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• The effect of different criteria on outcomes in ME/CFS trials
  Tom Kindlon
  Published on: 23 November 2015
• Conclusions Unsupported by the Evidence
  Jennifer M. Spotila
  Published on: 23 November 2015
• Inconsistencies, contradictions and controversies within the field of CFS/ME
  Robert Courtney
  Published on: 23 November 2015
• Re:High rates of deterioration following graded exercise therapy and cognitive behavioural therapy have been reported in patient surveys
  Kjetil G. Brurberg
  Published on: 23 November 2015
• Re:Re:The essence of ME vs CFS: post-exertional "malaise" vs fatigue
  Kjetil G. Brurberg
  Published on: 23 November 2015
• Re:The essence of ME vs CFS: post-exertional "malaise" vs fatigue
  Kjetil G. Brurberg
  Published on: 23 November 2015
• Re:People with a label of ME remain ill because they *are* ill
  Kjetil G. Brurberg
  Published on: 23 November 2015
• Research into biomedical mechanisms of disease is essential
  Robert Courtney
  Published on: 23 November 2015
• Re:Re:High rates of deterioration following graded exercise therapy and cognitive behavioural therapy have been reported in patient surveys
  Tom P Kindlon
  Published on: 23 November 2015
• Re:Case definitions for ME or CFS reflect instability, confusion and contestation inherent in the field.
  Kjetil G. Brurberg
  Published on: 23 November 2015
• Re:Confusion re criteria for ME
  Kjetil G. Brurberg
  Published on: 23 November 2015
• Re:The essence of ME vs CFS: post-exertional "malaise" vs fatigue
  R Simpson
  Published on: 23 November 2015
• Case definitions for ME or CFS reflect instability, confusion and contestation inherent in the field.
  Angela P. Kennedy
  Published on: 23 November 2015
• The essence of ME vs CFS: post-exertional "malaise" vs fatigue
  Frank N.M. Twisk
  Published on: 23 November 2015
• People with a label of ME remain ill because they *are* ill
  Nasim Marie Jafry
  Published on: 23 November 2015
• High rates of deterioration following graded exercise therapy and cognitive behavioural therapy have been reported in patient surveys
  Tom P Kindlon
  Published on: 23 November 2015
• Confusion re criteria for ME
  Ellen M Goudsmit
  Published on: 23 November 2015

• Published on: 23 November 2015

  The effect of different criteria on outcomes in ME/CFS trials

  • Tom Kindlon, Information Officer

  The authors discuss the PACE Trial: "Hence, primary studies and systematic reviews on prognosis and therapy are alternative sources to evaluate the usefulness of different case definitions of CFS/ME. We have identified only one such publication, the PACE trial.(1) Here, participants were diagnosed according to the Oxford- 1991 criteria, Empirical criteria-2007/Reeves and London ME-1994/National Task Force criteria, and th...

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  The authors discuss the PACE Trial: "Hence, primary studies and systematic reviews on prognosis and therapy are alternative sources to evaluate the usefulness of different case definitions of CFS/ME. We have identified only one such publication, the PACE trial.(1) Here, participants were diagnosed according to the Oxford- 1991 criteria, Empirical criteria-2007/Reeves and London ME-1994/National Task Force criteria, and then randomised to either standard medical treatment, graded exercise therapy, cognitive behaviour therapy or pacing. The results showed that the effectiveness of the treatments was similar across groups, irrespective of the case definition which had been used."

  This is what has been reported by the PACE Trial investigators. However there appears to be problems with how the criteria were used and operationalized.

  Ellen Goudsmit, one of the co-authors of the London criteria, has posted on PubMed Commons (2): "As a co-author of the London criteria for myalgic encephalomyelitis, I wish it to be known that this study did not use the criteria and that their citation refers to an incomplete and flawed version written by someone without permission from the original authors. It is therefore unclear if there were any patients with ME who participated in this trial." Dr Goudsmit gave more details about her concerns in a comment on another PACE Trial paper (3).

  I also question whether all those defined as having ME in the PACE Trial would all be seen as having ME by others: 97% (329 out of 340) of those that who did not have a psychiatric disorder who satisfied the Oxford criteria for CFS (4,5), which basically just requires chronic fatigue, were classed as satisfying the ME criteria.

  Regarding the Reeves criteria, it is first important to point out that it was the Reeves et al (2003) criteria that were used rather than the Reeves empirical criteria. These criteria were operationalized in a non-standard way in the PACE Trial, as the authors explained: "For the purposes of this study, the four or more symptoms needed to be present within the previous week of the assessment date, rather than the previous 6 months (Reeves et al. 2003)."

  In a trial of chronic fatigue (8), which is not that different from a trial of Oxford criteria CFS, investigators found the following: "Meeting the criteria for chronic fatigue syndrome was the most powerful predictor of poor outcome and this negative effect was enhanced by greater functional impairment or greater perceived negative consequences, but was not further enhanced by both." They are referring to the Fukuda criteria for CFS in this case (9).

  I discuss the heterogeneity of patients in a section of a paper of mine entitled, "Recognize heterogeneity of patients with a diagnosis of ME/CFS" (10).

  References:

  (1) White PD, Goldsmith KA, Johnson AL, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011;377:823-36.

  (2) Goudsmit EM. Comment on: Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. http://www.ncbi.nlm.nih.gov/pubmed/21334061#cm21334061_1177

  (3) Goudsmit EM. RE: Recovery from chronic fatigue syndrome after treatments given in the PACE trial. https://listserv.nodak.edu/cgi- bin/wa.exe?A2=ind1301E&L=CO-CURE&P=R1285&I=-3&d=No+Match%3BMatch%3BMatches

  (4) KindlonT. PACE Trial - 97% of the participants who didn't have a psychiatric disorder satisfied the definition of M.E. used. https://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind1106A&L=CO-CURE&P=R2764&I= -3&d=No+Match%3BMatch%3BMatches&m=21522

  (5) Sharpe MC, Archard LC, Banatvala JE, et al. A report--chronic fatigue syndrome: guidelines for research. J R Soc Med 1991;84:118-21.

  (6) Reeves WC, Lloyd A, Vernon SD, et al; International Chronic Fatigue Syndrome Study Group (2003). Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BioMed Central Health Services Research 3, 25.

  (7) White PD1, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013;43:2227-35. doi: 10.1017/S0033291713000020.

  (8) Darbishire L1, Seed P, Ridsdale L. Predictors of outcome following treatment for chronic fatigue. Br J Psychiatry. 2005;186:350-1.

  (9) Fukuda, K., Straus, S. E., Hickie, I., et al (1994) The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Annals of Internal Medicine. 1994;121:953-959.

  (10) Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bulletin of the IACFS/ME. 2011;19(2):59-111.

  Conflict of Interest:

  I do various types of voluntary work for the Irish ME/CFS Association

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Conclusions Unsupported by the Evidence

  • Jennifer M. Spotila

  I read the systematic review by Brurberg et al. (1) with great interest, and found it particularly timely in light of the Institute of Medicine study to create new diagnostic criteria for ME/CFS. (2) However, I believe that Brurberg and colleagues drew several conclusions that were unsupported by their analysis.

  First, the authors stated, "We found no empirical evidence supporting the hypothesis that some case...

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  I read the systematic review by Brurberg et al. (1) with great interest, and found it particularly timely in light of the Institute of Medicine study to create new diagnostic criteria for ME/CFS. (2) However, I believe that Brurberg and colleagues drew several conclusions that were unsupported by their analysis.

  First, the authors stated, "We found no empirical evidence supporting the hypothesis that some case definitions more specifically identify patients with a neuroimmunological condition." However, the validation studies applied case definitions by questionnaire or retrospective analysis. The studies examined by the authors did not take a group of patients, separate them by case definition, and then look for signs of a neuroimmunological condition. There are studies that do conduct such experiments - testing for immune markers, gene expression response to exercise, etc. - but the authors did not look at those studies because their systematic review was not designed to capture them. It is an overstatement to claim that no empirical evidence was found without acknowledging that the review did not examine studies that may have provided such evidence.

  Furthermore, I direct the authors' attention to a recent study by Jason et al. (3), which appears to use their Model A for testing case definitions. Three case definitions (Fukuda, Canadian 2003 and ICC 2011) were applied to a population of healthy controls and patients diagnosed using Fukuda or Canadian 2003. When appropriate symptom and severity thresholds were applied, significant differences emerged among the subject groups. However, this study has the same limitation as others examined by Brurberg et al., insofar as no gene expression, imaging, immune or exercise testing of the subjects was a part of its design.

  Second, Brurberg et al. argued that for clinical purposes, a broad definition can be helpful because it identifies more patients who may benefit from treatment. They pointed to the PACE trial as showing the effectiveness of CBT and GET "irrespective of the case definition which had been used." But they failed to acknowledge methodological problems with the PACE trial, including the fact that application of the CDC definition in assessing recovery "may have been inaccurate because we only examined for accompanying symptoms in the previous week, not the previous 6 months" as required by the CDC criteria. (4) It is possible, if not likely, that a patient cohort without six months of Fukuda accompanying symptoms may have a different treatment response from those who do have such symptoms for six months. PACE did not adequately test the hypothesis. Bruberg et al. also stated "existing evidence indicates that side effects of cognitive behavioural treatments or graded exercise therapy are negligible." This conclusion ignores analysis by Tom Kindlon of the problems with reporting harms in studies like PACE, (5) and published data from trials that did not find treatment benefit for CBT/GET. (6)

  Third, the authors argued that the organic vs. psychic disorder debate should be abandoned because most medical disorders have a complex aetiology, and psychological treatments can have benefit in "clear-cut somatic disorders." But they then point the finger at patients: "Unfortunately, patient groups and researchers with vested interests in the belief that ME is a distinct somatic disease seem unwilling to leave the position that ME is an organic disease only. This position has damaged the research and practice for patients suffering from CFS/ME." The authors presented no evidence to support their accusation that the organic disease -only position has damaged research and clinical practice. Furthermore, they completely ignored the very real and logical possibility that the reverse is true. In other words, it is equally possible that the people with vested interests in the belief that ME/CFS has psychosocial causes are unwilling to leave that position, and have damaged the research and practice for patients suffering from the disease.

  Fourth, the authors concluded that, "Development of further case definitions of CFS/ME should be given low priority." Instead, "Priority should be given to further development and testing of promising treatment options for patients with CFS/ME." However, without an accurate and validated case definition, it will be difficult if not impossible to identify and test effective treatments. The authors admitted that classifying severity and symptom patterns to identify potential predictors of treatment benefit "might be useful." I would say that such work is essential. Furthermore, given the many methodological criticisms of validation studies raised by these authors, their analysis seems to support a strong argument for further work on validating and refining case definitions, rather than assuming that such work is not necessary or unlikely to advance the field.

  Overall, the authors' collection and review of the ME/CFS case definitions and validation studies will be very useful as a future reference. But they leap far ahead of what their review data suggests, and draw multiple conclusions with little or no supporting evidence.

  REFERENCES

  [1] Brurberg K, Fonhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open2014;4:e003973 doi:10.1136/bmjopen- 2013-003973

  [2] http://www.iom.edu/Activities/Disease/DiagnosisMyalgicEncephalomyelitisChronicFatigueSyndrome.aspx (Accessed March 10, 2014)

  [3] Jason LA, Sunnquist M, Brown A, Evans M, Vernon SD, Furst JD, Simonis V. Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis. Fatigue: Biomedicine, Health & Behavior 2013; DOI:10.1080/21641846.2013.862993

  [4] White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M, et al. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine 2013; 43: 2227-2235. doi:10.1017/S0033291713000020

  [5] Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bulletin of the IACFS/ME. 2011;19(2):59-111. http://iacfsme.org/BULLETINFALL2011/Fall2011KindlonHarmsPaperABSTRACT/tabid/501/Default.aspx (Accessed: March 10, 2014)

  [6] Nunez M, Fernandez-Sola J, Nunez E, Fernandez-Huerta JM, Godas- Sieso T, Gomez-Gil E. Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1 year of follow-up. Clin Rheumatol. 2011 Mar;30(3):381-9. doi: 10.1007/s10067- 010-1677-y. Epub 2011 Jan 15.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Inconsistencies, contradictions and controversies within the field of CFS/ME

  • Robert Courtney

  The review of chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) case definitions by Brurberg et al. (2014) [1] reflects the inconsistencies, contradictions and controversies that are commonly witnessed within the field of CFS/ME.

  Brurberg et al. note that the quantity of high quality and consistent research for CFS/ME is sparse which raises a question in relation to the value of a systematic review o...

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  The review of chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) case definitions by Brurberg et al. (2014) [1] reflects the inconsistencies, contradictions and controversies that are commonly witnessed within the field of CFS/ME.

  Brurberg et al. note that the quantity of high quality and consistent research for CFS/ME is sparse which raises a question in relation to the value of a systematic review of the literature. For example, the authors are dismissive of the 2003 Canadian Consensus Criteria (CCC) [2] and the 2011 International Consensus Criteria (ICC) [3] mainly on the basis of a lack of supportive empirical evidence. However, the ICC have only recently been developed, and the CCC are a relatively recent set of consensus criteria, which are being increasingly used for research, so it is possibly premature to carry out a review of related literature.

  Brurberg et al. assert that CFS "is a serious disorder characterised by persistent postexertional fatigue", and later conclude their discussion by arguing in favour of inclusive (broad) criteria, suggesting Fukuda [4] as a suitable candidate. However, the authors fail to discuss the fact that Fukuda does not require post-exertional fatigue or other post- exertional symptomatic exacerbation, whereas the CCC and the ICC do require post-exertional symptomatic exacerbation (including post- exertional fatigue, malaise or neuro-immune exhaustion.) So the authors appear to favour a set of criteria which do not require a defining symptom of the illness.

  Brurberg et al. claim that "research requires uniform and reproducible criteria, suitable for unambiguous definitions of the target population", and they select Fukuda as a suitable candidate. However, far from providing an unambiguous definition, Fukuda selects a broad and inclusive patient cohort for which Brurberg et al. say "disease mechanisms are complex, with no single causal factor identified." They go on to suggest that "It is likely that all CFS/ME case definitions capture conditions with different or multifactorial pathogenesis and varying prognosis."

  In a review of diagnostic criteria for CFS/ME, Brown et al. suggest that the Fukuda criteria's polythetic approach for assessing symptomatology (i.e. "a set of symptoms in which not all need to be present to make a diagnosis") may select a more heterogeneous cohort than criteria such as the CCC which require specific symptoms, although the authors acknowledge that there is a lack of supporting empirical evidence for the CCC [5]. In another review, Jason et al. suggest that the polythetic nature of the Fukuda criteria "increases the heterogeneity of the population and not only complicates identification of comparable samples, but is a likely cause of the inconsistent findings reported in the literature on CFS" [6].

  So the claim, by Brurberg et al., that broad and inclusive CFS criteria unambiguously define the target population is questionable.

  Brurberg et al. argue that "Case definitions for clinical practice should [...] provide a tool which can relieve patient's uncertainty ...", and suggest that the broad and inclusive Fukuda criteria may be the most appropriate for such a function. However, the authors acknowledge that broad criteria may select a heterogeneous cohort "with no single causal factor identified". The broad and inclusive Oxford criteria [7] requires only 'fatigue' as a symptom, but fatigue is universally experienced by the healthy population, and so provides little certainty in relation to disease etiology. In the case of Fukuda, patients must suffer from fatigue with some other common symptoms such as headaches and sore throat, also providing little certainty about a CFS patient's illness.

  Brurberg et al. report that they "found no empirical evidence supporting the hypothesis that some case definitions more specifically identify patients with a neuroimmunological condition." Upon settling on Fukuda as a favoured case definition, with the largest research base, the authors then go on to conjecture that "It is likely that all CFS/ME case definitions capture conditions with different or multifactorial pathogenesis and varying prognosis." So, perhaps it is wise not to dismiss all current and future case definitions of CFS/ME that attempt to define a more homogeneous patient cohort. Further research is needed to test the more selective criteria that have been relatively recently created, such as the CCC and ICC.

  The authors berate patient groups and researchers who consider ME to be an organic illness only. However, it has been demonstrated that interventions designed to treat a cognitive-behavioural model of CFS/ME fail to significantly improve objectively measured disability in the largest clinical trials [8], and fail to significantly improve physical function in clinical settings [9]. This suggests that the cognitive- behavioural model of illness may not address the underlying pathology of the illness, and an organic cause is perhaps more likely.

  The relative lack of compelling evidence in relation to CFS/ME suggests that further biomedical investigations into cause and treatments are essential to move this inconsistent and contradicted field of medicine forwards.

  References:

  1. Brurberg KG, F?nhus MS, Larun L, Flottorp S, Malterud K. (2014) Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open 4:e003973.

  2. Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles AC, Sherkey JA, van de Sande MI. (2003) Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. Journal of Chronic Fatigue Syndrome 11:7-115.

  3. Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles AC, Speight N, Vallings R, Bateman L, Baumgarten-Austrheim B, Bell DS, Carlo-Stella N, Chia J, Darragh A, Jo D, Lewis D, Light AR, Marshall-Gradisbik S, Mena I, Mikovits JA, Miwa K, Murovska M, Pall ML, Stevens S. (2011) Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 270:327 -38.

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

  5. Brown AA, Jason LA, Evans MA, Flores S. (2013) Contrasting Case Definitions: The ME International Consensus Criteria vs. the Fukuda et al. CFS Criteria. North American Journal of Psychology 15:103-20.

  6. Jason LA, Damrongvachiraphan D, Hunnell J, Bartgis L, Brown A, Evans M, Brown M. (2012) Myalgic Encephalomyelitis Case Definitions. Automatic Control of Physiological State and Function 1.

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

  8. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. (2011) Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 377:823- 36.

  9. Crawley E, Collin SM, White PD, Rimes K, Sterne JA, May MT; CFS/ME National Outcomes Database. (2013) Treatment outcome in adults with chronic fatigue syndrome: a prospective study in England based on the CFS/ME National Outcomes Database. QJM 106:555-65.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
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• Published on: 23 November 2015

  Re:High rates of deterioration following graded exercise therapy and cognitive behavioural therapy have been reported in patient surveys

  • Kjetil G. Brurberg, Researcher
  • Other Contributors:
    • Marita S. Fonhus, Lillebeth Larun, Signe Flottorp and Kirsti Malterud

  We want to thank Tom P. Kindlon for his interest in our article (1). Our review is not aimed at summarizing what is known about the effects of various interventions, but to identify existing diagnostic criteria for CFS/ME and studies aimed at validating them. In the absence of a reference test we agree with Reitsma et al (2) that diagnostic criteria can be validated and compared by relating them to clinical data such as h...

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  We want to thank Tom P. Kindlon for his interest in our article (1). Our review is not aimed at summarizing what is known about the effects of various interventions, but to identify existing diagnostic criteria for CFS/ME and studies aimed at validating them. In the absence of a reference test we agree with Reitsma et al (2) that diagnostic criteria can be validated and compared by relating them to clinical data such as history, future clinical events (prognosis) and response to therapy (effectiveness of interventions). Where we claim that evidence indicates that the side effects of cognitive behavioural treatment or graded exercise therapy are negligible, it is with references to other systematic reviews and trials.

  1. Brurberg KG, Fonhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open 2014;4:e003973 doi:10.1136/bmjopen -2013-003973

  2. Reitsma JB, Rutjes AW, Khan KS, et al. A review of solutions for diagnostic accuracy studies with an imperfect or missing reference standard. J Clin Epidemiol 2009;62:797-806.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Re:Re:The essence of ME vs CFS: post-exertional "malaise" vs fatigue

  • Kjetil G. Brurberg, Researcher
  • Other Contributors:
    • Marita S. Fonhus, Lillebeth Larun, Signe Flottorp and Kirsti Malterud

  We have read Simpson's response on our review (1) with interest and find it timely to provide some clarifications. We recognize that some patients, patient groups, health professionals and researchers consider ME as an organic disease only. The aim of our study was not to negate this hypothesis. Yet, our synthesis of the evidence regarding ways of diagnosing CFS/ME did not provide support for the idea that it is possible...

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  We have read Simpson's response on our review (1) with interest and find it timely to provide some clarifications. We recognize that some patients, patient groups, health professionals and researchers consider ME as an organic disease only. The aim of our study was not to negate this hypothesis. Yet, our synthesis of the evidence regarding ways of diagnosing CFS/ME did not provide support for the idea that it is possible to separate patients with "organic ME" from patients with "psychological" or other types of CFS. More specifically, we do not believe and have not concluded in our analysis that CFS/ME is a psychological disease. We agree that we should concentrate our efforts on developing better knowledge about this debilitating illness, its causes and management. Well conducted relevant clinical trials can make important contributions to our understanding of CFS/ME.

  1. Brurberg KG, Fonhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open 2014;4:e003973 doi:10.1136/bmjopen -2013-003973

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Re:The essence of ME vs CFS: post-exertional "malaise" vs fatigue

  • Kjetil G. Brurberg, Researcher
  • Other Contributors:
    • Marita S. Fonhus, Lillebeth Larun, Signe Flottorp and Kirsti Malterud

  We are pleased to note that Frank N.M. Twisk concludes that our review and analysis (1) has yielded useful insights. We believe that introducing new diagnostic criteria without subjecting them to a satisfactory validation process will cause unnecessary confusion and disagreement. We recommend that more effort should be focused at exploring and refining existing case definitions in methodologically rigorous ways rather th...

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  We are pleased to note that Frank N.M. Twisk concludes that our review and analysis (1) has yielded useful insights. We believe that introducing new diagnostic criteria without subjecting them to a satisfactory validation process will cause unnecessary confusion and disagreement. We recommend that more effort should be focused at exploring and refining existing case definitions in methodologically rigorous ways rather than to develop new sets of diagnostic criteria based on hypothesized and unsubstantiated distinctions between patients regarding etiology, prognosis or expected response to treatments.

  1. Brurberg KG, Fonhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open 2014;4:e003973 doi:10.1136/bmjopen -2013-003973

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Re:People with a label of ME remain ill because they *are* ill

  • Kjetil G. Brurberg, Researcher
  • Other Contributors:
    • Marita S. Fonhus, Lillebeth Larun, Signe Flottorp and Kirsti Malterud

  We appreciate Nasim Marie Jafry's interest in our review (1) and this opportunity to respond. First, we have no doubt that people with ME really are ill, and we agree that it is a relief for most people with severe symptoms to get at diagnosis. We also acknowledge that the average results of studies of many patients do not necessarily fit with the experience of every single patient.

  Second, one way to validate dia...

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  We appreciate Nasim Marie Jafry's interest in our review (1) and this opportunity to respond. First, we have no doubt that people with ME really are ill, and we agree that it is a relief for most people with severe symptoms to get at diagnosis. We also acknowledge that the average results of studies of many patients do not necessarily fit with the experience of every single patient.

  Second, one way to validate diagnostic criteria is to assess their ability to predict future events or prognosis. If prognosis differs between patients with different diagnostic labels, it is logical to think that this is either because the criteria have captured different conditions destined to different prognosis, or there might be a "labeling effect"; diagnostic labels might themselves interfere with the prognosis. These two explanations are not necessarily mutually exclusive.

  Jafry also refer to a ScotPHN report supporting the distinction between CFS and ME. We do not state that this distinction is wrong. Our analysis demonstrated, however, that we currently lack evidence supporting the hypothesis that existing case definitions are able to distinguish between subpopulations in a clinically meaningful way.

  From a methodological point of view, it is important to emphasize the difference between systematic reviews examining the existing evidence and clinical guideline recommendations. In a guideline process, one needs to consider both evidence on benefits versus harms and patients' values and preferences before making specific recommendations (2). Sometimes, these sources of information appear mutually contradictory and complicates the guideline process (3). It is therefore important that values and preferences are presented in an explicit and transparent way (2, 3).

  1. Brurberg KG, Fonhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open 2014;4:e003973 doi:10.1136/bmjopen -2013-003973

  2. Andrews J, Guyatt G, Oxman AD, et al. GRADE guidelines: 15. Going from evidence to recommendations: the significance and presentation of recommendations. J Clin Epidemiol. 2013:66:719-725

  3. Smith C, Wessely S, Unity of opposites? Chronic fatigue syndrome and the challenge of divergent perspectives in guideline development. J Neurol Neurosurg Psychiatry 2014:85:214-219

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Research into biomedical mechanisms of disease is essential

  • Robert Courtney

  In a review of case definitions for chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) Brurberg et al. (2014) claim (without providing evidence to support their assertion) that patient groups and researchers who believe that ME is an organic illness have "damaged the research and practice for patients suffering from CFS/ME". Brurberg et al. then proceed to discuss the potential of psychological therapies as a...

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  In a review of case definitions for chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) Brurberg et al. (2014) claim (without providing evidence to support their assertion) that patient groups and researchers who believe that ME is an organic illness have "damaged the research and practice for patients suffering from CFS/ME". Brurberg et al. then proceed to discuss the potential of psychological therapies as a useful tool for CFS/ME patients [1].

  The Medical Research Council (MRC) is the UK government's main research funding body. An analysis showed that approximately 91% of the total grant-spend on CFS/ME by the MRC from 2003 to 2008 went towards trials of "management and coping strategies", including cognitive- behavioural research [2]. The MRC has invested many millions of UK pounds into large studies investigating cognitive-behavioural interventions [3,4].

  With millions of dollars invested into cognitive-behavioural therapies for CFS/ME, globally, over many years, it is perhaps now fair to conclude that the research outcomes, from the largest and most robust studies, do not support a model of illness whereby symptoms are primarily propagated by psychological and behavioural factors.

  For example, the PACE Trial (n=641) is the largest research trial to investigate outcomes for treatments based upon a cognitive-behavioural model of CFS/ME. The trial demonstrated that objectively measured physical disability is not improved by cognitive-behavioural therapy (CBT), as assessed by the six minute walking distance test, indicating that the illness itself is not treated or reversed with CBT [3].

  As with all cognitive-behavioural studies, the PACE trial was open- label. It also failed to include a placebo control. Taking this into account, the 11-13% net clinical response rates after treatment with CBT for the self-report primary outcomes (Chalder fatigue and SF-36 physical function) were compatible with a placebo response [5].

  For the PACE trial, CBT had moderate efficacy at improving self- reported fatigue and physical function [3], which is typical of similar smaller studies [6,7,8].

  However, in real-world clinical settings, outcomes are even less favourable than in the PACE trial. A large investigation (n=1643) of specialist CFS/ME clinics in England's National Health Service (NHS), using the same primary outcomes as the PACE trial, demonstrated that specialist cognitive-behavioural treatment has no efficacy at improving physical function [9], reflecting the objective outcomes of the PACE trial. For self-reported fatigue, a moderate efficacy was recorded, which is in line with the PACE trial results, but no placebo control was included in either study, so these modest self-reported improvements are not supported by a robust study methodology.

  Trials using a waiting list control have demonstrated that CBT has similar efficacy to the waiting list, for self-reported outcomes in CFS/ME patients. Price et al. (2008) conjecture that the reason for this is that a waiting list exerts a positive influence on patients [6], thus a waiting list may act as a placebo control in such trials. CBT's therapeutic equivalence to a waiting list control illustrates the methodological weakness of open-label cognitive-behavioural studies that do not adequately control for placebo effect.

  The largest studies have demonstrated that interventions designed to treat an illness propagated by psychological and behavioural factors fail to benefit the vast majority of CFS/ME patients [3,4], and fail to improve objectively measured disability [3], and have no efficacy at improving physical function in clinical settings [9].

  As patients are so under-served by the cognitive-behavioural model of illness, it would be understandable if patient advocacy groups wish to see more research into biomedical mechanisms of disease.

  Biomedical investigations into mechanisms of illness are clearly needed to improve the lives of the majority of patients who are currently unserved by therapies based on an unproven cognitive-behavioural model of illness.

  References:

  1. Brurberg KG, F?nhus MS, Larun L, Flottorp S, Malterud K. (2014) Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open 4:e003973.

  2. ME Research UK. The Medical Research Council: a case to answer? (Internet) (Last accessed 12th Feb 2014) http://www.meresearch.org.uk/information/publications/mrc-case-to-answer/

  3. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. (2011) Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 377:823- 36.

  4. Wearden AJ, Dowrick C, Chew-Graham C, Bentall RP, Morriss RK, Peters S, Riste L, Richardson G, Lovell K, Dunn G; Fatigue Intervention by Nurses Evaluation (FINE) trial writing group and the FINE trial group. (2010) Nurse led, home based self help treatment for patients in primary care with chronic fatigue syndrome: randomised controlled trial. BMJ 23;340:c1777.

  5. Cho HJ, Hotopf M, Wessely S. (2005) The placebo response in the treatment of chronic fatigue syndrome: a systematic review and meta- analysis. Psychosom Med 67:301-13.

  6. Price JR, Mitchell E, Tidy E, Hunot V. (2008) Cognitive behaviour therapy for chronic fatigue syndrome in adults. Cochrane Database Syst Rev CD001027.

  7. Castell BD, Kazantzis N, Moss-Morris RE. (2011) Cognitive behavioral therapy and graded exercise for chronic fatigue syndrome: A meta- analysis. Clinical Psychology: Science and Practice 18:311-24.

  8. Malouff JM, Thorsteinsson EB, Rooke SE, Bhullar N, Schutte NS. (2008) Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: a meta-analysis. Clin Psychol Rev 28:736-45.

  9. Crawley E, Collin SM, White PD, Rimes K, Sterne JA, May MT; CFS/ME National Outcomes Database. (2013) Treatment outcome in adults with chronic fatigue syndrome: a prospective study in England based on the CFS/ME National Outcomes Database. QJM 106:555-65.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Re:Re:High rates of deterioration following graded exercise therapy and cognitive behavioural therapy have been reported in patient surveys

  • Tom P Kindlon, Information Officer

  I would like to thank the authors for replying to my e-letter (1). However, I do not believe they have justified their claim. They say: "Where we claim that evidence indicates that the side effects of cognitive behavioural treatment or graded exercise therapy are negligible, it is with references to other systematic reviews and trials." Firstly, it should be pointed out that important harms-related data is often derived...

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  I would like to thank the authors for replying to my e-letter (1). However, I do not believe they have justified their claim. They say: "Where we claim that evidence indicates that the side effects of cognitive behavioural treatment or graded exercise therapy are negligible, it is with references to other systematic reviews and trials." Firstly, it should be pointed out that important harms-related data is often derived outside of clinical trials (2).

  Secondly, I do not believe systematic reviews state what they claim.

  For example, a systematic review by Chambers and colleagues (3) concluded, "There is limited evidence about adverse effects associated with behavioural interventions. Withdrawals from treatment in RCTs suggest that there may be an issue but the evidence is often difficult to interpret because of poor reporting."

  One of the authors (Larun Lillebeth) previously published a Cochrane collaboration systematic review of trials of graded exercise therapy which found that no data on adverse effects had been reported (4). They concluded: "... studies of higher quality are needed that involve different patient groups and settings, and that measure additional outcomes such as adverse effects ...".

  As I highlighted previously (2), the Cochrane Collaboration: "similarly reviewed RCTs of CBT for CFS in 2000 (5) and performed an update in 2008 (6). Out of 14 separate RCTs examined, only one had any data to assess patient acceptability and none of the studies had good quality data related to adverse effects. In the "Selective outcome reporting" subsection of "Risk of bias in included studies", the Collaboration authors wrote (6): "Whilst Lloyd 1993 collected data concerning the adverse effects of DLE injection, data referring to adverse effects of psychological treatment was not systematically presented by any study." Drop-out rates averaged 16% across studies but definitions for what constituted "drop-outs" varied and reasons for attrition were not detailed; a third of the studies had drop-out rates over 20%. The authors finished by asserting that future studies should incorporate data on adverse effects and acceptability among other outcome measures."

  Due to this poor reporting of harms in trials, among other reasons, I do not accept we have sufficient evidence for the authors to claim "the side effects of cognitive behavioural treatment or graded exercise therapy are negligible."

  References:

  1. Brurberg Kjetil G., Fonhus Marita S., Larun Lillebeth, Flottorp Signe, Malterud Kirsti. Re:High rates of deterioration following graded exercise therapy and cognitive behavioural therapy have been reported in patient surveys http://bmjopen.bmj.com/content/4/2/e003973.full/reply#bmjopen_el_7759

  2. Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bulletin of the IACFS/ME. 2011;19(2):59-111. http://iacfsme.org/BULLETINFALL2011/Fall2011KindlonHarmsPaperABSTRACT/tabid/501/Default.aspx (Accessed: February 7, 2014)

  3. Chambers D, Bagnall AM, Hempel S, Forbes C. Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review. J R Soc Med. 2006;99:506-20. Review.

  4. Larun L, McGuire H, Edmonds M, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No.: CD003200. DOI: 10.1002/14651858.CD003200.pub2

  5. Price JR, Couper J. Cognitive behaviour therapy for adults with chronic fatigue syndrome. Cochrane Database Syst Rev 2000;(2):CD001027 [review].

  6. Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behaviour therapy for chronic fatigue syndrome in adults. Cochrane Database Syst Rev. 2008;(3):CD001027.

  Conflict of Interest:

  I am the Information Officer and Assistant Chairperson of the Irish ME/CFS Association. All my work for the Association is unpaid.

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Re:Case definitions for ME or CFS reflect instability, confusion and contestation inherent in the field.

  • Kjetil G. Brurberg, Researcher
  • Other Contributors:
    • Marita S. Fonhus, Lillebeth Larun, Signe Flottorp, and Kirsti Malterud

  We have read Angela P. Kennedys response on our review (1) with interest. Some of the issues she rises are covered by our previous comments/responses. Moreover, we disagree with the statement that problems of validity remain no matter how much "empirical" research is done. Research regarding etiology, prognosis and therapy is important to increase our knowledge about CFS/ME, this also implies a need to validate and compa...

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  We have read Angela P. Kennedys response on our review (1) with interest. Some of the issues she rises are covered by our previous comments/responses. Moreover, we disagree with the statement that problems of validity remain no matter how much "empirical" research is done. Research regarding etiology, prognosis and therapy is important to increase our knowledge about CFS/ME, this also implies a need to validate and compare various diagnostic criteria.

  1. Brurberg KG, Fonhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open 2014;4:e003973 doi:10.1136/bmjopen -2013-003973

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Re:Confusion re criteria for ME

  • Kjetil G. Brurberg, Researcher
  • Other Contributors:
    • Marita S. Fonhus, Lillebeth Larun, Signe Flottorp and Kirsti Malterud

  We appreciate Dr. Goudsmit's interest in our paper (1) and thank her for pointing out a potential confusion. The revised 2009 criteria could have been included in the list of list of existing case definitions had we identified them. Nonetheless, our main objective was to demonstrate that it is possible to validate diagnostic studies, even in the absence of a reference standard and to summarize existing validation studies....

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  We appreciate Dr. Goudsmit's interest in our paper (1) and thank her for pointing out a potential confusion. The revised 2009 criteria could have been included in the list of list of existing case definitions had we identified them. Nonetheless, our main objective was to demonstrate that it is possible to validate diagnostic studies, even in the absence of a reference standard and to summarize existing validation studies. We do not claim that existing case definitions are unable to distinguish between sub -populations, but we cannot reliably reach such conclusions based on the current evidence base. If we have missed important validation studies, conducted in accordance with our inclusion criteria and consistent with one of the three validation models we outline in our review, we would be happy to receive the references.

  1. Brurberg KG, Fonhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open 2014;4:e003973 doi:10.1136/bmjopen -2013-003973

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Re:The essence of ME vs CFS: post-exertional "malaise" vs fatigue

  • R Simpson

  In Brurberg et al, BMJ 7 February 2014 "Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review" the authors make the following comment:

  "Psychological treatments are often helpful also for clear-cut somatic disorders. Unfortunately, patient groups and researchers with vested interests in the belief that ME is a distinct somatic disease seem unwilling to leave the p...

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  In Brurberg et al, BMJ 7 February 2014 "Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review" the authors make the following comment:

  "Psychological treatments are often helpful also for clear-cut somatic disorders. Unfortunately, patient groups and researchers with vested interests in the belief that ME is a distinct somatic disease seem unwilling to leave the position that ME is an organic disease only. This position has damaged the research and practice for patients suffering from CFS/ME."[1]

  These are odd comments to make by authors who are so heavily involved in the CBT/GET model for this condition themselves.

  As one of those patient groups believing in an organic cause for ME we feel we need to comment on this.

  Patients have never objected to psychological treatments in the way they are used for clear-cut somatic disorders. Patient organisations have objected to the types of psychological treatments offered to ME patients.

  For example, the so called PACE trial that the authors refer to in this article state in their CBT manuals for therapists

  "Participants are encouraged to see symptoms as temporary and reversible and not as signs of harm or evidence of fixed disease pathology. In this way it is anticipated that they will gain more control of their lives, as they, and not their symptoms, dictate what they do".[2]

  Is this not this clear evidence of a group of researchers having a position of ME/CFS as somatoform disease only?

  How does this compare to the supportive psychological treatments offered to clear cut somatic conditions?

  Dr Ian Gibson's report on ME from 2006 had the following observation [3] -

  "There have been numerous cases where advisors to the DWP have also had consultancy roles in medical insurance companies. ........ Given the vested interest private medical insurance companies have in ensuring CFS/ME remain classified as a psychosocial illness there is blatant conflict of interest here. The Group find this to be an area for serious concern and recommends a full investigation of this possibility by the appropriate standards body. It may even be that assessment by a medical 'expert' in a field of high controversy requires a different methodology of benefit assessment"

  At the 8th Invest in ME International ME Conference 2013 [4] Dr Clare Gerada, chair of RCGPs, stated that patients usually know their illness better than doctors.

  Patients are living with this disease and it would be odd if they did not question research that is at odds with their lived experience.

  We are sure cancer patients would find it unacceptable too if all they were offered were psychological assurances that there was nothing organically wrong with them and research was done on a broad spectrum of cancer patients without any attempt to select homogeneous groups of patients to find the cause and cure for the many different forms of cancer.

  Invest in ME is a charity run by volunteer patients and carers. We have organised eight international ME/CFS biomedical research conferences so far and this year we shall show more biomedical research at our ninth. [5]

  The BMJ sent a representative to attend our conference three years ago and they encouraged us to initiate good quality clinical trials.

  We can now inform the BMJ and anyone else interested in the organic origins of ME/CFS that we have since initiated a gut microbiota project involving ME/CFS patients at IFR/UEA, Norwich.

  We have also raised funds for a clinical trial to treat ME/CFS patients with rituximab at UCL following on from the promising results in Haukeland University, Bergen, Norway.

  We have sent an invitation to the BMJ to attend again this year to see the progress that has been made.

  It would be of great benefit to the patient doctor relationship if doctors and other healthcare professionals came to listen and learn about these exciting new developments into ME/CFS that will be on display in London on May 30th.

  Far from damaging the research and practice for patients suffering from ME it is actually patients who removing the myths about this disease

  References

  1. Kjetil Gundro Brurberg, Marita Sporst?l F?nhus, Lillebeth Larun, Signe Flottorp, Kirsti Malterud. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open 2014;4:e003973

  2. http://www.pacetrial.org/docs/cbt-therapist-manual.pdf

  3. Inquiry into the ,status of status of ,CFS / M.E. and M.E. and ,research into research into ,causes and ,treatment http://bit.ly/1aL8Cmw

  4. http://bit.ly/1lLrvXV

  5. http://www.investinme.eu/

  Conflict of Interest:

  Trustee ME Charity

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Case definitions for ME or CFS reflect instability, confusion and contestation inherent in the field.

  • Angela P. Kennedy, University Lecturer

  There are a number of issues raised by this review:

  1. There are a large amount of CFS (and/or ME) case definitions/criteria, some of which were actually left out in this review, and this situation likely reflects the instability, confusion and contestation inherent in the field. A key and worrying problem with reviews such as these is the inability to critically analyse this crucial and highly problematic pheno...

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  There are a number of issues raised by this review:

  1. There are a large amount of CFS (and/or ME) case definitions/criteria, some of which were actually left out in this review, and this situation likely reflects the instability, confusion and contestation inherent in the field. A key and worrying problem with reviews such as these is the inability to critically analyse this crucial and highly problematic phenomenon: just how unstable, confusing, and, most importantly, contested the various case definitions are, and what this means for patient safety. Instead, the authors, like many before them, 'pin their ribbons' onto the ones they, ideologically, support. I discuss some key competing definitions, demonstrating their instability, discrepancies and confusions, in my book (Kennedy, 2012: 116-128). These problems rest on the fact that there are competing views on the nature of ME or CFS by doctors. The race to get the most empirical evidence on one's favoured case definition does not alter this problem. If a case definition has problems of validity, then no matter how much 'empirical' research is done supporting it, those problems of validity remain.

  2. I use the term 'ideologically' above, because of one of the (clearly and astoundingly polemic) final paragraphs, where the authors commit a non sequitur to the rest of the article in making these comments:

  "It is likely that all CFS/ME case definitions capture conditions with different or multifactorial pathogenesis and varying prognosis. The futile dichotomy of 'organic' versus 'psychic' disorder should be abandoned. Most medical disorders have a complex aetiology. Psychological treatments are often helpful also for clear-cut somatic disorders. Unfortunately, patient groups and researchers with vested interests in the belief that ME is a distinct somatic disease seem unwilling to leave the position that ME is an organic disease only. This position has damaged the research and practice for patients suffering from CFS/ME."

  Blaming the patients for the confusion, instability and contestation of the nature of their illness by doctors is inappropriate, but the authors also make the mistake of uncritically accepting the psychogenic explanations for the illnesses being diagnosed as 'CFS' or 'ME', and this final paragraph contains a number of problematic and unsubstantiated claims. Psychological therapy for 'clear-cut somatic' (bodily or physical) disorders are only used as psychological support for the majority of illnesses such as cancer. However, there are broadly two philosophical (or ideological) approaches to the CBT model of treatment for CFS or ME. One (for example, Carruthers et al, 2003) presumes that the physiological pathology of CFS or ME is (currently, at least) largely irreversible, but considers changes in patient understanding and coping behaviour may achieve some improvement in quality of life: an approach Sharpe appears to reject. The second approach considers the pathophysiology to be: "entirely reversible and perpetuated only by the interaction of cognition, behaviour and emotional processes. According to this model CBT should not only improve the quality of the patients' life, but could be potentially curative." (Sharpe, 1996: 248)

  When a cognitive-behavioural therapist, therefore, attempts to give such therapy to a patient with a somatic illness, her mode of therapy that she intends to apply can be one of two, based on the above contradictory approaches (which may not be revealed to the hapless patient before therapy commences). If she subscribes to the second approach, she is likely to have assumed that: the patient's illness is psychogenic; the patient is psychologically disturbed; they have caused symptoms and impairments by 'catastrophizing', so that misinterpretation of benign symptoms has led to fear avoidance and inactivity and, consequently, deconditioning; that the patient's illness is under their control, that they have somehow thought themselves ill, and that they need to be encouraged to 'reattribute' their illness causation to their own behaviour, as if they were somehow "authors of their own misfortune" (McWhinnie et al, 1997), taking responsibility for their illness to the point of blame. Furthermore, she will believe they should ignore what might be warning signs of organic dysfunction and work on increasing their physical activity, and that they will not be harmed by this: indeed she will believe they may be 'cured'. She will either disregard or be ignorant of the medical evidence contra-indicating increasing exertion.

  As these beliefs, belonging to the therapist (but likely informed by others such as psychiatrists who have trained the therapist), are generated by the key logical fallacies inherent in psychogenic explanations, she will be working to her own fallacious reasoning, and exhorting the patient to accept this as rational and correct. This may cause further physical harm to the patient, in terms of psychogenic dismissal of serious somatic illness, and attempting to increase activity where this is physiologically contra-indicated: and may also cause further psychological distress (such as the impact of self-blame) for that patient. These problems of reasoning by therapists in CBT approaches to CFS or ME, and that the majority are practicing a reattribution rather than coping model of CBT upon CFS or ME patients, are indicated by the CBT literature both in clinical and research settings, for example Bleijenberg et al, 2003; Stulemeijer et al, 2004.

  3. This leads to the point that, despite the attempts by the authors to postulate a 'third way' by doing away with the dichotomy of 'organic versus psychic', such a position is logically, logistically and conceptually untenable. There has always been a special pleading when it comes to illnesses deemed psychogenic in nature, and, despite the lofty claims to have transcended mind-body dualism as implied in the authors' comments (and elsewhere), those promoting psychogenic explanations for physical illnesses are invested in privileging the metaphysical power of 'minds' over bodies, believing people can recover from physical impairment by the power of 'correct thinking', ironically practising the Cartesian dualism they claim to have transcended.

  4. Psychogenic explanations themselves are subject to a large amount of fallacies in medical reasoning, and this makes them scientifically unsound, and dangerous for patients. My own findings on this issue are discussed in my book, based on 10 years of academic research. To blame patients for daring to rationally object to a problematic construct that psychogenic explanations represent, to the point that even medics and other researchers also contest them, and accuse patients, of all people, of damaging research and practice into this area, is not only unfair: it is untenable.

  REFERENCES

  Bleijenberg G. et al. (2003) 'Cognitive-behavioral therapies' in Jason et al, (eds.) 493-526.

  Carruthers, B. et al. (2003) "Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols" Journal of Chronic Fatigue Syndrome 11. 1: 7-115.

  Jason, L. A. Fennell, P. A. Taylor, R. R. (eds.) (2003) Handbook of Chronic Fatigue Syndrome New York: Wiley.

  Kennedy, A. (2012) Authors of our own Misfortune? The Problems with Psychogenic Explanations for Physical Illnesses Market Rasen: The Village Digital Press.

  McWhinney, I. R. et al. (1997) 'Rethinking somatization' uwo.ca/fammed/ian/somatizationmain.htm. Accessed 20 November 2010.

  Sharpe, M. (1996) 'Cognitive-behavioural therapy for patients with chronic fatigue syndrome: how?' in Demitrack and Abbey, 240-262.

  Sharpe, M. et al. (1996) 'Cognitive behaviour therapy for the chronic fatigue syndrome: a randomised controlled trial' British Medical Journal 312: 22-26.

  Stulemeijer, M. et al. (2005) 'Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial' British Medical Journal 330: 14.

  Conflict of Interest:

  Sociologist critically analysing psychogenic explanations for physical illnesses; mother and carer of a daughter with a disability.

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  The essence of ME vs CFS: post-exertional "malaise" vs fatigue

  • Frank N.M. Twisk, Researcher

  With interest I have taken knowledge of the facts presented by Brurberg and colleagues in BMJ Open 1 with regard to the case definitions and prevalences of Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS).
  
  However, the conclusion to give low priority to development and/or refinement of (new) case definitions of CFS (CFS/ME) are incompatible with the usefulness of classification of patients according to...

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  With interest I have taken knowledge of the facts presented by Brurberg and colleagues in BMJ Open 1 with regard to the case definitions and prevalences of Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS).
  
  However, the conclusion to give low priority to development and/or refinement of (new) case definitions of CFS (CFS/ME) are incompatible with the usefulness of classification of patients according to symptom patterns to predict prognosis or effectiveness of therapies, as also concluded by the authors.
  
  It has been acknowledged that the most frequently applied case definition for CFS 2 defines a heterogeneous patient population with chronic fatigue as the principle symptom, while neurological, immunological and other symptoms are mandatory for the diagnosis ME according to (proposed) case definitions 3. Above all, all ME (ME/CFS) case definitions require post-exertional malaise: a long-lasting aggravation of distinctive symptoms after a minor exertion 3. ME and CFS are by definition distinct clinical entities 4. Based upon 1, 5 and other studies it is estimated that 40-60% of patients fulfilling the criteria for CFS suffer from post-exertional malaise and other symptoms, characteristic for ME 3. Chronic fatigue is not obligatory in the ME case criteria, implicating that ME patients do not have to meet the diagnostic criteria for CFS 4.
  
  There is sufficient evidence that a subdivision based upon the presence or absence of post-exertional malaise is essential, e.g. to predict the outcomes of two therapies proposed by the authors to be effective and safe for ME and CFS: Cognitive Behavorial Therapy (CBT) and Graded Exercise Therapy (GET). This subdivision, which seem to be reflected by distinct (exercise-induced) immunological abnormalities 4,5, is crucial, because the (prolonged) negative physiological effects of exertion, e.g. a substantial decrease of the workload and oxygen uptake at exhaustion and at the anaerobic threshold at a second exercise test 24 hours later, are likely to predict negative effects of (graded) exercise regimes, like CBT and GET. Post-exertional abnormalities in ME / CFS are essential, irrespective of a 'specific hypothesised pathophysiology' 1.
  
  The authors suggest that CGT and GET are effective therapies for ME and CFS. However, looking at the results of a large scale trial in the UK 6, one must conclude that the minimal improvement after CBT and GET in objective terms is by far insufficient to qualify as clinical improvement of CFS patients and the ME patient subgroup.
  
  The authors blame 'patient groups and researchers with vested interests in the belief that ME is a distinct somatic disease seem unwilling to leave the position' 1. A division between ME and CFS had nothing to do with a dichotomy of an 'organic' (ME) versus 'psychic' (CFS) disorder, since both ME and CFS seem to be accompanied by organic abnormalities. The discussion is not about whether psychosocial aspects should be taken into consideration, but about the disproportionally great emphasis on these psychosocial aspects 7.
  
  Lastly, the authors state that causal explanations for ME/CFS are limited. However, there is sufficient evidence of (reactivating) infections, distinct immunological abnormalities (inflammation, immune activation, immunosuppression and immune dysfunction), neurological aberrations, oxidative and nitrosatieve stress, gastro-intestinal dysbiosis and inflammation, cardiovascular abnormalities and circulatory deficits, mitochondrial dysfunction, decreased oxygen uptake/consumption, HPA axis hypofunction (hypocortisolism and blunted response to provocation), increased sensitivity of the (cellular) immune system and HPA axis to glucocorticoids, and (long-lasting) deviant physiological responses to exertion in CFS 2 patients or substantial subgroups thereof 3,7.
  
  In conclusion, the analysis conducted by Brurberg and colleagues has yielded very useful insights. However, the recommendation to give low priority to development and/or refinement of (new) case definitions of CFS (CFS/ME) are at odds with the usefulness of classification of patients according to symptom patterns (post-exertional malaise or not) to predict prognosis or effectiveness of therapies, as stipulated by the authors, and the observation that "CFS" patients with post-exertional malaise have distinctive abnormalities and react physiologically different to exertion, when compared to "CFS" patient without post-exertional malaise, which are likely to predict effects of exercise regimes, like CBT and GET.
  
  
  
  Frank Twisk
  
  ME-de-patieten Foundation
  Zonnedauw 15
  1906 HB Limmen
  The Netherlands
  frank.twisk@hetnet.nl
  
  
  
  References
  1. Brurberg KG, Fonhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open 2014 Feb 7;4:2 e003973. doi: 10.1136/bmjopen-2013-003973. link.
  2. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994;121:953-9. doi: 10.7326/0003-4819-121-12-199412150-00009. link.
  3. Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: international consensus criteria. J Intern Med 2011;270:327-38. doi: 10.1111/j.1365-2796.2011.02428.x. link.
  4. Twisk FNM, Arnoldus RJ. Comment and reply on: ME is a distinct diagnostic entity, not part of a chronic fatigue spectrum. Expert Opin Med Diagn. 2013 Jul;7(4):413-5. doi: 10.1517/17530059.2013.795147. link.
  5. Maes M, Twisk FNM, Johnson C. Myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data. Psychiatry Res 2012;200:754-60. doi: 10.1016/j.psychres.2012.03.031. link.
  6. White PD, Goldsmith KA, Johnson AL, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011;377:823-36. doi: 10.1016/S0140-6736(11)60096-2. link.
  7. Maes M, Twisk FNM. Chronic fatigue syndrome: Harvey and Wessely's (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. BMC Med. 2010 Jun 15;8:35. doi: 10.1186/1741-7015-8-35. link.
  
  
  

  Conflict of Interest:

  None

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  People with a label of ME remain ill because they *are* ill

  • Nasim Marie Jafry, author of The State of Me, ME for 30 years

  I read the following statement with interest: 'A study comparing the prognosis of different diagnostic labels of fatigue found that patients with ME had the worst prognosis while patients with postviral fatigue syndrome had the best.61 This could mean that the patients destined to the worst prognosis were labelled with the ME diagnosis, or it might be explained as an adverse effect of being labelled with ME.'

  Th...

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  I read the following statement with interest: 'A study comparing the prognosis of different diagnostic labels of fatigue found that patients with ME had the worst prognosis while patients with postviral fatigue syndrome had the best.61 This could mean that the patients destined to the worst prognosis were labelled with the ME diagnosis, or it might be explained as an adverse effect of being labelled with ME.'

  This is at complete variance with my own experience, and in fact contradicts my own experience as I was diagnosed in early 1984 with 'myalgic encephalomyelitis - severe postviral fatigue syndrome' by a consultant neurologist. According to your research, I should be both recovered and not recovered.

  My illness is 'classic ME' as defined by the late Dr Melvin Ramsay, the author of Postviral Fatigue Syndrome: the saga of Royal Free Disease (1986). I had never heard of ME when I was diagnosed in 1984, I was just hugely relieved to find out why I was so ill, 16 months after becoming infected with Coxsackie B4 virus (there had been an outbreak of Coxsackie in west of Scotland at this time). And like many people with ME, I fought against my illness for the first decade, pushing myself to recover, much to my detriment.

  Thirty years later, I remain ill, simply because I *am* ill, it has nothing to with being told I had ME (as opposed to being labelled with anything else). It is also worth noting that when I was diagnosed, the CFS terminology had not yet come into use. In my opinion, the conflation of CFS and ME has caused untold problems and will continue to do so, until the conditions are separated by accurate, universal criteria such as Canadian or ICC-2011. The Scottish Public Health Network (ScotPHN) has actually written a report (2009) in support of this separation (link below).

  http://www.scotphn.net/pdf/Microsoft_Word_-_Report_- _National_Consultation_Final_-_main_text_proofed.pdf

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  High rates of deterioration following graded exercise therapy and cognitive behavioural therapy have been reported in patient surveys

  • Tom P Kindlon, Information Officer

  I question the authors' claim that "existing evidence indicates that side effects of cognitive behavioural treatment or graded exercise therapy are negligible" (1).

  I reviewed various myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients surveys from different countries and found that 51% of survey respondents (range 28-82%, n=4338, 8 surveys) reported that graded exercise therapy (GET) worsened th...

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  I question the authors' claim that "existing evidence indicates that side effects of cognitive behavioural treatment or graded exercise therapy are negligible" (1).

  I reviewed various myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients surveys from different countries and found that 51% of survey respondents (range 28-82%, n=4338, 8 surveys) reported that graded exercise therapy (GET) worsened their health while 20% of respondents (range 7-38%, n=1808, 5 surveys) reported similar results for cognitive behaviour therapy (CBT) (2). While there are various methodological issues with such data, as I discussed, the consistently high rates of deteriorations, especially with GET, should be of some concern. The validity of the models underlying CBT and GET for ME/CFS (3-5) is very questionable given they ignore the numerous abnormal responses to exercise found in the condition (2,6).

  References:

  1. Brurberg KG, F?nhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open 2014;4:e003973 doi:10.1136/bmjopen -2013-003973

  2. Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bulletin of the IACFS/ME. 2011;19(2):59-111. http://iacfsme.org/BULLETINFALL2011/Fall2011KindlonHarmsPaperABSTRACT/tabid/501/Default.aspx (Accessed: February 7, 2014)

  3. Bavinton J, Darbishire L, White PD - on behalf of the PACE trial management group. Graded Exercise Therapy for CFS/ME (Therapist manual): http://www.pacetrial.org/docs/get-therapist-manual.pdf (Accessed: February 7, 2014)

  4. Burgess M, Chalder T. PACE manual for therapists. Cognitive behaviour therapy for CFS/ME. http://www.pacetrial.org/docs/cbt-therapist- manual.pdf . (Accessed: February 7, 2014)

  5. Bazelmans E, Prins JB, Bleijenberg G. Cognitive behavior therapy for relatively active and for passive CFS patients. Cogn Behav Pract. 2006;13:157-166.

  6. Twisk FNM, Maes M. A review on Cognitive Behavorial Therapy (CBT) and Graded Exercise Therapy (GET) in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuro Endocrinol Lett. 2009;30:284-299.

  Conflict of Interest:

  I am the Information Officer and Assistant Chairperson of the Irish ME/CFS Association. All my work for the Association is unpaid.

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  Conflict of Interest:
  None declared.

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• Published on: 23 November 2015

  Confusion re criteria for ME

  • Ellen M Goudsmit, Psychologist

  Brurberg et al's analysis of the various criteria for ME/CFS is timely and important[1]. However, the information about the 'London' criteria for classic ME is misleading and they missed the more recent, updated case definition [2]. The 'London' criteria (LC) devised by Dowsett et al were not published in the Taskforce Report. The latter reproduced a rewritten version by an unknown person which missed the last part of th...

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  Brurberg et al's analysis of the various criteria for ME/CFS is timely and important[1]. However, the information about the 'London' criteria for classic ME is misleading and they missed the more recent, updated case definition [2]. The 'London' criteria (LC) devised by Dowsett et al were not published in the Taskforce Report. The latter reproduced a rewritten version by an unknown person which missed the last part of the paper. To my knowledge, that version was never used. In contrast, the LC were used in at least four studies, sometimes alongside the Oxford criteria. I know that as I was the Chair of the Research Working Group at AFME at the time and involved in the funding of studies. We had few conditions but one was the use of the LC. Consequently, AFME was one of the few organisations to continue to study classic ME at a time when attention had been diverted to CFS. Some of the published papers refer to the LC in the text and references; others to criteria developed by AFME, or wrongly, to the TaskForce report. With only one exception, all the studies using the LC selected a homogeneous group with abnormalities in 100% of those tested. One of these showed that it was possible to objectively measure the cardinal symptom of classic ME (criterion 1). This information is included in the revised guidelines published in 2009.

  Until two years ago, journals had little interest in classic ME, that is, the illness described by physicians since the 1950s. However, recent attempts to refine case definitions led to a review of the knowledge collected since 1955 and a group recently updated the relevant research supporting 2009 criteria for classic ME [3].

  It may well be that there is no difference between samples selected using the CDC, and the newer criteria for ME/CFS and classic ME. However, assumptions require testing which is why scientists still require sound case definitions for ME. To ignore them may undermine efforts to increase diagnostic precision.

  1. BMJ Open 2014 4:e003973; doi:10.1136/bmjopen-2013-003973 2. Goudsmit EM, Shepherd C., Dancey CP, Howes S. ME: Chronic fatigue syndrome or a distinct clinical entity? Health Psychology Update, 2009;18(1):26-33. http://www.bpsshop.org.uk/Health-Psychology-Update-Vol-18-No-1-2009- P797.aspx Updated by EMG in 2012 and available from: http://www.foodsmatter.com/me_and_cfs/cfs_me_causes_general/articles/goudsmit -me-clinical%20entity-10-12.html 3. Howes S, Goudsmit E, Shepherd C. Myalgic encephalomyelitis. Criteria and clinical guidelines 2014. Available from: http://www.axfordsabode.org.uk/me/mecrit2014.htm

  EM Goudsmit FBPsS

  Conflict of Interest:

  I was a co-author of two sets of criteria for classic ME

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  Conflict of Interest:
  None declared.

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