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Recent eLetters

Displaying 11-20 letters out of 214 published

  1. Conclusions Unsupported by the Evidence

    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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  2. Response to: Socioeconomically disadvantaged smokers' ratings of plain and branded cigarette packaging

    Dear Editor, We read with great interest the article by Guillaumier et al [1] reporting on socioeconomically disadvantaged smokers' perceptions of plain cigarette packaging. Understanding the impact of plain packaging on smoking behaviour is a key Public Health priority. The authors reported that exposure to plain packaging was associated with significantly reduced positive ratings of pack design and preference compared to currently available branded packs. We wish however to highlight several important issues raised by the manuscript. Firstly, smokers were defined as i) those who smoked daily or ii) 'occasional smokers who have smoked at least 100 total cigarettes in their life'. This non-standard definition reduces generalizability and the comparability of results with other studies, and the heterogeneity of the group could result in a wide variety of internal smoking behaviour and perceptions. Secondly, there is also potential for bias in smokers' responses. It is not clear whether participants were aware of the study aims or whether the available monetary incentive was offered pre- or post-test - either of which may have impacted upon participants' responses. The physical presence of a research assistant in the interview room could additionally influence responses. Preventing initiation of smoking, especially in younger people, is one of the central objectives of plain packaging strategies [2,3]. However, young people who had never smoked were not included in the study and therefore findings are not directly relevant to key groups targeted by plain packaging legislation (young people considering initiating smoking). The study could have been strengthened by the inclusion of non-smokers as a comparison group, as well as by stratified analysis of survey responses by age group. Without these considerations in the study design, there is a risk of muddying the water with regards to ongoing policy debate. Tobacco companies and lobbyists frequently claim that the majority of evidence supporting the individual and public health benefits of plain packaging is weak, coming from small studies with flawed methodology [4,5]. We fear that, because of the limitations in study design, this paper will provide further ammunition to those making such claims. Although we appreciate the challenges and difficulties of undertaking large projects, there is a need to focus on fewer, larger studies and we eagerly await the results of these to show the impact of plain packaging strategies on rates of smoking initiation. References 1 Guillaumier A, Bonevski B, Paul C, et al. Socioeconomically disadvantaged smokers' ratings of plain and branded cigarette packaging: an experimental study. BMJ Open 2014;4:e004078. doi:10.1136/bmjopen-2013-004078 2 DiFranza JR, Wellman RJ, Sargent JD, et al. Tobacco promotion and the initiation of tobacco use: assessing the evidence for causality. Pediatrics 2006;117:e1237-48. doi:10.1542/peds.2005-1817 3 Lovato C, Watts A, Stead LF. Impact of tobacco advertising and promotion on increasing adolescent smoking behaviours. Cochrane database Syst Rev 2011;:CD003439. doi:10.1002/14651858.CD003439.pub2 4 Hatchard JL, Fooks GJ, Evans-Reeves KA, et al. A critical evaluation of the volume, relevance and quality of evidence submitted by the tobacco industry to oppose standardised packaging of tobacco products. BMJ Open 2014;4:e003757. doi:10.1136/bmjopen-2013-003757 5 Philip Morris Limited. Standardised tobacco packaging will harm public health and cost UK taxpayers billions: a response to the Department of Health consultation on standardised packaging of tobacco products. London: Philip Morris Limited,. 2012. Available at: http://www.pmi.com/eng/tobacco_regulation/submissions/documents/submission%20and%20all%20annexes%20(combined).pdf (Accessed 18 Feb 2014)

    Conflict of Interest:

    None declared

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  3. Evidence of lots of testing is not proof or 'overtesting'

    The study by Bailey et al. http://www.ncbi.nlm.nih.gov/pubmed/22338984 "Vitamin D Testing Patterns Among Six Veterans Medical Centers in the Southeastern United States: Links With Medical Costs" indicated that increased rates of vitamin D testing led to treatment of deficiency and/or insufficieny and that this in turn was correlated with a reduction in net costs (and improvement with health) due to fewer illnesses.

    Conflict of Interest:

    None declared

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

    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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  5. Related editorial published in The BMJ

    This topic is discussed further in the editorial by Associate Professor John Muscedere in The BMJ here http://www.bmj.com/content/348/bmj.g1469. Please note that access to the full article may requirement payment.

    Conflict of Interest:

    I am assistant editor of BMJ Open

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

    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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  7. Research into biomedical mechanisms of disease is essential

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

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

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

    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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