1st May 2001

Sally Montague, Malcolm Hooper

                                                                    Address for correspondence:

                                                                   Professor M Hooper

                                                                   Emeritus Professor of Medicinal Chemistry

                                                                   Department of Life Sciences

                                                                   University of Sunderland

                                                                   SR2  7EE



I am happy to be associated with this challenging document written out of the “white heat” of the suffering and neglect that is so often the lot of people with ME, 25% of whom are severely affected and wheelchair, house or bed bound.

The need for good science is emphasised throughout the document; this provides a sound basis for the diagnosis of ME, which is a multi-faceted condition.  These studies need to be kept in the forefront of the minds of decision makers who are responsible for advice that will affect the care and management of ME sufferers.  It is notable that some of these studies are supported by funds provided by the UK ME Association (1) and must therefore have been approved by the Medical Director.

It is essential to address ME holistically. The growing body of scientific literature clearly shows that there are profound disturbances of and damage to the neuro-endocrine-immune systems which must be understood as inter-connected systems that share many common messenger molecules.

Functional Medicine provides an essential paradigm that identifies the need not only to determine blood or urine levels of significant marker molecules but also to understand the functional efficiency of the systems with which they are associated. The paradox of euthyroid levels of thyroid hormones associated with reduced thyroid function raises difficult and demanding questions.  It is not enough simply to measure certain parameters.

Such measurements must be allied to understanding how the whole system is integrated into the functioning of the whole person. (2)

Overlapping syndromes which share many common symptoms together with an emerging pattern of biochemical dysfunction (3) are providing new insights into “syndromes of uncertain origin” which require non-routine tests for their identification. (4)   These include myalgic encephalomyelitis, chronic fatigue syndrome, Gulf War Syndrome, Fibromyalgia, Multiple Chemical Sensitivity and pesticide (OP) poisoning.

Treatment needs to be prioritised and structured. This requires a holistic understanding which considers support structures including the environment, nutrition and nutritional supplements, particularly as drug therapy in these patients is often precluded by serious adverse reactions.


1.       Millennium Medical Review. ME Association Special Edition, Issue 73. December 1999

2.       Rigden S.  Functional Medicine Adjunctive Nutritional Support for Chronic Fatigue Syndrome. The Institute for Functional Medicine Inc.  PO Box 1729 Gig Harbour WA. USA. (Editorial Board includes Charles Lapp MD)

3.       Hooper M   IAG: a marker molecule for dietary intervention in Overlapping Syndromes.

      J Nutrition Practitioner 2000:2:35-36

4.       Syndromes of Uncertain Origin.  Merk Manual Millennium Edition. Merk & Co Inc. Rahway 1999

Malcolm Hooper, May 2001

 Concerns about the forthcoming UK Chief Medical Officer’s Report on ME and    

               CFS, notably the intention to advise clinicians that only limited      

                                       investigations are necessary

                                                       1st May 2001

In addition to the matters raised in our April 2001 posting entitled Information on Cognitive Behavioural Therapy, Professor Simon Wessely and PRISMA (, there are further matters of continuing concern relating to the UK Chief Medical Officer’s forthcoming Report on ME/CFS which are so important that we believe they should be in the public domain.

We are aware that it is quite probable that some members of the Key Group  (the “inner circle” of the CMO’s Working Group on ME/CFS) intend to recommend that the CMO’s Report should advise clinicians that only limited investigations are necessary for ME/CFS patients.  Our understanding is that this specific advice comes from the Medical Director of the UK ME Association (Dr Charles Shepherd) and from those members of the Key Group who are known adherents of the “Wessely School”.  Such advice is merely repeating the message of the 1996 report on CFS of the UK Joint Royal Colleges, which states unequivocally that no investigations should be done to confirm the diagnosis of ME/CFS. (1)  That Report was psychiatrically biased  (half of the 256 cited references were by the same or associated group of authors, with 10% of the references being by Professor Simon Wessely himself; nine had not been published or reviewed);  it was deficient in mention of references to the organic basis of ME/CFS and it was heavily criticised on both sides of the Atlantic. (2, 3, 4, 5, 6, 7) 

 We are unable to agree with advice to clinicians that only limited investigations are necessary or appropriate for ME/CFS sufferers and believe that such a view is medically and scientifically untenable; hence we believe there is a legitimate case for making this known in advance of the Report being issued. In our opinion, it is entirely unacceptable to advise clinicians that investigations on ME/CFS patients should be limited to a minimal basic routine screen, especially as basic screening is known to be often normal in ME/CFS.

In our view, as Medical Director of the ME Association, Dr Shepherd is supposed to be representing members of the ME Association and he therefore has an obligation to represent the best interests of all members of the ME Association who have to rely on his advocacy.

We believe that this should involve actively pressing for the setting up of research units and specialist clinics within the National Health Service for ME/CFS sufferers, certainly not concurring with the psychiatrists’ recommendation and advising that only limited investigations are necessary for such patients.

Dr Shepherd’s own private beliefs are a matter only for him, but at present his private beliefs seem to be influencing his professional obligations to the patients he represents and to be adversely affecting decisions which are being made on behalf of those patients.

We believe that such advice is at variance with good medical practice and that assessment of these patients should be particularly thorough; we are not alone in this view, because US Professors Fred Friedberg and Leonard Jason make the point in their recent book (8), noting that “Some physicians make the odd assumption that we know all we need to know about these illnesses, thus obviating the need for further research and greater understanding of these patients”.

We find it difficult to overcome our concern about the fact that the most influential members of the CMO’s Working Group are all members of Healthwatch;  Healthwatch is funded by drug companies and in its literature, its clearly-stated aims are to promote the use of pharmacological interventions and to oppose “Diagnoses…that may encourage unnecessary treatment for non-existent diseases”.  Specifically, Healthwatch members are opposed to the use of non-pharmacological interventions such as homoeopathy, acupuncture, dietary modulation or vitamin supplementation and they are vociferously opposed to all practitioners of alternative or complementary medicine. Membership of Healthwatch is open only to those who promote the pharmacological industry (9).  Notably, the Medical Adviser to the UK ME Association (Dr Charles Shepherd) is a member of Healthwatch, and the involvement of both Professor Anthony Pinching (Deputy Chair of the CMO’s Working Group) and Professor Simon Wessely (a very influential member of the Reference Group to the CMO’s Working Group) has long been known. (9)   Wessely has had connections with Healthwatch since its inception in 1989 (9) and he unceasingly promotes his view that ME is a non-existent disease and that CFS is a psychiatric disorder which is amenable to antidepressants and psychotherapy. (For a comprehensive referenced review of Wessely’s published works on ME / CFS and related subjects (eg. Gulf War Syndrome), see Denigration by Design?  E.Marshall & M Williams. Volume I (1987-1996) and Volume II (1996-1999), pp 488. Available at cost price from (UK) 0208-554-3832).

We believe that investigation is the only way forward towards understanding these complex disorders and we regret that the CMO’s Report is intending to amalgamate ME with CFS as a single disorder despite having had it clearly pointed out that ME and CFS have differing case definitions:  by virtue of the current CFS case definitions (Oxford 1991 and CDC 1994), CFS has no physical signs whatever, which is certainly not the case in ME.  Our belief and experience is that only by looking will we learn.

To put this important issue in context, we briefly list some of the findings which were presented at the American Association of Chronic Fatigue Syndrome (AACFS) Fifth International Research and Clinical Conference held in Seattle in January 2001, which indicate just how essential it is for such patients to be comprehensively investigated.

Some findings presented at the AACFS Conference, Seattle, January 2001

It is perhaps worth reiterating that the American term “CFS” usually reflects patients who are likely to have ME / “core” CFS rather than psychiatric disorder as facilitated by the Oxford 1991 CFS case definition (still widely used by UK psychiatrists of the Wessely School who were participants in its formulation): this situation is one which requires immediate international input to end what is obviously a most confusing and unsatisfactory situation for all involved.

Brain studies / Neurology

Different neurobiological profiles are found in CFS patients compared with healthy controls.  Using assays which measured hormones and cytokines with a potential for affecting the central nervous system (cortisol, prolactin, oestrogen, progesteron, CRP, neopterin, TNFalpha, TGFbeta, DHEA-s), significant differences were found in CFS patients compared with controls.  (10)

Both baseline heart rate and plasma epinephrine were increased in CFS patients, suggesting an activated sympathoadrenal state. (11)

Sympathetic nervous system dysfunction is integral to CFS pathology. (12)

A wealth of studies (about 85%) confirm autonomic nervous system (ANS)  dysfunction in up to 90% of CFS patients, with resulting effects on many vital functions (blood pressure, pulse rate, breathing and body temperature).   Professor Komaroff said that there is substantial evidence that both the sympathetic and parasympathetic nervous systems are abnormal in CFS. 

CFS patients showed reduced activation of medial/basal frontal regions but a greater activation of dorsolateral frontal and temporal lobes than controls.  This MRI study showed unique features of cognitive impairment, demonstrating that more areas of brain activity were used in task solving than in controls  ie.  CFS patients are working harder than controls to solve the same problem and use more brain areas than controls. (13)

 A quantitative volumetric study suggests that some CFS patients show a lateral ventricular enlargement, which may be associated with white matter loss in the frontal as well as the parietal lobes. (14)


CFS patients do not display the same improvement with treatment as seen in depressed patients. Little overall change is seen in CFS patients on either physical or mental scores after antidepressant treatment. (15)

Findings from one of the largest well-studied patient groups in the world which used a factor analysis (done by computer, which eliminates all bias by the researcher) suggests that psychiatric disorder is not a core aspect of CFS and that this is a strong argument against CFS being a psychosomatic or “functional somatic” disorder. (16)

Whilst significant neuropsychological impairment was found in CFS patients, no subject performed in the range suggesting lack of effort or feigned impairment. (17)

The often-proposed hypothesis that CFS is a form of somatisation disorder was tested.

It is apparent that there is no relationship between the number of medically unexplained symptoms and psychiatric diagnosis. CFS has no relation to somatisation disorder. (18)

Visual processing disabilities

Investigation of the biological basis of visual processing disability in CFS showed that alteration in visual processing response is associated with evidence of altered connective tissue turnover. (19)


Symptom expression is associated with changes in serum lipid levels. Significant changes in glucose, amino acid and inflammatory mediating fatty acids may be involved in

symptom expression. Increases in levels of polyunsaturated fatty acids had the highest correlation with both fatigue and muscle pain scores. (20)

Objective examination of skeletal muscle tissue in CFS patients (biopsy of the vastus lateralis muscle) showed that activity of all skeletal muscle anti-oxidative enzymes was significantly increased in CFS patients compared with controls.  Lipid analysis showed fatty acid modifications in patients but not in controls. Fluorescence polarisation showed a significant decrease of membrane rigidity with a consequent increase in membrane fluidity.

There is evidence of a dengenerative process of the muscle tissue in CFS patients, as typically occurs in mitochondrial myopathies. This may contribute to muscle fatiguability and it supports an organic origin for CFS. (21)


CFS patients with active HHV6 infection (viraemia) have activation of coagulation and are hypercoagulable.  Since HHV6 is known to infect endothelial cells, there may be a resultant endothelial cell dysfunction triggering the coagulation system. (22)

Genetic abnormalities

Recent studies have demonstrated circulating plasma RNA in Gulf War Syndrome patients. A study was therefore conducted to determine the presence or absence of RNA in  CFS patients and to determine if the amplified sequences of RNA were similar to or

different from those found in GWS.  All chronic illnesses studied (including GWS, CFS, AIDS and multiple myeloma) show prominent RNA not observed in normal controls.

Prominent RNA bands so far sequenced show homology with human genes which are noted for their tendency for gene rearrangement under severe physiologic stress.  The most amplified sequences appear to be disease specific.  (23)

Dr N.Afari, Associate Director of the University of Washington CFS Research Centre said that genetic abnormalities may team up with environmental influences to produce CFS.  Environmental influences which worldwide researchers are investigating include the frequent pairing of CFS with food and chemical sensitivities. (24)


The dysregulation of the important anti-viral 2-5 RNase L pathway in CFS is a potential biomarker for the disorder. The RNase L pathway is a series of enzymatic reactions which go on inside white blood cells when they perceive themselves to be challenged by viruses and possibly also by some toxic exposure. Elevated levels of RNase L are associated with reduced maximal oxygen consumption (VO2max) and exercise duration in patients with CFS.  Both abnormal RNase L activity and low oxygen consumption were observed in most patients with CFS. These findings demonstrate that patients’ extremely low tolerance for physical activity is likely to be linked to abnormal oxidative metabolism, perhaps resulting from defective interferon responses. (25)

Much of the Belgian work focused on the abnormal enzyme pathways found in CFS. In healthy people, the enzyme breaks down viral RNA and destroys the infected cell. Instead of the normal size 80kDa (kiloDalton) enzyme, those with CFS show only a 37 kDa size enzyme.  This 37 kDa  low molecular weight (LMW) RNase L fragment found in CFS patients is produced by calpain ( an apoptotic enzyme) cleavage, and the whole process affects the calcium and potassium channel mechanisms. The channelopathy will lead to low body potassium. Testing the ratio of the 37kDa and 80kDa enzymes has revealed that a high ratio is associated with more severe clinical symptoms.  The 37kDa RNaseL is associated with incomplete cell death, which means that the cell constituents cannot be recycled for use by other cells. (26)

Patients suffering from CFS present many symptoms, including pain, which are likely to reflect dysregulation in cellular ion transport. Fragments released by a pathological protein cleavage result in dysregulation of sodium channels, which play a major role in the generation of pain and hyperalgesia in peripheral neurons, with a resultant shift in the pain sensitivity threshold as well as causing (if occurring in epithelial cells) drenching sweats. An improper function of the sulfonylurea receptor (SUR1) could lead to an extreme loss of cellular potassium. ATP is the main energy releasing source of the cell: improper function of  ATP binding cassette (ABC) transporters leads to serious neurological dysfunction.  Common symptoms of CFS could be due to a malfunction of various ABC transporters. (27) 


Increased apoptosis (programmed cell death) in peripheral blood mononuclear cells (PBMC) of patients with CFS has been suggested to contribute to the symptomatology. RNase L activation has been directly linked to the induction of apoptosis. This study showed that the activation of RNase L in the PBMC of CFS patients upregulates apoptotic activity in these cells. This suggests that the peturbed apoptotic process may play a role in the altered immunologic functions in CFS.  (28)

A large number of CFS patients have an abnormal immunological profile which can result in the production of immunologic mediators such as interferon, interleukin and other cytokines. The upregulation of the 2-5A Synthetase /Rnase L pathway shown in CFS patients indicates an activated immune state. According to their immunologic profile, CFS patients were divided into three groups. The results show that the presence of an increased amount of LMW RNase L correlates with higher levels of interferon gamma. (29)

Autoimmunity in CFS was reviewed. Low titres of antinuclear antibodies have been found in CFS patients.  A major multi-centre study looked at the presence of autoantibodies to a cellular protein expressed primarily in nerve cells ( microtubule-associated protein 2 or MAP2). Initial studies with immunohistochemistry showed a high percentage of CFS sera reactive to centrosomes. Preliminary evidence shows that other proteins beside MAP2 might also be target antigens in CFS autoimmunity.  Of interest is the high frequency of reactors in lupus and rheumatoid arthritis as well as in CFS patients. (30)

The intracellular content of the Natural Killer (NK) cell is perforin, a cell lytic protein common in many cells of the immune system which correlates with the cytolytic potential of the cell. In CFS, this chemical is reduced in NK cells. This finding substantiates claims of an NK associated defect in CFS and suggest a molecular basis for the reduced cytotoxicity (immune system killer cell function).  This defect may not be NK specific but may encompass the cytotoxic T cell subset as well.  Mice which were genetically engineered to have low or absent levels of perforin show the same immune abnormalities as CFS. Other abnormalities found include activated lymphocytes in various subsets, elevated levels of immunoglobulins (IgG in particular) and increased levels of immune molecules called pro-inflammatory cytokines. Also found was a reduced activity of delayed hypersensitivity. (31)

Overlapping symptomatologies between CFS and Gulf War Syndrome have been observed by different investigators. It was therefore of great importance to verify whether various immunologic abnormalities found in CFS are also found in GWS.  Overall differences between the two groups were not significant. The results indicate that, as in the case of CFS, Gulf War veterans are suffering from neuroimmunological disorder. Importantly, it was shown that basic laboratory testing is not sufficient for these groups of patients and that advanced immunological tests including immune function and antibodies to the neurological system are needed.  (32)

 This should be compared with the recommendations in the UK 1996 Joint Royal Colleges’ Report on CFS (1), which specifically state that no investigations should be performed to confirm the diagnosis (page 45) and that immunological abnormalities should not “deflect the clinician from the biopsychosocial approach….and should not focus attention….towards a search for an ‘organic’ cause(page 13).  

It may also be salutary to reflect on the opinion expressed by Professor Pinching (deputy Chair of the CMO’s Working Group) in his article on CFS in Prescribers’ Journal ie. that “over-investigation can (cause patients) to seek abnormal test results to validate their illness”. (33)   Prescribers’ Journal was a publication of the UK Department of Health but is no longer produced.

In our opinion, when taken in consideration of all that is already known about the biomarkers of ME/CFS, the evidence of serious pathology presented at Seattle emphasises the unacceptability of advising that such pathology should not be fully investigated.  It also underlines the fallaciousness of advising that such substantial pathology can be satisfactorily treated by cognitive behavioural therapy or graded exercise; thus we believe it is imperative for people to be aware that the most influential members of the CMO’s Working Group are apparently still determined to proceed along such avenues despite all the evidence which has been put before them.

Advice from Members of the CMO’s Working Group about Testing for RNase L and urinary markers in ME / CFS

RNase L in ME/CFS

We are particularly concerned about the advice which may be issued in the CMO’s Report  that tests for RNase L and tests for urinary markers should not be performed on UK patients: we understand this is because the Medical Director of the UK ME Association (Dr Charles Shepherd) regards them as  (quote)  “unnecessary and unproven”.  We understand he is further advising that tests for viral antibody titres are also unnecessary and unproven.

We understand that in a forthcoming edition of Perspectives (the magazine of the UK ME Association), Dr Shepherd intends to inform readers that his view of the well-conducted international work on RNase L  is that it  may involve what I and many of my colleagues regard as over-investigation for highly speculative abnormalities in antiviral pathway activity”. 

We compare the personal opinion about the significance of RNase L of the Medical Director of the UK ME Association not only with the evidence demonstrated in the Seattle presentations outlined above but also with what Professor Anthony Komaroff wrote about the work on RNase L of De Meirleir et al 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), lending credibility to the result”. (34)   We further compare Dr Shepherd’s view with that of Shetzline and Suhadolnik, who in a detailed study of the RNase L enzyme have not only identified the 37kDa form of the enzyme as being part of the underlying pathology of ME/CFS,  but with sophisticated labelling techniques have shown that there is an increased rate of RNA hydrolysis by this enzyme and that the low molecular weight enzyme (37 kDa instead of the normal 80 kDa weight) is hydrolysing three times faster than the normal 80 kDA enzyme. Significantly, the researchers have used a specific probe which unequivocally identifies the faulty enzyme.  (35)

We note that those with ME/CFS show both an upregulation of the antiviral pathway and an abnormal version of the RNase L enzyme  (ie a low molecular weight of 37 kDa); patients who express this abnormal RNase L enzyme suffer an even greater depletion of ATP reserves and an inhibition of protein synthesis (ie. when the various protein kinase enzymes become activated and elevated, protein synthesis is inhibited). 

Expression of this low molecular weight RNase L can cause problems with enzymatic detoxification pathways, particularly in the liver  (see below).  Measurements of protein kinase 1 are very important in studying mechanisms of interference with signal transduction in lymphocytes, and distinct abnormalities are seen in ME / CFS.

In our opinion, for the Medical Director of the UK ME Association to advise that no RNase L investigations are necessary defies reason.  Accumulating evidence (of which the CMO’s Working Group ought to be aware) dictates that such investigations are essential if this serious disorder is ever to be understood.

Possibly of relevance to Dr Shepherd’s advice are the significant findings by Professor Vojdani and Dr Charles Lapp, namely their discovery that this same antiviral pathway can be damaged by chemicals.  (36)   This work relates to the findings of Dr Howard Urnovitz from the Chronic Illness Research Foundation at Berkeley, California, whose work has been published in the Journal of the American Society for Microbiology and in Clinical Microbiology Reviews; he has demonstrated a fundamental breakthrough linking toxic exposure with chronic diseases such as ME/CFS and other autoimmune disorders; (37)

 he and others suggest that the huge increase in chemical usage is chronically stimulating the immune system.  Clearly, such findings might be unpalatable to members of Healthwatch and to the chemical and pharmacological giants whose interests Healthwatch was set up to serve.

Urinary markers in ME/CFS

Another area where we disagree with Dr Shepherd’s advice to the CMO’s Key Group concerns his recommendation that there should be no investigation of urinary markers in ME/CFS.  We believe several urinary markers are important and that where certain

markers are positive, dietary modulation can result in alleviation of distressing gastro-intestinal symptoms.  Given that the remit of the CMO’s Working Group is to assess treatment and management of these patients, assessment of something which can deliver any relief should surely be a priority.

We make particular mention of just three urinary markers which in our view merit inclusion in the assessment of patients suspected of having ME/CFS:

(i)     CFSUM1  (Chronic fatigue syndrome urinary marker 1).  In February 1995 Dr Neil McGregor of the University of Newcastle (Australia) CFS research team presented information at a CFS Conference in Sydney about the nature of the novel chemical which his team had found in the urine of people with ME/CFS; the urine concentration appeared to correlate strongly with a number of ME/CFS symptoms.  The chemical name for this marker is amino-hydroxy-N-methyl-pyrrolidine.  The base structure of this compound is similar to the base structure of many pesticides.  This team went on to characterise more markers: at the Brussels World Congress in September 1999, another member of the Newcastle team (Dr Hugh Dunstan) presented evidence of UM 27 (urinary metabolite 27); this marker molecule was elevated in ME/CFS and there was a positive correlation with elevation and symptomatology.

(ii)   IAG TESTING  (indolylacroylglycine, a tryptophan metabolite).  This is a test for urinary markers which is almost 100% positive in ME/CFS. It is inexpensive and is available at a British university. We believe that screening for allergies and hypersensitivities should be mandatory in these patients, as the cost is minimal and the benefit is considerable; thus the cost-benefit ratio is eminently justified.  It is our opinion that specific advice should be given in the CMO’s report about the very real value of elimination diets in cases of ME/CFS where there is reproducible and reliable evidence of a leaky gut, in which high levels of small peptides cross the damaged gut membrane, leading to changes in brain chemistry which have behavioural, cognitive, neurological, endocrinological and immunological consequences. The well-validated IAG urine test is a test for an aberrant metabolite of tryptophan and if positive, is indicative of a malfunctioning and leaky gut;  it indicates a compromised digestive process which in turn leads to opioid excess as a result of mal-digestion and uptake of opioid peptides derived from dietary sources.  The main culprits are well-known as being the opioid precursor peptides gluten and casein, with casein from cows milk causing more problems than casein from sheeps milk; they are broken down in the gut to opioid peptides, namely gliadomorphin and casomorphin and it is these which readily cross the damaged gut membrane and give rise to a cascade of multi-systemic problems.  These “escaped” peptides are scientifically measurable in urinary peptide profiles. (38)  Significantly, if the gut is leaky, the same factors also cause the blood brain barrier to be leaky, with resultant effects of opioids on the central nervous system; this causes not only a local, but also a systemic, reaction.  Studies show that this is not a genetic phenomenon but an acquired one. On this same aspect, we note that Wessely himself (perhaps the archetype non-investigator) is now recommending that all ME/CFS patients be routinely screened for undiagnosed coeliac disease, stating  “there is now evidence from primary care of a surprisingly high frequency of unsuspected EMA tests (endomysial antibodies) in people with non-specific symptoms….we now suggest that  screening for CD  (coeliac disease) should be added to the relatively short list of  mandatory investigations in cases of suspected CFS”.  (39)  Both these factors may relate to the increased incidence of irritable bowel syndrome in ME/CFS, which is high:  73% as opposed to 22% in the general population.  (40) 

(iii)   Urinary creatine test  At the British Society of Rheumatologists’ Conference in Edinburgh, April 2001, evidence was presented which showed that patients with ME/CFS are excreting in their urine significant levels of creatine and other muscle related metabolites including choline and glycine.  (53% of ME/CFS patients were positive compared with 0% of healthy controls). This may well represent evidence of on-going muscle damage in ME/CFS.  Creatine has previously been shown to be a sensitive marker of muscle inflammation. (41)

From these illustrations, we believe it may be appropriate for the Medical Director of the UK ME Association to be required to supply a credible explanation as to why he recommends that investigation of urinary markers in ME/CFS is “unnecessary and unproven”.

General observations

Whilst it is true that there is as yet no single, definitive laboratory test for ME/CFS, there is a spectrum of abnormalities which, if positive, enable a diagnosis to be made with reasonable certainty; if minimal routine investigations are to be carried out on UK sufferers, then no progress will be made in the medical understanding of ME/CFS and unnecessary suffering will continue.  In our view, that is unacceptable.

Immunological testing

The immune abnormalities documented in ME/CFS follow a recongisable, reproducible and consistent pattern, with clear evidence of an immune activation state.  In our view, screening for NK levels and function per cell (and not just gross killing) is mandatory, as is measurement of the CD4-CD8 ratio; other immunological tests should routinely include testing for ANAs (antinuclear antibodies), IgGs, including IgG3, CICs (circulating immune complexes), IL2; IL4 (interleukin 2 + 4), measurement of Th1 - Th2 response and mitogen stimulation tests. In particular, tests should be performed for thyroid antibodies (see below). It has been demonstrated that in ME/CFS, changes in different immunological parameters correlate with particular aspects of disease symptomatology and with measures of disease severity. (42).  Further consolidation of the correlation between ME/CFS symptomatology and evidence of immune dysfunction is to be found in the convincing work of Natelson et al who have demonstrated the link between IL4 and a type 2 cytokine pattern in ME/CFS; a preponderance of a Th2 response is consistent with autoimmunity. (43, 44).

 In particular, we suggest that ME/CFS patients should be screened for evidence of autoimmunity.  There is increasing evidence of antilamin antibodies in ME/CFS: specifically, antilamin antibodies have been found in the blood of ME/CFS patients  (antibodies against this protein are proof of autoimmunity and of damage to brain cells).  It has been demonstrated that 52% of patients with ME/CFS develop autoantibodies to components of the nuclear envelope (NE), suggesting that in addition to the other disturbances of the immune system, humoral autoimmunity against polypeptides of the NE is a prominent immune derangement in ME/CFS. The occurrence of autoantibodies to an intracellular protein like lamin B 1 provides laboratory evidence for an autoimmune component in ME/CFS.  No patients with depression or atopy showed reactivity to NE proteins.  Autoantibodies to NE proteins are relatively infrequent in routine ANA serology and most of these fall into the broad category of an unusual connective tissue disease subset which is characterised by brain or skin vasculitis. (45,46)   As mentioned above, results of a multicentre study looking at autoimmunity in ME/CFS presented at the AACFS Fifth International Research and Clinical Conference at Seattle in January 2001 looked at the presence of autoantibodies to a cellular protein expressed primarily in neuronal cells (MAP2). Immunohistochemistry results showed a high reactivity in ME/CFS patients, as also in patients diagnosed with lupus and rheumatoid arthritis. (30)  Mindful of the serious and costly consequences (both human and financial) flowing from undiagnosed AI (autoimmune disease) and bearing in mind the present body of evidence, we fail to understand the re-emergence in the UK of advice that such investigations are “unnecessary” and “inappropriate”.

Virological screening

We again point out the importance of screening for viral antibodies as early in the diagnostic process as possible:  it is imperative to ascertain any viral trigger but antiviral antibody levels fall off after three months. It is crucial to look for viral markers because management interventions must always refrain from doing harm and the enforcement of unvalidated exercise regimes upon such patients could, in our opinion, result in indefensible legal action. There is a body of published, competent medical opinion which supports the involvement of CBV (Coxsackie B virus) in at least a subgroup of ME/core CFS, especially those with cardiac, pancreatic and gut dysfunction (47, 48, 49, 50, 51);                   this being so, the CMO’s guidelines on ME/CFS management cannot afford to ignore or dismiss it.  We believe that this aspect should be brought to the specific attention of clinicians.

Endocrine testing

We also suggest that detailed endocrine function studies be included in the recommendations to clinicians. The endocrine system is uniquely disrupted in ME/CFS. (52,53,54)  A key feature is the demonstrated defect in HPA axis function (55, 56) and patients are severely limited by the loss of dynamic hormone responses.  There is an abnormality of adrenal function and CT scans have shown that both the right and left adrenal glands are reduced by 50% when compared with controls. (57)  In one of the larger studies,  Lucinda Scott MB, MRCPsych  (part of the Scott / Dinan team of ME researchers) looked at the common neuroendocrine tests (which are often normal in ME/CFS) and concluded the tests were inadequate for ME/CFS patients. (58)

 Specifically, we believe that thyroid function needs careful evaluation in ME/CFS: it has long been noted by practitioners that ME/core 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. (59)  Abnormal thyroid hormone levels have been described in autoimmune disease. (60)  In our opinion, particular attention needs to be paid to investigating the bioavailablity of T3.  In ME/core CFS, T3 levels are often low (or at the low end of the normal range).  We therefore suggest that selenium levels be investigated in patients with ME/core 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  (61),  thus it is advisable to establish baseline levels of selenium in ME/CFS patients whose T3 levels are low. Additionally, recent evidence demonstrates a lymphoctyic thyroiditis in chronic fatigue. (62)

Central, autonomic and peripheral nervous system testing

There is a universally acknowledged dysfunction of all nervous systems in ME/core CFS. (63)  Testing for Rombergism and nystagmus is mandatory in ME/CFS but often overlooked. Nystagmus is jelly-like and variable: a patient examined in the morning might have nystagmus, which would disappear at midday, recur later, disappear and recur the next day (64); thus a once-only cursory examination could be misleading.

Given what is now known, we believe that tests for sympathetic over-activity and for orthostatic hypotension in ME/CFS should not be omitted. (65)

Nuclear imaging

There is objective evidence of brain impairment in the majority of patients with ME/CFS

(66, 67, 68, 69); such patients show a particular pattern of hypoperfusion of the brain stem and this brain perfusion impairment provides objective evidence of central nervous system dysfunction. Brain magnetic resonance imaging (MRI) data have demonstrated that the presence of brain abnormalities in ME/CFS are significantly related to subjective reports of physical function  ie. ME/CFS patients with MRI brain abnormalities are more physically impaired than those without MRI brain abnormalities. (70)

Tests for hypercoagulability and vascular dysfunction

There is increasing evidence of hypercoagulability in ME/CFS.  Researchers in Phoenix, Arizona have demonstrated a model of coagulation activation in ME/CFS; using five tests

( fibrinogen, prothrombin fragment 1+2, thrombin / anti-thrombin complexes, soluble fibrin monomer and platelet activation by flow cytometry), they have shown that ME/CFS can be classified as a type of antiphospholipid antibody syndrome. (71)  Phospholipids are constituents of all tissues and organs, especially the brain; they are synthesised in the liver and small intestine and are involved in many of the body’s metabolic processes. An antiphospholipid antibody syndrome is a clinical disorder with recurrent arterial and venous thrombotic events; the heart, central nervous system and skin may be affected. This is significant because in ME/CFS, vascular problems are well-documented: at the World Congress on ME/CFS in Brussels 1999, it was stated that vasculitic patterns are identical to those in HIV patients. (72)  Scientists in Dundee, Scotland have demonstrated the presence of a defect in peripheral cholinergic activity within the vascular endothelium; this abnormality affecting the blood vessels may provide an explanation for some of the vascular features seen in ME/CFS. (73)  In addition, increased sensitivity to glucocorticoids in peripheral blood mononuclear cells has been demonstrated (74), which is important evidence of a biological marker in ME/CFS.

Lung function testing

Tests have shown that compared with controls, patients with ME/CFS showed a significant reduction in all lung function parameters. (75)  There is repeated reference to respiratory problems throughout the ME/CFS related literature. (76, 77) 

Tests of exercise capacity

 Investigation of exercise capacity (VO2 max) ie. measurement of maximal oxygen uptake  and investigation of oxygen delivery to muscle are essential in patients with ME/CFS; oxidative metabolism is known to be reduced in ME/CFS. (78)  This could affect patients’ physical abilities to a severe degree.  ME/CFS patients have recovery rates for oxygen saturation that are 60% lower than normal controls. (79)  It is imperative to ascertain oxygen delivery status before insisting on inappropriate interventions  eg. CBT / graded exercise.

Tests for cardiac anomalies

Cardiac anomalies are well-documented in the ME literature. (80, 81, 82)  In our opinion, such anomalies should always be looked for in ME/CFS patients.

Tests for liver dysfunction

Given the evidence of hepatic dysfunction in ME/CFS, we suggest that liver involvement should always be assessed. (83, 84, 85). In our experience, this rarely happens.

Ocular tests

Ocular problems are common in ME/CFS  (86, 87,88) and we believe ocular testing should be carried out on ME/CFS patients.


We acknowledge that this summary discusses international research findings which have been carried out in centres of excellence, and that it is unrealistic to expect all tests mentioned to be readily available at all hospitals throughout the country.  Nevertheless, we believe that the need for specialist ME/CFS units (providing both complex investigative and assessment facilities, together with the necessary care provision) are long overdue, and that advice contained in the forthcoming CMO’s Report should reflect this need.

This summary is merely an outline of just some of the abnormalities which are known to be present in ME/CFS; it is by no means a comprehensive list (for example, it does not include reference to neuropsychological assessment in ME/CFS patients, which is known to produce a distinctive pattern of abnormalities).

It is hoped that it might serve to motivate people into contacting their Member of Parliament, their legal advisers and the media about the continuing exclusion of patients with ME/CFS from NHS provision and delivery of care as at present, and about the apparent determination of some members of the CMO’s Key Group to advise in the forthcoming Chief Medical Officer’s Report on CFS/ME that for such patients, “only a limited set of investigations are necessary”.  Given the extent of the evidence of such complex underlying patholology, we believe such advice is indefensible.

Finally, we again draw attention to the factual evidence set out in our observations on claims by psychiatrists of the Wessely School that CBT is the evidence-based treatment of choice for ME/CFS  (Information on Cognitive Behaviour Therapy, Professor Simon Wessely and PRISMA, April 2001, and in this respect we would draw attention to the mounting evidence that cognitive behavioural therapy has been shown to be of no long-term benefit in disorders other than ME/CFS:

in a multi-centre study, researchers from the Department of Psychiatry and Behavioural Sciences at The Royal Free and University College Medical School, London, have found that there are no differences in clinical outcomes between cognitive behavioural therapy and the usual general practitioner care at 12 month follow-up for patients suffering from depression and from depression with co-existing anxiety. (89). Members of the CMO’s Working Group may wish to take note.


1.     Chronic Fatigue Syndrome.  Report of a Joint Working Group of the Royal Colleges 

of Physicians, Psychiatrists and General Practitioners (CR54).  RCP Publications 

Unit,  October 1996

2.     The Royal Colleges’ Report on CFS: Insidiously Biased and Potentially Harmful.

Terry Hedrick. CFIDS Chronicle 1997:10:1:8-13

3.     The response of the UK ME Charities Alliance sent to the Chief Medical Officer on

31 January 1997

4.     Editorial: Frustrating survey of chronic fatigue. Lancet 1996:348:971

5.     Why doctors are failing ME sufferers. Richard Horton. Observer Life, 23 March 1997

6.     The Organic Basis of ME  a compilation of references and data presented in person to the CMO on 11 March 1998 by The Countess of Mar.  Copies available at cost price from (UK)  0208-554-3832

7.     Petition to Her Majesty’s Government presented to the Minister of State for Health by The Countess of Mar, House of Lords, 26 November 1997 (Hansard)

8.   A Clinician’s Guide to Controversial Illnesses.  Chronic Fatigue Syndrome, 

      Fibromyalgia, Multiple Chemical Sensitivities.  Renee R Taylor, Fred Friedberg,

      Leonard A Jason.  pp 165. Pub. Professional Resource Press, Sarasota Fl, 2001

9.     Dirty Medicine. Martin J Walker. Pub. Slingshot Publications, London 1993

10. Neuroendocrinological Profiles in Patients with Chronic Fatigue Syndrome.

      B Evengaard et al.  AACFS Fifth International Research & Clinical Conference,  

      Seattle, January 2001 #001

11. Orthostatic intolerance and sympathoadrenergic reactivity in chronic fatigue

      syndrome.  PMMB Soetekouw et al. Ibid  #085

12. Sympathetic dysfunction demonstrated by isometric hand-grip response in Chronic 

      Fatigue Syndrome.  JN Baraniuk et al  ibid  #126

13. Brain correlates of cognitive effort in chronic fatigue syndrome and healthy control

      subjects. Mahurin RK, Buchwald DS et al  ibid  #088

14. Chronic Fatigue Syndrome: Quantitative Assessment of Cerebral Volumes.

      Gudrun Lange, Benjamin Natelson et al   ibid  #045

15. A comparison of treatment outcomes in CFS and major depression. SN Schwartz,

      R Jones  ibid   #106

16. A factor analysis study of symptoms in 1573 patients with chronic fatigue syndrome.

      P de Becker, N McGregor, K de Meirleir   ibid  #020

17. Malingering in chronic fatigue syndrome: a neuropsychological investigation.

      Lana Tiersky, Benjamin Natelson   ibid  #102

18. The relationship between medically unexplained somatic symptoms and

      psychopathology in chronic fatigue syndrome.    Daniel Cukor, Lana Tiersky,

      Benjamin Natelson   ibid  # 028

19. Scotopic vision alterations in chronic fatigue syndrome. NR McGregor, RH Dunstan

      et al  ibid #057

20. Analysis of serum lipid changes associated with self-reported fatigue, muscle pain and

      the different chronic fatigue syndrome factor analysis symptom clusters.

      McGregor NR, Dunstan RH, De Meirleir K et al  ibid  #059

21. Oxidative Damage in Chronic Fatigue Syndrome. D Racciatti et al  ibid  #150

22. Hypercoaguable state associated with active Human Herpes Virus 6 (HHV6) viraemia in patients with CFS. J Brewer, D Berg   ibid  # 098

23. RNAs in the plasma of patients with chronic fatigue syndrome: a novel mechanism for chronic illness expression with both treatment and diagnostic implications.

      PR Cheney, HB Urnovitz  ibid #074

24. Dr N Afari. Reporting on AACFS Conference.   Judith Blake.

     Seattle Times 26 January  2001

25. Comparison of maximal oxygen consumption and RNase L enzyme in patients with

      chronic fatigue syndrome.  C Snell et al  AACFS Fifth International Research & 

      Clinical Conference, Seattle, January 2001  #026

26. The low molecular weight ribonuclease L present in peripheral blood mononuclear

      cells of CFS patients is formed by proteolytic cleavage of the native enzyme.

      P Englebienne, RJ Suhadolnik et al  ibid  #065

27. The interaction of RNase L ankyrin domain with ABC transporters might explain pain 

      and many of the physiological disorders of CFS.  P Englebienne, K De Meirleir et al

      ibid  #069

28. Apoptotic dysfunction consecutive to RNase L cleavage is likely to be central to the

      maintenance of chronic fatigue syndrome. P Englebienne, K De Meirleir et al 

      ibid   #068

29. Cytokine levels in patients with a different immunological profile. Kenny De Meirleir

      et al   ibid  #017

30. A multi-centre study of autoimmunity in CFS. K Sugiura, D Buchwald, A Komaroff

      et al   ibid  # 037

31. Flow cytometric measurements of perforin and natural killer cell activiry.

      Kevin Maher, Nancy Klimas, Mary Ann Fletcher   ibid  #047

32. Immunological studies on the blood of patients with Gulf War Syndrome.

      A Vojdani   ibid  #076

33. Chronic fatigue syndrome. Anthony J Pinching. Prescribers’ Journal 2000:40:2:


34. Editorial: The Biology of the Chronic Fatigue Syndrome. Anthony Komaroff.

      Am J Med 2000:108:169-171

35. Characterization of a 2-5A dependent 37-kDa RNase L 2.Azido photoaffinity labelling

      and 2-5A dependent activation.  Shetzline SE, Suhadolnik RJ. J Biol Chem 2001

     April 25 (epub)

36. Interferon-induced proteins are elevated in blood samples of patients with chemically or virally induced chronic fatigue syndrome. Vojdani A, Lapp CW.  Immunopharmacol  Immunotoxicol  May 1999:21(2):175-202  

37. Human endogenous retrovirus: nature, occurrence and clinical implications in human disease. Urnovitz HB.  Clin Microbiol Rev 1996:(1):72-99

38. Rapid Analysis of Low Levels of Indolylacrolylglycine in Human Urine.

      Shattock P et al.    J Chromatography 1998:B:712:51-58

39. High prevalence of serum markers of coeliac disease in patients with chronic fatigue

      syndrome.  A.Skowera, S.Wessely et al.    Journal of Clinical Pathology 2001:    


40. Prevalence of irritable bowel syndrome in chronic fatigue.  Gomborone JE et al. 

     Journal of The Royal College of Physicians,      London, 1996:30:5:512=513

41. Muscle metabolites detected in urine in fibromyalgia and chronic fatigue syndrome

      may suggest on-going muscle damage. SCM Richards, J Bell, L Cheung, A Cleare,

      DL Scott. # 382  Conference Proceeding of the British Society of Rheumatologists,

     April 2001, Edinburgh, Scotland

42. A Study of the Immunology of the Chronic Fatigue Syndrome: Correlation of 

      Immunologic Parameters to Health Dysfunction. IS Hassan, W Weir et al. Clin

      Immunol Immunopathol  1998:87:60-67

43. Detection of Immunologically Significant Factors of Chronic Fatigue Syndrome using

      Neuronal-Network Classifiers. Hanson SJ, Gause W, Natelson B.  Clin Diagn Lab

      Immunol 2001:8 (3):658-662

44. Immunotherapy of chronic fatigue syndrome: therapeutic interventions aimed at

modulating the Th1/Th2 cytokine expression balance. Patarca-Montero R, Klimas N,

Fletcher MA. JCFS 2001:8:1:3-37

45. Autoantibodies to Nuclear Envelope Antigens in Chronic Fatigue Syndrome.

      Dedra Buchwald, J Jones. J Clin Invest 1996:98:8:1888-1896

46. Antinuclear envelope antibodies: Clinical associations. Nesher G, Margalit R,

      Ashkenazi YJ  Semin Arthritis Rheum 2001:Apr 30 (5):313-320

47. Enteroviral sequences detected by polymerase chain reaction in muscle biopsies of

      patients with postviral fatigue syndrome.  Gow JH, Behan WMH, Clements GB et al

      BMJ 1991:302:692-696

48. Persistence of entervirus RNA in muscle biopsy samples suggests that some cases of

       chronic fatigue syndrome result from a previous, inflammatory viral myopathy.

       Bowles NE, Lane RJM, Cunningham L and Archard LC. Journal of Medicine


49.  Enterovirus in the chronic fatigue syndrome. McGarry F et al.  Ann Int Med 1994:


50.  Detection of enterovirus-specific RNA in serum: the relationship to chronic fatigue.

       Clements GB et a.   J med Virol 1995:45:156-161

51. Myalgic encephalomyelitis - a persistent enteroviral infection?   Dowsett EG,

      Ramsay AM. Postgraduate Medical Journal 1990:66:526-530

52. Evidence that abnormalities of central neurohormonal systems are key to

      understanding fibromyalgia and chronic fatigue syndrome. Leslie J Crofford,

      Mark A Demitrack. Rheum Dis Clin North America 1996:22:2:267-284

53. Neuroendocrine correlates of chronic fatigue syndrome: a brief review.

      Mark A Demitrack J Psychiat Res 1997:31:1:69-82

54. Dehydroepiandrosterone (DHEA) response to i.v. ACTH in patients with chronic

      fatigue syndrome. De Becker P, De Meirleir K et al  Horm Metab Res 1999:1:18-21

55. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients

      with chronic fatigue syndrome. Demitrack MA et al   Journal of Clinical

      Endocrinology and Metabolism 1991:73:1224-1234

56. Disturbance of hypothalamic function and evidence for persistent enteroviral infection 

      in patients with chronic fatigue syndrome. Richardson J. JCFS 1995:1:2:59-66

57. Adrenal size in chronic fatigue syndrome. Teh J, Scott L, Dinan T et al. Radiology

      1998:209P (Suppl):411-412).

58. The role of the HPA axis in chronic fatigue syndrome.  LV Scott. PhD Thesis. 

      British Library, 1997

59. Clinical Review 86. Euthyroid sick syndrome: is it a misnomer? Chopra IJ

 J Clin Emdocrinol Metab 1997:82(2):329-334

60. Sick euthyroid syndrome. PM Camacho, AA Dwarkanathan. Postgraduate Medicine


61. Medicine Endocrinology 2 3-24-98 html.  Thyroid. Lecturer: Dr Blum

62. Fine needle aspiration cytology of the thyroid in chronic fatigue  B.Wickland et al. 

     Lancet 2001:357:956-957

63. The Clinical and Scientific Basis of Myalgic Encephalomyelitis Chronic Fatigue 

      Syndrome. Ed. BM Hyde, Jay Goldstein, Paul Levine. pub. The Nightingale Research

      Foundation, Ottawa, 1992

64. A Clinical Description of a Disease resembling Poliomyelitis seen in Adelaide

      1949-1951. Pellew RAA. Medical Journal of Australia 1951:944-946

65. Neurally Mediated Hypotension and Chronic Fatigue Syndrome. Peter C Rowe,

      Hugh Calkins. Am J Med 1998:105(3A):15S-21S

66. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and

active Human Herpes Virus Type 6 infection.  Buchwald D, Peterson DL, Gallo RC,

      Komaroff AL et al  Ann Int Med 1992:116:2:103-113

67. Detection of intracranial abnormalities in patients with chronic fatigue syndrome: 

comparison of MR imaging and SPECT. Schwartz RB, Komaroff AL et al

Am J Roentgenology 1994:162:4:936-941

68. Brainstem perfusion is impaired in patients with chronic fatigue syndrome. Costa DC,

      Tannock C, Brostoff J. Quarterly Journal of Medicine 1995:88:767-773

69. Brain positron emission tomography (PET) in chronic fatigue syndrome.

      Tirelli U, Tavio M et al  Am J Med 1998:105:3A:54S-58S

70. Relationship of brain MRI abnormalities and physical function status. Cook DB,

      Lange G, DeLuca J, Natelson BH  Int J Neurosci 2001:107 (1-2):1-6

71. Chronic fatigue syndrome and / or fibromyalgia as a variation of antiphospholipid 

      antibody syndrome.  Berg D, Harrison H et al.   Blood Coagul Fibrinolysis 


72. The Technological Investigation of ME/CFS Patients. BM Hyde. Second World Congress on Chronic Fatigue Syndrome, Brussels  9-12 September 1999.

73. Enhanced Sensitivity of the Peripheral Cholinergic Vascular Response in Patients with

      Chronic Fatigue Syndrome. Vance A Spence, Faisel Khan, Jill JF Belch

      Am J Med 2000:108:736-739

74. Increased sensitivity to glucocorticoids in peripheral blood mononulcear cells of

      chronic fatigue syndrome patients, without evidence for altered density or affinity of

      glucocorticoid receptors. Visser J et al  J Investig Med 2001:49(2):195-204

75. Lung Function Test Findings in Patients with Chronic Fatigue Syndrome. De Lorenzo 

      et al. Australia and New Zealand Journal of Medicine 1996:26:4:563-564.

76. Pulmonary Function and the Chronic Fatigue Syndrome. CB Payne, HE Sloan

Ann Intern Med 1989:111(10):860

77. Respiratory Symptoms and Lung Function Testing in Chronic Fatigue Syndrome

Patients. P De Becker, K De Meirleir et al  Fourth International AACFS Research

and Clinical Conference, Cambridge, Massachusetts, October 1998:104

78. Exercise Capacity in Chronic Fatigue Syndrome.  Pascale De Becker, Neil McGregor,

      Kenny De Meirleir et al.  Arch Intern Med 2000:160:3270-3277

79. Impaired oxygen delivery to muscle in chronic fatigue syndrome. Kevin K McCully 

      and Benjamin H Natelson Clinical Science 1999:97:603-608).

80. Post-viral Fatigue Syndrome and the Cardiologist. RG Gold. In: Postviral Fatigue

     Syndrome. Eds: Rachel Jenkins and James Mowbray. John Wiley & Sons 1991:

227- 231

81. Cardiac and Cardiovascular Aspects of ME/CFS: A Review. B Hyde, A Jain

      In: The Clinical and Scientific Basis of Myalgic Encephalomyelitis Chronic Fatigue 

     Syndrome. Eds BM Hyde, Jay Goldstein, Paul Levine. pub; The Nightingale Research

      Foundation, Ottawa, 1992

82. Cardiac Involvement in Patients with Chronic Fatigue Syndrome as Documented with

     Holter Monitor and Biopsy Data in Birmingham, Michigan, 1991-1993.

     AM Lerner et al  Infectious Diseases in Clinical Practice 1997:6:327-333

83. Chronic Fatigue Syndrome in Northern Nevada. SA Daugherty, BE Henry et al

      Rev Inf Dis 1991:13 (Suppl 1): S39-S44

84. Chronic Fatigue Syndrome and Depression: Biological Differentiation and Treatment.

      CM Jorge, PJ Goodnick  Psychiatric Annals 1997:27:5:365-366

85. Symptom patterns in long-duration chronic fatigue syndrome. Fred Friedberg,

      Lucy Dechene et al  J Psychosom Res 2000:48:59-68

86. Ocular Manifestations of Chronic Fatigue and Immune Dysfunction Syndrome.

      W.Potaznick, N Kozol  Optometry and Vision Science 1992:69:10:811-814

87. Survey of the Ocular Manifestations of Chronic Fatigue and Immune Dysfunction

     Syndrome. W Potaznick et al  Clinical Infectious Diseases 1994:18 (Suppl 1):S87

88. A study of the eye in patients with chronic fatigue syndrome in western New York

      ME Hartnell, RJ Lanham  CFIDS Chronicle Winter 1995:53

89. Randomised controlled trial of non-directive counselling, cognitive behaviour therapy

      and normal general practitioner care in the management of depression as well as mixed

      anxiety and depression in primary care. M King, B Sibbald et al  Health Technology

      Assessment 2000:4:19