And to reiterate the criticisms that have been made in so many pleases already.... you did not provide patients suitable for a replication study.

If the Lombardi team manageds to use the Canadian criteria then what is hte big problem for anyone in hte UK to utilise the Canadian criteria?

What are you all frightened of.

And further more, your patients were all patietns who had attended your clinics and had probalby taken part in other studies.

Well how about choosing patients that have never participated in studies before.

How about chosing patients who are severaly affected and unabe to get to your clinics or to hospital appointments?

The 25% ME group has hundreds of members - severely affected patients with ICD-10 G93.3 Myalgic Encephalomyelitis - a condition that none of you actually recognise.

And just to close - you claim that as a group of psychiatrsits with no specialist interests in retro-virology that your patients who were seen in departments of psychiatry were not primarily patients who had mental health problems.

Yet your colleages are busily trying to have CFS reclasified to a somatoform category in ICD-11 and your colleagues in psychiatry interested in CFS are also trying to get CFS included in DSM-V.

And if you do not consider CFS to be a mental health issue then why was the NICE Guideline 53 discussed under the heading of mental health in a 2008 report the details of which are given below....

http://62.204.33.138/file...

South London and Maudsley NHS Foundation Trust

TRUST BOARD OF DIRECTORS – SUMMARY REPORT

Date of Board meeting: 25th November 2008

Name of Report: Implementation of NICE guidance (Annual Report 2008)

Authors: Rosie Peregrine Jones and Dr Rosalind Ramsay

Approved by: (name of Exec Member) Dr Martin Baggaley

Presented by: Dr Ros Ramsay

Purpose of the report:

To outline progress within the Trust against the guidance issued by NICE which is relevant to mental health services

[ ... ]

Mental health clinical guidelines

[ ... ]

53 Chronic fatigue syndrome April 2007 May 2007 CAEC November 2008 SNIG

Alastair Santhouse

Ian Brown

[ ... ]

AMH [adult mental health]

Chronic Fatigue syndrome Lead: Alastair Santhouse

[ ... ]

A true replication study will not be a valid study until it uses the precise patient selection criteria as used by the Lombardi team.

A true replication study will not be a valid replication study until it uses the precise testing and evaluation techniques as used by the Lombardi team.

Anything less is scientifically flawed and open to legitimate deconstrucrtion and dismissal.

Use the Canadain criteria and do your work properly.

Use patients you usually ignore - patients severely affected and not before "screened" by the profession of psychiatry just to avoid any conflicts of interest.

After all one more XMRV positive CFS patient is one less patient recrutied for CBT and Graded Exercise isn't it?

I would like to state that, as a former patients at King's College Chronic Fatigue Clinic, I was offered none of the tests stated above. To quote:

'studies of PET and fMRI neuroimaging, autonomic dysfunction, neurochemistry, respiratory function, vitamin status, anti nuclear antibodies, immune function, neuroendocrine function and genetics (see references)'.

Nor was I offered a 9am cortisol test. I am in touch with many former patients of King's who similarly were never offered any bio-medical testing or bio-medical explanation of the disease. In contrast, we were given literature suggesting CFS was a result of bodily deconditioning occuring during an initial virus and later psycho-social maintaining factors.

I strongly dispute claims, as I know other patients will, that King's is committed to the type of bio-medical testing and research that this piece claims. It could be that the sample tested by the researchers had been subjected to such tests. However, neither myself nor anyone I am in contact with was offered anything in the way of testing, and had only had the most basic blood tests conducted by their GPs.

I believe the researchers at King's have a strong motive for wishing to contradict the findings of the WPI and judgement on these findings should be withheld until later, less biased tests are conducted.

The authors are quite right to resist unfair characterisations of the patients involved in this study.

Nevertheless, Professor Wessely has in at least two publications specifically stated that: "No consistent pattern of immunological abnormalities is identified" in CFS patients (1) and (2) - an assertion that is at odds both with your statement in this response and with numerous other published studies that have demonstrated immune dysfunction in well-defined ME/CFS patients. So which is it to be? And, if you do indeed recognise immune dysfunction as being a factor in ME/CFS, would you please, for the sake of clarity, consider publishing retractions of previous, possibly misleading statements?

The same goes for Professor Wessely's support, again in (2), for Koch, et al.'s "VAMPIRE" study (3) which argued for only very limited blood testing of patients presenting with fatigue - a position that is bound to create confusion about whether or not patients with an ME/CFS diagnosis really have the disease or whether they have simply not been fully investigated for conditions that could be diagnosed from standard lab work.

The point is that it is not surprising, given Professor Wessely's previous published output, that questions about his understanding of ME/CFS have spilled over over into the issue of patient selection in your XMRV study.

Now that we know that at least one UK patient has tested positive for XMRV via the US test at VIPdx (4) would not the most sensible way of resolving this dispute be to submit samples from your cohort to WPI to determine whether your test is comparable to theirs?


1. Lyall M, Peakman M, Wessely S. "A systematic review and critical evaluation of the immunology of chronic fatigue syndrome" in J Psychosom Res. 2003 Aug;55(2):79-90. Abstract: http://www.ncbi.nlm.nih.g...

2. Harvey SB, Wessely S. "Tired all the time" in British Journal of General Practice, Volume 59, Number 561, April 2009 , pp. 237-239(3). DOI: 10.3399/bjgp09X420284, online at: http://rcgp.publisher.ing...

3. Koch, H, et al. "Ordering blood tests for patients with unexplained fatigue in general practice: what does it yield? Results of the VAMPIRE trial " in British Journal of General Practice, Volume 59, Number 561, April 2009 , pp. e93-e100(1). Online at: http://rcgp.publisher.ing...

4. Phoenix Rising, online at: http://forums.aboutmecfs....

The authors’ reply to the concerns about patients selection for research for this paper raises more problems in addition to those of the original paper. My comments here should be read in addition to other problems raised by authors on this forum.

Firstly, the authors express some resentment towards those legitimately have questioned this research cohort and the criteria over the years, which is rather surprising. Contrary to the insinuation by the authors, no person on the Plosone responses forum has insinuated that the research cohort they use are somehow 'less deserving' than say, the WPI cohort, purely that they are a different type of patient, using different criteria that select a different population, and that this may cause problems with the findings, and claims made based on those findings, with regard to the British 'CFS' population. This is a reasonable concern to express, and such a deduction can be made based on the evidence the authors provide themselves in their paper, citations, and their response. For example, their paper states:

"Patients in our CFS cohort had undergone medical screening to exclude detectable organic illness".

In the authors’ response here, they also write:

"Thus patients in our service have also co operated in studies of PET and fMRI neuroimaging, autonomic dysfunction, neurochemistry, respiratory function,
vitamin status, anti nuclear antibodies, immune function, neuroendocrine function and genetics "

While patients being processed for a research cohort may well, indeed are likely, to have co-operated and had such tests done, this does not necessarily mean that patients with positive results are part of the research cohort. Indeed, positive results, which would indicate organic abnormality, would surely be likely to prevent a patient being selected for a cohort, by the very logic described in the author's paper here, by their own response (the additional tests are considered ‘not clinically necessary’?) and in at least one of their citations (Quarmby et al)? In the Quarmby et al paper, the cohort is described, in which the criteria used (in addition to 'Fukuda/CDC') is 'Oxford'. The Oxford criteria (Sharpe et al 1991) in particular actually do allow for patients who fulfil organic abnormality to be selected out of a research cohort. Indeed, Anthony David, referring to these, commented at the time:

"British Investigators have put forward an alternative, less strict, operational definition which is essentially chronic (6 months or more) severe disabling fatigue in the absence of neurological signs with myalgia, psychiatric symptoms and previous viral infections as common associated features.”

Here special attention needs to be paid to the term ‘previous viral infections’ and ‘absence of neurological signs’, in order to contextualise the cohort selection process applied using the Oxford Criteria.

It is therefore quite reasonable to presume that patients in the cohort described in the Erlwein et al paper are less likely to be suffering from organic abnormalities associated with 'CFS' populations than in other research cohorts. It is also rational to be concerned that the cohort described here may not be representative of many people diagnosed with 'CFS' in Britain. NICE guidelines for example, acknowledge that very little research has been done on ‘severely affected’ patients, who comprise, possibly at least 25% of the population of people given a ‘CFS’ diagnosis (though so little research has been done on ‘severely affected‘ in Britain, the true number is not yet clear). While patients potentially destined for a research cohort which weeds out ‘detectable organic abnormality’ may be subjected to a rigorous amount of investigations, those not undergoing this process do not undergo such testing, at least not in the NHS. Indeed, such investigations of clinical patients are severely proscribed in the majority of ‘guidelines’: NICE, and the RCPCH guidelines as just two examples. Ironically, Fukuda guidelines also make the following comment:

"The use of tests to diagnose the chronic fatigue syndrome should be done only
in the setting of protocol-based research.

In clinical practice, no additional tests, including laboratory tests and
neuro-imaging studies, can be recommended. Examples of specific tests (which
should not be done) include serologic tests for enteroviruses; tests of
immunologic function, and imaging studies, including magnetic resonance imaging
scans and radionuclide scans (such as single photon emission computed tomography
(SPECT) and positron emission tomography (PET) of the head.

We consider a mental status examination to be the minimal acceptable level of
assessment." (1994:)

That clinical populations are not to be afforded the types of investigations given to research populations makes the whole idea of ‘medically unexplained’ or ‘unexplained by disease’, or ’functional’ (as synonymous with ’non-organic’ or not discernibly organic‘) as common characterisations of CFS (including by at least one of the authors themselves in previous publications, for just one example, Page et al, 2003) highly problematic at best.

It is also significant that ‘CFS’ is so often described as a ‘diagnosis of exclusion’ (see, for example, the Centre for Disease Control CFS information website (Footnote: http://www.cdc.gov/cfs/cf...) . Certain research case definitions comply with this assumption, such as the Oxford Criteria (Sharpe et al, 1991) and CDC Criteria (Fukuda et al, 1994) Here, ‘diagnosis of exclusion’ also functions as a euphemism of ‘medically unexplained’. The key problem within this recurring theme in the literature, which most frequently remains un-addressed, is how a clinical patient’s condition can all too easily become ‘medically unexplained’ because of the practice of encouraging doctors to severely limit investigations in the first place: except, it would appear, ironically, in research populations in which ‘organic’ illness is being weeded out to provide the type of cohort that might fulfil ‘not organically ill’ definitions.

The issue of ‘disability’ also needs to be clarified. The references cited in the Erlwein paper to support the statement that the patient cohort was of ’high levels of disability’ refer only to ’disability’ in psycho-social terms or feelings of ‘fatigue‘, and not in terms of physical impairment, a key omission. Mundt et al’s paper in particular focuses on specific mental health problems and the social exclusionary effects of living with these. While in no way invalidating or trivialising the disability caused by mental health problems, it must be pointed out that both Mundt et al and Chalder Scales nevertheless fail to elucidate a high level of physical or physiological (say, for example, neurological, mitochondrial and/or cardiovascular) impairment, key problems present in people given a clinical diagnosis of ‘CFS’, usually related to specific organic abnormalities that can be found, if they are tested for in the first place.

With regard to the Canadian criteria (Carruthers et al), in fact they have undergone some ‘validation’. Jason et al found:

“…Canadian criteria selecting cases with less psychiatric co-morbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurologic symptoms. The overall findings suggest that the Canadian clinical criteria appear to select a more symptomatic group of individuals than the CFS criteria, and these individuals do demonstrate less current and lifetime psychiatric impairment than those selected according to the CFS criteria. In contrast, the CFS group was not significantly different from the Chronic fatigue-psychiatric group in psychiatric impairment. Predictably, the Chronic fatigue-psychiatric group evidenced the highest frequency of current and lifetime psychiatric disorders… Overall, there were 17 significant symptom differences between the Canadian and Chronic fatigue-psychiatric group, but only 7 significant symptom differences between the CFS and Chronic fatigue-psychiatric group. Findings suggest that the Canadian criteria select a group of patients with more symptoms, and the Canadian criteria identify a group with higher levels of physical functional impairment and less psychiatric comorbidity. Findings from the present study indicate that the Canadian criteria does capture many of these cardiopulmonary and neurological abnormalities, which are not currently assessed by the current CFS case definition (Fukuda et al., 1994). However, it is worth noting that when the Fukuda et al. (1994) CFS case definition was conceived, the research had not yet been done investigating these abnormalities. In combination with symptom patterns, it is possible to conclude that the Canadian group does select individuals with greater impairment, particularly given the physical composite score, fatigue/weakness, neurologic and neuropsychiatric symptoms, as these symptoms can interfere with daily living and occupational performance. Results from this present investigation highlight the importance of contrasting different diagnostic criteria in order to gain a greater understanding of the syndrome now known as CFS. The findings do suggest that the Canadian criteria point to the potential utility in designating post-exertional malaise and fatigue, sleep dysfunction, pain, clinical neurocognitive, and clinical autonomic/ neuroimmunoendocrine symptoms as major criteria for future attempts to define this syndrome...” (http://www.mefmaction.net...)

In addition to using the Carruthers et al criteria (or ‘Canadian Criteria‘), the WPI give this information about their patient cohort in their supporting online material:

"Their diagnosis of CFS is based upon prolonged disabling fatigue and the presence of cognitive deficits and reproducible immunological abnormalities. These included but were not limited to peturbations of the 2-5A synthetase/RNase L antiviral pathway, low natural killer cell cytotoxicity (as measured by standard diagnostic assyas) and elevated cytokines particularly interleukin-6 and interleukin-8. In addition to these immunological abnormalities, the patients characteristically demonstrated impaired exercise performance with extremely low VO2 max measured on stress testing..." (www.sciencemag.org/cgi/co...)

It is therefore highly unlikely, as the authors indeed acknowledge in their reply here, that Erlwein et al were testing the same type of patient as those tested by the WPI, which inevitably makes the Erlwein et al findings- and perhaps some of the wilder claims that they have ‘cast serious doubt’ on the WPI‘s findings, unfortunately made in some of the lay media- not scientifically tenable. The failure of Erlwein et al to include such type of patient in their cohort, however. does not mean that such patients do not exist in Britain. Copious patient anecdotal experience, research reports, and charity surveys indicate that they do exist. Whether XMRV is present or not is another matter, but there are enough identifiable problems around patient selection alone with the Erlwein et al paper to indicate this is not a definitive disproving of the existence of the virus in Britain.

Ongoing neglect of the importance of establishing a possible ‘CFS’ patient population in Britain, clinically and in research settings, using the Canadian Guidelines, is preventing the development of knowledge that might help extremely ill and disabled people here in Britain.

The problems I have briefly outlined here do not fully express the range and depths of problems with regard to: the identity of an accurate ‘CFS’ population; the instabilities of ‘CFS’ criteria per se; the faulty concepts of ‘medically unexplained’ or ‘functional‘ and relation to ‘psychogenic‘ explanations for somatic illness; the vagaries of criteria that claim to facilitate a ‘diagnosis of exclusion’; and the psychogenic dismissal of serious organic dysfunction of patients given a ’CFS’ diagnosis, problems that have happened for many years. These problems are relevant to the Erlwein et al paper. Furthermore, they are highly relevant to all research that claim a psychological and/or behavioural aetiology to the condition or conditions that get deemed as ‘CFS’.

REFERENCES

Carruthers, B. et al (2003) “Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols” Journal of Chronic Fatigue Syndrome, Vol. 11(1), pp 7 - 115.

Chalder, T. Berelowitz, G. Pawlikowska, T. Watts, L. Wessely, S. Wright, D. Wallace, E. P. 'Development of a fatigue scale' Journal of Psychosomatic Research Vol 37: Issue 2: Feb 1993: 147-153.

David, A.S. ‘Postviral syndrome and psychiatry‘ British Medical Bulletin: 1991: 47: 4: 966-988

Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. 'The chronic fatigue syndrome: a comprehensive approach to its definition and study' Ann Intern Med. 1994 Dec 15;121(12):953-9.

Jason LA, Torres-Harding SR, Jurgens A, Helgerson J. “Comparing the Fukuda et al. Criteria and the Canadian Case Definition for chronic Fatigue Syndrome”. Journal of Chronic Fatigue Syndrome 12(1):37-52, 2004

Mundt, J.C. Marks, I.MShear, K. Griest, J.H. 'The work and social adjustment scale: a simple measurement of impairment in functioning' British Journal of Psychiatry (2002) 180: 461-443

Page, L.A. Wessely, S. 'Medically unexplained symptoms: exacerbating factors in the doctor–patient encounter' J R Soc Med 2003;96:223-227

Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ, et al ' Chronic fatigue syndrome: guidelines for research' J R Soc Med. 1991 Feb;84(2):118-21.

I found the following statement in point 3 of Dr Cleare's response (below) to be quite extraordinary:

"We follow the same psychiatric exclusion criteria as mandated by the Fukuda criteria......In addition, we also exclude patients with chronic somatisation disorder as defined by DSM-IV, which is not required by the Fukuda criteria, but most experts and clinicians agree are a different population."

Why extraordinary?

Because of Professor Wessely and colleagues' long held and widely publicised view that CFS is a somatisation disorder (or medically unexplained syndrome, MUS)(1)(2)(3)(4)(5)

This theory is in complete defiance of the scientific evidence which clearly shows CFS to be an organic disease. As such, by definition, CFS cannot be a somatisation disorder.(8)(9) The same holds true for other terms like MUS and psychosomatic (1) (2) (3)

Somatoform disorder is defined in DSM-IV as follows:
"The most common characteristic of the somatoform disorder is the appearance of physical symptoms or complaints for which they have no organic basis."(6)

With such a profound turn around in thinking (if this really is the case) it would be helpful to all concerned if the authors could please clarify the following points:

1. Could you please state how all the authors defined CFS at the time of carrying out this research and do you still hold that perspective?

Lombardi et al unequivocally, on the basis of the scientific evidence, view CFS as an organic disease.

2. Could you please explain why you did not state in the paper that you had excluded patients with somatoform disorders.

3. If, as you say, you excluded patients in this research who had somatisation disorders, can you please explain why you cited papers in your reference list (for example, reference 9 by Wessely et al, "Chronic fatigue syndrome. A Practical Guide to Assessment and Management", 1997) which clearly classes CFS as a somatisation disorder.

3. And could you please explain why you did not cite papers, such as in Ref 8 & 9 below, which clearly show the organic basis of this disease?

4. Could you please inform readers when the 186 blood samples were taken, since, at least up until March 2009, Professor Wessely viewed CFS as a somatisation disorder(2).

Was the blood drawn after you had changed your minds about CFS being a somatoform disorder or before you changed your mind?

5.Could you please explain what has led to such a change of mind, no longer viewing CFS as a somatisation disorder?

Thank you for your time.

.............................................................

REFERENCES
1. http://www.scielo.br/scie...
Chronic fatigue syndrome: an overview.
Cho HJ, Wessely S.
Rev. Bras. Psiquiatr. vol.27 no.3 São Paulo Sept. 2005
"Chronic fatigue syndrome is an exemplar of a medically unexplained syndrome."
"Similarly,functional somatic syndromes refer to groups of symptoms lacking disease-specific, demonstrable abnormalities of structure, and are usually defined by specialty or organ system. They include irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, multiple chemical sensitivity, chronic pelvic pain, temporomandibular joint dysfunction and more recently Gulf War syndrome."

This paper is titled "CFS: An Overview" yet please note that the references,(consisting of 6 papers) do not include any papers on biomedical research.

2. http://www.newscientist.c...
New Scientist, Opinion, "Mind over body?", Professor Simon Wessely, 13 March 2009. Please note that there is no mention of all the biomedical research showing CFS to be an organic disease.

3. http://www.iop.kcl.ac.uk/...
Research carried out at the Institute of Psychiatry, Kings College London, where three of the authors of this paper are based.
Part 4- The Project and the Post
"Background: Anorexia Nervosa (AN) and Chronic Fatigue Syndrome (CFS)are classical psychosomatic disorders......Aberrant emotional processing is a strong candidate as a maintaining factor for these disorders."

4. http://www.meactionuk.org...
From "Corporate Collusion?" by Professor Malcolm Hooper, Eileen Marshall and Margaret Williams, comments made by Professor Wessely over the years about CFS and CFS patients clearly showing how he views these patients and the disease:

"Wessely is on record as asserting that ME is merely a “belief” held by those who think they suffer from it; that ME patients’ muscle weakness is “simulated”; that efforts are made to over-interpret laboratory findings; that the average doctor will see ME patients are neurotic and will often be disgusted with them; that blaming a virus for the illness conveys advantages by protecting the victim from personal blame; that symptoms are simply normal sensations and are the result of “body-watching”; that ME is a “myth”; that ME is “learned helplessness”; that once validation is granted by a doctor, the ME patient may assume the “advantages of the sick role -- sympathy, time off work, benefits etc”; that ME symptoms have no anatomical or physiological basis; that patients’ aberrant beliefs are maintaining factors and that patients with ME exert a large and avoidable financial burden on health and social services.
(For individual references, see the December 2003 Briefing Paper for the House of Commons Health Select Committee: The Mental Health Movement: Persecution of Patients? which is available online at
http://www.meactionuk.org... )."

5. http://www.ncbi.nlm.nih.g...
Medically Unexplained Symptoms:Exacerbating Factors in the Doctor-patients Encounter, L A PAge, S Wessely, Journal of thew Royal Society of Medicine 2003:96:223-227
"This term (MUS) is now used in preference to "somatisation"

However I cannot find MUS in the DSM-IV

6. http://www.psychnet-uk.co...
Definition of somatisation disorder

7. http://www.meactionuk.org...
"Wessely’s Way: Rhetoric or Reason?"
Professor Malcolm Hooper and Margaret Williams
22nd March 2008

8. http://www.meactionuk.org...
List of reference and abstracts for some of the many biomedical research papers on CFS, plus inquest and autopsy information, see item 47 and 48.

9. Two further important references, 2009.
http://www.ncbi.nlm.nih.g...
J Clin Pathol. 2009 Dec 2.
Microbial infections in eight genomic subtypes of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME).
Zhang L, Goudh J, Christmas D, Mattey D, Richards S, Main J, Enlander D, Honeybourne D, Ayres J, Nutt DJ, Kerr J.
St George's University of London, United Kingdom;

http://www.ncbi.nlm.nih.g...
J Transl Med. 2009 Nov 12;7:96.
Plasma cytokines in women with chronic fatigue syndrome.
Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG.


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