there is little doubt that classic allergy and atopy are inexplicably prevalent in (ME)CFS. In a recent study, a high proportion (50%) of patients were found to be reactive to a variety of inhalant or food allergens when inoculated epicutaneously in the classic manner. Certainly patients with (ME)CFS differ immunologically from their healthy counterparts and it is this observation, more than any other today, that is evoked in support of the organic hypothesis of disease causation” (Stephen E Straus. Review of Infectious Diseases 1991:13: Suppl 1: S2-S7).


A major study looking at neurological, immunological and virological aspects in 259 (ME)CFS patients found that neurological symptoms, MRI findings and lymphocyte phenotyping studies suggest that patients “may have been experiencing a chronic, immunologically mediated inflammatory process of the central nervous system and that “ We think that this is probably a heterogeneous illness that can be triggered by different environmental factors (including stress, toxins and infectious agents), all of which can lead to immune dysfunction and the consequent reactivation of latent viruses” (D Buchwald, Paul Cheney, Daniel Peterson, Robert C Gallo, Anthony Komaroff et al. Ann Int Med 1992:116:2:103-113).


At the 1993 Los Angeles Conference on (ME)CFS, evidence was presented by Professor Nancy Klimas from the University of Miami that she and her team have been able to accurately predict 88% of (ME)CFS patients with a mathematical model of immunological parameters. This model combines levels of activated T cells and CD4 inducers of cytotoxic T cells with NK cell count and function: “In a normal population, 20% of lymphocytes are active at any given time. ‘In (ME)CFS, up to 80% of the cells are working’. These lymphocytes and cytokines are so up-regulated that they cannot be driven any harder. It is as if they have been pushed as far as they can go and the immune system is completely exhausted” (CFIDS Chronicle: Summer 1993).



Using the immunophenotypic data presented, we were able to demonstrate that almost 50% of (ME)CFS patients, especially those with severe symptoms, showed signs of CD8+ cell activation and an abnormal suppressor / cytotoxic CD8+ cell ratio. Our observations strongly suggest that a large population of (ME)CFS patients have immunologic disorders and that their symptoms could be explained by a chronic immune activation state (and) that (ME)CFS represents a type of autoimmune disease in which a chronically activated immune system reacts against the host. The 3:1 female/male ratio would not be unexpected: autoimmune syndromes are more common in women. Because of the autoreactive nature of this condition, it might also lead to other immune disorders, such as well-recognised autoimmune diseases and multiple sclerosis” (Jay A Levy et al. Contemp Issues Infec Dis 1993:10:127-146).


According to Dr Elizabeth Dowsett, former President of the ME Association, at least 13% of ME/CFS patients are indistinguishable from patients with multiple sclerosis (personal communication).


The chronic fatigue immune dysfunction syndrome (CFIDS) is a major subgroup of the chronic fatigue syndrome (CFS). We and other investigators have reported a strong association between immune dysfunction and a serological viral activation pattern among patients in this group. This finding appeared similar to that for a variety of conditions, such as chronic active hepatitis and systemic lupus erythematosus, in which a definite association between a particular HLA-DR/DQ haplotype and increased disease frequency has been reported. We thus elected to examine a cohort of patients with CFIDS, with use of HLA-DR/DQ typing. A significant association between CFIDS and the presence of HLA-DQ3 was noted. The association with HLA-DQ3 could represent an additive effect for patients who also have HLA-DR4 and/or HLA-DR5. (Our) results are intriguing. DQ3 was significantly more prevalent in patients than controls. It is possible that DR4 and DR5 are also associated with an increased risk of developing CFIDS. These findings strongly suggest that further evaluation of persons with CFIDS, including an investigation of an HLA Class I linkage dysequilibrium, are warranted. The data presented herein suggest that CFIDS, together with a variety of immune-mediated diseases, may share similar sequences of pathogenic mechanisms (and) in a subpopulation (of CFIDS), a genetic predisposition may be triggered immunologically by any number of potential stimuli, resulting in a state of chronic immune dysequilibrium. This model could easily explain findings with regard to viral infection (and) allergies” (RH Keller, N Klimas et al. Clin Inf Dis 1994:18: (Suppl 1): S154-156).


These data suggest a correlation between low levels of NK cell activity and severity of CFIDS. Compromised or absent natural immunity is associated with acute and chronic viral infections such as AIDS, CFIDS and various immunodeficiency syndromes. Stratification of patients with CFIDS into distinct groups according to the severity or duration of physical abnormalities might allow identification of laboratory abnormalities that are associated with severity. The fact that NK cell activity decreases with increased severity and duration of certain clinical variables suggests that measurement of NK cell function could be useful for stratification of patients and possibly for monitoring therapy for and / or the progression of CFIDS (EA Ojo-Amaize et al. Clin Inf Dis 1994:18: (Suppl 1):S157-159).


The immune system is a readily accessible, sensitive indicator of environmental or internal changes, and studies conducted by different groups over the past few years have provided valuable evidence for changes in immune status among individuals with (ME)CFS. To gain insight into the nosology and aetiology of (ME)CFS, we assessed patterns of soluble immune mediator expression at the protein and mRNA levels in individuals with (ME)CFS. The data presented in this report are consistent with previous evidence of immune dysregulation among patients with (ME)CFS and point to a dysregulation of TNF (tumour necrosis factor) expression as a distinctive feature of this condition. Imbalances in TNF and associated changes in levels of other cytokines may underlie many of the characteristic features of (ME)CFS. In addition, TNF- can have deleterious effects on the central nervous system(Roberto Patarca, Nancy G Klimas et al. Clin Inf Dis 1994:18: (Suppl 1):S147-153).

Tumour necrosis factor is a cytokine involved in systemic inflammation. Its primary role is in the regulation of immune cells. Increased TNF causes apoptosis, inflammation and tumorigenesis.


The up-regulated 2-5A pathway in (ME)CFS is consistent with an activated immune state and a role for persistent viral infection in the pathogenesis of (ME)CFS. The object of this study was to measure key parameters of the 2-5A synthetase/RNase-L antiviral pathway in order to evaluate possible viral involvement in (ME)CFS. The data presented suggest that 2-5A synthetase/RNase L pathway is an important biochemical indicator of the anti-viral state in (ME)CFS. Evidence that this pathway is activated in (ME)CFS was identified in this subset of severely disabled individuals as related to virological and immunologic status. This pathway phenotype could result from chronic over-stimulation due to chronic viral reactivation (RJ Suhadolnik et al. Clin Inf Dis 1994:18(Suppl 1):S96-S104).


In the study of a complex illness such as (ME)CFS, the most important aspect is case definition. Patients whose symptoms are primarily related to upper respiratory tract infections may have different precipitating agents and pathogenesis than those with predominantly gastrointestinal disturbances. It has been noted for a number of years that a history of allergies appears to be an important risk factor for (ME)CFS. In addition to a history of allergy, other factors, such as exposure to chemicals, were noted to be possible triggers. The spectrum of illnesses associated with a dysregulated immune system now must include (ME)CFS (Paul H Levine. Clin Inf Dis 1994:18(Suppl 1):S57-S60).


Abnormalities of immune function, hypothalamic and pituitary function, neurotransmitter regulation and cerebral perfusion have been found in patients with (ME/CFS). Recent research has yielded remarkable data. The symptoms of (ME)CFS have long been viewed as a neurologic pattern, as confirmed by other names such as myalgic encephalomyelitis. A link is being forged between the symptoms pattern of (ME)CFS and objective evidence of central nervous system dysfunction. The view that (ME)CFS is a primary emotional illness has been undermined by recent research” (David S Bell: Instructor in Paediatrics, Harvard Medical School: Chronic fatigue syndrome update: Findings now point to CNS involvement: Postgraduate Medicine 1994:98:6:73-81).


One rationale for the immunological approach stems from the experience accumulated with similar syndromes such as autoimmune and environmentally-triggered diseases. (ME)CFS may be associated with certain HLA Class II antigens, as are some forms of environmental disease. These observations underscore the distinction between (ME)CFS and psychiatric maladies. Viruses are frequently reactivated in association with immune system dysregulation in (ME)CFS and may contribute to symptomatology (Roberto Patarca. JCFS 1995:vol I:3/4:195-202).


An important paper from Konstantinov and Tan et al demonstrated the occurrence of autoantibodies to a conserved intracellular protein (lamin B1), which provides laboratory evidence for an autoimmune component in ME/CFS. The authors found that 52% of patients with ME/CFS develop autoantibodies to components of the nuclear envelope (NE), mainly nuclear lamins, suggesting that in addition to the other documented disturbances of the immune system, humoral autoimmunity against polypeptides of the NE is a prominent immune derangement in ME/CFS. 67% of ME/CFS patients were positive for NE reactivity compared with 10% of normal controls. Autoantibodies to NE proteins are relatively infrequent and most fall into the category of an unusual connective tissue disease characterised by brain or skin vasculitis. The authors concluded that such activationcould be the result of various triggering agents, such as infections or environmental toxins. Future work should be directed at a better understanding of the autoimmune response of (ME)CFS patients to other NE antigens (K Konstantinov et al. J Clin Invest 1996:98:8:1888-1896).


In 1996, Hilgers and Frank developed a score for severity of ME/CFS to correlate with parameters of immune activation. This was effected by a 30-point criteria score, basic laboratory programmes and immunological profiles in 505 patients. In addition, tests of the complement system, immune activation markers, hormones and viral / bacterial intracellular serology were evaluated. Seventeen significant symptoms not currently in the CDC case definition were added, these being respiratory infections, palpitations, dizziness, dyspepsia, dryness of mouth / eyes, allergies, nausea, paraesthesia, loss of hair, skin alterations, dyscoordination (sic), chest pain, personality changes, eczema, general infections, twitches and urogenital infections. A significant correlation between the criteria score and immunological parameters could be evaluated in 472 of the 505 patients. The data confirm that a reduced or unstable immune control or delayed immune reaction to persisting viruses or bacterial intracellular pathogens, possibly triggered by common infections or other environmental factors, can lead to a chronic neuroimmune activation state and autoimmune disorders (JCFS 1996:2: (4):35-47).


The level of bioactive transforming growth factor was measured in serum from patients with (ME)CFS and compared with normal controls, patients with major depression, patients with systemic lupus erythematosus and patients with multiple sclerosis. Patients with (ME)CFS had significantly higher levels of bioactive TGF than the healthy controls, patients with major depression, patients with systemic lupus erythematosus and patients with multiple sclerosis. Of greatest relevance to (ME)CFS are the effects of TGF on cells of the immune and central nervous systems. There is accumulating evidence that TGF may play a role in autoimmune and inflammatory diseases (AL Bennet, AL Komaroff et al. J Clin Virol 1997:17:2:160-166).




(ME)CFS is associated with dysregulation of both humoral and cellular immunity, including mitogen response, reactivation of viruses, abnormal cytokine production, diminished natural killer (NK) cell function, and changes in intermediary metabolites. The biochemical and immunologic data presented here identified a subgroup of individuals with (ME)CFS with an RNase L enzyme dysfunction that is more profound than previously observed (and) is consistent with the possibility that the absence of the 80-kDa and 40-kDa RNase L and presence of the LMW RNase L correlate with the severity of (ME)CFS clinical presentation” (Robert Suhadolnik, Daniel Peterson, Paul Cheney et al. Journal of Interferon and Cytokine Research 1997:17:377-385).


Professor Suhadolnik explained in lay terms the significance of this paper (reported by Patti Schmidt in CFIDS Chronicle, Summer 1997, page 17): “He has found a particular place in the immune system, the 2-5 RNase L antiviral pathway, where something is wrong. ‘The whole antiviral pathway heats up out of control’ explained Suhadolnik. ‘You’re really sick physiologically. Your body just keeps going and going like the Energiser bunny, making ATP and breaking it down. No wonder you’re tired’. He’s found a novel protein in CFIDS patients in that viral pathway. ‘In most cases, the human body is able to resist infection thanks to a cascade of biochemical events triggered by the body’s immune system. If these antiviral defence pathways are functioning correctly, the spread of the virus is prevented’. Suhadolnik believes that (ME)CFS patients’ bodies are responding to a central nervous system virus that interferes with their viral pathways’ ability to fight off infection ”.



A highly-respected paper by Vojdani and Lapp et al stressed the importance of cell apoptosis (and the pivotal role of protein kinase RNA in this) in ME/CFS: “A prominent feature of (ME)CFS is a disordered immune system. Recent evidence indicates that induction of apoptosis might be mediated in a dysregulated immune system by the up-regulation of growth inhibitory cytokines. The purpose of this study was to evaluate the apoptotic cell population, interferon- and the IFN-induced protein kinase RNA (PKR) gene transcripts in the peripheral blood lymphocytes of (ME)CFS individuals, as compared to healthy controls. One of the distinguishing manifestations of (ME)CFS is abnormal immune function, characterised by a decreased NK cell-mediated cytotoxic activity, reduced mitogenic response to lymphocytes, altered cytokine production, elevated titres of antibodies to a number of viruses, and abnormal production of interferon (IFN). The induction of apoptosis through immune defence mechanisms is an important mechanism for elimination of cancer cells as well as virus-infected cells. In the present study, the up-regulation of IFN- and the IFN-induced PRK in (ME)CFS individuals is accompanied by the induction of apoptosis. In addition, dysregulation of cell cycle progression is associated with the induction of apoptosis in (ME)CFS individuals. Quantitative analysis of apoptotic cell population in (ME)CFS individuals has shown a statistically significant increase compared to healthy controls. The population of apoptotic cells in 76% of (ME)CFS individuals was well above the apoptotic cell population in the control cells. Activation of PKR can result in induction of apoptosis. This activation of the PRK pathway could result from (a) dysregulated immune system or chronic viral infection” (A Vojdani et al. Journal of Internal Medicine 1997:242:465-478).



Previous studies from this laboratory have demonstrated a statistically significant dysregulation in several key components of the 2’ 5’A synthetase / RNase L and PKR antiviral pathways in (ME)CFS. The 2-5A synthetase I RNase L pathway is part of the antiviral defence mechanism in mammalian cells. An accumulating body of evidence suggests that (ME)CFS is associated with dysregulation of both humoral and cellular immunity, including mitogen response, reactivation of viruses, abnormal cytokine production, diminished natural killer (NK) cell function and changes in intermediary metabolites. Marked and striking differences have been observed in the molecular mass and RNase L enzyme activity of 2-5A binding proteins in extracts of PBMC from individuals with (ME)CFS compared with healthy controls. The biochemical and immunological data presented in this paper have identified a potential subgroup of individuals with (ME)CFS with an RNase L enzyme dysfunction that is more profound than previously observed in (ME)CFS, and which the authors believe is related to the severity of (ME)CFS symptoms” (Daniel L. Peterson, Paul R. Cheney, Kenny de Meirleir et al; Journal of Interferon and Cytokine Research 1997:17:377-385).


The increased expression of Class II antigens and the reduced expression of the co-stimulatory receptor CD28 lend further support to the concept of immunoactivation of T-lymphocytes in (ME)CFS and may be consistent with a viral aetiopathogenesis in the illness. We report, for the first time, increased expression of the apoptosis repressor protein bcl-2 (and) we demonstrated changes in different immunological parameters, each of which correlated with particular aspects of disease symptomatology (and) measures of disease severity (IS Hassan, WRC Weir et al. Clin Immunol & Immunopathol 1998:87:1:60-67).


The purpose of this study was to investigate the relationship between immunologic status and physical symptoms in (ME)CFS patients. The findings suggest that the degree of cellular immune activation is associated with the severity of (ME)CFS physical symptoms. Specifically, elevations in the T-helper / inducer cells, activated T-cells, activated cytotoxic / suppressor T-cells, and CD4 / CD8 ratio are associated with greater disease severity(Immunological Status Correlates with Severity of Physical Symptoms in Chronic Fatigue Syndrome Patients. S Wagner N Klimas et al Presented at the Fourth International AACFS Research & Clinical Conference on CFIDS 1998: Mass. USA. Abstract page 28).


It is of great importance to develop biomarker(s) for differentiation between viral induced (ME)CFS (without sensitivity to chemicals) versus chemically-induced (ME)CFS. Since interferon induced proteins 2-5A Synthetase and Protein Kinase RNA (PKR) have been implicated in the viral induction of (ME)CFS, the objective of this study was to utilise 205A and PKR activity for differentiation between (ME)CFS induced by either viruses or chemicals. A clear induction of 2-5A and PKR was observed when MDBK cells were exposed to HHV6, MTBE, and benzene. We conclude that 2-5A and PKR are not only biomarkers for viral induction, but biomarkers to other stressors that include (chemicals) (Vojdani A, Lapp CW. Immunopharmacol Immunotoxicol 1999:21(2):175-202).


An article from researchers at the Institute of Immunology in Moscow discussed immunity impairment as a result of neurohormonal disorders and noted that at the base of (ME)CFS lie disturbances of the central nervous system, the endocrine system and the immune system: “It was found back in 1987/8 that there is an increase in the level of HLA DR and IL-2 receptors and an increase in the ratio CD4/CD8 in patients suffering from this syndrome” (Artsimovich NG et al. Russ J Immunol 1999:4(4):343-345).


The purpose of the present study was to investigate the relationship between immunologic status and physical symptoms in (ME)CFS. (Results) revealed significant associations between a number of immunologic measures and severity of illness. Specifically, elevations of T-helper/inducer cells, activated T cells, activated cytotoxic/suppressor T cells, and CD4/CD8 ratio were associated with greater severity of several symptoms. Furthermore, reductions in T-suppressor/cytotoxic cells also appeared related to greater severity of some (ME)CFS-related physical symptoms and illness burden (SE Cruess, Nancy Klimas et al. JCFS 2000:7(1):39-52).


Blood and lymph nodes samples were obtained from patients with (ME)CFS. While a greater proportion of T lymphocytes from both lymph nodes and peripheral blood of (ME)CFS patients are immunologically naïve, the proportions of lymphocytes with a memory phenotype predominate in lymph nodes and peripheral blood of (ME)CFS patients. (ME)CFS has been proposed to be a disease of autoimmune aetiology and in this respect it is interesting to note that decreased proportions of CD45RA+T (naïve) cells are also seen in the peripheral blood of patients with autoimmune diseases (Mary Ann Fletcher, Nancy Klimas et al. JCFS 2000:7(3):65-75).


A major and detailed Review of the immunology of (ME)CFS was published by internationally-renowned immunologists Professors Robert Patarca and Nancy Klimas, together with the distinguished long-time ME/CFS research immunologist Mary Ann Fletcher. It contains 212 references. It is clear that people with (ME)CFS have two basic problems with immune function: (1) immune activation and (2) poor cellular function. These findings have a waxing and waning temporal pattern consistent with episodic immune dysfunction. The interplay of these factors can account for the perpetuation of (ME)CFS with remission / exacerbation cycles. The Review considers the evidence of immune cell phenotypic distributions; immune cell function; cytokines and other soluble immune mediators; immunoglobulins; autoantibodies; circulating immune complexes; Type I to Type II cytokine shift and the relationship between stressors, cytokines and symptoms. The data summarised indicate that (ME)CFS is associated with immune abnormalities that can account for the physiopathological symptomatology, and recommends that future research should further elucidate the cellular basis for immune dysfunction in (ME)CFS and its implications (JCFS 2000:6(3/4):69-107).


Of significant interest was the fact that, of all the cytokines evaluated, the only one to be in the final model was IL-4 (which) suggests a shift to a Type II cytokine pattern. Such a shift has been hypothesised, but until now convincing evidence was lacking” (Hanson et al; Clin Diagn Lab Immunol 2001:8(3)658-662).


There is considerable evidence already that the immune system is in a state of chronic activation in many patients with (ME)CFS” (Anthony Komaroff, Assistant Professor of Medicine, Harvard Medical School: American Medical Association Statement, Co-Cure, 17 July 2001).


The present review examines the cytokine response to acute exercise stress. The magnitude of this response bears a relationship to the intensity of effort but many environmental factors also modulate cytokine release. The main source of exercised-induced IL-6 production appears to be the exercising muscle. Cytokine concentrations are increased in (ME)CFS. Exercise-induced modulations in cytokine secretion may contribute to allergies (and) bronchospasm (Shepherd RJ. Crit Rev Immunol 2002:22(3):165-182).


A study was carried out by Belgian researchers to determine whether bronchial hyper-responsiveness (BHR) in patients with (ME)CFS is caused by immune system abnormalities. Measurements included pulmonary function testing, histamine bronchoprovocation test, immunophenotyping and ribonuclease (RNase) latent determination. There were 137 (ME)CFS participants. Seventy three of the 137 patients presented with bronchial hyper-responsiveness. The group of patients in whom BHR was present differed most significantly from the control group, with eight differences in the immunophenotype profile in the cell count analysis, and seven differences in the percentage distribution profile. We observed a significant increase in cytotoxic T-cell count and in the percentage of BHR+ patients. Immunophenotyping of our sample confirmed earlier reports on chronic immune activation in patients with (ME)CFS compared to healthy controls, (with) BHR+ patients having more evidence of immune activation” (Nijs J, De Meirleir K, McGregor N et al. Chest 2003:123(4):998-1007).


Japanese researchers focused on immunological abnormalities against neurotransmitter receptors in (ME)CFS using a sensitive radioligand assay. They examined serum autoantibodies to recombinant human muscarinic cholinergic receptor 1 (CHRM1) and other receptors in patients with (ME)CFS and the results were compared with those in patients with autoimmune disease and with healthy controls. The mean anti-CHRM1 antibody index was significantly higher in patients with (ME)CFS and with autoimmune disease than in controls. Anti-nuclear antibodies were found in 56.7% of patients with (ME)CFS. The patients with positive autoantibodies to CHRM1 had a significantly higher score of ‘feeling muscle weakness’ than negative patients among (ME)CFS patients. The authors conclude: “Autoantibodies to CHRM1 were detected in a large number of (ME)CFS patients and were related to (ME)CFS symptoms. Our findings suggest that subgroups of (ME)CFS are associated with autoimmune abnormalities of CHRM1” (Tanaka S, Kuratsune H et al. Int J Mol Med 2003:12(2):225-230).


Looking at complement activation in (ME)CFS in the light of the need to identify biological markers in (ME)CFS, US researchers used an exercise challenge to induce symptoms of (ME)CFS and to identify a marker that correlated with those symptoms. “Exercise challenge induced significant increases of the complement split product C4a at six hours after exercise only in the (ME)CFS group (Sorensen B et al. J All Clin Immunol 2003:112(2):397-403).


(ME)CFS is an increasing medical phenomenon leading to high levels of chronic morbidity. The aim of this study was to screen for changes in gene expression in the lymphocytes of (ME)CFS patients. In a small but well-characterised population of (ME)CFS patients, differential display has been used to clone and sequence genetic markers that are over-expressed in the mononuclear cells of (ME)CFS patients. Many researchers have recognised that current methods of diagnosis lead to the selection of a heterogeneous sample, and these data support that view. It is encouraging that the wide ‘spread’ of data seen in (ME)CFS patients is not seen in the control samples. The data presented here add weight to the idea that (ME)CFS is a disease characterised by over-expression of genes, some of which are known to be associated with immune system activation. Identifying the triggering events for the induction of these genes will increase our understanding of this disease. Some interesting possibilities include viral infection, neuroendocrine disturbances, and allergen exposure. A link with allergy may be particularly pertinent since approximately 80% of (ME)CFS patients are atopic. Some of the genes identified in this study may therefore be linked with the increase in allergic effects seen in (ME)CFS (R Powell, S Holgate et al. Clin Exp Allergy 2003:33:1450-1456).


In an Invited Review, Patrick Englebienne from the Department of Nuclear Medicine, Vrije University, Brussels, explained in simple terms the significance of RNase L: “RNase L (2-5-oligoadenylate-dependent ribonuclease L) is central to the innate cellular defence mechanism induced by Type I interferons during intracellular infection. In the absence of infection, the protein remains dormant. Recent evidence indicates, however, that the protein is activated in the absence of infection and may play a role in cell differentiation (and) immune activation. A de-regulation of this pathway has been documented in immune cells of (ME)CFS patients. This protein escapes the normal regulation (resulting in) a cascade of unwanted cellular events. Recent data indicate that the RNase L system role is not limited to the cell defence mechanism against intracellular infection but extends to the complete innate and adaptive immune systems, including NK and T-cell proliferation and activation, as well as to cell differentiation and proliferation. The presence of unregulated active RNase L fragments in immune cells may lead to deleterious effects which are inherent to the cellular targets of the protein (because) an unregulated destruction of rRNA and of mitochondrial RNA leads to cell apoptosis. Should the RNase L de-regulation exist in muscle cells, it would necessarily restrain normal muscular development and hence activity (and) muscular weakness is a common feature of (ME)CFS(JCFS 2003:11(2):97-109).


The exacerbation of symptoms after exercise differentiates (ME)CFS from several other fatigue-associated disorders. Research data point to an abnormal response to exercise in patients with (ME)CFS compared to healthy sedentary controls, and to an increasing amount of evidence pointing to severe intracellular immune dysregulation in (ME)CFS patients. The dysregulation of the 2-5A synthetase/RNase L pathway may be related to a channelopathy, capable of initiating both intracellular hypomagnesaemia in skeletal muscles and transient hypoglycaemia. This might explain muscle weakness and the reduction of maximal oxygen uptake, as typically seen in (ME)CFS patients. The activation of the protein kinase R enzyme, a characteristic feature in at least a subset of (ME)CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with (ME)CFS. Elevated NO is known to induce vasodilation, which may cause and enhance post-exercise hypotension” (J Nijs, K De Meirleir, N McGregor, P Englebienne et al. Med Hypotheses 2004:62(5):759-765).


Immunological aberration (in ME/CFS) may be associated with an expanding group of neuropeptides and inappropriate immunological memory. Vasoactive neuropeptides act as hormones, neurotransmitters, immune modulators and neurotrophes. They are immunogenic and known to be associated with a range of autoimmune conditions. They are widely distributed in the body, particularly in the central, autonomic and peripheral nervous systems and have been identified in the gut, adrenal gland, reproductive organs, vasculature, blood cells and other tissues. They have a vital role in maintaining vascular flow in organs and are potent immune regulators with primary anti-inflammatory activity. They have a significant role in protection of the nervous system (from) toxic assault. This paper provides a biologically plausible mechanism for the development of (ME)CFS based on loss of immunological tolerance to the vasoactive neuropeptides following infection or significant physical exercise. Such an occurrence would have predictably serious consequences resulting from the compromised function of the key roles these substances perform” (Staines DR. Med Hypotheses 2004:62(5):646-652).


Patients (with ME/CFS) are more likely to have objective abnormalities of the immune system than control subjects. We measured the frequency of certain HLA antigens (and) restricted our analysis to Class II molecules, as these appear to be more specific predictors of susceptibility to immunologically-based disorders. The frequency of the HLA-DQ1 antigen was increased in patients compared to controls. This association between (ME)CFS and the HLA-DQ1 antigen translates into a relative risk of 3.2 (RS Schacterle, Anthony L Komaroff et al. JCFS 2004:11(4):33-42).


(ME)CFS is a serious health concern (and) studies have suggested an involvement of the immune system. A Symposium was organised in October 2001 to explore the association between immune dysfunction and (ME)CFS, with special emphasis on the interactions between immune dysfunction and abnormalities noted in the neuroendocrine and autonomic nervous systems of individuals with (ME)CFS. This paper represents the consensus of the panel of experts who participated in this meeting (which was co-sponsored by the US Centres for Disease Control and the National Institutes of Health). Data suggest that persons with (ME)CFS manifest changes in immune responses that fall outside normative ranges. It has become clear that (ME)CFS cannot be understood based on single measurements of immune, endocrine, cardiovascular or autonomic nervous system dysfunction. The panel encourages a new emphasis on multidisciplinary research into (ME)CFS. The panel recommends the implementation of longitudinal studies that include the following key elements: well-characterised cases and controls; assays designed to measure immune function: (a) natural killer cell activity; (b) percentage of peripheral blood lymphocytes expressing activation markers; (c) pro-inflammatory cytokines and soluble receptors; (d) Th-1 and Th-2 responses; (e) activity of the 2-5A synthetase pathway, and (f) serum immunoglobulin levels; selected measures of autonomic nervous system and neuroendocrine functioning; functional magnetic resonance imaging studies; studies to demonstrate the presence or absence of viral/microbial genetic material. The use of interdisciplinary, multi-site (including international) longitudinal studies to explore links between the variations noted in (ME)CFS patients’ immune, neuroendocrine, and cardiovascular systems is critical. Three primary methodological barriers impair the investigations of (ME)CFS: poor study design, the heterogeneity of the CFS population, and the lack of standardised laboratory procedures. The quality of previous CFS research (is hampered by) multiple differences in methods of subject recruitment and classification (and) clinical definitions applied and outcome measures used. It is our obligation to overcome the methodological barriers outlined above(Gerrity TR et al. Neuroimmunomodulation 2004:11(6):351-357).


Many patients with (ME)CFS have symptoms that are consistent with an underlying viral or toxic illness. Because increased neutrophil apoptosis occurs in patients with infection, this study examined whether this phenomenon also occurs in patients with (ME)CFS. Patients with (ME)CFS had higher numbers of apoptotic neutrophils, lower numbers of viable neutrophils, and increased expression of the death receptor, tumour necrosis factor receptor-1 on their neutrophils than did healthy controls. These findings provide new evidence that patients with (ME)CFS have an underlying detectable abnormality in their immune cells(Kennedy G et al. J Clin Pathol 2004:57(8):891-893).

Commenting on this paper, Dr Neil Abbot, Director of Operations at ME Research UK, noted: “The new paper by Dr Gwen Kennedy (MERGE Research Fellow) and colleagues reports evidence of increased neutrophil apoptosis (programmed cell death) in ME/CFS patients. Neutrophils represent 50-60% of the total circulating white blood cells and are fundamental to the functioning of an intact immune system. The data presented in this report are consistent with the presence of an underlying, detectable abnormality in immune cell behaviour of many ME/CFS patients, consistent with an activated inflammatory process, or a toxic state(Co-Cure RES MED 30th July 2004).


Arguments exist as to the cause of (ME)CFS. Some think that it is an example of symptom amplification indicative of psychogenic illness, while our group thinks that some (ME)CFS patients may have brain dysfunction. We did spinal taps (lumbar puncture) on (ME)CFS patients. We found that significantly more (ME)CFS patients had elevations either in protein levels or numbers of cells than healthy controls and (some) patients had protein levels and cell numbers that were higher than laboratory norms. In addition, of the 11 cytokines detectable in spinal fluid, (some) were lower in patients than in controls (and some) were higher in patients. The results support two hypotheses: that some (ME)CFS patients have a neurological abnormality and that 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 (ME)CFS provides additional evidence for this hypothesis” (Benjamin H Natelson et al. Clin Diagn Lab Immunol 2005:12(1):52-55).


An article in The Scientist pointed out the need to measure cytokines in diverse disorders: “The immune system is often likened to the military. The body’s army has weapons such as antibodies and complement, and soldiers such as macrophages and natural killer cells. The immune system sports an impressive communications infrastructure in the form of intracellular protein messengers called cytokines and the cellular receptors that recognise them. The cytokine family consists of such soluble growth factors as the interleukins, interferons, and tumour necrosis factor, among others. Their measurement has become an integral part of both clinical diagnostics and biomedical research (JP Roberts. The Scientist 2005:19:3:30).

It needs to be noted that the NICE Clinical Guideline 53 proscribes such measurements in people with ME/CFS, as did the MRC’s “CFS/ME Research Advisory Group Research Strategy” Report of 1st May 2003, as did the CMO’s Report of 2002, and as did the Joint Royal Colleges Report (CR54) of 1996.




Hyperactivation of an unwanted cellular cascade by the immune-related protein RNase L has been linked to reduced exercise capacity in persons with (ME)CFS. This investigation compares exercise capabilities of (ME)CFS patients with deregulation of the RNase L pathway and CFS patients with normal regulation. The results implicate abnormal immune activity in the pathology of exercise intolerance in (ME)CFS and are consistent with a channelopathy involving oxidative stress and nitric-oxide toxicity(Snell CR et al. In Vivo 2005:19(2):387-390).




Diminished NK cell cytotoxicity is a frequently reported finding (in ME/CFS). However, the molecular basis of this defect has not been described. Perforin is a protein found within intracellular granules of NK and cytotoxic T cells. Quantitative fluorescence flow cytometry was used to the intracellular perforin content in (ME)CFS subjects and healthy controls. A significant reduction in the NK cell associated perforin levels in samples from (ME)CFS patients compared to healthy controls was observed. There was also an indication of a reduced perforin level within the cytotoxic T cells of (ME)CFS subjects, providing the first evidence (of) a T cell associated cytotoxic deficit in (ME)CFS. Because perforin is important in immune surveillance and homeostatis of the immune system, its deficiency may prove to be an important factor in the pathogenesis of (ME)CFS and its analysis may prove useful as a biomarker in the study of (ME)CFS” (Maher KJ, Klimas NG, Fletcher MA. Clin Exp Immunol 2005:142(3):505-511).



Previous research has shown that patients with (ME)CFS present with an abnormal exercise response and exacerbations of symptoms after physical activity. The highly heterogeneous nature of the CFS population and the lack of uniformity in both diagnostic criteria and exercise testing protocols preclude pooling of data. Still, we conclude that at least a subgroup of CFS patients present with an abnormal response to exercise. Importantly, the exacerbation of symptoms after exercise is seen only in the (ME)CFS population and not in fatigue-associated disorders such as depression. Earlier (studies) revealed that in (ME)CFS patients, irrational fear of movement is not related to exercise performance. The aim of this study was to examine the interactions between several intracellular immune variables and exercise performance in (ME)CFS. These data add to the body of literature showing impairment of intracellular immunity in patients with (ME)CFS. The results provide evidence for an association between intracellular immune dysregulation and exercise performance in patients with (ME)CFS” (J Nijs, N McGregor, K De Meirleir et al. Medicine & Science in Sports & Exercise 2005:Exercise Immunology in CFS:1647-1654).



The hypothesis of the present study is that the appearance of cell-specific autoimmune antibodies may define subsets of (ME)CFS. (ME)CFS is clinically similar to several autoimmune disorders that can be diagnosed and characterised by autoantibody profiles. For this reason, we conducted an exhaustive evaluation of 11 ubiquitous nuclear and cellular autoantigens in addition to two neuronal specific antigens. Very few studies have evaluated the presence of autoantibodies in people with (ME)CFS. The findings of this study hint that evaluation of certain autoantibodies may give clues to on-going pathology in subsets of (ME)CFS subjects. Among (ME)CFS subjects, those who had been sick longer had higher rates of autoantibodies(S Vernon et al. Journal of Autoimmune Diseases May 25th, 2005:2:5).


The diagnostic criteria of CFS define a heterogeneous population composed of several subgroups. This study was designed to examine NK cell activity as a potential subgroup biomarker. The results (provide) evidence in support of using NK cell activity as an immunological subgroup marker in (ME)CFS. Improved treatment options will only come with better understanding of the syndrome’s underlying pathophysiology. The present study specifically investigated the existence of an immunological subgroup of CFS patients. Reduced NK cell activity may contribute to enhanced cytokine production. Given the role that NK cells play in targeting virally infected cells, a clinically significant reduction in NK cell activity may lead to activation of latent viruses and new viral infections. (ME)CFS is a misunderstood condition. Research in the last two decades has produced little advancement in the understanding of the pathophysiology of (ME)CFS. Unfortunately, this lack of progress seems to have further contributed to the belief among some members of the medical community that (ME)CFS is not an actual organic condition (Scott D Siegel, Mary Ann Fletcher, Nancy Klimas et al. J Psychosom Res 2006:60:6:559-566).



(ME)CFS is a poorly defined medical condition which involves inflammatory and immune activation. The Type I interferon antiviral pathway has been repeatedly shown to be activated in the most afflicted patients. An abnormal truncated form of ribonuclease L (37-kDa RNase L) is also found in (ME)CFS patients and this protein has been proposed as a biological marker for (ME)CFS (M Fremont, K De Meirleir et al. JCFS 2006:13(4):17-28).



For decades, (ME)CFS patients were – and still are – dismissed as lazybones or hypochondriacs. Many medical doctors and insurance companies still assert that (ME)CFS is a mental condition. The mainstream treatment for (ME)CFS is CBT, which means that patients with (ME)CFS are being treated as having a mental illness with ‘treatments’ that do not treat any underlying cause. Doctors who treat (ME)CFS patients as suffering from an organic disorder and scientists who examine the biological causes of (ME) are often considered quacks by their colleagues (and) insurance companies, which are sometimes even officially supported by governments in their attempts to eliminate the scientific view that (ME)CFS is an organic disorder. The official acceptance of the latter obviously would mean that the national health care systems are obliged to financially support those patients who are now considered hypochondriacs and, therefore, may easily be suspended from the national health care systems. There is, however, evidence that (ME)CFS is a severe immune disorder with inflammatory reactions and increased oxidative stress. Maes et al show that patients with (ME)CFS show very high levels of nuclear factor kappa beta in their immune cells. NFk is the major mechanism which regulates inflammation and oxidative stress. Thus, the increased production of NFk in the white blood cells of patients with (ME)CFS is the cause of the inflammation and oxidative stress (seen) in (ME)CFS” (Maes et al. Neuroendocrinology Letters, 2007).


Recent research has evaluated genetic signatures, described biologic subgroups, and suggested potential targeted treatments. Acute viral infection studies found that initial infection severity was the single best predictor of persistent fatigue. Studies of immune dysfunction (have) extended observations of natural killer cytotoxic cell dysfunction of the cytotoxic T cell through quantitative evaluation of intracellular perforins and granzymes. Other research has focused on a subgroup of patients with reactivated viral infection. Our expanded understanding of the genomics of (ME)CFS has reinforced the evidence that the illness is rooted in a biologic pathogenesis that involves cellular dysfunction and interactions between the physiologic stress response and inflammation. A large body of evidence links (ME)CFS to a persistent viral infection. (ME)CFS patients exhibited a distinct immune profile compared with fatigued and non-fatigued individuals. These patients displayed increased anti-inflammatory cytokines. Investigators noted the tropism with brain and muscle and suggested that the neuroinflammation seen in neuroimaging studies of a subgroup of CFS patients may result from enteroviral infection. The clinical implications are consistent with an immune system that may allow viral reactivation and raises a concern for tumour surveillance as well. The preponderance of available research confirms that immune dysregulation is a primary characteristic of (ME)CFS. These advances should result in targeted therapies that impact immune function, hypothalamic-pituitary-adrenal axis regulation, and persistent viral reactivation” (Nancy G Klimas et al. Current Rheumatology Reports 2007:9:6:482-487).


In “Contemporary Challenges in Autoimmunity”, the Annals of the New York Academy of Sciences published several articles looking at autoimmunity in (ME)CFS. One such paper by Ortego-Hernandez et al states: “In association with (ME)CFS physiopathology, immune imbalance, abnormal cytokine profile or cytokine genes, and decreased serum concentrations of complement components have been reported…Many studies have shown the presence of several autoantibodies in (ME)CFS patients. Antibodies to diverse cell nuclear components, phospholipids, neuronal components, neurotransmitters, as well as antibodies against some neurotransmitter receptors of the central nervous system have been described”. The authors consider the different types of antibodies that have been reported in (ME)CFS patients and consider in particular antibodies to nuclear components (52% of (ME)CFS patients are reported as having autoantibodies to components of the nuclear envelope, particularly to lamin B1 molecule); to neurotransmitters and receptors (especially to neurotransmitters such as serotonin (5H-T), adrenals, ACTH and to receptors such as muscarinic cholinergic receptor I and -opioid receptor 1), and to diverse microorganisms, noting that serum levels of IgA were significantly correlated to the severity of illness. The authors state that the results showed that enterobacteria might be involved in the aetiology of (ME)CFS and that an increased gut-intestinal permeability could cause dysregulation of the immune response to the LPS of gram-negative enterobacteria. The authors note that for many years, enterovirus infection has been associated with (ME)CFS and they note: “However, several negative studies, combined with the rise of the psychiatric ‘biopsychosocial model’ of (ME)CFS have led to a diminished interest in this area (Ann N Y Acad Sci 2009:1173:600-6009).


(For the avoidance of doubt, in the above paper the authors cite only two “negative studies” associated with enteroviral infection in (ME)CFS: the first by Lindh G et al [Scand J Infect Dis 1996:28:305-307] used the 1994 CDC criteria which do not exclude those with psychiatric disorder, and the second by McArdle A et al [Clin Sci 1996 90:295-300] was co-authored by Richard Edwards, known for his belief that “many of the symptoms of these patients could be a consequence of their reduced habitual activities” [Ergonomics 1988:31:11:1519-1527] and his objection to the publishing by the ME Association of “substantial amounts of information on the ‘disease’ “).

Documented hair loss in ME/CFS



Hair loss is listed as a feature of ME/CFS, known as CFIDS in some quarters in the US (Chronic Fatigue and Immune Dysfunction Syndrome: A Patient Guide. CFIDS Association, North Carolina Newsletter 1989).




Hair loss is listed in 20% of ME/CFS patients (The Disease of a Thousand Names. DS Bell. Pollard Publications, New York 1991).


It is a rare woman with Chronic Fatigue Syndrome who has not had hair loss” (Jay Goldstein. In: The Clinical and Scientific Basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Ed: Byron M Hyde, Jay Goldstein, Paul Levine. The Nightingale Research Foundation, Ottawa, Canada 1992 pp 247-252).


Hair loss is again listed as a symptom of ME/CFS (CFIDS Association of America Leaflet 1993).


The authors developed a score for severity of (ME)CFS that correlated with parameters of immune activation and association with pathogens; they found that comparison of patients with healthy controls led to a 30-criteria score that included 17 further significant criteria in addition to the CDC (Fukuda 1994) criteria. Those further 17 criteria included loss of hair (Hilgers A, Frank J. Journal of Chronic Fatigue Syndrome 1996:2:4:35-47).



His sleep pattern changed…and his hair and eye lashes began to fall” (John Richardson. Journal of Chronic Fatigue Syndrome 2001:9: (3-4):15-19).

Documented abnormalities in the gastro-intestinal system


(see also Section 1 above: Attempts to reclassify irritable bowel syndrome as a mental disorder).



Hyman and Wasser found evidence that abdominal pain is due to unilateral segmental neuropathy and consider their findings to be of pathophysiological significance, since lymphocytes and other immune products are in intimate contact with the gut wall and would have an influence on both gut motility and luminal contents. The authors conclude that the classification of irritable bowel syndrome should be modified to include a subset of patients who have a combination of CFS and IBS (Gastrointestinal Manifestations of Chronic Fatigue Syndrome: JCFS 1998:4(1):43-52).


Aaron et al noted a growing literature suggesting that IBS and CFS may commonly co-exist, and that lifetime rates of IBS were particularly striking in patients with CFS (92%) compared with controls (18%) (Arch Intern Med 2000:160(2):221-227).


Skowera and Wessely et al demonstrated a high prevalence of serum markers of coeliac disease in patients with chronic fatigue syndrome and suggested: “screening for coeliac disease should be added to the relatively short list of mandatory investigations in suspected cases of CFS” (Journal of Clinical Pathology 2001:54:335-336).


Gastrointestinal symptoms are common in patients with (ME)CFS…GI symptoms in patients with (ME)CFS are associated with objective changes of upper GI motility….Abdominal pain is distressing, often requiring analgesia for relief. A previously unrecorded symptom in (ME)CFS patients is nocturnal diarrhoea, which disrupts an already disturbed sleep pattern. These observations indicate that there is measurable disturbance in upper gut motility corresponding with symptoms (and) the more prominent delay in liquid rather than solid emptying may point to a central rather than peripheral aetiology” (RB Burnett et al. BMC Gastroenterology 2004:4:32).

Because ME/CFS is a multi-system disorder, there are many references to gut dysfunction and symptomatology in ME/CFS patients documented throughout the ME/CFS literature.

Documented liver and spleen problems in ME/CFS



Hepatic enlargement was also noted….” (ED Acheson. Am J Med April 1959:569-595).




Physical findings may include…hepatitis” (AM Ramsay, EG Dowsett et al. BMJ 21st May 1977: 1350).




In many of these patients, the fatigue was associated with….splenomegaly or hepatomegaly…….palpable splenomegaly (was found in) 87% (and) palpable hepatomegaly (in) 20%…In addition to their severe and persistent fatigue, case-patients were significantly more likely to have had palpable splenomegaly noted in their medical records” (Gary P Holmes et al. JAMA 1st May 1987:257:17:2297-2302).




22% had mildly deranged liver function tests” (BD Calder et al. JRCGP 1987:37:11-14).




There may be splenomegaly or hepatomegaly” (M. Fisher Portwood. Nurse Practitioner 1988:13:2:11-23).




Enlargement of the spleen and liver is also not unusual” (SA Daugherty, BE Henry, DL Peterson et al. Reviews of Infectious Diseases 1991:13 (Suppl 1):S39-44).




Up to 20% of (ME)CFS patients were noted to have hepatomegaly and splenomegaly (Anthony L Komaroff. CFS: CIBA Foundation Symposium 173: John Wiley, Chichester, 1993:43-61).




A significant number of patients with ME have exactly the same liver abnormality…that is seen in Gilbert’s syndrome” (Charles Shepherd, Perspectives, Medical Matters: September 1993: iv).



CFIDS patients have been reported to have multiple (physical) findings (including) hepatomegaly” (CM Jorge, PJ Goodnick. Psychiatric Annals 1997:27:5:365-366).




Hepatitis was found in 13.6%” (Fred Friedberg et al. J psychsom Res 2000:48:59-68).




Animals subjected to both chemicals and stress exhibited dramatic increase in blood brain barrier permeability. Histological changes were also present in the liver and were particularly severe when the combination was used” (MB Abou-Donia. Presented at The Alison Hunter Memorial Foundation Third International Clinical and Scientific Conference on ME, 1st-2nd December 2001, Sydney, Australia).

Documented respiratory abnormalities in ME/CFS



Payne and Sloan noted exertional dyspnoea in ME/CFS, with lung function studies showing a reduced forced expiratory flow (70% of the predicted value) and abnormalities of small airways and gas transport that might lead to reduced exercise tolerance shown in these patients (Ann Intern Med 1989:111:10:860).


De Lorenzo et al noted that compared with controls, patients with ME/CFS showed a significant reduction in all lung function parameters tested (Australia and New Zealand Journal of Medicine 1996:26:4:563-564).



De Becker et al reported on the prevalence of respiratory symptoms in a cohort of ME/CFS subjects; patients showed a significant decrease in VC (vital capacity), possibly due to a significant increase of RV (residual volume) and the authors commented: “These observations can, at least partially, explain the respiratory symptoms in these patients”. The researchers recorded cough, medical history of allergy, chest tightness, and a remarkably high incidence of bronchial hyper-responsiveness, but the major complaint was pronounced exercise-induced dyspnoea (Fourth International AACFS Research & Clinical Conference on ME/CFS, Massachusetts, October 1998).




Farquhar et al studied blood volume in relation to peak oxygen consumption and physical activity: “….hypovolaemia, through its interaction with central haemodynamics, would contribute to the exercise intolerance associated with this disorder. We examined blood volume, peak aerobic power, habitual physical activity, fatigue level and their inter-relations to understand the physiological basis of this disorder. Patients displayed a trend for a 9% lower blood volume and had a 35% lower peak oxygen consumption. Peak ventilation was significantly lower in the patients. In conclusion, individuals with CFS have a significantly lower peak oxygen consumption compared with controls, indicating that blood volume is a strong physiological correlate of peak oxygen consumption in patients with CFS” (Am J Physiol Heart Circ Physiol 2002:282(1):H66-H71).



Ravindran, Petrie and Baraniuk observed that CFS subjects complain of shortness of breath; they therefore assessed dyspnoea associated with five activities of daily living. The sum was the Dyspnoea Score, which was compared between CFS patients and healthy controls. The MVV% (maximum voluntary ventilation, which is the total volume of air exhaled during 12 seconds of rapid deep breathing) was significantly higher for CFS patients than controls, indicating that CFS subjects might exert considerable respiratory effort. The CFS group also reported higher chest discomfort intensity after the first spirometry series and they also complained of greater difficulty tolerating the MVV manoeuvre. Borg scores (a measure of breathlessness in relation to heart rate – see Section 4 below) were higher for CFS patients than controls after both the first and second sets of spirometry (Journal of Allergy and Clinical Immunology February 2009: S260: Abstracts).

Documented abnormal gene expression in ME/CFS


There are more abnormal genes in ME/CFS than there are in cancer (personal communication from a research scientist).

There can no longer be any doubt from both US and UK research that in ME/CFS there are proven abnormalities in numerous genes and that such abnormalities are acquired as a result of interactions with the environment as opposed to being hereditary.

Gene expression describes the behaviour of certain genes when attacked by an infection or other insult: some genes become over-active and produce chemicals that cause symptoms seen in ME/CFS, while other genes become under-active or shut down (The Chronic Fatigue Syndrome Research Foundation Newsletter 10, November 2004).

In the UK, Jonathan Kerr from London has been leading the CFS Research Foundation’s work in this area: using micro arrays and Taqman PCR techniques, his team has found numerous genes to be abnormal and these genes showed problems in various body systems including the immune system, in neurological function and in mitochondrial metabolism (ie. in the production of cellular energy). As the CFSRF Newsletter of November 2004 made plain: “It is clear that in ME/CFS patients the gene function has changed and these changes can be detected and measured”.

In the US Suzanne Vernon and her team showed that differentially expressed genes are related to energy metabolism, muscle and immune response (T-cell associated chemokines and receptors) and that several of these genes are involved in transcriptional regulation, metabolism and the immune response; Vernon et al have put forward mechanisms possibly associated with exacerbation of symptoms in ME/CFS and with differences in how patients cope with stress compared with controls (Co-Cure 14th March 2005).

The key question associated with genetic abnormalities is whether or not the detected abnormalities are associated with changes in the function of the gene that would lead to changes in the gene product(s), so it is the functional changes that are critical to understanding the relevance of these observations. It is necessary to understand how the biochemical changes relate to the gene changes because it is the genetic changes that drive the biochemical processes associated with the gene product(s) --- in other words, the observed biochemical abnormalities are a reflection of gene abnormalities.

The work of US immunologist Roberto Patarca-Montero illustrates how changes in just one single gene can have wide-ranging consequences: he has identified an abnormal gene in ME/CFS patients that is multi-factorial, affecting the immune response to infection and the regulation of calcium and phosphate in bone metabolism and the expression of autoimmune disease, showing that acquired changes in a single gene can result in a compromised response to infection, to disordered calcium and phosphate metabolism and to increased susceptibility to autoimmune disease (Chronic Fatigue Syndrome, Genes, and Infection: the Eta-1 /Op Paradigm. Roberto Patarca-Montero, Howarth Medical Press, 2003).

Patarca-Montero’s gene studies also reveal consequences within the cardiovascular system in respect of the response to injury of the normal artery wall: endothelial cell migration is stimulated through a co-operative mechanism with other gene products, and these gene products affect vascular permeability, compromising the cardiovascular system and the nerves and tissues it supplies, with potential implications for the ability to exercise without biological consequences that are damaging.

On 18th March 2008 The Daily Telegraph carried an item entitled “ME: ‘Invisible disease’ is now easier to read” by Bob Ward, who reported on Kerr’s work (published in the Journal of Clinical Pathology and presented at an ME Research UK [MERUK] biomedical conference at the University of Cambridge on 6th May 2008). The article pointed out that Kerr’s team has identified 88 genes that produce different levels of proteins and other molecules in ME/CFS compared with controls.  In 2005 Kerr had carried out a complex analysis and found that patients with ME/CFS can be divided into seven clinical sub-types according to specific gene combinations and the severity of symptoms.  The most severely affected patients had 71 of the 88 gene abnormalities.  In his follow-up paper to which the Telegraph article referred, Kerr’s earlier work was confirmed: (J Clin Pathol 2007: doi:10.1136/jcp.2007.053553) – see below.

There is now a substantial evidence-base demonstrating abnormal gene expression in ME/CFS patients and the following examples are barely illustrative:


The objective of this study was to determine if gene expression profiles of peripheral blood mononuclear cells (PBMC) could distinguish between subjects with CFS and healthy controls…..The classification algorithms grouped the majority of CFS cases together, and distinguished them from healthy controls…These results successfully demonstrate the utility of the blood for gene expression profiling to distinguish subjects with CFS from healthy controls (and) for identifying biomarkers…It is noteworthy that one gene, the CMRF35 antigen precursor, was detected as differentially expressed by all analytical approaches. This gene encodes a cell membrane antigen that is a member of the immunoglobulin superfamily (and) is thought to control interactions between T cells and antigen presenting cells or target (virus-infected or mutated) cells that have to be killed…The CMRF35 antigen was highly expressed in the CFS group…All of these genes implicate immune dysfunction in the pathophysiology of CFS (Suzanne D Vernon et al. Disease Markers 2002:193-199).



We used differential-display PCR of PMBCs to search for candidate biomarkers for CFS….86% of the differences were present at baseline. Differential expression of ten genes was verified by real-time reverse transcription PCR: five (including perforin) were downregulated and the remaining five genes were upregulated…Many of these genes have known functions in defence and immunity, thus supporting prior suggestions of immune dysregulation in the pathogenesis of CFS…Differential-display PCR is a powerful tool for identification of candidate biomarkers…Six of the ten genes with verified differential expression have functions related to immune response. This adds strength to the theory that dysregulation of immunity plays a major role in the biology of CFS(Martin Steinau et al. Journal of Molecular Medicine 2004: 10.1007/s00109-004-0586-4).


To test the hypothesis that there are reproducible abnormalities of gene expression in (ME)CFS patients compared with healthy controls, Jonathan Kerr’s team analysed and compared gene expression in peripheral blood mononuclear cells of ME/CFS patients with matched blood-donor controls. Sixteen genes were significantly different and were confirmed as having an expression profile associated with ME/CFS. “These genes may be important in the pathogenesis of (ME)CFS and can be grouped according to immune, neuronal, mitochondrial and other functions…These findings are consistent with previous work showing that patients with (ME)CFS have evidence of immune activation, such as increased numbers of activated T cells and cytotoxic cells, and raised circulating cytokine concentrations…NTE (neuropathy target esterase) is a target for organophosphates and chemical warfare agents, both of which may precipitate (ME)CFS…. EIF2B4 is a mitochondrial translation initiation factor and one of the EIFB2 family, within which mutations have been shown to be associated with central nervous system hypomyelination and encephalopathy…. 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 (N Kaushik, ST Holgate, JR Kerr et al. J Clin Pathol 2005:58:826-832).

(Neuropathy target esterase (NTE) is inhibited by several OP pesticides, chemical warfare agents, lubricants, and plasticisers, leading to OP-induced delayed neuropathy in humans, with over 30,000 cases of human paralysis -- Gary Quistad et al. PNAS June 24, 2003:100:13:7983-7987).



The single most influential gene was sestin 1 (SESN1), supporting recent evidence of oxidative stress involvement in (ME)CFS…results suggest a common link between oxidative stress, immune system dysfunction and potassium imbalance in (ME)CFS leading to impaired sympatho-vagal balance strongly reflected in an abnormal HRV (heart rate variability) (Gordon Broderick, Nancy Klimas et al. Pharmacogenomics 2006:7(3):407-419).


In a study of cytokine genomic polymorphisms in (ME)CFS, Italian researchers found “a highly significant increase in TNF-857 and CT genotypes among patients with respect to controls and a significant decrease of IFN gamma low producers among patients with respect to controls…We hypothesise that (ME)CFS patients can have a genetic predisposition to an immunomodulatory response of an inflammatory nature probably secondary to one or more environmental insults” (N Carlo-Stella et al. Clin Exp Rhuematol 2006:24(2):179-182).


Kerr et al reported in detail the genomic and phenotypic differences in 7 genomically-defined subtypes of CFS: “In this study, for each CFS/ME subtype, we determined those genes whose expression differed significantly from that of normal blood donors.  Genomic analysis was then related to clinical data for each CFS/ME subtype. Genomic analysis revealed some common (neurological, haematological, cancer) and some distinct (metabolic, endocrine, cardiovascular, immunological, inflammatory) disease associations among the subtypes. Subtypes 1,2 and 7 were the most severe, and subtype 3 was the mildest…It is particularly interesting that in these genomically derived subtypes, there were distinct clinical syndromes… as would be expected in a disease with a biological basisIt has long been recognised that subtypes of CFS/ME exist (but Professor Anthony Pinching, Chairman of the Investment Steering Group that devised the process and criteria for setting up the CFS Clinics and who oversaw the assessment of bids and who allocated funds -- and who is lead advisor on “CFS/ME” to the Department of Health -- is on record in the CMO’s Working Group 2002 Report (Annex 4: section 3) as asserting that subgrouping “may be considered a matter of semantics and personal philosophy”)…It is intriguing that within our 88 gene signature, there are several genes with links to various aetiological triggering factors. For example, virus infection (EIF4G1, EB12) and organophosphate exposure (NTE). EIF4G1 is an eukaryotic translation initiation factor which is bound and cleaved by a range of viruses, including enteroviruses which both trigger and persistently infect CFS patients….We have previously documented upregulation of NTE in (ME)CFS. NTE is the primary site of action of organophosphate (OP) compounds….Exposure to OP compounds may trigger CFS/ME and Gulf War illness(Jonathan Kerr et al. J Clin Pathol 2007: doi:10.1136/jcp.2007.053553).

Commenting on this paper, Dr Neil Abbot, Director of Operations at the charity ME Research UK, said:

These genes can be subdivided into categories by diseases and disorders or by molecular and cellular functions. The research team says that three of the genes identified are directly linked with mitochondrial function, and a further ten have indirect links with mitochondrial metabolism…

Important disorders and functions associated with some of the genes in the putative ME/CFS gene ‘signature’ (include):

Diseases: Haematological (22 genes); Immunological (14 genes); Cancer (31 genes); Dermatological (3 genes); Endocrine system (9 genes)

Molecular and cellular function: Cellular development (26 genes): Cell death (33 genes); gene expression (31 genes); Cellular growth and proliferation (31 genes); Cellular assembly and organisation (15 genes)

Physiological system development and function: Haematological system (22 genes); Nervous, immune and lymphatic system (18 genes); Tissue morphology (18 genes); Survival (17 genes); Immunity (20 genes)” (Breakthrough, Spring 2008:3).


We have reported the differential expression of 88 human genes in patients with CFS; 85 of these genes were upregulated and 3 downregulated. Highly represented functions were haematological disease and function, immunological disease and function, cancer, cell death, immune response and infection…Research studies have identified various features relevant to the pathogenesis of CFS/ME such as viral infection, immune abnormalities and immune activation, exposure to toxins, chemicals and pesticides….Various studies have analysed the gene expression in peripheral blood of patients with CFS/ME and in all of these, genes of immunity and defence are prominent….Progress is being made towards an understanding of the pathogenesis of this intriguing and devastating disease” (Jonathan Kerr. Current Rheumatology Reports 2008:10:482-491).



“…expression of several complement genes remained at higher level in CFS subjects before and post-exercise, indicating a lack of acute phase transcriptional response by these genes which may lead to localised and uncontrollable inflammation mediated tissue damage (Sorensen B et al. Mol Med 2008: Nov 16: Epub ahead of print).




We used global transcriptome analysis to identify genes that were differentially expressed in the vastus lateralis muscle of female and male CFS patients. We found that the expression of genes that play key roles in mitochondrial function and oxidative imbalance…were altered, as were genes involved in energy production, muscular trophism and fibre phenotype determination. Importantly, the expression of a gene encoding a component of the nicotinic cholinergic receptor binding site was reduced, suggesting impaired neuromuscular transmission. We argue that these major biological processes could be involved in and/or responsible for the muscle symptoms of CFS (Pietrangelo T, Fulle S et al. Int J Immunpathol Pharmacol 2009:22(3)795-807).



Referring to earlier work that demonstrated 88 abnormal genes, the authors state: “We set out to determine whether these findings were reproducible in fresh subjects (and) whether the previously-reported dysregulation of these genes also occurred in drug-free patients with endogenous depression…Results show that these findings are reproducible, and that gene expression in endogenous depression patients was markedly different to that in CFS/ME patients and was similar to that in normal controls in terms of these 88 human genes…In the present study, we have confirmed this differential expression in 62 additional and previously untested CFS/ME patients…We have addressed the question of the specificity of these 88 genes to CFS/ME by testing drug-free patients with endogenous depression. The fact that only 5 of these genes were abnormally expressed in endogenous depression patients as compared with normals supports the view that CFS/ME and endogenous depression are biologically distinct, and that the psychological features of CFS/ME are in fact secondary to the pathogenesis (Lihan Zang, Jonathn Kerr et al. J Clin Pathol 2009: doi 10.1136/jcp2009.072561).

Documented ocular abnormalities in ME/CFS



David J Browning found that the most common ocular symptoms in ME/CFS (CFIDS) are floaters, transient blurring of vision, transient double vision, extreme light sensitivity, burning and pain in the eyes (CFIDS Chronicle October 1988:6-7).



Nystagmus at a rate 230 times normal, poor fixation stability, and ratchet vision were reported (Meeting-Place 1992: 38:38-40).



Potaznick and Kozol evaluated 25 ocular symptoms in 190 ME/CFS patients and concluded that the ocular symptoms are genuine and that for all but one symptom (teary eyes), the patients’ responses were found to be statistically significant. The authors concluded: “Statistical analysis shows that the increased rate at which patients with (ME/CFS) CFIDS report ocular symptoms is not explained by chance alone…Many patients experience very troubling and disabling symptoms” (Optometry and Vision Science 1992:69:10:811-814).


Potaznick and Kozol reported ocular symptomatology in relation to the visual, functional, perceptual and pathological aspects of the visual system and repeated their message that the symptoms are genuine (Clin Inf Dis 1994:18 (Suppl 1):S87).


Caffery et al showed that ME/CFS affects the ocular system in many ways. The authors stated: “It appears that the ocular system may be very much affected by this systemic disease. The objective findings of the anterior segment suggests an organic aetiology…The ocular neurological symptoms that presented in such a large number of ME/CFS patients suggests a possible neurological basis for this disease” (Journal of the American Optometric Association 1994:65:187-191).


Vedelago reported that the visual symptoms commonly encountered in ME/CFS patients include blurred vision, difficulty focusing, difficulty tracking lines of print, diplopia or ghosting of images, problems with peripheral vision, misjudging distances, inability to tolerate looking at moving objects, floaters and halos, intolerance to glare, grittiness, burning, dryness or itchiness and photophobia. Objective ocular findings included poor oculomotor control, exophoria (the tendency for one eye to diverge when the other eye is covered), remote near-point of convergence, poor convergence, constricted peripheral fields, incomplete blinking, small pupils, visual midline shift, and low grade chronic allergic conjunctivitis (The CFS Research Review 2000: 4-9).

Documented involvement of viruses in ME/CFS



Describing an outbreak of infection of the central nervous system complicated by intense myalgia in late summer 1952 affecting nurses at the Middlesex Hospital, London, the author (ED Acheson, who later became UK Chief Medical Officer) reported the clinical features to be severe muscular pain affecting the back, limbs, abdomen and chest, with evidence of mild involvement of the central nervous system, diarrhoea, vomiting, respiratory distress, paresis and brain stem involvement that included nystagmus, double vision and difficulty in swallowing; additionally, bladder symptoms occurred in more than half the patients. Acheson highlighted this small outbreak because of the similarity to atypical poliomyelitis (ED Acheson. Lancet: Nov 20th 1954:1044-1048). The label of “atypical poliomyelitis” was originally given to ME (The Disease of a Thousand Names. David S Bell. Pollard Publications, Lyndonville, New York, 1991). Many patients today experience exactly the symptoms described by Acheson, but such symptoms are dismissed by the Wessely School as somatisation and as hypervigilance to normal bodily sensations.




Acheson described and compared the outbreak at the Royal Free in 1955 with the outbreak at The Middlesex in 1952, noting the relatively prolonged active course of the disease, marked muscular pain and spasm, involvement of the lymph nodes, liver and spleen, tenderness under the costal margins, and ulcers in the mouth, all of which – if looked for and if not dismissed as somatising -- are still to be found in “pure” ME today (ED Acheson. Lancet: Aug 20th 1955:394-395).



In his detailed review of numerous outbreaks of Benign Myalgic Encephalomyelitis from 1934, Acheson described the common characteristics of the disease and clinical picture, which included agonising muscular pain, headache, nausea, sensory disturbances, stiffness of the neck and back, dizziness, muscular twitching, tremor and in-coordination, localised muscular weakness, emotional lability, problems with memory and concentration, hyperacusis, somnolence and insomnia, with relapses being almost inevitable, together with variability of symptoms. Signs included hepatic enlargement, lymphadenopathy and evidence of CNS involvement, nystagmus being “almost invariable” in some of the outbreaks. The question of hysteria was addressed and discounted: “Final points against mass hysteria as a major factor in the syndrome are the consistency of the course of the illness and the similarities in the symptoms…The disorder is not a manifestation of mass hysteria” and Acheson specifically warned that the diagnosis of ME should be reserved for those with (virally induced) evidence of CNS damage: “If not, the syndrome will become a convenient dumping ground for non-specific illnesses characterised by fluctuating aches and pains, fatigue and depression, exactly the situation that exists in the UK 50 years after Acheson’s prophecy (ED Acheson. American Journal of Medicine, April 1959:569-595).


The clinical picture was variable both in the time pattern of its progression and the severity of the symptoms…It became clear early on in the outbreak that there was organic involvement of the central nervous system (and) there was objective evidence of involvement of the central nervous system…The most characteristic symptom was the prolonged painful muscle spasms…Bladder dysfunction occurred in more than 25% of all the patients…Case to case contact between patients and their relatives also occurred…McEvedy and Beard’s conclusions (of mass hysteria) ignore the objective findings of the staff of the hospital of fever, lymphadenopathy, cranial nerve palsies and abnormal signs in the limbs…Objective evidence of brain stem and spinal cord involvement was observed” (Nigel D Compston. Postgraduate Medical Journal 1978:54:722-724).


Virological studies revealed that 76% of the patients with suspected myalgic encephalomyelitis had elevated Coxsackie B neutralising titres (and symptoms included) malaise, exhaustion on physical or mental effort, chest pain, palpitations, tachycardia, polyarthralgia, muscle pains, back pain, true vertigo, dizziness, tinnitus, nausea, diarrhoea, abdominal cramps, epigastric pain, headaches, paraesthesiae, dysuria)….The group described here are patients who have had this miserable illness. Most have lost many weeks of employment or the enjoyment of their family (and) marriages have been threatened…” (BD Keighley, EJ Bell. JRCP 1983:33:339-341).


“…from an immunological point of view, patients with chronic active EBV infection appear ‘frozen’ in a state typically found only briefly during convalescence from acute EBV infection” (G Tosato, S Straus et al. The Journal of Immunology 1985:134:5:3082-3088. Note that ”CFS” was then thought to be caused by EBV).


Epstein-Barr virus infection may have induced or augmented an immunoregulatory disorder that persisted in these patients” (Stephen E Straus et al. Ann Intern Med. 1985:102:7-16).


The clinical, pathological, electrophysiological, immunological and virological abnormalities in 50 patients with the postviral fatigue syndrome are recorded. These findings confirm the organic nature of the disease (and) suggest that it is associated with disordered regulation of the immune system and persistent viral infection” (PO Behan, WMH Behan, EJ Bell. Journal of Infection 1985:10:211-222.


Ninety percent of the patients tested had antibodies to Epstein-Barr virus and 45% tested had antibodies to cytomegalovirus…if this fatigue syndrome is triggered by an infectious agent, an abnormal immune response may be involved” (TJ Marrie et al. Clinical Ecology 1987:V:1:5-10).


Recently associations have been found between Coxsackie B infection and a more chronic multisystem illness. A similar illness…has been referred to as… myalgic encephalomyelitis…140 patients presenting with symptoms suggesting a postviral syndrome were entered into the study…Coxsackie B antibody levels were estimated in 100 control patients…All the Coxsackie B virus antibody tests were performed blind…Of the 140 ill patients, 46% were found to be Coxsackie B virus antibody positive…This study has confirmed our earlier finding that there is a group of symptoms with evidence of Coxsackie B infection. We have also shown that clinical improvement is slow and recovery does not correlate with a fall in Coxsackie B virus antibody titre” (BD Calder et al. JRCGP 1987:37:11-14).


The illness has an acute onset after a variety of infections and then enters a chronic phase characterised by fatigue and numerous other symptoms….Other findings include a sleep disorder, mild immunodeficiency, slightly low complement, anti-DNA antibodies and elevated synthetase which is an interferon-associated enzyme commonly increased in viral infections” (Irving E Salit. Clinical Ecology 1987:V:3:103-107).


These results show that chronic infection with enteroviruses occurs in many PVFS (post-viral fatigue syndrome, a classified synonym for ME/CFS) patients and that detection of enterovirus antigen in the serum is a sensitive and satisfactory method for investigating infection in these patients….Several studies have suggested that infection with enteroviruses is causally related to PVFS…The association of detectable IgM complexes and VP1 antigen in the serum of PVFS patients in our study was high…This suggests that enterovirus infection plays an important role in the aetiology of PVFS” (GE Yousef, EJ Bell, JF Mowbray et al. Lancet January 23rd 1988:146-150).


Myalgic encephalomyelitis was thought for some time to be produced by a less virulent strain of poliovirus…chronic, persistent viruses may often be reactivated during this illness…once reactivated, do these viruses then go on to produce many of the symptoms of the disease? And what reactivates these endogenous viruses? Could it be environmental toxins? Could it be infection with other, exogenous lymphotropic viruses?” (Anthony L Komaroff. Journal of Virological Methods. 1988:21:3-10).

(In the light of the discovery in 2009 of the XMRV retrovirus – see below -- this paper by Professor Komaroff 21 years in advance of that discovery showed remarkable prescience).


Postviral fatigue syndrome / myalgic encephalomyelitis… has attracted increasing attention during the last five years…Its distinguishing characteristic is severe muscle fatiguability made worse by exercise…The chief organ affected is skeletal muscle, and the severe fatiguability, with or without myalgia, is the main symptom. The results of biochemical, electrophysiological and pathological studies support the view that muscle metabolism is disturbed, but there is no doubt that other systems, such as nervous, cardiovascular and immune are also affected…Recognition of the large number of patients affected…indicates that a review of this intriguing disorder is merited….The true syndrome is always associated with an infection…Viral infections in muscle can indeed be associated with a variety of enzyme abnormalities…(Electrophysiological results) are important in showing the organic nature of the illness and suggesting that muscle abnormalities persist after the acute infection…there is good evidence that Coxsackie B virus is present in the affected muscle in some cases” (PO Behan, WMH Behan. CRC Crit Rev Neurobiol 1988:4:2:157-178).


The main features (of ME) are: prolonged fatigue following muscular exercise or mental strain, an extended relapsing course; an association with neurological, cardiac, and other characteristic enteroviral complications. Coxsackie B neutralisation tests show high titres in 41% of cases compared with 4% of normal adults…These (chronic enteroviral syndromes) affect a young, economically important age group and merit a major investment in research” (EG Dowsett. Journal of Hospital Infection 1988:11:103-115).


Ten patients with post-viral fatigue syndrome and abnormal serological, viral, immunological and histological studies were examined by single fibre electromyographic technique….The findings confirm the organic nature of the disease. A muscle membrane disorder…is the likely mechanism for the fatigue and the single-fibre EMG abnormalities. This muscle membrane defect may be due to the effects of a persistent viral infection…There seems to be evidence of a persistent viral infection and/or a viral-induced disorder of the immune system…The infected cells may not be killed but become unable to carry out differentiated or specialised function” (Goran A Jamal, Stig Hansen. Euro Neurol 1989:29:273-276).


Skeletal samples were obtained by needle biopsy from patients diagnosed clinically as having CFS (and) most patients fulfilled the criteria of the Centres for Disease Control for the diagnosis of CFS (Holmes et al 1988)…These data are the first demonstration of persistence of defective virus in clinical samples from patients with CFS…We are currently investigating the effects of persistence of enteroviral RNA on cellular gene expression leading to muscle dysfunction” (L Cunningham, RJM Lane, LC Archard et al. Journal of General Virology 1990:71:6:1399-1402).


Myalgic encephalomyelitis is a common disability but frequently misinterpreted…This illness is distinguished from a variety of other post-viral states by a unique clinical and epidemiological pattern characteristic of enteroviral infection…33% had titres indicative and 17% suggestive of recent CBV infection…Subsequently…31% had evidence of recent active enteroviral infection…There has been a failure to recognise the unique epidemiological pattern of ME…Coxsackie viruses are characteristically myotropic and enteroviral genomic sequences have been detected in muscle biopsies from patients with ME. Exercise related abnormalities of function have been demonstrated by nuclear magnetic resonance and single-fibre electromyography including a failure to coordinate oxidative metabolism with anaerobic glycolysis causing abnormal early intracellular acidosis, consistent with the early fatiguability and the slow recovery from exercise in ME. Coxsackie viruses can initiate non-cytolytic persistent infection in human cells. Animal models demonstrate similar enteroviral persistence in neurological disease… and the deleterious effect of forced exercise on persistently infected muscles. These studies elucidate the exercise-related morbidity and the chronic relapsing nature of ME” (EG Dowsett, AM Ramsay et al. Postgraduate Medical Journal 1990:66:526-530).


A paper reporting the discovery of a retrovirus associated with (ME)CFS (Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Elaine DeFreitas, Paul R Cheney, David S Bell et al. Proc Natl Acad Sci USA 1991:88:2922-2926) is addressed in detail in the section “The role of Viruses in ME/CFS”.


Persistent enteroviral infection of muscle may occur in some patients with postviral fatigue syndrome and may have an aetiological role….The features of this disorder suggest that the fatigue is caused by involvement of both muscle and the central nervous system…We used the polymerase chain reaction to search for the presence of enteroviral RNA sequences in a well-characterised group of patients with the postviral fatigue syndrome…53% were positive for enteroviral RNA sequences in muscle…Statistical analysis shows that these results are highly significant…On the basis of this study…there is persistent enteroviral infection in the muscle of some patients with the postviral fatigue syndrome and this interferes with cell metabolism and is causally related to the fatigue” (JW Gow et al. BMJ 1991:302:696-696).


The findings described here provide the first evidence that postviral fatigue syndrome may be due to a mitochondrial disorder precipitated by a virus infection…Evidence of mitochondrial abnormalities was present in 80% of the cases with the commonest change (seen in 70%) being branching and fusion of cristae, producing ‘compartmentalisation’. Mitochondrial pleomorphism, size variation and occasional focal vacuolation were detectable in 64%…Vacuolation of mitochondria was frequent…In some cases there was swelling of the whole mitochondrion with rupture of the outer membranes…prominent secondary lysosomes were common in some of the worst affected cases…The pleomorphism of the mitochondria in the patients’ muscle biopsies was in clear contrast to the findings in normal control biopsies…Diffuse or focal atrophy of type II fibres has been reported, and this does indicate muscle damage and not just muscle disuse” (WMH Behan et al. Acta Neuropathologica 1991:83:61-65).


Considerations in the Design of Studies of Chronic Fatigue Syndrome. Reviews of Infectious Diseases. Volume 13, Supplement 1: S1 – S140. University of Chicago Press. Contributing authors included Anthony L Komaroff, David S Bell, Daniel L Peterson, Sandra Daugherty and Sheila Bastien, whose work has been referred to in other parts of this Report.


Postviral Fatigue Syndrome. British Medical Bulletin 1991:47:4: 793-907. Churchill Livingstone.

This major publication, published by Churchill Livingstone for The British Council, includes papers by the Wessely School considered by some to be misrepresentative of ME/CFS (for example: “History of postviral fatigue syndrome” by S Wessely; “Postviral fatigue syndrome and psychiatry” by AS David -- in which David, a co-author of the Oxford criteria, confirmed that “British investigators have put forward an alternative, less strict, operational definition which is essentially chronic…fatigue in the absence of neurological signs, (with) psychiatric symptoms…as common associated features” (AS David; BMB 1991:47:4:966-988) and “Psychiatric management of PVFS” by M Sharpe) but also contains the following:

Molecular viral studies have recently proved to be extremely useful. They have confirmed the likely important role of enteroviral infections, particularly with Coxsackie B virus” (Postviral fatigue syndrome: Current neurobiological perspective. PGE Kennedy. BMB 1991:47:4:809-814)

Our focus will be on the ability of certain viruses to interfere subtly with the cell’s ability to produce specific differentiated products as hormones, neurotransmitters, cytokines and immunoglobulins etc in the absence of their ability to lyse the cell they infect. By this means viruses can replicate in histologically normal appearing cells and tissues…Viruses by this means likely underlie a wide variety of clinical illnesses, currently of unknown aetiology, that affect the endocrine, immune, nervous and other …systems” (JC de la Torre, P Borrow, MBA Oldstone. BMB 1991:47:4:838-851).

We conclude that persistent enteroviral infection plays a role in the pathogenesis of PVFS…The strongest evidence implicates Coxsackie viruses…Patients with PVFS were 6.7 times more likely to have enteroviral persistence in their muscles” (JW Gow and WMH Behan. BMB 1991:47:4:872-885).

The postviral fatigue syndrome (PVFS), with profound muscle fatigue on exertion and slow recovery from exhaustion seems to be related specifically to enteroviral infection. The form seen with chronic reactivated EBV infection is superficially similar, but without the profound muscle fatigue on exercise (JF Mowbray, GE Yousef. BMB 1991:47:4:886-894).


We will report at the First International Research Conference on Chronic Fatigue Syndrome to be held at Albany, New York, 2-4 October 1992, our new findings relating particularly to enteroviral infection…We have isolated RNA from patients and probed this with large enterovirus probes…detailed studies...showed that the material was true virus…Furthermore, this virus was shown to be replicating normally at the level of transcription. Sequence analysis of this isolated material showed that it had 80% homology with Coxsackie B viruses and 76% homology with poliomyelitis virus, demonstrating beyond any doubt that the material was enterovirus” (Press Release for the Albany Conference, Professor Peter O Behan, University of Glasgow, October 1992).


Samples from 25.9% of the PFS (postviral fatigue syndrome) were positive for the presence of enteroviral RNA, compared with only 1.3% of the controls…We propose that in PFS patients, a mutation affecting control of viral RNA synthesis occurs during the initial phase of active virus infection and allows persistence of replication defective virus which no longer attracts a cellular immune response” (NE Bowles, RJM Lane, L Cunningham and LC Archard. Journal of Medicine 1993:24:2&3:145-180).


These data support the view that while there may commonly be asymptomatic enterovirus infections of peripheral blood, it is the presence of persistent virus in muscle which is abnormal and this is associated with postviral fatigue syndrome…Evidence derived from epidemiological, serological, immunological, virological, molecular hybridisation and animal experiments suggests that persistent enteroviral infection may be involved in… PFS” (PO Behan et al. CFS: CIBA Foundation Symposium 173, 1993:146-159).


Individuals with CFS have characteristic clinical and laboratory findings including…evidence of viral reactivation…The object of this study was to evaluate the status of key parameters of the 2-5A synthetase/RNase L antiviral pathway in individuals with CFS who participated in a placebo-controlled, double-blind, multi-centre trial…The present work confirms the finding of elevated bioactive 2-5A and RNase L activity in CFS…RNase L, a 2-5A-dependent enzyme, is the terminal effector of an enzymatic pathway that is stimulated by either virus infection or exposure to exogenous lymphokines. Almost two-thirds of the subjects…displayed baseline RNase L activity that was elevated above the control mean” (Robert J Suhadolnik, Daniel L Peterson, Paul Cheney et al. In Vivo 1994:8:599-604).

A note on the significance of this paper

Viral infections of cells results in the production and secretion of cytokines, including the interferons. Interferons control the way that cells respond to a virus by means of a group of inter-related enzymes that comprise an anti-viral pathway. This pathway is known as the 2’,-5’-oligoadenylate synthetase/RNase L pathway.

RNase L (ribonuclease latent) is the key enzyme in the antiviral pathway and is designed to degrade viral RNA. It has to be “turned on” by a small molecule, 2-5 A. Binding of 2-5A to RNase L changes the enzyme from its latent (inactive) state to its active state. When active, RNase L inhibits viral protein synthesis and thereby prevents viral replication.

Several critical parts of the anti-viral pathway are not functioning correctly in ME/CFS.

The level of RNase L enzyme activity has been demonstrated to be upregulated (ie. increased) by as much as 1,500 times above normal levels, and researchers at Temple University School of Medicine, Philadelphia, have shown that not only is the activity of the RNase L enzyme significantly higher in patients with (ME)CFS than in controls, but also that there is a significant increase in the level of 2-5A (the molecule that converts RNase L from its latent to its active state) and in the level of 2-5A synthetase (the enzyme that synthesises the 2-5A activator molecule).

The most striking finding in patients with (ME)CFS is, however, that they have a unique form of the RNase L enzyme. The size of the RNase L protein is normally 80 kDa (kiloDaltons), but in many people with (ME)CFS, this 80 kDa enzyme is either scarce or missing altogether. Instead, a unique low molecular weight (LMW) form of RNase L is observed (30 kDa). Besides its smaller size, the LMW RNase L seen in (ME)CFS patients has other biochemical differences from the 80 kDa RNase L. The LMW RNase L binds its activator more tightly and is more potent than the 80 kDa form of RNase L.

Studies have revealed several connections between the RNase L pathway and the clinical status of (ME)CFS patients, demonstrating that the increased activity of the RNase L pathway is an indication of a lower state of health and that all three measurements of the pathway are abnormal in (ME)CFS.

Studies carried out in various countries apart from the US (including Australia, Belgium, France and Germany) have all confirmed the presence of the LMW RNase L in (ME)CFS; moreover, two different methods using different probes to detect RNase L accurately identified (ME)CFS patients.

Importantly, the RNase L ratio also distinguished individuals with (ME)CFS from those with fibromyalgia or depression.

In addition, studies have shown that the presence of LMW RNase L is independent of the duration of (ME)CFS symptoms: the LMW RNase L was detected in individuals who had (ME)CFS symptoms for as long as 19 years.

The presence of the LMW RNase L identifies a group of people with (ME)CFS who have an abnormally elevated anti-viral response, and the anti-viral RNase L protein level and enzyme activity are potentially powerful diagnostic tools for (ME)CFS (with grateful acknowledgement to Nancy Reichenbach, associate scientist in the Department of Biochemistry at Temple University School of Medicine, and to the CFIDS Association of America: ).

Although these important abnormalities were known about in 1994, and despite the evidence of the reliability and reproducibility of RNase L testing that was presented in 1999 at the Second World Congress on (ME)CFS in Brussels, in the UK there has been continued opposition to such testing, not only by the Wessely School (who consistently advise that only limited investigations should be carried out), but also by the ME Association.

For example, the Medical Director of the ME Association, Dr Charles Shepherd, apparently intended to inform readers of the ME Association’s Newsletter (Perspectives) that his view of the international work on RNase L was that it “may involve what I and many of my colleagues regard as over-investigation for highly speculative abnormalities in antiviral pathway activity”, which seemed to echo Professor Anthony Pinching’s view that “over-investigation can (cause patients) to seek abnormal test results to validate their illness” (Prescribers’ Journal 2000: 40:2:99-106). The Spring 2001 Issue of the ME Association’s Medical and Welfare Bulletin stated (on page 9) about RNase L testing: “Having discussed the possible value of this type of blood test with members of the MEA’s Scientific and Medical Advisory Panel, there is general agreement that insufficient evidence exists to recommend that this test should be carried out for either diagnostic or management purposes” (members of the SMAP included Professor Peter Behan, Professor Leslie Findley, Dr John Gow, Professor Anthony Pinching and Dr Shepherd himself).

The ME Association did, however, co-fund with The Linbury Trust studies examining RNase L activity: blood from patients attending the Fatigue Service at St Bartholomew’s Hospital and from Romford, Essex, was sent to Dr John Gow, who was working with Professors Peter and Wilhelmina Behan and Dr Abhijit Chaudhuri, all then at the University of Glasgow. Gow et al’s work on a total of 22 patients with CFS was published in Clinical Infectious Diseases (2001:33:12:2080-2081), the conclusion being that “patients with CFS showed no significant activation” of either part of the RNase L pathway, and that “assay of antiviral pathway activation is unlikely to form a rational basis for a diagnostic test for CFS”.

Professors Suhadolnik and De Meirleir robustly showed that Gow et al’s study was fundamentally flawed. Pointing out that “Over the years, our teams have repeatedly observed an activation at the enzymatic level of the antiviral pathway in subsets of CFS patients”, they noted that Gow et al had (1) misunderstood the established knowledge of the IFN pathway, (2) did not confirm their observations of genetic expression at the transcriptional level (which would have clarified their results), (3) used the terms “genetic expression” and “activity” interchangeably, when they are not necessarily synonymous (particularly when the research involves enzymes). They also noted that confusion in the mind of Gow et al about these issues led them to misquote their articles: “On the basis of their limited observations, Gow et al challenge our observations and further deny any rational basis to our proposal regarding the use of 37-kDa RNase L detection as a biological marker for CFS. In our study, which they clearly misquoted, we did not measure the enzymatic activity of the fragment and, hence, the 2-5A pathway activation as Gow and colleagues claimed. Instead, we limited our study to the quantitative detection of the 37-kDa truncated enzyme…We observed a significant increase in the 37-kDa RNase L level in patients with CFS compared with that observed in healthy control subjects, patients with fibromyalgia, and patients with depression….Consequently, this does not support the claim that the presence of the 37-kDa RNase L in CFS could only be imparted to non-specific increases in the antiviral pathway activation…Our data demonstrate that there is a more comprehensive downstream cellular role for the signal transduction by IFN than what Gow and colleagues pretend to present to the readers of Clinical Infectious Diseases” (Clin Inf Dis 2002:34:1420-1421).

The ME Association and its medical advisors, however, remained convinced that Gow et al were correct: “A very important conclusion from this study is that costly investigations such as the RNase L test, which assess the amount of antiviral activity in ME/CFS, are unlikely to provide the basis for a diagnostic test. Such tests are therefore of very questionable value in the assessment of people with ME/CFS” (MEA Medical and Welfare Bulletin, Spring 2002, Issue No 6, page 10).

At the AACFS International Research Conference in 2003 held in Washington, Wilhelmina Behan, as co-author of the Gow et al study, was publicly challenged by Professor Suhadolnik to defend it, but was unable to so.

Notwithstanding, on the basis of the Gow / Behan results, the ME Association’s Medical Advisor remains of the view that “the presence of …abnormalities in antiviral pathways has been assessed in research studies funded by the ME Association” and that the results of these tests are not “of proven value” (ME/CFS/PVFS: An exploration of the key clinical issues. Dr Charles Shepherd and Dr Abhijit Chaudhuri, for The ME Association, 2007).

In contrast to such UK views about the significance of RNase L, in 2000 Professor Anthony Komaroff from Harvard had written about Professor De Meirleir’s work on RNase L in an Editorial in the American Journal of Medicine: “What is this research telling us? It is another piece of evidence that the immune system is affected in chronic fatigue syndrome and it reproduces and extends the work of another investigator (Professor Suhadolnik from the US), lending credibility to the result” (Am J Med 2000:108:169-171).

Eight years after the Second World Congress on (ME)CFS in Brussels, advised by psychiatrists of the Wessely School, the NICE Guideline of 2007 makes no mention of the abnormalities in the RNase L antiviral pathway and recommends limited serology testing for certain viruses only, which exclude testing for Coxsackie B virus (testing for EBV, a particular interest of Professor Peter White is, however, permitted).

Given that a classified synonym for ME/CFS is “post-viral fatigue syndrome” (ICD-10 G93.3) and given that the NICE Guideline purports to apply to people with “CFS/ME”, it is striking that the Guideline states on page 141: “Serological testing should not be carried out unless the history is indicative of an infection. It is notable that the PACE Trial Investigators did not include virological testing of participants in their trial that is based on their theory that patients with “CFS/ME” are deconditioned, so it needs to be ascertained what, exactly, do the Wessely School psychiatrists understand the term “post-viral” to mean if not a history indicative of an infection?

It is worth noting that elevated levels of RNase L are associated with reduced maximal oxygen consumption (VO2 max) and exercise duration in ME/CFS patients; Snell et al found that both abnormal RNase L activity and low oxygen consumption were observed in most (ME)CFS patients, findings that demonstrate that patients’ extremely low tolerance for physical activity is likely to be linked to abnormal oxidative metabolism, perhaps resulting from defective interferon responses (Comparison of maximal oxygen consumption and RNase L enzyme in patients with CFS. C Snell et al. AACFS Fifth International Research and Clinical Conference, Seattle, January 2001; #026).

It is also worth noting that the 37 kDa LMW RNase L fragment found in ME/CFS patients is produced by cleavage of calpain (an apoptotic enzyme), and the whole process affects the calcium and potassium ion channels, a channelopathy that will lead to low body potassium (a known finding in ME-CFS patients --Burnett et al found that total body potassium (TBK) was lower in patients with (ME)CFS and suggest that abnormal potassium handling by muscle in the context of low overall body potassium may contribute to fatigue in (ME)CFS (Medical Journal of Australia, 1996:164:6:384).


It is also important to note that patients who express the low molecular weight RNase L may have problems with enzymatic detoxification pathways, particularly in the liver. This is significant because of the resultant adverse effect on thyroid function.

It has long been noted by practitioners that ME/CFS patients are often clinically hypothyroid even though biochemically euthyroid. Evidence suggests that such patients may not really be euthyroid, especially at the tissue level. (Chopra IJ. J Clin Endocrinol Metab 1997:82(2):329-334), so particular attention needs to be paid to investigating the bioavailablity of T3 because in ME/CFS, T3 levels are often low (or at the low end of the normal range). Consequently, selenium levels need to be investigated in patients with ME/CFS who have reduced T3 levels: this is because selenium (as selenocysteine) is an integral component of two important enzymes, glutathione peroxidase and iodothryonine deiodinase; it is expressed in the liver and it regulates the conversion of thyroxine (T4) to the active and more potent T3. Individuals who have a deficiency of 5’ deiodinase cannot produce T3 from T4, thus it is necessary to establish baseline levels of selenium in ME/CFS patients whose T3 levels are low.

In the UK, the NICE Guideline does not recommend such testing.

In relation to RNase L, a recent literature review of the immunological similarities between cancer and (ME)CFS pointed out:“Cancer and CFS are both characterised by fatigue and severe disability (and) certain aspects of immune dysfunctions appear to be present in both illnesses…A literature review of overlapping immune dysfunctions in CFS and cancer is provided. Abnormalities in ribonuclease (RNase L) and hyperactivation of nuclear factor kappa-beta (NF-kappa) are present in CFS and in prostate cancer. Malfunctioning of natural killer (NK) cells has long been recognised as an important factor in the development and recurrence of cancer, and has been documented repeatedly in CFS patients. The dysregulation of the RNase L pathway, hyperactive NF-kappa leading to disturbed apoptotic mechanisms and oxidative stress or excessive nitric oxide, and low NK activity may play a role in the two diseases (and)… are present in both diseases. These anomalies may be part of the physiopathology of some of the common complaints, such as fatigue” (Meeus M et al. Anticancer Res 2009:29(11):4717-4726).

It seems that, even if not a specific biomarker for ME/CFS, the significance of the abnormal RNase L anti-viral pathway in ME/CFS patients cannot be sufficiently emphasised, but through the undoubted influence of the Wessely School, ME/CFS sufferers in the UK are not permitted to have their anti-viral pathway status investigated.


Chronic Fatigue Syndrome: Current Concepts. Clinical Infectious Diseases 1994: Volume 18: Supplement 1: S1 – S167. Ed. Paul H Levine. University of Chicago Press. Contributing authors include: Paul H Levine, Alexis Shelokov, Anthony L Komaroff, David S Bell, Paul R Cheney, Leonard H Calabrese, Leonard A Jason, Seymour Grufferman, Hirohiko Kuratsune, Charles Bombadier, Nancy G Klimas, Mary Ann Fletcher, Roberto Patarca-Montero, Benjamin H Natelson, Robert J Suhadolnik, Daniel L Peterson, Dharam V Ablashi, Fred Friedberg, Jay A Levy, Peter O Behan, Wilhelmina MH Behan and Mark O Loveless.


In his Summary of the Viral Studies of CFS, Dr Dharam V Ablashi concluded: “The presentations and discussions at this meeting strongly supported the hypothesis that CFS may be triggered by more than one viral agent…Komaroff suggests that, once reactivated, these viruses contribute directly to the morbidity of CFS by damaging certain tissues and indirectly by eliciting an on-going immune response” (Clin Inf Dis 1994:18 (Suppl 1):S130-133). It is recommended that the entire 167-page Journal be read to show how ill-founded is the Wessely School’s “CBT model” of ME/CFS.


In their Closing Remarks, Professors Komaroff and Klimas said: “Few studies by psychiatrists are presented in this supplement. Many investigators who have argued that CFS is primarily a psychiatric disorder chose not to present their work (Clin Inf Dis 1994:18:(Suppl 1):S166-167).


These results suggest there is persistence of enterovirus infection in some CFS patients and indicate the presence of distinct novel enterovirus sequences…Several studies have shown that a significant proportion of patients complaining of CFS have markers for enterovirus infection….From the data presented here…the CFS sequences may indicate the presence of novel enteroviruses…It is worth noting that the enteroviral sequences obtained from patients without CFS were dissimilar to the sequences obtained from the CFS patients…This may provide corroborating evidence for the presence of a novel type of enterovirus associated with CFS (DN Galbraith, C Nairn and GB Clements. Journal of General Virology 1995:76:1701-1707).



In the CFS study group, 42% of patients were positive for enteroviral sequences by PCR, compared to only 9% of the comparison group…Enteroviral PCR does, however, if positive, provide evidence for circulating viral sequences, and has been used to show that enteroviral specific sequences are present in a significantly greater proportion of CFS patients than other comparison groups (C Nairn et al. Journal of Medical Virology 1995:46:310-313).



To prove formally that persistence rather than re-infection is occurring, it is necessary to identify a unique feature retained by serial viral isolates from one individual. We present here for the first time evidence for enteroviral persistence (in humans with CFS)…” (DN Galbraith et al. Journal of General Virology 1997:78:307-312).



Recent developments in molecular biology…have revealed a hitherto unrecognised association between enteroviruses and some of the most disabling, chronic and disheartening neurological, cardiac and endocrine diseases…Persistent infection (by enteroviruses) is associated with ME/CFS…The difficulty of making a differential diagnosis between ME/CFS and post-polio sequelae cannot be over-emphasised…(EG Dowsett. Commissioned for the BASEM meeting at the RCGP, 26th April 1998:1-10).




An important paper by Ablashi and Peterson et al suggested that in both multiple sclerosis (MS) and (ME)CFS, HHV-6 reactivation plays a role in the pathogenesis.

Two disorders of significant importance, MS and CFS, appear to be associated with HHV-6 infection…the data presented here show that both MS and CFS patients tend to carry a higher rate of HHV-6 infection or reactivation compared to normal controls. This immunological and virological data supports a role of HHV-6 in the symptomatology of these diseases…Based on biological, immunological and molecular analysis, the data show that HHV-6 isolates from 70% of CFS patients were Variant A…Interestingly, the majority of HHV-6 isolates from MS patients were Variant B…These data demonstrate that the CFS patients exhibited HHV-6 specific immune responses…Seventy percent of the HHV-6 isolates from CFS patients were Variant A, similar to those reported in AIDS…It has already been shown that active HHV-6 infection in HIV-infected patients enhanced the AIDS disease process. We suspect that the same scenario is occurring in the pathogenesis of MS and CFS…The immunological data presented here clearly shows a significantly high frequency of HHV-6 reactivation in CFS and MS patients. We postulate that active HHV-6 infection is a major contributory factor in the aetiologies of MS and CFS” (DV Ablashi, DL Peterson et al. Journal of Clinical Virology 2000:16:179-191).


(HHV-6 is one of eight known members of the human herpesvirus family. It has two variants [A and B]; the A strain is much more pathogenic and infects the immune and central nervous systems. Reactivation in adults has been associated with glandular fever, autoimmune disorders and diseases of the nervous system. Active HHV-6 infections are not found in healthy people without disease associations and reactivation can result in suppression of bone marrow function and inflammation, and can cause damage in tissues such as brain, liver or lungs. HHV-6 has been specifically linked to MS, AIDS and (ME)CFS [Co-Cure MED: 2nd March 2002]. HHV-6 used to be called human B-lymphotropic virus (HBLV); it was discovered in 1986 from the blood of patients with AIDS. HHV-6 also correlates with 37kDa – the low molecular weight form of RNase L that is known to exist as part of a dysregulated antiviral pathway in ME/CFS patients).


Over the last decade a wide variety of infectious agents has been associated with CFS by researchers from all over the world. Many of these agents are neurotrophic and have been linked to other diseases involving the central nervous system (CNS)…Because patients with CFS manifest a wide range of symptoms involving the CNS as shown by abnormalities on brain MRIs, SPECT scans of the brain and results of tilt-table testing, we sought to determine the prevalence of HHV-6, HHV-8, EBV, CMV, Mycoplasma species, Chlamydia species and Coxsackie virus in the spinal fluid of a group of patients with CFS. Although we intended to search mainly for evidence of actively replicating HHV-6, a virus that has been associated by several researchers with this disorder, we found evidence of HHV-8, Chlamydia species, CMV and Coxsackie virus in (50% of patient) samples…It was also surprising to obtain such a relatively high yield of infectious agents on cell free specimens of spinal fluid that had not been centrifuged” (Susan Levine. JCFS 2002:9:1/2:41-51).

(HHV-8 is associated with Kaposi’s sarcoma and with some B-cell lymphomas).


Nicolson et al showed that multiple co-infections (Mycoplasma, Chlamydia, HHV-6) in blood of chronic fatigue syndrome patients are associated with signs and symptoms: “Differences in bacterial and/or viral infections in (ME)CFS patients compared to controls were significant…The results indicate that a large subset of (ME)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” (Nicolson GL et al. APMIS 2003:111(5):557-566).


Seeking to detect and characterise enterovirus RNA in skeletal muscle from patients with (ME)CFS and to compare efficiency of muscle metabolism in enterovirus positive and negative (ME)CFS patients, Lane et al obtained quadriceps biopsy samples from 48 patients with (ME)CFS. Muscle biopsy samples from 20.8% of patients were positive, while 100% of the controls were negative for enterovirus sequences. Lane et al concluded: “There is an association between abnormal lactate response to exercise, reflecting impaired muscle energy metabolism, and the presence of enterovirus sequences in muscle in a proportion of (ME)CFS patients” (RJM Lane, LC Archard et al. JNNP 2003:74:1382-1386).


In their presentation to the US Assembly Committee, Drs Dharam Ablashi and Kristin Loomis said:

Reasons to suspect viruses as a cause of CFS and MS: In CFS, symptoms wax and wane; antiviral pathways are activated; symptoms are similar to many viral conditions; geographic outbreaks have been reported; gene expression profiling found genetic variants that reduce antiviral defences. In MS, antiviral pathways are activated; geographic outbreaks have been reported; all demyelinating disorders with known aetiology have been caused by viruses; symptoms wax and wane and worsen with viral infections.

Evidence of central nervous system abnormalities in (ME)CFS are similar to those in MS: reduced grey matter volume in bilateral prefrontal cortex; abnormal uptake of acetyl-L carnitine in the prefrontal cortex; enlarged ventricle volumes; increased small punctate lesions on MRI in MS and in a subset of (ME)CFS; fatigue is present in more than 85% of people with MS and in 100% of people with (ME)CFS; reduced information processing speed; memory and cognitive problems”.

Ablashi and Loomis pointed out that an analysis of studies of HHV-6 in (ME)CFS differentiated between active and latent virus, with 83% being positive (Assessment and Implications of Viruses in Debilitating Fatigue in CFS and MS Patients. Dharam V Ablashi et al. HHV-6 Foundation, Santa Barbara, USA. Submission to Assembly Committee/Ways & Means, Exhibit B1-20, submitted by Annette Whittemore 1st June 2005).



In a review of the role of enteroviruses in (ME)CFS, Chia noted that initial reports of chronic enteroviral infections causing debilitating symptoms in (ME)CFS patients were met with scepticism and largely forgotten, but observations from in vitro experiments and from animal models clearly established a state of chronic persistence through the formation of double stranded RNA, similar to findings reported in muscle biopsies of patients with (ME)CFS. Recent evidence not only confirmed the earlier studies, but also clarified the pathogenic role of viral RNA (JKS Chia. Journal of Clinical Pathology 2005:58:1126-1132).



We now recognise that the immune system plays a crucial role in the pathogenesis of (ME)CFS…A disruption of the HPA axis has been implicated in the pathogenesis of (ME)CFS…A link between the immune system and the HPA axis has long been established…it is likely that HPA axis dysfunction is not the cause of (ME)CFS, but that it is secondary to the primary pathogenesis. However, once invoked, HPA axis dysfunction may contribute towards the perpetuation of the illness…Stress is known to have a significant modulating effect on the pathogenesis of viral infection (and) the principal means by which this influence occurs is likely to be via the HPA axis…Early beliefs that (ME)CFS may be triggered or caused by a single virus have been shown to be unsubstantiated (and) it is likely that different viruses affect different individuals differently, dependent upon the …immune competence of the individual…Infections are known to trigger and perpetuate the disease in many cases. Therefore, one valuable approach that has not been widely adopted in the management of (ME)CFS patients is to exhaustively investigate such patients in the hope of identifying evidence for a specific persistent infection (but in the UK, NICE specifically does not permit such investigations)….Enteroviruses have been reported to trigger approximately 20% of cases if (ME)CFS…Antibodies to Coxsackie B virus are frequently detected in (ME)CFS patients, and enterovirus protein and RNA occur in the muscle and blood of (ME)CFS patients and their presence has been associated with altered metabolism in the muscle upon exercise in the context of (ME)CFS”.

Kerr et al then go on to provide evidence of other triggers of (ME)CFS which include Parvovirus; C. pneumoniae; C. burnetti; toxin exposure and vaccination including MMR, pneumovax, influenza, hepatitis B, tetanus, typhoid and poliovirus (LD Devanur, JR Kerr. Journal of Clinical Virology 2006: 37(3):139-150).



Having carried out a prospective cohort study of post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens, the authors concluded: The syndrome was predicted largely by the severity of the acute illness rather than by demographic, psychological or microbiological factorsImportantly, premorbid and intercurrent psychiatric disorder did not show predictive power for post-infective fatigue at any time point…We propose that …neurobiological mechanisms triggered during the severe, acute illness…underpin the persistent symptoms domains of post-infective fatigue syndrome” (Ian Hickie et al. BMJ 2006: 333:575).


CFS is a poorly-defined medical condition…which, besides severe chronic fatigue as the hallmark symptom, involves inflammatory and immune activation…The type I interferon antiviral pathway has been repeatedly shown to be activated in peripheral blood mononuclear cells of the most severely afflicted patients…Recently, the levels of this abnormal protein have been significantly correlated to the extent of inflammatory symptoms displayed by (ME)CFS patients. We report here that active double-stranded RNA-dependent kinase (PKR) is expressed and activated in parallel to the presence of the 37 kDa RNase L and to an increase in nitric oxide production by immune cells…These results suggest that chronic inflammation due to excess nitric oxide production plays a role in (ME)CFS and that the normal resolution of the inflammatory process by NFK- activation and apoptotic induction is impaired” (Marc Fremont, Kenny De Meirleir et al. JCFS 2006:13:4:17-28).


(ME)CFS is associated with objective underlying biological abnormalities, particularly involving the nervous and immune system. Most studies have found that active infection with HHV-6 – a neurotropic, gliotropic and immunotropic virus – is present more often in patients with (ME)CFS than in healthy control subjects…Moreover, HHV-6 has been associated with many of the neurological and immunological findings in patients with (ME)CFS” Anthony L Komaroff. Journal of Clinical Virology 2006:37:S1:S39-S46.


Research studies have identified various features relevant to the pathogenesis of CFS/ME such as viral infection, immune abnormalities and immune activation, exposure to toxins, chemicals and pesticides, stress, hypotension…and neuroendocrine dysfunction….Various viruses have been shown to play a triggering or perpetuating role, or both, in this complex disease….The role of enterovirus infection as a trigger and perpetuating factor in CFS/ME has been recognised for decades…The importance of gastrointestinal symptoms in CFS/ME and the known ability of enteroviruses to cause gastrointestinal infections led John and Andrew Chia to study the role of enterovirus infection in the stomach of CFS/ME patients…They describe a systematic study of enterovirus infection in the stomach of 165 CFS/ME patients, demonstrating a detection rate of enterovirus VP1 protein in 82% of patients…the possibility of an EV outbreak…seems unlikely, as these patients developed their diseases at different times over a 20 year period” (Jonathan R Kerr. Editorial. J Clin Pathol 14th September 2007. Epub ahead of print).



Since most (ME)CFS patients have persistent or intermittent gastrointestinal (GI) symptoms, the presence of viral capsid protein 1 (VP1), enterovirus RNA and culturable virus in the stomach biopsy specimens of patients with (ME)CFS was evaluated…Our recent analysis of 200 patients suggests that… enteroviruses may be the causative agents in more than half of the patients…At the time of oesophagogastroduodenoscopy, the majority of patients had mild, focal inflammation in the antrum…95% of biopsy specimens had microscopic evidence of mild chronic inflammation…82% of biopsy specimens stained positive for VP1 within parietal cells, whereas 20% of the controls stained positive…An estimated 80-90% of our 1,400 (ME)CFS patients have recurring gastrointestinal symptoms of varying severity, and epigastric and/or lower quadrant tenderness by examination…Finding enterovirus protein in 82% of stomach biopsy samples seems to correlate with the high percentage of (ME)CFS patients with GI complaints…Interestingly, the intensity of VP1 staining of the stomach biopsy correlated inversely with functional capacity…A significant subset of (ME)CFS patients may have a chronic, disseminated, non-cytolytic form of enteroviral infection which can lead to diffuse symptomatology without true organ damage” (Chia JK, Chia AY. J Clin Pathol 13th September 2007 Epub ahead of print).



As mentioned above, researchers from the Enterovirus Research Laboratory, Department of Pathology and Microbiology, University of Nebraska Medical Centre wrote a specially-commissioned explanatory article for the UK charity Invest in ME, in which they stated that human enteroviruses were not generally thought to persist in the host after an acute infection, but they had discovered that Coxsackie B viruses can naturally delete sequence from the 5’ end of the RNA genome, and that this results in long-term viral persistence, and that “This previously unknown and unsuspected aspect of enterovirus replication provides an explanation for previous reports of enteroviral RNA detected in diseased tissue in the apparent absence of infectious virus particles” (S Tracy and NM Chapman. Journal of IiME 2009:3:1).



In her lecture in November 2009 at the University of Miami, Professor Nancy Klimas said about viruses and ME/CFS that much of the research at Miami and internationally found that the viruses studied all have several things in common: they infect cells of the immune system and the neurological system; they are capable of causing latent infections and they can reactivate under certain conditions.

She also said that their early work at Miami in the late 1980s (published in the Journal of Clinical Microbiology in 1989) showed that ME/CFS patients had immune activation and poor anti-viral cell function. She then went on to discuss the importance of the findings of the retrovirus XMRV (evidence of which was published in Science on 8th October 2009 -- see below), saying that it was “very impressive work”. She continued: “This Science paper was amazing for a number of reasons. First, this team had put together such strong science that they could go for a Science paper. Science is like the Mecca of publication. If you get your stuff in Science, that’s the best place you could possibly (get it published). And they don’t take just anything and they sure, sure, sure don’t take anything unless it’s extremely well done, validated and tested out. So they took this paper – they not only took it, they put it in Science Express. They thought it was so important, they published on a very fast track…The way (the researchers at the Whittemore Peterson Institute) looked is very sophisticated…They then tried to find (the virus) in all these other ways…they looked from a whole different angle. Still found it. Backed up and looked from another angle. Still found it…they had five different kinds of ways they looked for this virus. And they were able to find the virus. That’s why Science was so impressed…It is a virus that can infect tissues that aren’t white blood cells…We’ve always thought something like that has to go on in (ME)CFS because you all have some neuro-inflammation. Your brain has a low grade level of inflammation. And you have some inflammation in the tissues that make hormones, particularly in the hypothalamic-pituitary-axis. And this is a virus that infects that type of tissue…It’s pretty impressive that out of 101 (ME)CFS cases defined by clinical case definition or a research case definition that they found 99 with the virus…And, oh, by the way, we have a biomarker. Not a small deal. A biomarker – the virus itself. No better biomarker than something that’s clearly, tightly associated with an illness…So the conclusion, it really is a big thing. It’s a big thing…That work we were already doing plays right into this. All the genomics work and all the immunology work. This is all critical to the better understanding of this illness and how this virus plays into it” (with grateful acknowledgement to PANDORA and

The Whittemore-Peterson Institute’s study that found the new human retrovirus XMRV was listed as one of the top 100 scientific discoveries in 2009 in Discovery magazine’s January 2010 issue (Co-Cure NOT: 30th December 2009).

The role of viruses in ME/CFS

For decades it has been known and shown that viruses play a role in ME/CFS. Now there is evidence of a direct link with a virus that disables the immune system, thus allowing numerous latent viruses to re-activate, which may result in the protean symptomatology.

In relation to “CFS”, the most-studied viruses have been the Epstein-Barr Virus (EBV) and the Human Herpes Virus-6 (HHV-6).

In relation to “pure” ME, the most studied viruses (and for which there is extensive evidence) have been the enteroviruses, usually Coxsackie B (CBV).

There is increasing awareness that the dysregulated immune system that is a hall-mark of ME/CFS allows multiple latent viruses and microbial agents to become reactivated (Co-Cure NOT:12th November 2009).

Moreover, recent research has shown that even viruses which were hitherto believed not to persist after an acute infectious episode are capable of long-term viral persistence.


Dr John Chia, an infectious diseases specialist from Torrance, California, who specialises in ME/CFS, is on record: “I believe that the main reason (ME)CFS patients are symptomatic is due to continuing inflammatory response toward viruses living within the cells, enteroviruses in most of the cases I see. We have clearly documented certain enterovirus infections triggering autoimmune responses in some patients…Can you imagine how we would feel if there are viruses surviving in our muscles, brains, hearts and gastrointestinal tracts triggering ongoing immune responses?” (


The CFIDS Chronicle (Research Update, Summer 1993) explained viruses and retroviruses as follows:


A virus is a microscopic organism that lives within the cells of another living organism. Viruses cause disease at the most basic level, by damaging the cells of living things. By themselves, viruses are lifeless particles incapable of reproduction, but once they enter the cell of another living thing they become active organisms that can multiply hundreds of times.

Viruses are comprised of two parts – a core of either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and a protective envelope of protein. RNA viruses are smaller than DNA viruses and sometimes contain a special enzyme called reverse transcriptase which allows them to convert RNA to DNA. These specialised viruses are known as retroviruses and have a unique ability to merge with the host’s own genetic material.

Retroviruses have the unique ability to replicate themselves by (i) making a double-stranded DNA copy called a ‘pro-virus’ once they enter living cells. Pro-viruses integrate themselves into the human chromosome and become part of the host’s genetic code (ii) alter the host’s immune response by evading detection as a ‘hidden invader’ (iii) remain hidden and latent, spliced within the host’s DNA, for long periods of time. Retroviruses are known to be potent stimulators of cytokines”.


On 8th October 2009 the premier journal Science published a paper online showing a direct link between a retrovirus and ME/CFS (Detection of infectious retrovirus XMRV, in blood cells of patients with chronic fatigue syndrome. Lombardi VC, Ruscetti FW, Peterson DL, Silverman RH, Mikovits JA et al) which caused global reverberations (see below).

However, this was not the first time that a retrovirus had been associated with ME/CFS.


The first time was in 1991 when, using polymerase chain reaction and in situ hybridisation, Dr Elaine De Freitas, a virologist at the Wistar Institute, Philadelphia (which is America’s oldest independent institution devoted to biological research) and Drs Daniel Peterson, Paul Cheney, David Bell et al found such an association (Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proc Natl Acad Sci USA 1991:88:2922-2926). It is notable that co-author Hilary Koprowski is a distinguished virologist and Professor Laureate who was Director of the Wistar Institute from 1957-1991; he is a member of the US National Academy of Sciences and is Director of the Centre for Neurovirology at Thomas Jefferson University.

Before publication, the findings were presented on 4th September 1990 by Elaine De Freitas at the 11th International Congress of Neuropathology in Kyoto, Japan.

Ten days later, on 14th September 1990 Dr Peter White (as he then was) and other members of the Wessely School dismissed the findings: “in the vast majority of CFS cases there is a psychological component. About 75% of CFS sufferers are clinically depressed, according to Peter White, senior lecturer in the department of psychiatric medicine at St Bartholomew’s Hospital in London. White said he believes depression is often a cause, rather than a consequence, of CFS…Les Borysiewicz, a clinical virologist at Addenbrookes Hospital in Cambridge (who, as noted above, is now Chief Executive of the MRC, having succeeded Professor Colin Blakemore) (said) ‘Whatever causes CFS, it isn’t the virus itself’…Anthony Clare, psychiatrist and medical director of St Patrick’s Hospital in Dublin (now deceased), pointed out that…there have been many ‘fatigue’ diseases with shifting causes: ’Neurasthenia, food allergies, now viruses. Some people would always rather have a disease that might kill them than a syndrome they have to live with’ ” (Science 1990:249:4974:1240).

In their PNAS article that was published in April 1991, De Freitas et al noted that chronic fatigue immune dysfunction syndrome (CFIDS) “may be related or identical to myalgic encephalomyelitis” and examined adult and paediatric CFIDS patients for evidence of human retroviruses (HTLV types I and II). As the CFIDS Chronicle article noted, the Wistar team looked at the peripheral blood DNA to see if they could find messenger RNA (mRNA) encoding for a viral segment of the HTLV-II virus.

At that time, known human retroviruses were the human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2) which are known to cause AIDS, and human T-lymphotropic viruses HTLV-I which causes lymphoma and HTLV-II which causes leukaemia (Hunter-Hopkins ME-Letter, October 2009). The four segments of the HTLV-II virus are referred to as the env, gag, pol and tax.

After a two-year study, De Freitas et al provided evidence for HTLV-II-like infection of blood cells from CFIDS patients (and also to a lesser extent from people closely associated with them). This evidence was further substantiated by patient reactivity to proteins with the molecular weights reported for HTLV-I and HTLV-II antigens.

In their article, De Freitas et al said: “The frequency of these antibodies in CFIDS patients compared with healthy non-contact controls suggests exposure / infection with an HTLV-like agent rare in healthy non-contact people”.

Whilst none of the CFIDS patients’ blood samples contained detectable HTLV-I gag sequences, DNA from at least two separate bleedings was positive for the HTLV-II gag subregion in 83% of adult and 72% of paediatric CFIDS patients, and the authors pointed out that “similar frequencies of PBMCs (peripheral blood mononuclear cells) expressing retroviral mRNA have been reported for HIV-infected individuals…The clinical histories of these CFIDS patients do not reveal behavioural or genetic factors usually associated with retroviral infection. Yet our data suggest that not only are these HTLV-II-like genes and HTLV-reactive antibodies associated with CFIDS in patients but that samples from a significant proportion of their non-sexual contacts are positive”.

De Freitas et al were careful to emphasise that “Although our data support an association between an HTLV-like agent and CFIDS, we cannot, as yet, define the agent’s role in the disease process. It may be a secondary infection to which immunologically compromised patients are susceptible. Alternatively, it may be one of two viruses that, when co-infecting the same haematopoetic cells, induce immune dysfunction”.

Following the Wistar findings, researchers at the US Centres for Disease Control (CDC) allegedly attempted to replicate De Freitas’ work but failed to do so; this was suggested to be because certain scientists appeared eager to discount any possibility of a retroviral association with CFIDS. De Freitas defended her work and insisted that the CDC investigators had modified her assays, with the result that her work could not be replicated by the CDC. It is known that attempts to replicate De Freitas’ work differed substantially from her own work in a number of ways, including the clinical definition of patients studied; uniform failure to use a “hot start” procedure with the PCR assay to maximise the efficiency of the PCR reaction, and the use of experimental conditions for the PCR assay that differed significantly from those used by De Freitas et al (Co-Cure RES: 6th March 2002).

De Freitas was publicly discredited; her research funding was discontinued and her research abandoned; she was subjected to what appeared to be attempts to destroy her professional reputation. Commenting on the subsequent discovery of XMRV (see below), ME/CFS expert Dr Paul Cheney of The Cheney Clinic was unambiguous: “Her work was unfortunately assaulted by the CDC. Her proposal to fly to the CDC in Atlanta to physically run the assays side by side with the CDC scientists was dismissed by the CDC” ( ).

In August 1991, together with co-author Brendan Hilliard, Elaine De Freitas applied for a world patent that was subsequently issued in April 1992. Detailed information has been provided by Dr Alan Cocchetto, Medical Director of The National CFIDS Association ( Cocchetto is clear: “the contents of this paper have major implications due to the depth and scientific quality of the work…The entire patent is approximately 40 pages. If the NIH ignored the depth of this work… then the NIH dropped the ball on this one and should be held accountable. The inventors even state: ‘The ability to screen blood samples infected by CAV (CFIDS-associated virus) enables producers and distributors of blood products, eg. the American Red Cross, to identify and discard donated blood…intended for use in transfusions…If unscreened, the use of such blood and blood-derived products could contribute to the spread of CFIDS’. The inventors reveal: ‘Neither HTLV-I, II, nor HIV virions have ever been found inside mitochondria…the positive results support the possibility that this CAV is capable of casual transmission to non-infected persons’. If the NIH ignored this last comment, then something is dramatically wrong with the agency that is supposed to protect and safeguard the welfare of the citizens of the United States. Again, the implications here are just staggering…The only conclusion that can be reached is that this work is very thorough and extensive. It has been funded by the NIH….Any retrovirus that can invade the mitochondria directly indicates trouble. As far as I’m concerned, there needs to be a criminal investigation of the NIH regarding why they refused to fund upon submission of all this data”.

It has been said that De Freitas’ reputation was intentionally destroyed because her research did not support the theory that (ME)CFS is a psychoneurosis, and that her public discrediting caused others to fear following up her work (Co-Cure;NOT: 16th October 2009).

As Neenyah Ostrom commented: “CFS and AIDS do not exist primarily in a scientific environment: they exist, for the most part, in an extremely political environment” (New York Native, 28th November 1994).

There undoubtedly seems to be collaboration about policy concerning ME/CFS between the UK Wessely School and Dr William (Bill) Reeves, Principal Investigator of the CDC’s CFS research programme, who is held in the same disregard in the US as Professor Simon Wessely is held in the UK (see below).

Regarding blood donation by people with ME/CFS, it is a matter of record that in reply to a letter dated 21st December 1991 from the late Joan Irvine, on 16th January 1992 Dr George Rutherford, Chief of the Infectious Diseases Branch of the US Department of Health and Human Services, replied to her query about blood donation by people with (ME)CFS:

“…a number of researchers have postulated that it may be caused by an infectious agent or agents, such as a virus…Based on our knowledge of infectious diseases of the immune system, it is not impossible that one or more of these suggested agents might potentially be able to be transmitted through blood-to-blood contact, as occurs in blood transfusions…I think that it is best to await further research findings before resuming blood donation”.

Also on 16th January 1992, the same Dr William Reeves of the CDC wrote to Joan Irvine about the same issue:

“…since on-going research indicates an infectious agent may be involved in some cases of CFS it would seem prudent to refrain from donating blood until this issue is resolved” ( ).

As noted above, people in the UK with ME have been permanently excluded from donating blood since at least 1989 (Guidelines for the Blood Transfusion Service in the UK, 1989: 5.4; 5.42; 5.43; 5.44; 5.410).

This was subsequently upheld by the Parliamentary Under Secretary of State The Lord Warner, who confirmed in writing on 11th February 2004 in a letter to the Countess of Mar that people with ME/CFS are not permitted to be blood donors. Lord Warner was unambiguous: "We have checked with the National Blood Service and they have provided the following information. The NBS guidelines on donor selection on ME refer to those on Post Viral Fatigue Syndrome. The Guidance is: defer from blood donation until recovery. The underlying logic is that this condition is possibly viral and therefore the NBS cannot accept the risk of possible transmission by blood. Since the condition is very variable and sometimes prolonged, it could become a lifetime ban in any particular case. I have copied this letter to the House (of Lords) library".

Given the (re)-discovery of a direct link between a retrovirus and ME/CFS, the importance of this cannot be over-stated.

Notably, those with a behavioural disorder are not prevented from donating blood.

XMRV (retrovirus associated with ME/CFS)

As mentioned above, in October 2009 the journal Science published a paper by collaborators from the Whittemore Peterson Institute, the US National Cancer Institute and The Cleveland Clinic that demonstrated a direct link between the retrovirus XMRV and ME/CFS (Science: 8th October 2009:10.1126/science.1179052).

XMRV stands for xenotropic murine leukaemia virus-related virus (xenotropic meaning a virus that can grow in the cells of a species foreign to the normal host species, ie. a virus that is capable of growing in a foreign environment).

XMRV is a member of the same family of retroviruses as the AIDS virus. A retrovirus inserts itself into the host’s genetic material by copying its genetic code into the DNA of the host by using RNA and once there, it stays for the life of the host.

It is understood that Mikovits’ discovery was deemed to be of such magnitude by the world’s most prestigious science journal that the authors’ paper (which was submitted on 6th May 2009) was sent to three times the customary number of referees prior to acceptance and publication.

Shortly before the Mikovits et al paper was published, on 24th September 2009 the Whittemore Peterson Institute (WPI) announced that Dr Mikovits and collaborator Dr Jonathan Kerr of St George’s, London, had been awarded a $1.6 million five-year grant by the US National Institute of Allergy and Infectious Diseases for research into the causes and diagnosis of neuro-immune diseases ( ). The Project Number is 1R01A1078234-01A2 and the description provided by the applicants says: “CFS is a complex disease estimated to affect between 0.5% - 2% of the population of the Western world. Its pathogenesis is thought to involve both inherited and environmental (including viral) components, as with other chronic inflammatory diseases such as multiple sclerosis…Consistent with this chronic inflammatory context, CFS patients are known to have a shortened life-span and are at risk for developing lymphoma. We hypothesise that chronic inflammatory stimulation from active and recurrent infections of multiple viruses on a susceptible host genetic background leads to the pathogenesis characterised by CFS. The overall goal of this research project is to define those viral and host parameters…The proposed research will provide significant insight into the disease mechanism of Chronic Fatigue Syndrome so accurate testing and specific treatments can be developed with a goal of curing the disease and preventing life-threatening complications” (Co-Cure NOT:RES:21st October 2009).

It is worth noting that three days before the Mikovits et al article was published in Science, on 5th October 2009 Professor Peter White in collaboration with Dr Bill Reeves of the CDC published a paper in which they described endophenotypes of CFS (which White talked about in his presentation at Bergen on 20th October 2009 – see below). According to Wikipedia, “endophenotype” is a psychiatric concept, the purpose of which is to divide behavioural symptoms into separate phenotypes with clear genetic connections. The relevance of this to the neuro-immune disease ME/CFS has not been explained, but White and Reeves et al concluded: “The data do not support the current perception that CFS represents a unique homogeneous disease” (Population Health Metrics 2009:7:17doi:10.1186/1478-7954-7-17).

In contrast, in their article in Science Mikovits et al deal with science, not speculation:

Chronic fatigue syndrome (CFS) is a debilitating disease of unknown aetiology that is estimated to affect 17 million people worldwide.

Studying peripheral blood mononuclear cells (PBMCs) from CFS patients, we identified DNA from a human gammaretrovirus (XMRV) in 68 of 101 patient (67%) compared to 8 of 218 (3.7%) healthy controls” (gammaretroviruses are known to cause cancer, immunological and neurological diseases in animals).

Cell culture experiments revealed that patient-derived XMRV is infectious and that both cell-associated and cell-free transmission of the virus are possible”.

CFS affects multiple organ systems in the body. Patients with CFS display abnormalities in immune system function, often including chronic activation of the innate immune system and a deficiency in natural killer (NK) cell activity. A number of viruses, including ubiquitous herpesviruses and enteroviruses have been implicated as possible environmental triggers of CFS. Patients with CFS often have active herpesevirus infections, suggesting an underlying immune deficiency.

The recent discovery of a gammaretrovirus, XMRV, in the tumour tissue of a subset of prostate cancer patients prompted us to test whether XMRV might be associated with CFS. Both of these disorders, XMRV-positive prostate cancer and CFS, have been linked to alterations in the antiviral enzyme RNase L” (as noted above, RNase L is the terminal enzyme in the 2-5A synthetase/RNase L antiviral pathway in the immune system. It plays an essential role in the elimination of viral mRNA. Deregulation of this pathway in subsets of ME/CFS patients has been reported extensively in the scientific literature. In ME/CFS, a wide spectrum of cleavage of RNase L is observed, a phenomenon also seen in MS patients, and such altered RNase L activity profoundly affects cellular physiology, including apoptosis or programmed cell death – Dr Neil Abbot: Co-Cure RES:MED: 16th October 2009).

Neurological maladies and immune dysfunction with inflammatory cytokine and chemokine up-regulation are some of the most commonly reported features associated with CFS…The presence of infectious XMRV in lymphocytes may account for some of these observations of altered immune responsiveness and neurological function in CFS patients.

In summary, we have discovered a highly significant association between the XMRV retrovirus and CFS.

This observation raises several important questions. Is XMRV infection a causal factor in the pathogenesis of CFS or a passenger virus in the immunosuppressed CFS patient population?…Conceivably these viruses could be co-factors in pathogenesis, as is the case for HIV-mediated disease, where co-infecting pathogens play an important role. Patients with CFS have an elevated risk of cancer.

It is worth noting that 3.7% of the healthy donors in our study tested positive for XMRV sequences. This suggests that several million Americans may be infected with a retrovirus of as yet unknown pathogenic potential”.

The published supplementary material confirms: “Banked samples were selected for this study from patients fulfilling the 1994 CDC Fukuda Criteria for Chronic Fatigue Syndrome and the 2003 Canadian Consensus Criteria for Chronic fatigue syndrome / myalgic encephalomyelitis and presenting with severe disability”.

Commenting on this discovery, Professor John Coffin from the Department of Molecular Microbiology, Tufts University, Boston, a National Academy of Sciences member and expert retrovirologist who edited the 1997 reference book “Retroviruses” (proclaimed as “outstanding” by the New England Journal of Medicine) who was not involved with the study and who was at first highly sceptical but who was converted by the WPI team’s independent lines of evidence, together with Jonathan Stoye from the UK National Institute for Medical Research, Mill Hill, London, (who is Head of the Virology Division at the Medical Research Council), stated:

Although chronic inflammation is often found in these patients, no infectious or toxic agent has been clearly implicated in this disease….Chronic fatigue syndrome is not the first human disease to which XMRV has been linked. The virus was first described about three years ago in a few prostate cancer patients and recently detected in nearly a quarter of all prostate cancer biopsies. It has been isolated from both prostate cancer and chronic fatigue syndrome patients, and is similar to a group of endogenous murine leukaemia viruses (MLVs)…There is more than 90% DNA sequence identity between XMRV and xenotropic MLV, and their biological properties are virtually indistinguishable.

There are several lines of evidence that transmission happened in the outside world and was not a laboratory contaminant. One is that XMRVs from disparate locations and from both chronic fatigue syndrsome and prostate cancer patients are nearly identical…Other evidence includes the presence of XMRV and high amounts of antibodies to XMRV and other MLVs in chronic fatigue syndrome and prostate cancer patients.

Two characteristics of XMRV are particularly noteworthy. One is the near genetic identity of isolates from different diseases and from individuals in different parts of the United States. The two most distantly related genomes sequenced to date differ by fewer than 30 out of about 8,000 nucleotides. Thus, all of the XMRV isolates are more similar to each other than are the genomes isolated from any one individual infected with the human immunodeficiency virus.

Another notable feature of XMRV is that the frequency of infection in nondiseased controls is remarkably high.

If these figures are borne out in larger studies, it would mean that perhaps 10 million people in the United States and hundreds of millions worldwide are infected with a virus whose pathogenic potential for humans is still unknown”

( ).

Announcing their groundbreaking discovery, a press release by R&R Partners on behalf of the Whittemore Peterson Institute said: “Since the original Science paper was submitted, we have continued to refine our test for XMRV and have surprisingly found that 95% ME/CFS samples tested positive for XMRV antibodies in the plasma. ‘This finding clearly points to the retrovirus as a significant contributing factor in this illness’ said Judy Mikovits, director of research for WPI. This landmark study was the first to isolate XMRV particles from the blood and show that it can be transmitted between blood cells. Researchers have confirmed that this retrovirus is transmitted through body fluids and is not airborne”

( ).

Commenting on this further information, ME/CFS expert Dr Paul Cheney said: “The finding of antibody or active virus in 95% of CFS and 4% of controls is a result that argues for causality, in my opinion….This retrovirus could easily …induce all manner of pathogens as seen in CFS (and) could corrupt the gut ecology …observed in CFS and lead to environmental illness as well. Time will tell, but I think Dr Mikovits is right to suspect causality

( ).

On the day that the news broke of the XMRV link with ME/CFS, it was widely reported; prominent sources included AFP; Reuters; Wall Street Journal; Washington Post; New York Times; Nature; Scientific American; New Scientist; NIH News; Science News; NCI Press Release; Scientist, and many national newspapers such as the UK’s Daily Telegraph and The Independent.

The Wall Street Journal quoted Judy Mikovits as saying that the XMRV virus creates an underlying immune deficiency which might make people vulnerable to a range of diseases, and it continued: “Although Thursday’s scientific paper doesn’t demonstrate conclusively that XMRV is the cause of CFS, additional unpublished data make it a very strong possibility…’Just like you cannot have AIDS without HIV, I believe you won’t be able to find a case of CFS without XMRV’ Dr Mikovits said. …Dr Mikovits also said they also found XMRV in people with autism, atypical multiple sclerosis and fibromyalgia…Robert Silverman, a professor at the Cleveland Clinic Lerner Research Institute who is one of the co-authors of the study and one of the discoverers of the XMRV virus, said ‘in most cases, people’s immune systems are probably able to control the virus’….Researchers are already starting to test anti-retroviral therapies developed for AIDS to see if they are effective against XMRV”.

AFP (Agence France Presse) quoted Mikovit’s co-author Francis Ruscetti of the Laboratory of Experimental Immunology at the National Cancer Institute: “These compelling data allow the development of a hypothesis concerning a cause of this complex and misunderstood disease, since retroviruses are a known cause of neurodegenerative diseases and cancer in man”. The AFP report continued: “Retroviruses like XMRV have also been shown to activate a number of other latent viruses. This could explain why so many different viruses…have been associated with CFS”.

The NIH National Cancer Institute’s press release (“Consortium of Researchers Discover Retroviral Link to Chronic Fatigue Syndrome”) said: “Scientists have discovered a potential retrovirus link to chronic fatigue syndrome….’We now have evidence that a retrovirus named XMRV is frequently present in the blood of patients with CFS. This discovery could be a major step in the discovery of vital treatment options for millions of patients’ said Judy Mikovits, leader of the team that discovered this association….The virus, XMRV, was first identified by Robert H Silverman, professor in the Department of Cancer Biology at the Cleveland Lerner Research Institute…The research team not only found that blood cells contained XMRV but also expressed XMRV proteins at high levels and produced infectious viral particles…These results were also supported by the observation of retrovirus particles in patient samples when examined using transmission electron microscopy. The data demonstrate the first direct isolation of infectious XMRV from humans….Retroviruses like XMRV have also been shown to activate a number of other latent viruses. This could explain why so many different viruses…have been associated with CFS. Dan Peterson, medical director of WPI, added: ‘Patients with CFS deal with a myriad of health issues as their quality of life declines. I’m excited about the possibility of providing patients who are positive for XMRV (with) a definite diagnosis and, hopefully very soon, a range of effective treatment options’


Science News pointed out: “The researchers also show that the retrovirus can infect human immune cells’This is a very striking association – two thirds of the patients’ says John Coffin, a virologist at Tufts University in Boston….Mikovits asserts that the retroviral infection might result in an immune deficiency that leads to chronic fatigue symptoms. Retroviruses are known to attack the immune system, with HIV being the best-known example. In this study, researchers showed that XMRV infected immune cells in the blood…Retroviruses can awaken latent viruses already in cells. It is possible that symptoms are caused not by XMRV but by other viruses that it activates”.

The Scientific American noted: “Chronic fatigue…is a misnomer. The syndrome often has more to do with immune system abnormalities than pervasive tiredness…XMRV has recently been linked to strong cases of prostate cancer. Like CFS, this cancer involves changes in an antiviral enzyme (RNase L)…To find the virus, Mikovits and her team studied documented cases, such as CFS outbreaks in a symphony orchestra in North Carolina and in Incline Village, Nevada. ‘We found the virus in the same proportion in every outbreak’, she says….Experiments in Mikovits’ lab proved that the retrovirus can be transmitted via blood by infecting healthy cells drawn from volunteers with material from XMRV-positive CFS patients”.

Ewen Callaway (New Scientist) also quoted Mikovits as confirming that her team had found antibodies against XMRV in 95% of nearly 300 patients they tested, but these further results have yet to be published in a journal. Antibodies are a more sensitive test than looking for viral genes, as they pick up people who have had XMRV in the past, not just those who still have it. Callaway noted that Mikovits also pointed out a very significant fact: not only do characteristics of the virus match the symptoms of (ME)CFS, but viruses related to XMRV can cause blood vessels around the body to leak, a common symptom of (ME)CFS. Quoting Jonathan Kerr of St George’s University of London, Callaway said: “ ’XMRV infection of natural killer cells may affect their function…This does fit’ ”. Callaway continued: “That sentiment is echoed by John Coffin…’This looks like a very, very interesting start’, he says. ‘It’s not impossible that this could cause a disease with neurological and immunological consequences’ “.

The UK’s Daily Telegraph proclaimed on 9th October 2009: “Most cases of chronic fatigue syndrome or ME may be linked to a virus, according to research that could lead to the first drug treatments for the disorder that affects millions around the world…Symptoms…can be as disabling as multiple sclerosis…Dr Mikovits’ team said further research must now determine whether XMRV directly causes CFS, is just a passenger virus in the suppressed immune systems of sufferers or a pathogen that acts in concert with other viruses that have been implicated in the disorder by previous research”.

Also on 9th October 2009, The Independent’s Science Editor, Steve Connor, reported the ground-breaking research on the front page. He said that Dr Judy Mikovits, senior author of the study and Director of Research at the Whittemore Peterson Institute in Reno, Nevada, had confirmed that “further blood tests have revealed that more than 95% of the patients with the syndrome have antibodies to the virus, indicating that they have been infected with XMRV…’With these numbers, I would say yes, we have found the cause of chronic fatigue syndrome. We also have data showing that the virus attacks the human immune system’ ”. Connor reported that Dr Mikovits is testing a further 500 blood samples gathered from chronic fatigue syndrome patients diagnosed in London. “ ’The same percentages are holding up’ she said”.

Of note is that the UK’s NHS Knowledge Service (for several years the NHS has persisted in including ME/CFS in its mental health minimum dataset despite frequent requests to categorise it correctly) said: “CFS affects a range of organs in the body, and patients show abnormal immune system function…one theory is that certain viruses trigger the disease…Overall, samples from the people with CFS were 54 times as likely to contain viral sequences as samples from healthy controls”

( ).

On 8th October 2009 Hillary Johnson, outspoken author of “Osler’s Webb: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic” (Crown Publishing Inc, New York, 1996), was blunt: “A generation of quacks and sub-par investigators will be in retreat…The real scientists have arrived and they’ll be studying XMRV- associated neuro-immune disease, (i.e.) XAND….the Whittemore Peterson Institute and its collaborators have turned a 20-year crime story back into a science story. Mikovits found XMRV in a sample of frozen blood that had been saved by Dan Peterson as long ago as 1984. The blood happened to have been drawn from a patient who went on to die of mantle cell lymphoma, another disease XMRV is suspected of causing…the failure of the Centres for Disease Control to respond professionally and rationally when presented with a novel retrovirus in patients and their close contacts in 1991 by Elaine De Freitas needs to be revisited immediately…We’ve monitored the agency’s wilful ignorance of – indeed, their extreme hostility to – the science in this field….if it turns out that their failure to replicate Elaine de Freitas’ findings of a novel retrovirus in this disease, followed by their attempt to destroy her professional reputation, was purposeful, then…the CDC is as much a crime scene as it is a federal science agency. How could our government and the governments of other nations dismiss and then ignore millions who suffered from ‘an infectious disease of the brain’ as Hilary Koprowski of the Wistar Institute called it publicly in 1992. Koprowski was an expert in neurological diseases – he knew one when he saw one…they will talk about the dangers of scientific bias and the near-criminal manner in which a disease could be defined, for so long and in spite of so much contrary evidence – as a personality disorder…The years of our lives during which thousands of research papers were written by psychiatrists purporting to explain away a life-destroying disease with discussions of personality disorders, exercise and activity phobia, malingering, hysteria, sexual abuse, school phobia, attention-seeking behaviour must be respected (and) the papers saved for posterity. Princeton English professor Elaine Showalter’s book equating this disease with fantasies of alien abduction probably deserves its own shelf in this pantheon of the grotesque…All these works will be examined, in time, by researchers who seek to understand the human capacity for delusion, ignorance and greed

( ).

Particularly notable was the BBC’s reporting of the comments of Tony Britton, the (lay) Publicity Manager at the UK ME Association: “This is fascinating work, but it doesn’t conclusively prove a link between the XMRV virus and chronic fatigue syndrome or ME”, a statement that should be compared with what was published in Science: “we have discovered a highly significant association between the XMRV retrovirus and CFS” and with the WPI press release: “This finding clearly points to the retrovirus as a significant contributing factor in this illness”.

It is regrettable that the UK ME Association’s Publicity Manager seems not to distinguish between proving a conclusive cause and proving a direct link, a link that certainly satisfied the many prestigious referees who advised the journal Science.

It also satisfied Richard T Ellison III, Professor of Medicine, Molecular Genetics and Microbiology in the Division of Infectious Diseases and Immunology at the University of Massachusetts Medical School (Deputy Editor of Journal Watch Infectious Diseases since 1988), who commented: “These studies provide clear evidence that active XMRV infection occurs in many CFS patients” (Co-Cure RES: 22nd October 2009).

Moreover, as Hillary Johnson reported in the New York Times on 21st October 2009, Judy Mikovits had worked for the National Cancer Institute for 22 years and she was impressed that Dan Peterson “had built an extraordinary repository of more than 8,000 chronic fatigue syndrome tissue samples going back as far as 1984…What (Mikovits) found was live, or replicating, XMRV in both frozen and fresh blood and plasma, as well as saliva. She has found the virus in samples going back to 1984 and in nearly all the patients who developed cancer. She expects the positivity rate will be close to 100% in the disease. ‘It’s amazing to me that anyone could look at these patients and not see that this is an infectious disease that has ruined lives,’ Dr Mikovits said. She has also given the disease a properly scientific new name: X-associated neuroimmune disease (XAND)”.

On 20th October 2009 Judy Mikovits herself was interviewed; she said: John Coffin is a member of the US National Academy of Sciences. No greater authority on these viruses exists. Three members of the US National Academy of Sciences reviewed this work and all are convinced of the sciencethey are convinced of the infection and the public health risk

( ).

Interviewed live by Rene Montagne, when asked why people thought sufferers don’t really have a disease, Dr Daniel Peterson, medical director of the WPI, was clear: “I think the reason for that is the abnormalities of the immune system are initially very subtle. And if a physician does just routine testing – you find they’re normal. It isn’t until you look at the immune system that you realise there’s substantial dysregulation…It’s very similar to asymptomatic carriers of HIV. They look just fine until time passes and their illness evolves and more symptoms are found. But I never felt this was predominantly a psychiatric disease or malingering. There was never any evidence to support that theory…Once it was demonstrated that the patients had impairment of the natural killer cells function, regardless of what country they were in, we knew that there was immune impairment…Back in the 1990s, I was associated with Temple University and researchers (who) looked at the antiviral pathway…found very substantial abnormalities in the patients who had chronic fatigue syndrome. And the illness is totally compatible with a viral illness that just doesn’t go away” ( ).

Following the (re)discovery of a direct link between a retrovirus and ME/CFS, there has been much internet traffic about the dismissing and ignoring by US agencies of state of Dr De Freitas et al’s work two decades ago that demonstrated a potential retroviral link, particularly in relation to possible transmission via blood products.

This down-playing has been ascribed by some people to (i) a possible UK/US collaboration over the use of biowarfare agents, including borrelia (“US Government Admits Lyme Disease Is A Bioweapon”: ), (ii) the CDC’s apparent determination to prevent at any cost public panic over the emergence of another AIDS-like pandemic and (iii) the wish to protect insurers from having to make payments for another chronic disease, factors that may be instrumental in Dr Bill Reeves’ dismissive comments about the latest discovery of an association between a retrovirus and ME/CFS:

  • the journal Nature reported: “William Reeves, principal investigator for the Centres for Disease Control and Prevention (CDC)’s CFS public health research programme, says the findings are ‘unexpected and surprising’ and that it is ‘almost unheard of to find an association of this magnitude between an infectious agent and a well-defined chronic disease, much less an illness like CFS…Until the work is independently verified the report represents a single pilot study’. He also notes that CFS…likely arises from a combination of many factors”

  • the Los Angeles Times also reported Reeves’ comments, adding his comment that: It is extremely difficult to prove causation with a ubiquitous virus like XMRV, and it ‘is even more difficult in the case of CFS, which represents a clinically and epidemiologically complex illness’ he said. Unfortunately, Reeves said, the major flaw of the study is that there is not enough information about how subjects were selected to rule out any bias in choosing them”

  • the New York Times (13th October 2009) reported Reeves as saying “he was surprised that a prestigious journal like Science had published it….We and others are looking at our own specimens and trying to confirm it…If we validate it, great. My expectation is that we will not’….Many patients and a community of doctors and researchers who specialise in the syndrome take issue with the (CDC’s) approach to the illness and the way it defines who is affected. They claim that the CDC includes people whose problems are purely psychiatric, muddying the water and confounding efforts to find a physical cause” (it is the case that the CDC now uses Reeves’ own (2005) definition that does not distinguish between CFS and major depressive disorder, so it is to be anticipated that the CDC will not replicate the Mikovits et al findings).

Against this background, there are mounting calls for the removal of Dr Reeves from his position as principal investigator of the CDC’s CFS research programme (“Support the 500 Professionals of the IACFS/ME – Reeves Must Go”):

On May 27th and May 28th, 2009, the Chronic Fatigue Syndrome Advisory Committee (CFSAC) convened in Washington, D.C. Among their recommendations to the Secretary of Health and Human Services was a call for new and progressive leadership at the CDC's ME/CFS research division. Under Bill Reeves' regime, funding has routinely decreased and increasingly broad definitions which have ceased to have any clinical meaning or research value have been implemented…. Under Reeves' direction the CFS program is being slowly strangled…. What does Reeves say about Mikovits’ recent discovery? Without doing any study or due diligence, Reeves dismisses the findings Inaccurate stereotypes persist because Bill Reeves has not been accurately educating the public on the
seriousness of this disease”
(Co-Cure ACT: 25th October 2009).


Comments such as that by Tom Kindlon from the Irish ME/CFS Association reflect the position of many in the international ME/CFS community: “What does he mean ‘much less an illness like CFS’? CFS is much more like a chronic viral disease than most chronic diseases. Why is he heading a programme based in the viral section of the CDC if he has this attitude? (Co-Cure ACT:8th October 2009).

In her customary robust manner, Hillary Johnson in the US is scathing about Bill Reeves: There isn’t anything Reeves said to the press that was scientifically correct, one of the scientists associated with this work told me recentlyHow about Bill’s comment, expressed to the New York Times, that he was ‘surprised’ a ‘prestigious journal like Science’ had published the study…Frank Ruscetti isolated the first human retrovirus infection HTLV (Human T-cell Leukaemia / Lymphoma Virus) at the National Cancer Institute 30 years ago. Bill thinks Ruscetti doesn’t know what he’s doing? Bob Silverman was a co-discoverer of XMRV; Silverman doesn’t know what he’s doing? Science was duped? Is he kidding? Bill also suggested the paper didn’t mean much because he, Bill, didn’t know how the patients were selected. The patients were clinically defined by every medical criteria, including the CDC’s. What more does Bill want? By now, most will have heard about Bill’s comment that XMRV is a ubiquitous virus. That must have been a whoo-hoo moment for the Science collaborators. These collaborators didn’t just arrive on the scene last month…they knew going into this work what the CDC did to Elaine De Freitas and her retrovirus finding in 1991. They understood the politics. They were aware of the agency’s multi-million dollar propaganda war on a million very sick people. They were prepared. They CDC-proofed this study. The rigour in the Mikovits-Ruscetti-Silverman paper was such that Science had to take the paper” (Co-Cure NOT: 25th October 2009).

Notably, Dr Stuart Le Grice, head of the Centre of Excellence in HIV/AIDS and cancer virology at the National Cancer Institute went on record saying: “NCI is responding like it did in the early days of HIV” (in other words, by dismissal and denial of the significance). As Cort Johnson observed: “Neither the CDC nor the NIH (with the exception of NK cells) have shown any interest in pathogens of the immune system in over ten years. Research into ME/CFS has declined precipitously in both institutions over the past five years” ( ).

In response to an article in Nature by Lizzie Buchen who quoted Judy Mikovits as saying: “I can’t wait to be able to tell my patients…It’s going to knock their socks off. They’ve had such a stigma. People have just assumed they were just complainers who didn’t handle stress well”, a comment posted on Nature News by John Smith captures the reality: “The nature of this seriously disabling disease has taken so long to establish because of the paucity of serious biomedical research into the condition and the failure of government to support such research. As a scientist who has suffered from it for over 25 years following viral infection I have watched, appalled, as scientific politics have deflected funding away from biomedical studies towards psychosocial ones. This is nothing short of a scientific scandal” ( ).


In the UK, Simon Wessely is similarly unpopular, and for similarly well-founded reasons. On 5th February 1999 the New Statesman carried an article by Ziauddin Sardar about Wessely (Ill-defined notions) in which Sardar wrote:

Once upon a time, if you were sick, you were really sick. You had a collection of recognisable symptoms. Now if you are ill there may not be a ‘cause’. You may be suffering from something but you may not be ill at all — according to the medical establishment anyway (because) the ‘cause’ of some illnesses is better seen as a lifestyle than a pathogen.

Sickness is no longer simply a personal matter; it has become social, political, bureaurocratic….When is someone sick, really sick? Who decides? By what criteria and procedures?…The only thing that is certain is that the patient himself / herself has little power and cannot answer any of these questions. You are ill only when someone says you are ill.

Consider syndromes. Once this was a name for a collection of symptoms for which no clear cause had yet been found. Now it stands for a bunch or bunches of symptoms lacking even the security of certainty that they are actually there…Most notorious is “chronic fatigue syndrome”. At the far extreme, it is known as “ME”…From its first recognition as a large-scale problem....horror stories abound of people (some of them children) whom the medical and psychiatric experts considered to be just faking...

The same can be said of Gulf War syndrome.…again, there are lots of nasty symptoms: mild to moderate chronic fatigue, double vision, severe urinary and sexual problems, memory loss, joint and muscular pain — to start with…But even though 400 veterans have actually died and some 5,000 are suffering from illnesses related to Gulf War syndrome, the syndrome does not officially exist.

All the actors involved in this drama have their own perspective.…the government with avoiding paying compensation at all costs. So one would expect the Ministry of Defence to deny the existence of Gulf Way syndrome and it does, operating on the simple basis of “no bug, no dosh”.

...this makes life very hard for sufferers. They not only have to survive their disease: they must also fight for elementary decency. And that is a long and bitter task in itself.

But what of researchers? Why should they deny the existence of Gulf War syndrome? The struggle over recognition hinges on research. But this research is a totally different exercise...How do you investigate this mess of symptoms? Not with biochemistry, but with psychiatry.

The new societal syndrome of syndromatic diseases requires a new speciality, a syndromologist. Fortunately, one is to hand. His name is Professor Simon Wessely, consultant psychiatrist at the School of Medicine, King’s College, London.

Wessely has been arguing that ME is a largely self-induced ailment that can be cured by the exercise programme on offer at his clinic.

Recently he published the results of “the most definitive study” of Gulf War syndrome in.. .the Lancet... .It concluded — surprise, surprise — that there is no such thing as Gulf Way syndrome.

So Wessely, who occupies a key position in our socio-medical order, denies the existence of Gulf War syndrome, just as he denies the existence of ME.

Clearly, he is a follower of Groucho Marx: ‘Whatever it is, I deny it’. Not surprisingly, lots of people hate him.

If Simon Wessely is our syndromologist-in-chief, who has chosen and vetted him for that post, and by what criteria and procedures? Where is the debate over the shaping of such research?…When will we have the first officially sponsored study of such a problem which the sufferers do not have the occasion to call a whitewash?”.

Since at least 1994, when the CFIDS Chronicle published an article titled “The Views of Dr Simon Wessely on ME: Scientific Misconduct in the Selection and Presentation of Available Evidence?” (Spring 1994:14-18) valid criticisms of Wessely have continued to mount, some of which can be accessed on .

In his article in New Scientist on 9th October 2009 (referred to above), Ewen Callaway noted Professor Wessely’s position regarding the discovery of XMRV in CFS patients: “Wessely points out that XMRV fails to account for the wide variety of other factors associated with the CFS, including childhood trauma…’Any model that is going to be satisfactory has to explain everything, not just little bits’ he says”. Wessely’s belief that childhood trauma causes ME/CFS takes no account of those who had a happy, secure childhood within a stable and loving family but who still developed severe ME/CFS.

Similar points are reflected in the many online comments posted to the New Scientist. These were highly critical of Wessely’s dismissive attitude, and provided examples of the adverse impact on patients of his ill-grounded beliefs about ME/CFS, for example:

Dr Wessely had the chance to prove he had some kind of humility with regard to his disgraceful behaviour towards ‘CFS’ ”

Now if that’s not the sound of a desperate drowning man clinging to the sinking wreckage of his fatally flawed theory for ME. Give it up, Wessely, sink to the bottom of the sea, vanish without trace. The time has come once and for all to banish these primitive psychological theories to the dustbin of medical history, where they so rightfully belong”

Completely agreed – Simon Wessely, the medical establishment and local authorities that have taken children into care, sectioned adults, forced harmful treatment, ruined lives, should be made to apologise to every single one of their victims, not only here but worldwide”

Holding a different evidence-based view-point is one thing – ignoring evidence and letting ego condemn patients to grotesque suffering and death as a physician is evil and should be dealt with as such”

I look forward to seeing the psychological research by Professor Wessely published in the journal Science”

I was diagnosed with ME in 1992–3…I’m a former clinical specialist in life-support technology, qualified in medicine, perfusion science and life-support technology, so I know a bit about all this. I empathise with anyone who has genuinely suffered this condition, especially when they have not had good treatment from their own doctors”

To the Editor: It remains a mystery as to why you bother including the unsubstantiated opinion provided by Dr Simon Wessely. He continues to profit from the prescription of cognitive therapy for this serious illness, despite the fact that the majority of patients fail to benefit from such interventions. By any other model, insistence upon cognitive therapy as the default model for treatment should constitute malpractice”

I saw on my doctor’s notes that the symptoms were all in my ‘mind’. This was despite a low white cell count, inflamed spleen and swollen lymph nodes. Yep, the low white cell count was because of my ‘mind’. If they dismissed cancer this way the overpaid morons would be sued for malpractice;

Those physicians may have some red-faced explaining to do if this research pans out”

“ ’Red-faced’ – no, they should be sued for negligence. Sorry, but I was damn near killed by such idiocy so I have not the slightest sympathy for such bigoted physicians…I want several prominent persons responsible for this terrible abuse of millions of ill people across the globe criminally charged and tried for negligence…Many people have DIED because of this, either by direct abuse by doctors, or by disdainful refusal to aid, or actively preventing research into physical causes. Sophia Mirza is only one such victim, most others just sank without trace as it was ‘inconvenient’ and their death or suicides were ‘all their own fault as it was all in their heads’. But when a physician deliberately ignores his duties because of prejudice – that, sir, is ABUSE. Imagine how an MS sufferer would feel if they were ignored, abused, even sectioned by the very physician who swore an oath to help them. And then the very person at the top of the pyramid of abuse was allowed to publish articles about MS…”

But, Simon, you said they thought themselves sick…Wessely points out that XMRV fails to account for the wide variety of other factors associated with the CFS, including childhood trauma….but Professor Wessely was quite happy to lead nations to think that these unfortunate people were all suffering from ‘abnormal illness beliefs’. Why was he so happy to ignore biomedical research which demonstrated that this disease was not a mental illness?”

Simon Wessely…(has) a lot to answer for…I have yet to meet someone with ME who hasn’t inspired me with their strength. It’s just a shame there is so much to fight against”

The idea that ME was somehow linked to childhood trauma was always nonsense…Way back when I was first ill, researchers were looking for a retrovirus. The problem was that no-one would fund them and allow then to continue their work. They were repeatedly turned down and their work blocked. This retrovirus should have been discovered at the same time as AIDS and the last few miserable decades of my life could have been avoided…No more excuses and no more psychobabble”

Tragically for sufferers, the psychological zealots are ruling the asylum and they have steered successive definitions away from viral, inflammatory disease and to their beloved ‘unexplained fatigue’ and disingenuous ‘psychological factors’. Mediocre findings of CBT/GET have been spun more than a New Labour carousel leading a character assassination on the ME community, creating an ideological distortion of the very presentation of the disease, whereby misled doctors dismiss such unfortunate patients as ‘pond life’ or ‘ME lunatics’ and deny even the most severely affected (eg bedbound) patients access to investigation, treatments, monitoring, advocacy and education of social and welfare support networks, while taking no interest in/dismissing the literature themselves. Cue great neglect, suffering, exploitation, wasted generations and premature deaths. Will the psych/med profession apologise? Just as with past outrages against multiple sclerosis (and) Parkinsons, will they hell”


Other similar comments about Wessely were posted in response to The Independent’s coverage of the XMRV discovery, for example:

This is the time for Simon Wessely to walk away and shut the door. We don’t want to see him ever again mentioned in relation to this disease. Didn’t he read the news – 500 blood samples form London are being tested and the figures are holding up…I have spent my entire adult life with this disease and I would like to have some illness-free years before I die. The UK government and medical research council squandered millions chasing a psychological cause”

I know as bad as things are in the U.S. in regard to ME, the UK seems even worse. That Wessely guy is a total moron. This disease has so many consistent biological abnormalities across the ME/CFS population and they are continually being ignored. Will these people ever listen?”

Wessely, it is time for you to accept the truth and give up. I have had ME for 7 years and it has completely consumed my life. Money put into the research has been very limited, mostly due to the political connections of Wessely, his partner and the labour party. I know. I worked in there (Wessely’s wife was / is a senior policy advisor to the Department of Health; she is Vice Chair of Council of The Royal College of General Practitioners and is Chair of the RCGP Medical Ethics Committee)

It’s in Simon’s mind: I have lost 15 years to CFS and exhortations that CBT and graded exercise (which I have done in spades) have on more than one occasion pushed me to the edge…What a pathetic scam to let millions suffer on a pretence”

I wholeheartedly agree with comments made against Simon Wessely. His title says it all – professor of psychological medicine. Unfortunately there are a great many people like him who have held back the frontiers of modern research by dismissing the findings and instead promoting psychological causes”

Mr Wessely’s views. Time to put your cards on the table. I find it interesting that Wessely is so keen to keep ME ‘all in the mind’, especially with a growing mass of evidence to suggest otherwise. I’d like to see his funding resources revealed…I’m sure that behind closed doors there is more going on to douse the flame of truth than we actually know about”

I was very saddened to read Simon Wessely’s comments…and personally feel that the psychological explanation for ME/CFS is far from satisfactory”

I worked in the Civil Service for both Jacqui Smith and Alan Johnson (the former was Home Secretary and the latter was Secretary of State for Health). Once I became disabled with CFS I was horribly bullied by the Civil Service. It was a truly terrible time, trying to cope with a life-altering disability and an employer who did not care”.

On other sites (for example;, people recalled what Wessely has said and published about ME/CFS in the past, for example:


What lies behind all this talk of viruses and immunity?…..Talk of viruses and the immune system is now embedded in popular consciousness….Viruses are an attribution free from blame…there’s no blame, no shame and no stigma….And (mocking) here is the virus research doctor himself to protect us from that shame….And what is it he delivers? Respect” (Microbes, Mental Illness, the Media and ME: The Construction of Disease. 9th Eliot Slater Memorial Lecture, Institute of Psychiatry, 12th May 1994).

Wessely sees viral attribution as somatisation par excellence” (Helen Cope, Anthony David, Anthony Mann. Journal of Psychosomatic Research 1994:38:2:89-98).

In her exposition of the role of the late Dr Stephen Straus of the NIH in what seems unquestionably the ”cover-up” of ME/CFS by US agencies of state (PERP Walk: A Reality Crime:, Hillary Johnson supplies quotations of Straus’ own words in which he provided thousands of doctors with the “official” US government line on “CFS” (ie. that people who developed CFS had a life-time history of psychiatric illness, a view that was sent to approximately 500 reporters and news organisations, including television networks and the science and government writers for every major newspaper and wire service). This was based on a study of just 28 participants, one of whom (psychoanalyst Susan Simon) talked of suing Straus for medical malpractice; in 1993 she was killed instantly when a truck collided with her motorised scooter on a New York city street.

One comment about Johnson’s article on Straus may be pertinent:

Just because one is blessed with a keen mind and is granted a position of importance, it very obviously does not preclude the psychopaths, the bigots, the narrow minded or just plain xenophobic from taking control of areas of public office that have great bearing upon everyone’s lives. And then there is Straus – who fits the bill for all of the above – and of course he carried the child-like characteristic of being unable to accept that he was wrong…It is just a shame that people have to die for those with ME/CFS to get an answer. And by that I mean that people such as Straus should step out of the way when they have no answer. Wessely should. White should. Sharpe should”.

In a reply to someone who wrote to him on 12th November 2009 asking for his response to the XMRV findings, Wessely replied: “Could be a real breakthrough, even if I still don’t understand how they made the leap from prostate cancer to CFS”, which seems to indicate that Wessely remains ignorant of or else does not understand what Judy Mikovits et al said: “both are linked to alterations in the antiviral enzyme RNase L”, a link that was clearly explained by David Bell in his Lyndonville News, volume 6, number 2, October 2009: “XMRV was first linked to human disease by Robert Silverman PhD at the Cleveland Clinic in patients with prostate cancer who also had a defect in the RNase L antiviral pathway. As this pathway has been known to be abnormal in CFS, it was reasonable to search for the virus in CFS”. Wessely then seemed to deny the association with XMRV and cancer: “I am worried that 20% of the CFS patients seem to have lymphoma (ie cancer), which might be fascinating for our knowledge of cancer but really isn’t relevant for CFS. Apparently adopting the same stance as Bill Reeves in the US, Wessely continued: “I would be very surprised indeed if others find rates of XMRV at the same level as this paper” (Co-Cure ACT: 12th November 2009).

There is international recognition that Wessely “is employed by the Ministry of Defence and NATO (he chaired a committee on psychological responses to WMD – weapons of mass destruction) and heavily backed by corporate interests to deny the reality of chronic illnesses such as ME/CFS, Gulf War Illness, Lyme Disease, Multiple Chemical Sensitivity and others…Wessely’s name is known to the thousands of sufferers of chronic illnesses in Britain and abroad who have been hurt by his philosophy…For years Wessely has been the outspoken proponent of the view that chronic physical conditions such as Gulf War Illness, ME/CFS, fibromyalgia, Lyme Disease, MCS and others are simply ‘all in the head’ of the sufferer. This view has received great support from the Government and from the Army, both here and in America. It has also been enthusiastically promoted by insurance companies and the Department for Work and Pensions. Millions of public research funds have gone into the pockets of psychiatrists following the Wessely school of thought. The result: seriously ill patients have been denied recognition and treatment, disability benefits and dignity. They have been ridiculed by doctors and vilified in the press. Stigmatised by Wessely and his followers as malingerers, hypochondriacs, or simply ‘mad’, sufferers of chronic physical illnesses have been left untreated for years, sometimes ending up paralysed, amnesic or even dying. Some commit suicide under the pressure of isolation and never-ending pain. Providing no evidence base for his conclusions, Wessely nevertheless rides roughshod over published medical studies linking vaccine damage, chemical exposure etc with Gulf War Illness (and) toxic chemical exposure (and) viruses with fatiguing illnesses. He does not disprove the evidence of physical causes for these diseases – he just ignores it



As long ago as 1998, in his article “Dr Simon Wessely: Prophet or Profit?”, Dr Ken Jolly, a GP in New Zealand who had to give up his medical practice because of ME/CFS, published his concern that Wessely et al had come to dominate thinking about ME/CFS even in New Zealand, saying that they had achieved such influence by producing vast volumes of papers on CFS and obtaining funding for their own work. Jolly was forthright:

I feel it is time sufferers in NZ became aware of his growing influence. The existence of this influence is no new to UK sufferers and it has affected how they are being treated, as well as their accessibility to aid and financial assistance. Clinicians with opposing views are being sidelined by most of the prestigious medical journals. Why this is so is unclear. Simon Wessely is very politically astute (and) has been able to sway many to his way of thinking. He has also developed a ‘patter’ which he uses to convince patients of the rightness of his model. In reality, this is a smokescreen which effectively covers his true underlying beliefs. But ‘the clincher’ for convincing many medical scientists of any theory is to back it up with reliable research data. He and his colleagues have ‘appeared’ to do this, almost putting an end to the oppositional cries from the physical camp. However, these trials have been flawed in every way imaginableUnfortunately people like Simon Wessely, in my opinion are not only using up large amounts of valuable research monies but are also diverting research along blind paths…I will now attempt to summarise Simon Wessely’s and colleagues’ views about ME. The reason I have chosen to mainly discuss Simon Wessely rather than the others of the group is because it so often appears that he is the mouthpiece for their statements”.

Dr Jolly then lists some of the more notorious of Wessely’s published views, including Wessely’s belief that CFS is merely the extreme end of normal fatigue which, as Jolly points out, totally ignores the cyclic nature of the disorder that is a pattern commonly seen in autoimmune diseases. Jolly also points out that Wessely’s claim that ME/CFS patients’ symptoms are caused by hypervigilance towards normal bodily sensations does not explain why the same symptoms are reported by thousands of patients worldwide (who may not even speak the same language). Jolly notes that many physically-based research findings “have frequently been ignored for the (Wessely) model to continue to fit”. Jolly is particularly scathing about Wessely’s view that patients perpetuate their own illness: “This is insulting to their intelligence. In my experience patients undergo enormous financial, social and relationship losses because of this illness. Additionally, they are prepared to go to almost any lengths to get better – NOT the actions of people perpetuating a condition associated with non-activity” ( ).

As Dr Jolly further noted: “The effect that Simon Wessely may have in the future on how doctors view ME cannot be underestimated. His viewpoint seems to have pervaded the thinking of the medical establishment in the UK. The most worrying aspect is that these theories suit those who are politically in charge and many institutions and governments are already being seduced to this way of thinking…Why Simon Wessely has pursued this theory with such tenacity somewhat eludes me. He has encountered massive opposition from many quarters”.

An internet search will quickly reveal that there is extensive outrage about Simon Wessely and his colleagues’ unproven beliefs, not only from ME/CFS patients and their long-suffering families, but also from international medical scientists and clinicians who are not blinded by ideology or vested interests.

In his article in The Independent on 9th October 2009 (referred to above), Steve Connor also quoted Professor Simon Wessely’s views on the implications of the XMRV discovery: “Other researchers emphasised that the numbers published so far are too small to conclude anything about the cause of chronic fatigue syndrome. ‘It’s spectacular but needs replicating. And I hope that no-one is thinking of prescribing anti-retrovirals on the basis of this, said Simon Wessely, professor of psychological medicine at King’s College, London. ‘It’s very preliminary and there is no evidence to say this is relevant to the vast majority of people in the UK with the condition’ ”.

However, in a Leading Article that same day, The Independent said:

“…for many years doctors argued that Chronic Fatigue Syndrome didn’t exist. They refused even to dignify it with the name Myalgic Encephalomyelitis. ME, they said, was just ‘me’ writ large… Scientists could be on the brink of a breakthrough. We must hope they are. That would – at least – go some way to compensating for the shameful manner in which sufferers were treated for so long by the medical profession”.

On 29th October 2009 Professor Coffin told a Department of Health and Human Services Committee that this discovery was of “potentially extraordinary importance”, not least, as Jack Johnson reported (Co-Cure NOT:16th November 2009), because it means validation and hope for millions of people suffering from (ME)CFS, often thought by many to be nothing more than the product of neurosis and even laziness and, as Jack Johnson pointed out: “CFS has long been thought to be linked to retroviral infection”.

As noted in “Denigration by Design? A Review, with References, of the Role of Dr (now Professor) Simon Wessely in the Perception of Myalgic Encephalomyelitis (Up-date) Volume II(, it seems that to Wessely and his closest associates, the belief of the moment represents the only truth.

They would do well to remember that in the early 1600s, King James of England (who was also King James VI of Scotland) wrote a book called “Demonology” and that book helped to send to their death women known as the Lancashire witches. Countless innocent women were persecuted, tortured and executed as witches, having been forced into admitting things they did not do, the majority being people who suffered from mental illness.

Incredibly, it was not until the 1950s that the Witchcraft Act was repealed in the UK. This must surely serve as a salutary reminder that the belief of the time (currently, that ME/CFS is a behavioural disorder) is not necessarily the truth, even though it might be promoted as the truth.

It is fair to say that the views of Wessely and his close colleagues (including those involved with the PACE Trial) are held in contempt by many people – medical and lay alike – who have to deal with the reality and severity of ME/CFS; yet injustice for those with ME/CFS continues. Cases of untold suffering and despair continue to accumulate, and this is very significantly because of the influence of the Wessely School.

One can but pray that along with his colleagues Peter White, Michael Sharpe and Trudie Chalder, Wessely’s power and influence – unlike that of demonology – will not remain enshrined for the next 350 years and that medical science may at last have provided the means to right the wrongs that the Wessely School have done so much to perpetrate upon those with ME/CFS.

That such wrongs exist in the US also is exemplified by the testimony of Kenneth Friedman on 30th October 2009 before the CFS Advisory Committee (Co-Cure NOT:MED: 4th November 2009). Friedman, a medical school professor at the Department of Pharmacology and Physiology, New Jersey Medical School, said:

I have been asked to comment upon the status of Chronic Fatigue Syndrome education in the United States.

The Director of the Office of Ethics and Compliance has informed me that my off-campus activities relating to CFS which include testifying before this Committee, serving on this Committee, providing continuing medical education courses, establishing medical student scholarships and assisting with healthcare legislation are not part of my responsibilities as a University Professor.

I am told that I will be punished with a penalty as severe as termination of my employment for these activities.

I am not a unique target. Colleague Ben Natelson (an ME/CFS researcher who was Professor in the Department of Neurosciences at New Jersey Medical School) has left the same school.

A different medical school has refused to permit access to their medical students to discuss CFS.

A statewide healthcare provider…refuses to permit a CFS training session for their physicians.

The failure of the CDC to convince the medical-academic establishment of the legitimacy of CFS, and the urgent need for its treatment, has created this environment”.

Could it be said that the Wessely School has created a similar environment in the UK and that the MRC PACE Trial is part of that constructed environment, just as the NICE Clinical Guideline and the actions of NICE which resulted in the failure of the Judicial Review were also part of it?

It is certainly the case that, to the great detriment of patients with ME/CFS, clinicians experienced in ME have been prevented from working in the “CFS” clinics that are often run by non-medical staff such as occupational therapists.

As Professor Leonard Jason pointed out on 30th May 2008 (New York Times Essentials):

With cancer or AIDS, you have an immediate feeling from your family, your work associates, your friends, that (these are) something we need to make accommodations for. What’s strikingly different about this illness is that the majority of people not only have to deal with a particularly debilitating health problem, they also have to deal with the stigma and societal reaction and disbelief and illegitimacy, and that is crushing.

If (the case definition) includes people who don’t have the illness…one needs to be wary of that, because …if you have patient samples that are different, ultimately what will happen is it’s very hard to find genetic or biological markers because there’s such imprecision in how it’s been identified. So what happens is that people will say ‘We can’t find anything, it must be psychogenic’.

The epidemiology done by the CDC was atrocious…it had a case definition that was put together by consensus and not by research methods (referring to the 1988 Holmes et al definition) and it had a name that was pretty trivialising. The prevalence research was very poorly done. The tests they were using were inappropriate and had a real bias for psychiatric morbidity”.

It could be said that, due to the influence of the Wessely School, exactly the same situation exists in the UK two decades later.

There are many more such papers; the above are merely illustrative of the significant evidence-base consisting of thousands of papers which demonstrate that ME/CFS is not a behavioural disorder as asserted by the Wessely School.

Objective signs in ME/CFS

From the above illustrations, it will be readily understood that, despite the Wessely School’s insistence that there are no objective signs of organic disorder in ME/CFS, there are numerous objective reproducible abnormal signs that are discernable by any reasonably competent physician. They include the following:

  • labile blood pressure (this is a cardinal sign); low systolic BP -- <100 in 50%

  • nystagmus and vestibular disturbance (vestibular dysfunction seen in 90%)

  • sluggish visual accommodation

  • fasciculation

  • hand tremor

  • neuromuscular incoordination

  • cogwheel movement of the leg on testing

  • muscular weakness

  • marked facial pallor

  • postural orthostatic tachycardia syndrome (POTS)

  • positive Romberg

  • abnormal tandem or augmented tandem stance

  • abnormal gait

  • evidence of Raynaud’s syndrome and vasculitis (vascular signs cross dermatomes)

  • mouth ulcers

  • hair loss

  • singular reduction in lung function (shortened breath-holding capacity seen in 60%)

  • enlarged liver (not usually looked for by psychiatrists)

The problem is that many doctors refuse to examine ME/CFS patients – or even to lay a finger on them – because ME/CFS patients are largely despised by the medical profession. Indeed, in 1994 one of the medical trade magazines published an article entitled “GPs despise the ME generation” (GP: April 1994). The article itself said at the time: “studies have shown that that most ME patients rate contact with medical services as unhelpful” and little has changed in the intervening fifteen years.

Abnormal findings on testing include flattened or even inverted T-waves on 24 hour Holter monitoring; abnormal glucose tolerance curves; elevated lactate levels in the ventricular system (seen in 70% of patients); neuronal destruction and elevated choline peaks (seen in 10% of patients); punctate lesions consistent with small strokes (seen in 78% of patients); very poor oxygen transport on pulse oximetry readings (seen in 90% of patients) and an abnormal venous blood gas picture.

None of these can rationally be explained as evidence of a behavioural disorder.

Symptoms and signs regularly noted in ME/CFS include:

extreme malaise; abdominal pain and diarrhoea; post-exertional exhaustion almost to the point of collapse; inability to stand unsupported for more than a few moments – this is a classic finding in ME/CFS; sometimes too weak to walk (different from deconditioning); inability to walk upstairs or to maintain sustained muscle strength, as in repeated brushing of hair with arms elevated, or inability to carry a shopping bag, or dry oneself after a bath, peel vegetables or prepare a meal; neuromuscular incoordination, not only of fine finger movement with clumsiness and inability to control a pen and to write legibly, but also of the larynx and oesophagus -- a frequent complaint is the need to swallow carefully to avoid choking; oesophageal spasm and pain; dysequilibrium ie. loss of balance; staggering gait (ataxia); bouts of dizziness and frank vertigo; difficulty with voice production, especially if speaking is sustained; aphasia (inability to find the right word); muscle cramps, spasms and twitching; black-outs and seizure-like episodes; spasmodic trembling of arms, legs and hands; episodes of angor animi (brought about by abrupt vasomotor changes that cause the sufferer to have uncontrollable shaking, like a rigor, and to think they are at the point of death) – it is essential to understand the terror that such attacks induce in a patient, and no patient can fake them; photophobia; difficulty focusing and in visual accommodation, with rapid changes in visual acuity; blurred and double vision, with loss of peripheral vision; eye pain; swollen and painful eyelids, with inability to keep eyelids open; tinnitus; hyperacusis, for example the noise of a lawnmower can cause acute distress and nausea; heightened sensory perception (for example, acute sensitivity to being patted on the back; inability to tolerate lights, echoes, smells, movement, noise and confusion such as found in a shopping mall or supermarket without being reduced to near-collapse); frequency of micturition, including nocturia; peripheral neuropathy; numbness in face; altered sleep patterns, with hypersomnia (in the early stages) and insomnia (in the later stages); alternate sweats and shivers; temperature dysregulation, with intolerance of heat and cold; parasthesias; sleep paralysis; intermittent palindromic nerve pains; tightness of the chest alternating with moist chest; muscle tenderness and myalgia, sometimes burning or vice-like; typically shoulder and pelvic girdle pain, with neck pain and sometimes an inability to hold the head up; orthostatic tachycardia; orthostatic hypotension, and symptoms of hypovolaemia, with blood pooling in the legs and feeling faint due to insufficient blood supply to the brain; labile blood pressure; intermittent chest pain akin to myocardial infarct; segmental chest wall pain; subcostal pain; vasculitic spasms, including headaches; cold and discoloured extremities, with secondary Raynaud’s; easy bruising; peri-articular bleeds, especially in the fingers; shortness of breath on minimal exertion; the need to sleep upright because of weakness of the intercostal muscles; pancreatic exocrine dysfunction leading to malabsorption; rashes (sometimes vasculitic in nature); flushing of one side of the face; ovarian-uterine dysfunction; prostatitis; hair loss, and mouth ulcers that make speaking and eating difficult. The notable point about symptoms in ME/CFS is their variability.

All the above symptoms and more are documented in the literature; they bear little resemblance to “chronic fatigue” or to a “continuum of on-going tiredness”, a description of “CFS/ME” often used by the Wessely School.

In summary, the MRC PACE Trial Principal Investigators ignore the published evidence (not hypotheses) of the following that have been documented in ME/CFS:

  • evidence of disrupted biology at cell membrane level

  • evidence of abnormal brain metabolism

  • evidence of a reduction in grey matter

  • evidence of widespread abnormal cerebral perfusion (hypoperfusion)

  • evidence of central nervous system / immune dysfunction

  • evidence of central nervous system inflammation and demyelination

  • evidence of hypomyelination

  • evidence of spatial disorientation

  • evidence that ME/CFS is a complex, serious multi-system autoimmune disorder (in Belgium, the disorder has now been placed between MS and lupus)

  • evidence of significant neutrophil apoptosis

  • evidence that the immune system is chronically activated (eg. the CD4:CD8 ratio may be grossly elevated, as seen in multiple hypersensitivities)

  • evidence that NK cell activity is impaired (ie. diminished)

  • evidence of hair loss in ME/CFS

  • evidence that the vascular biology is abnormal, with disrupted endothelial function

  • novel evidence of significantly elevated levels of isoprostanes (a marker for oxidative stress, which in ME/CFS goes up with exercise intolerance)

  • evidence of impaired proton removal from muscle during exercise

  • evidence of cardiac insufficiency and that patients are in a form of heart failure

  • evidence of autonomic dysfunction (especially thermo-dysregulation; frequency of micturition with nocturia; haemodynamic instability with labile blood pressure; pooling of blood in the lower limbs; reduced blood volume (with orthostatic tachycardia and orthostatic hypotension)

  • evidence of respiratory dysfunction, with reduced lung function in all parameters tested

  • evidence of neuroendocrine dysfunction (notably HPA axis dysfunction)

  • evidence of recovery rates for oxygen saturation that are 60% lower than those in normal controls

  • evidence that the average maximal oxygen uptake was only 15.2 ml/kg/min, whilst for controls it was 66.6 ml/kg/min

  • conclusive evidence of delayed recovery of muscles after exercise, with ME/CFS patients reaching exhaustion more rapidly than controls, with this failure to recover being more pronounced 24 hours after exercise (note: there is no evidence of de-conditioning)

  • evidence of mitochondrial metabolic dysfunction

  • evidence of inability to sustain muscle power

  • evidence of greatly increased REE (resting energy expenditure)

  • evidence of enteroviral particles in muscle biopsies

  • evidence of a sensitive marker of muscle inflammation (inflamed tissues should not be exercised)

  • evidence of on-going infection

  • evidence that the size of the adrenal glands is reduced by up to 50% (with reduced cortisol levels)

  • evidence that up to 92% of ME/CFS patients also have irritable bowel syndrome (80% of the immune system is located in the gut)

  • evidence of abnormal gene expression (at least 35 abnormal genes -- acquired, not hereditary), specifically those that are important in energy metabolism; there are more abnormal genes in ME/CFS than there are in cancer

  • evidence of profound cognitive impairment (worse than occurs in AIDS dementia)

  • evidence of adverse reactions to medicinal drugs, especially those acting on the central nervous system, such as anaesthetics

  • evidence that symptoms fluctuate from day to day and even from hour to hour

  • there is no evidence that ME/CFS is a psychiatric or behavioural disorder.

Dr Elizabeth Dowsett, a former President of the ME Association, was clear: “There is ample evidence that ME is primarily a neurological illness, although non-neurological complications affecting the liver, cardiac and skeletal muscle, endocrine and lymphoid tissues are also recognised. The commonest causes of relapse are physical or mental over-exertion. The prescription of increasing exercise can only be counter-productive. Some 20% have progressive and frequently undiagnosed degeneration of cardiac muscle which has led, in several cases, to sudden death following exercise. Neurological problems include exhaustion, weakness and collapse following mental or physical exertion beyond the patient’s capacity. This arises from metabolic damage. Problems with balance are common in ME due to involvement of spinal nerve tracts in the damaged brain stem. Over 70% of ME patients suffer from significant bone and muscle pain (a further consequence of brain stem damage which seriously affects their mobility). Other patients have in addition metabolic damage to muscle fibres. 30% of patients with abnormal exercise tests have evidence of persistent infection in the muscles, and evidence of muscle infarcts. (Patients with ME exhibit) jitter due to incoordinated muscle fibre action, following damage to the neuromuscular junction. Patients with ME suffer a variety of symptoms arising from autonomic nervous system dysfunction, including liability to a dangerous drop in blood pressure on standing for more than a few minutes”

(’s/mobility%20problems.htm ).

In November 2006, the US Centre for Disease Control (CDC) announced its “CFS Toolkit” to inform not just the US but the whole world about the nature and severity of ME/CFS. The following are extracts from the Press Conference

Dr Julie Gerberding, Director of the US CDC: “One of the things that CDC hopes to do is to help patients know that they have an illness that requires medical attention, but also to help clinicians be able to understand, diagnose and help people with the illness. But more importantly, to be able to validate and understand the incredible suffering that many patients and their families experience in this context. We are committed to improving the awareness that this is a real illness and that people need real medical care and they deserve the best possible help that we can provide. The science has progressed (which has) helped us define the magnitude and understand better the clinical manifestations (and this has) led to a sorely needed foundation for the recognition of the underlying biological aspects of the illness. We need to respect and make that science more visible. I have heard from hundreds and hundreds of people who are telling their stories – their courage, their commitment to try to live the best possible life they can (and) the tremendous impact that this is having on their ability to function”.

Dr William Reeves, Chief of Chronic Viral Diseases Branch at CDC: “We’ve documented, as have others, that the level of impairment in people who suffer from (ME)CFS is comparable to multiple sclerosis, AIDS, end-stage renal failure, chronic obstructive pulmonary disease. The disability is equivalent to that of some well-known, very severe medical conditions. We found that (ME)CFS follows a pattern of remitting and relapsing symptoms, the symptoms can change over time, and that spontaneous recovery is rare. We found that the best predictor for (ME)CFS was intensity of the initial infectious disease. The sicker the patient when s/he first got infected, the more likely they were to have persisting chronic symptoms. There were no other factors, psychological or biological, that held up under thorough analysis”

Professor Anthony Komaroff of the Harvard Medical School: There are now over 4,000 published studies that show underlying biological abnormalities in patients with this illness. It’s not an illness that people can simply imagine that they have and it’s not a psychological illness. In my view, that debate, which was waged for 20 years, should now be over. A whole bunch of studies show that the hormone system is different in patients with (ME)CFS than in healthy people, people with depression and other diseases. Brain imaging studies have shown inflammation, reduced blood flow and impaired cellular function in different locations of the brain. Many studies have found that the immune system appears to be in a state of chronic activation (and) genes that control the activation of the immune system are abnormally expressed in patients with this illness. A number of studies have shown that there probably are abnormalities of energy metabolism in patients with this illness”.

Professor Nancy Klimas, Professor of Medicine, University of Miami: “I’ve treated over 2,000 (ME)CFS patients. Today, there is evidence of the biological underpinnings. And there’s evidence that the patients with this illness experience a level of disability that’s equal to that of patients with late-stage AIDS, patients undergoing chemotherapy, patients with multiple sclerosis. And that has certainly given it a level of credibility that should be easily understood. There are diagnostic criteria that enable clinicians to diagnose (ME)CFS in the primary care setting”.

The full Press Conference is available at:

Despite repeated international calls for biomedical research and for appropriate investigations of patients with ME/CFS, including more accurate subgrouping of those with “CFS”, influenced by the Wessely School, the Medical Research Council maintains its psychiatric bias. From its own website, it is clear that approximately 91% of the MRC’s total grant-spend on ME/CFS in the five years from May 2003 has gone on psychiatric trials of behavioural interventions carried out by the Wessely School themselves. Furthermore, the MRC is known to have turned down no less than 33 biomedical and pathophysiological research projects on ME/CFS.

Wessely School psychiatrists have continued to publish studies on “CFS”, the results of which do not accord with existing biomedical science, for example: “It has been argued that perceived functional incapacity might be a primary characteristic of CFS. (Our) sample consisted of 73 patients with a diagnosis of CFS according to the Oxford criteria randomly selected from clinics in the Departments of Immunology and Psychiatry at St Bartholomew’s Hospital, London. The findings suggest that perceived functional incapacity is a primary characteristic of CFS” (Priebe S et al. Psychopathology 2008:41(6):339-345).

To refer to “perceived incapacity” in these patients is not only offensive to patients but is also an insult to the many clinicians and researchers who have uncovered the reality of the incapacity through the scientific process (in which psychiatry plays no part).

The assumption by the Wessely School that CFS/ME is a “faulty belief system” that can be “corrected” by CBT and incremental aerobic exercise is fallacious. The reality is that more than one UK Coroner (and many more internationally) has accepted ME/CFS as a cause of death, and the diagnosis appears on death certificates.

No-one who is aware of this wealth of information can credibly doubt the reality, the validity and the devastation of this organic multi-system disease.

Documented International Concerns about CBT/GET for patients with ME/CF

No consideration seems to have been given by the PACE Trial Principal Investigators --- nor indeed by the West Midlands Multi-centre Research Ethics Committee --- to the documented international concerns about CBT/GET for ME/CFS patients, for example:

United States:

Our reluctance to endorse graded activity arises from our vastly different clinical experience in the US” (Friedberg F, Jason LA. American Psychological Association, Washington, 1998).

Our clinical experience suggests that graded exercise / CBT for clients who do not exhibit fear-based avoidance may be counter-productive and trigger symptom flare-ups” (Fred Friedberg, Leonard A Jason, J Clin Psychol 2001:67:433-455).

Four US experts in ME/CFS are on record about the British approach to CBT

One of the most controversial treatments for ME/CFS is cognitive behavioural therapy. Some patients are fiercely opposed to it because they believe it suggests that if they’d just change their behaviour or their attitudes about the illness, they would get better. This opposition has been strengthened by the British approach to CBT”.

I don’t take the British point of view that CBT is the one thing you can do to effectively treat ME/CFS’ says (Professor) Klimas.


Dr Lapp agrees. ‘In my opinion CBT is widely but unfairly maligned because of the British approach, which presumes that ME/CFS has no organic basis and is therefore contradictory to current science. This type of CBT assumes somatic symptoms are perpetuated by errant illness beliefs and maladaptive coping’.

Dr Bell (says) ‘It won’t suddenly make patients better’.

Dr Peterson says he’s ‘not convinced of the efficacy of CBT’ ” (CFICS Chronicle Special Issue: The Science & Research of CFS: 2005-2006: 52-53).


Many (CBT/GET) studies have significant refusal and drop-out rates, which may reflect on the acceptability of the treatment regimens” (Royal Australasian College of Physicians Australian National Guidelines, M J Aust 2002:65:176 (8 Suppl):S17-S55).


Exercise programmes must be entered into cautiously as clinical studies have indicated that symptoms worsened in approximately half of the ME/CFS patients” (Canadian Guidelines on ME/CFS, produced by Health Canada Expert Medical Consensus Panel; JCFS 2003:11(1):7-115).

New Zealand:

GET may cause relapses and is therefore potentially harmful” (New Zealand Guidelines Group: Report to the Ministry of Health, November 2003).

The UK Chief Medical Officer’s Working Group Report

The UK Chief Medical Officer’s Working Group Report of 2002 on “CFS/ME” recorded concerns about GET: “Existing concerns include the view that patients have a primary disease process that is not responsive to or could progress with graded exercise. Substantial concerns exist about the potential for harm. No other treatment received such negative feedback” (

Unremitting concern

This concern is un-remitting: nine years ago (in June 2000) the Medical Advisor to the ME Association wrote in the charity’s Newsletter “Perspectives”: “The ME Association receives far more complaints about graded exercise regimes than any other management issues. Consequently, we are now informing our members that they should consider taking legal action against the health professionals concerned when an inappropriate ‘exercise prescription’ causes a relapse”.

In a keynote lecture at the ME Research UK international research conference held on 25th May 2007 in Edinburgh, Dr Eleanor Stein from Canada, a psychiatrist with a dedicated ME/CFS practice, denounced the Oxford criteria, which she said “could describe almost anybody. I do not believe that studies which use the Oxford criteria can be generalised to patients with ME/CFS”. She also said it is very clear that ME/CFS patients have “a host of physiological abnormalities that cannot be explained by psychiatric, attitudinal or behavioural hypotheses”. Stein was outspoken: “I would never in my practice use the Wessely model of cognitive therapy. I find it disrespectful to try to convince somebody they don’t have an illness that they clearly have”.

The Canadian Guidelines are rejected by the Wessely School, probably because they do not support the use of CBT/GET: Dr Bruce Carruthers, Fellow of the Canadian Royal College and principal lead of the international expert team that produced the highly respected ME/CFS Clinical Case Definition, states in the Overview (

“A hypothesis underlying the use of Cognitive Behaviour Therapy (CBT) for ME/CFS is based on the premise that the patient’s impairments are learned due to wrong thinking and ‘considers the pathophysiology of CFS to be entirely reversible and perpetuated only by the interaction of cognition, behaviour, and emotional processes. The patient merely has to change their thinking and their symptoms will be gone. According to this model, CBT should not only improve the quality of the patient’s life, but could be potentially curative’. Supporters suggest that ‘ideally general practitioners should diagnose CFS and refer patients to psychotherapists for CBT without detours to medical specialists as in other functional somatic syndromes’. Proponents ignore the documented pathophysiology of ME/CFS, disregard the reality of patients’ symptoms, blame them for their illness and withhold medical treatment. Their studies have often included patients who have chronic fatigue but excluded more severe cases as well as those who have other symptoms that are part of the clinical criteria of ME/CFS. Further, their studies fail to cure or improve physiological impairments”.

At the conference on “CFS” held on 28th April 2008 at The Royal Society of Medicine, PACE Trial Chief Investigator Peter White argued that the less symptoms a definition of “CFS” has, the better. To back up his claim, and using a graph from a study by Simon Wessely, White said: “You notice a fairly straight line showing the more physical symptoms you have, the more likely you are to meet the criteria for psychiatric distress. The cut-off for CIS (Clinical Interview Schedule, revised in 1990 by Wessely School psychiatrist Anthony Pelosi) for psychiatric morbidity is about 12. So once you get above 4 symptoms – you can see once you get 5,6,7,8 symptoms as the Canadian criteria suggest, you are more likely to find someone with a psychiatric disorder and not CFS/ME. So I would suggest you do not use the Canadian criteria (Co-Cure ACT: 1st July 2008).

International ME/CFS experts do not agree with the Wessely School’s dismissal of the Canadian criteria.

Although the 9th International Association for ME/CFS Research and Clinical Conference (formerly the American Association for CFS [AACFS] but now the IACFS/ME) held in Reno, Nevada in March 2009 took place after recruitment for the PACE Trial had ceased, evidence pertaining to the PACE Trial was presented by Belgian researchers Drs Greeta Moorkens and Elke van Hoof.

A Report of the conference written by Kim McLeary and Dr Suzanne Vernon from the US CFIDS Association shows that the Belgian research provides yet more evidence of the contra-indication of CBT for ME/CFS:

Dr Moorkens reported that the majority of 180 patients treated with 10 sessions of CBT over six months reported some improvement but did not show statistically significant improvement on fatigue or physical functioning scores. Dr van Hoof confirmed earlier studies that show a high percentage (30%) of drop-outs due to deterioration during CBT trials (and) her studies do not support large scale application of CBT”. (“ME Essential”, Issue 110, Summer 2009, pp 17-19).

At the same Reno conference, Professor Leonard Jason, a world-renowned ME/CFS investigator from De Paul University, USA, reported in his presentation “Activity Management” that one group of ME/CFS patients did not benefit from cognitive behavioural interventions: this was the subset of patients whose laboratory investigations showed them to be the most severely affected and who had increased immune dysfunction and low cortisol levels. This provides ever more evidence of the need for sub-grouping -- a need to which the Wessely School remains adamantly opposed.

In his Statement presented on 28th May 2009 to the US CFS Advisory Committee, the new President of the IACFS, Dr Fred Friedberg, commented on the lack of research into clinical treatment for ME/CFS:

This is a major concern given these three points: (1) the large number of severely ill and undiagnosed
patients, (2) the inadequacy of current subjective diagnostic criteria, and (3)
the absence of effective, evidence-based treatment options”.

The ME Association’s magazine (Issue 110, Summer 2009) carries information on management of ME/CFS based on the findings of the MEA “Big Survey”, which is a survey of around 3,500 on-line respondents and 750 paper respondents about management of ME/CFS.

Commenting on the GET aspect of this survey, Professor Christine Dancey from the Chronic Illness Research Team, School of Psychology, University of East London, states : “There were fewer people who said they were improved than expected. 512 said that GET made them worse, where 302 would be expected if there were no effect of GET. And only 194 said they remained unchanged, when we would expect 302 in this category. Based on the results of this survey, GET is a risky strategy”.

Patients with ME/CFS know this only too well, but their attempts to bring their concerns to the attention of those whose job is to support them constantly fall on deaf ears and blind eyes. It seems that too much is at stake for the plight of patients to take priority over professional reputations and corporate profits.



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Extracts from:


Background to, consideration of, and quotations from the Manuals for the

Medical Research Council’s PACE Trial of behavioural interventions for

Chronic Fatigue Syndrome / Myalgic Encephalomyelitis,

together with evidence that such interventions are unlikely to be effective

and may even be contra-indicated

Professor Malcolm Hooper; with contributions from members of the ME Community; Researched by Margaret Williams; February 2010.