ME är inte “trötthet”, del 2

Laura Hillenbrand, citat

“This illness is to fatigue what a nuclear bomb is to a match. It’s an absurd mischaracterization” ~ Laura Hillenbrand

Detta inlägg hör ihop med ett inlägg jag skrev häromdagen, ME är inte “trötthet”: Att försöka gömma en atombomb i en tändsticksask, med anledning av mediaspektaklet kring “kronisk trötthetssyndrom” tidigare i veckan. Läs gärna det inlägget först, om du inte redan gjort det.

Jag var väldigt frestad att ge detta inlägg rubriken “Får du mindre skador av att bli överkörd av tåget om du inte är rädd för att ställa dig mitt på spåret?“, men det var lite väl långt… ;)

Jag understryker återigen att långvarig trötthet INTE är samma sak som den neuroimmuna sjukdomen Myalgisk Encefalomyelit1.

Studien som låg bakom “nyhets”rapporteringen i veckan handlade alltså inte om ME eller Kroniskt trötthetssyndrom (enligt de diagnoskriterer som används här i Sverige), utan om generell långvarig trötthet. Tyvärr har de valt att presentera sina slutsatser på ett sensationalistiskt sätt som verkar utformat för att vilseleda… ett lockbete som svenska pressen bedrövligt nog nappade på, utan att bry sig om varken källkritik eller faktagranskning.

Det har efter mediaspektaklet tillkommit en rad mycket värdefulla och läsvärda kommentarer från olika experter i ämnet. Med tanke på att de nog inte kommer att få nån som helst uppmärksamhet i svensk media så vill jag hjälpa till att sprida dem på det här sättet istället.

Professor Mark VanNess, en högt ansedd amerikansk neurovetenskapsman känd bl a för sin världsledande forskning kring ansträngningsutlöst symptomökning hos ME-drabbade (Post-Exertional Neuroimmune Exhaustion/PENE, även känt under namnet Post-Exertional Malaise/PEM), och som forskat i ämnet i över tio år, skriver:

“Dear Joan,

I was saddened to see the press releases regarding the ME/CFS studies from Kings College London. It seems to me they’ve once again missed important nuances of the disease. Nearly all ME/CFS sufferers would either avoid or drop out of any experiment that employed exercise as a treatment because they know it exacerbates symptoms. The remaining subjects would either be very high functioning or consist of fatigued individuals that were incorrectly diagnosed as ME/CFS. Our studies clearly show that dynamic exercise like walking or jogging exacerbates symptoms associated with ME/CFS.

Fear and avoidance of what worsens symptoms is a natural defense mechanism against a harmful stimulus. In fact, many researchers here in the U.S. utilize graded aerobic exercise as a tool to worsen and amplify ME/CFS symptoms – not as a treatment meant to be beneficial. The therapeutic interventions we use are meant to improve quality of life for ME/CFS patients. These interventions focus primarily on strengthening muscles and improving range of motion; activities that get energy from normally functioning anaerobic metabolic mechanisms rather than impaired aerobic energy pathways. We even provide tools like heart rate monitors to help patients avoid significant aerobic exertion.

Fear of exercise is an understandable response in ME/CFS. For a patient with ME/CFS the fear of exercise is a reasonable, knowledgeable, and learned response to a noxious stimulus. If ME/CFS patients could exercise away their symptoms they most certainly would, regardless of the pain. But that is not the case. Our exercise physiologists carefully avoid aerobic exercise (which worsens the pathologies) and focus activity programs that utilize intact metabolic pathways with strength training and recumbent stretching (that help alleviate symptoms). These exercise recommendations are consistent with our understanding of ME/CFS pathology.

We would all hope that ME/CFS was viewed with attention given to immunological, metabolic, cardiovascular and neuroendocrinological dysfunction that has been demonstrated with previous research.

Good luck to you and your organization as you help us all accurately portray this illness.

Sincerely,

J. Mark VanNess, Ph.D.
Professor; Departments of Health and Exercise Science and Bioengineering
University of the Pacific
Stockton, California, USA”

Källa: Just ME: Prof. VanNess on recent news reports

Se även:
Mark VanNess ‘Exercise and ME/CFS’ at Bristol Watershed. Part One.

Följande kommentar är skriven av Dr. William Weir:

Rational understanding of the symptoms of ME/CFS.

The paradigm which states that the symptoms of ME have a psychological basis continues to be promoted. Most recently “exercise phobia” has been proposed as part of the problem although a study of which I was a co-author in 2005 explicitly disproved this proposition. This paradigm has no plausible scientific basis and can only be described as a doctrine whose adherents continue to ignore the biomedical evidence which amply confirms the organic basis of the condition. As someone with nearly 30 years’ experience of seeing patients with this severely disabling condition I continue to be dismayed by an irrational adherence by the psychological lobby to a doctrine that is not supported, even by their own studies, and which has been undermined by the published biomedical evidence.

The term “phobia” implies an irrational fear of exercise. The reason that ME sufferers avoid exercise is because they know from (sometimes bitter) experience that it makes them feel worse (often much worse) and results in post exertional malaise (PEM). This is one of the cardinal features of the condition and can last for days, often for weeks and not uncommonly, for months. PEM is not imagined and causes a rational apprehension of exertion which should no longer be labelled as “phobia”. ME sufferers therefore avoid exercise for reasons which are entirely rational, and Prof. Mark VanNess’ recent work (now replicated elsewhere) has put much flesh on the bones of this argument.

As a simple analogy, a newly broken leg causes pain and most people so affected have an entirely rational fear of walking or even bearing weight on the affected limb. The pathophysiological basis of pain caused by a fracture is well understood, and now Prof. VanNess’ work has provided considerable insight into the pathophysiology of PEM. Not only do his findings give a clearer understanding of this devastating symptom of ME but they also effectively dispose of the argument that ME patients have “exercise phobia” or indeed that the disease is caused by patients wrongly believing they are physically ill.

Unfortunately, promotion of the doctrine that ME/CFS has a psychological basis continues to be disseminated by the inappropriately named “Science” Media Centre. They are not, in respect of ME, disseminating science at all, and continue to promote scientifically unsustainable and disproven theory, simultaneously ignoring proper scientific evidence. Sadly this is not an abstruse controversy, and patients whose genuine incapacity continues to be attributed to the psychological paradigm suffer enormously. I regard this as morally indefensible.

WRCW

Dr W.Weir FRCP is an NHS Consultant Physician with long experience in M.E. He was a member of the Chief Medical Officer’s Working Group in M.E. in 2002 and is the Medical Advisor to Newry & Mourne ME Fibromyalgia Support Group.

Källa: Dr William Weir rejects “exercise phobia” in ME!

Debatten går het även på BMJ i skrivande stund, och även där finns värdefulla kommentarer som förtjänar att lyftas:

Jonathan Edwards, Emeritus Professor of Medicine, är en av de som upptäckte att cancermedicinen Rituximab (Mabthera) kan användas för att behandla Reumatoid artrit. Rituximab har visat sig ha mycket bra effekt även för ME-patienter (vilket tyder på en autoimmun komponent) och det pågår nu fler studier kring detta, där Edwards finns med i en rådgivande roll.

I am a retired academic physician and biomedical scientist who has become involved in advising on research directed at ME/CFS because of specific relevant expertise in therapeutic trials. This condition presents particularly severe methodological issues in trials because the desired primary endpoint is subjective and even supportive secondary endpoints are not as objective as one would wish. In this context, an unblinded trial such as PACE is simply uninterpretable. It does not provide useful information on which to base clinical protocols. There appear to have been a number of additional methodological problems with the trial, but those aside, the basic design does not allow of sufficient scientific rigour. A large number of patients are concerned that the trial should be used as a basis for recommending treatment and I think they are right to be concerned.

As far as I can see all that the PACE trial can tell us about is apparent changes in patients’ beliefs about their illness. The trial appears to be based on the supposition that these may be unrealistic beliefs, so it is hard to see why a shift in these beliefs should be considered even relevant unless there is some way of establishing that they become more realistic – which there is not. (Other measures suggest that any change was unwarranted.) We cannot even be sure that these are patients’ beliefs since an important part of the ‘placebo’ phenomenon (that demands blinded controls which are here impossible) is likely to be a response designed to please a therapist, perhaps because of fear of being discharged from care if not perceived as grateful. The fact that perceptions can modify behaviour seems to be acknowledged by the aims and design of the present study.

I do not treat people with this illness and have no other personal interest other than feeling that I may be of use in encouraging useful research. Apart from anything else I am saddened to see poor data of this sort being used in a way that will perpetuate the lack of trust between patients and their carers. The patients are very aware of the weaknesses of the study and I am surprised that those designing the study are not equally aware.

Källa

Irländska patientförespråkaren Tom Kindlons kommentarer är som alltid lysande, träffsäkra:

Objective measures found a lack of improvement for CBT & GET in the PACE Trial: subjective improvements may simply represent response biases or placebo effects in this non-blinded trial

This BMJ article and a flurry of articles in the lay media this week followed the publication in Lancet Psychiatry of an analysis of the mediators of change in the important PACE Trial, a chronic fatigue syndrome (CFS) trial which cost UK taxpayers £5 million[1,2]. What seems to have been lost in the coverage is that, although there were some modest improvements in the self-report measures, there was an almost complete absence of improvements in objectively measured outcomes for cognitive behavioural therapy (CBT) and graded exercise therapy (GET) compared to the control group (specialist medical care only (SMC)).

This is a non-blinded trial, where participants were told CBT and GET had previously been found to be effective in CFS and other conditions[3,4]: one way to look at the mediation results for subjective measures when there was a lack of objective improvements is that they may merely tell us how response biases and/or placebo effects are mediated[5].

The focus on subjective measures in some CFS studies was previously criticised in a systematic review published back in 2001 (long before the PACE Trial started)[6]. They suggested instead “a more objective measure of the effect of any intervention would be whether participants have increased their working hours, returned to work or school, or increased their physical activities.”

The model presented for cognitive behaviour therapy (CBT) in the PACE Trial manuals posits that the impairments and symptoms are reversible with the therapy[3,7]. However, the latest paper shows that fitness, as measured by a step test, didn’t improve following CBT[2]. An earlier PACE Trial publication reported that the addition of CBT to SMC did not result in an improvement in 6-minute walking test scores compared to SMC alone[8].

The PACE Trial was part funded by the UK Department of Work and Pensions, a rare move for them, presumably done due to an expectation that the therapies would improve measures of employment and levels of benefit receipt. However, again CBT brought about no improvement using objective measures, such as days of employment lost, levels of disability benefits received and levels of receipt of insurance payments[9].

These results are in line with earlier studies of CBT. For example, an analysis of three randomized controlled trials of CBT interventions for CFS found no improvement in objectively measured activity, despite participants reporting a reduction in (self-reported) fatigue and (sometimes) functional impairments[10]. Similar results were found in another uncontrolled trial where changes in objectively measured activity did not predict fatigue levels, and objectively measured activity on completion remained low compared to population norms[11]. An uncontrolled study found improvements in self-reported physical functioning and fatigue were reported despite a numerical decrease in (objectively measured) activity[12]. In another study, the level of self-reported cognitive impairment in CFS patients decreased significantly after CBT, however, cognition had not improved when it was measured objectively using neuropsychological test performance[13].

It is unsurprising that 15 sessions of CBT (and the associated homework exercises and management program) might alter how participants respond to self-report questionnaires. A PACE Trial manual itself says “the essence of CBT is helping the participant to change their interpretation of symptoms”: this could lead to altered or biased fatigue scores, one of the two primary outcome measures[14]. Also, one of the aims of CBT (for CFS) has been said to be “increased confidence in exercise and physical activity”[15]. The possible responses for the other primary outcome measure, the SF-36 physical functioning subscale, are “yes, limited a lot”, “yes, limited a little” and “no, not limited at all” to questions on a range of physical activities. Such responses could be easily be artificially altered following a therapy like CBT for CFS.

The results were not that different with the GET cohort in the PACE Trial. Again the manuals predicted that the impairments and symptoms are reversible using the intervention[4,15]. The model said there was no reason participants should not be able to get back to full functioning. Deconditioning was posited to be an important maintaining factor. However, GET did not result in an improvement in fitness, as measured by the step test. GET did result in a small improvement on the six minute walking test to a final distance of 379 metres, or 35 metres more than the SMC-only group[7]. However, as Knoop and Wiborg commented in an accompanying editorial in Lancet Psychiatry: “an increase in distance walked during a test situation without an increased fitness suggests that patients walk more because of a change in cognitive processes (eg, daring to do more or an increased self-efficacy with respect to activity), not because of a change in physiological capacity”[16]. The result remained very poor given that normative data would suggest a group of similar age and gender should walk an average of 644 or so metres[17]. The distance walked remained comparable to people with many serious conditions[18-21], and considerably worse than the distance walked by healthy elderly adults[22,23], despite the PACE trial cohort having a mean age of only 40[8]. Also, to be allowed entry into CFS research studies such as the PACE Trial one can not have a range of chronic illnesses so with genuine recovery one would expect results comparable to healthy people[8].

As with CBT, measures relating to employment showed no improvement following GET in days of work missed, which remained very high, nor a reduction in levels of benefits (financial support from the state) or payments from insurance companies[9].

These results are in line with an audit of Belgian rehabilitation centres for CFS offering CBT and GET[24-26]. Some improvements in subjective measures were found, but there was no improvement in the results of the exercise test and hours in employment actually decreased.

Probably the main contribution of the PACE Trial has been to add to a growing body of evidence that while CBT and GET for CFS have resulted in some changes on subjective measures, they haven’t lead to improvements on objective measures.

Källa

Denna kommentar från Carolyn E Wilshire, Senior Lecturer in Psychology, är också mycket välskriven och högst relevant:

In drug intervention studies, there is an agreed set of quality standards. These include the use of an appropriate placebo control, random allocation to treatment, and blinding of both patients and researchers. Also increasingly important is preregistration of outcome measures, so that authors do not selectively report only the most favourable outcome measures.

Studies of behavioural interventions, including the current PACE study and its predecessor, 1,2 have not consistently been evaluated by these standards, which has sometimes led to exaggerated claims as to their effectiveness. Here, I comment on this issue from the perspective of an experimental psychologist (I leave it to others to consider theoretical issues, such as validity of the authors’ underlying illness model).

The original PACE study reported that one year after a 24-week graded exercise therapy programme (GET), 61% patients improved on a combined self-rated measure of fatigue and physical function. 2 CBT yielded a similar improvement rate of 59%. On the face of it, that looks impressive. However, the control condition – specialist medical care – also yielded an impressive 45% improvement. This in itself casts doubt on the validity of the self-report measures used to assess improvement. But more importantly, this high level of baseline improvement means that conclusions rest on the differences in improvement rates between the various conditions, some 14-16% of participants. The design of the no-treatment control therefore becomes crucial.

Drug intervention studies include a placebo condition, which controls for spurious factors known to affect outcomes, such as the expectation for improvement, and the patient’s degree of investment. The baseline condition used in the PACE study (specialist medical care) is not adequate to control for either factor: patients in this condition would be unlikely to have the same expectations of improvement as those in the intervention groups (nor, arguably would those in the pacing intervention), nor would they be likely to invest as much effort into the “treatment”, or to develop the same kind of rapport with the therapist.

Recent evidence suggests that self-report measures are much more vulnerable to the placebo effect than more objective measures. 3,4 Given that treatment was unblinded, and not all factors influencing placebo responding were adequately controlled for, objective outcomes – from blinded raters – are essential in order to overcome these criticisms. However, the study reports only one such outcome: the average distance walked in six minutes increased after all treatments but reliably more so after GET. A number of other objective measures planned in the original protocol were simply never reported. 5 All other positive outcomes are from self report.

This leads us to a third major problem, the highly selective reporting of outcome measures. Selective reporting is a major criticism that has been raised against current psychological research standards. 6 The problem is quite simple: our criterion for statistical significance (less than 5% probability of obtaining a significant effect by chance alone) means that up to 1 in every 20 statistical results could very well be artefactual. The more outcomes one samples, the higher the chances of at least one effect being significant by chance alone. By measuring multiple outcomes, and selectively reporting only favourable ones, the researcher is concealing from the reader this heightened probability of a spurious result.

The most recent output from this group, the mediation study by Chalder and colleagues is therefore difficult to interpret, since it claims as its starting premise that the one-year outcomes of the original study demonstrate substantive evidence of genuine treatment effects. 1 Given the problems noted above, I would argue that this requirement has not been met.

The new paper’s most valuable contribution is that it reports one new objective measure: the fitness test (heart rate after a step exercise test). However, GET patients – the group predicted to show the greatest improvement – did not differ from the non-treatment control on this measure. This result, and its lack of prominence in the original paper, leads to further concerns about the selective reporting in the study and the heavy reliance on self-report.

One might object to these criticisms, arguing that in behavioral interventions adequate control conditions are difficult to design, and objective measures difficult to obtain. Both objections can be easily countered. Recently, Lynch, Laws and McKenna reviewed a selection of studies of CBT interventions for major depressive disorder and other severe psychiatric conditions. 7 They identified studies that: a) used control conditions meeting the requirements set out above (e.g., supportive therapy, psycho-education); and b) reported objective outcome measures, from blinded observers. Alarmingly, in a metanalysis of these studies, the treatment effect for CBT was much weaker and/or absent. When standards are raised to the same level as those required in drug interventions, outcomes look much less impressive.

Some might argue that the risk of harm is lower for behavioural than for drug interventions, so there is no need to adhere to the same rigorous standards. However, this assumption needs to be challenged: in the case of ME/CFS, there is evidence that GET may in fact result in adverse effects for some patients. 8 Also, drawing unwarranted conclusions from behavioural intervention studies can do great harm in less direct ways. For example, in the case of MECFS, if policy makers and practitioners believe that there is already a valid “treatment” out there for this condition, they may be less motivated to examine other, more valid treatment options. Even more seriously, we have seen in the British media this week that the results of such studies may be used support a view of MECFS that minimises is severity, exaggerates its responsiveness to treatment, and places responsibly for the illness back on the patient.

In the Psychology literature, there has recently been much discussion of some of the more general weaknesses in psychological methodology. 6 If medical and psychiatric journals wish to continue publishing behavioural studies, they need to make themselves more aware of this literature. Behavioural research should not have a “get out of jail free” card when it comes to scientific rigour.

Källa

Mer från Dr William Weir:

The paradigm which states that the symptoms of ME have a psychological basis continues to be promoted (Lancet Psychiatry 2015: http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(14)00069-8/abstract). Most recently “exercise phobia” has been proposed as part of the problem, although a study of which I was a co-author in 2005 explicitly disproved this proposition (J Psychosom Res 58 (2005): 367-373). This paradigm has no plausible scientific basis and can only be described as a doctrine whose adherents continue to ignore the biomedical evidence which amply confirms the organic basis of the condition. As someone with nearly 30 years’ experience of seeing patients with this severely disabling condition I continue to be dismayed by an irrational adherence by the psychological lobby to a doctrine that is not supported, even by their own studies, and which has been undermined by the published biomedical evidence.

The term “phobia” implies an irrational fear of exercise. The reason that ME sufferers avoid exercise is because they know from (sometimes bitter) experience that it makes them feel worse (often much worse) and results in post-exertional malaise (PEM). This is one of the cardinal features of the condition and can last for days, often for weeks and not uncommonly, for months. PEM is not imagined and causes a rational apprehension of exertion which should no longer be labelled as “phobia”. ME sufferers therefore avoid exercise for reasons which are entirely rational, and Dr Mark Van Ness’ recent work (now replicated elsewhere) has put much flesh on the bones of this argument.

As a simple analogy, a newly broken leg causes pain and most people so affected have an entirely rational fear of walking or even bearing weight on the affected limb. The pathophysiological basis of pain caused by a fracture is well understood, and now Dr Van Ness’ work has provided considerable insight into the pathophysiology of PEM. Not only do his findings give a clearer understanding of this devastating symptom of ME but they also effectively dispose of the argument that ME patients have “exercise phobia” or indeed that the disease is caused by patients wrongly believing they are physically ill.

Unfortunately, promotion of the doctrine that ME/CFS has a psychological basis continues to be disseminated by the inappropriately named “Science” Media Centre. They are not, in respect of ME, disseminating science at all, and continue to promote scientifically unsustainable and disproven theory, simultaneously ignoring proper scientific evidence. Sadly this is not an abstruse controversy, and patients whose genuine incapacity continues to be attributed to the psychological paradigm suffer enormously. I regard this as morally indefensible.

W.R.C.Weir FRCP, FRCP (Edin), Consultant Physician, 10 Harley Street, London W1G 9PF

Källa

Jag delar inte alltid Sonya Chowdhurys (Action for M.E) åsikter, men just här tycker jag hon uttryckte sig väldigt bra:

We have been astounded by the perpetuation of inaccurate and negative stereotypes in some of the press headlines about this research. This leads to ill-informed, judgemental and harmful treatment of people with this debilitating condition, many of whom are among the most neglected in society.

Källa

Även brittiska organisationen Invest in ME har skrivit ett officiellt yttrande i frågan. De tar bland annat upp många av de punkter jag skrev om i mitt förra inlägg. (Invest in ME gjorde även ett fenomenalt arbete med sina kommentarer med anledning av amerikanska P2P-processen.)

Högst relevant är även Jørgen Jelstads utmärkta inlägg Ville VG kjørt saken «Multippel sklerose: Tenk deg frisk»? som bl a tar upp medias brist på faktagranskning och kritiskt tänkande när det gäller nyhetsrapportering kring exempelvis ME och CFS.

Så, som sagt… mot bakgrund av allt detta hoppas jag verkligen att alla ser veckans “nyhets”rapportering i ett helt annat ljus. Jag hoppas innerligt på mer vetenskaplig och faktabaserad rapportering framöver!

*~

1) Myalgisk Encefalomyelit G93.3, snävt definierad enligt Kanadensiska konsensuskriterierna (CCC, Carruthers et al., 2003) eller de Internationella konsensuskriterierna (ME-ICC, Carruthers et al., 2011), som här i Sverige oftast kallas vid det väldigt missvisande namnet “Kroniskt trötthetssyndrom” och ofta slarvigt klumpas ihop med långvarig generell trötthet i benämningen ME/CFS, eller blandas ihop med utmattningssyndrom/utmattningsdepression. Olika definitioner används i olika länder, vilket naturligtvis lätt leder till förvirring och felaktiga antaganden.

UPPDATERING 22 jan: Nytt inlägg med fler citat från de världsledande experterna, ME är inte “trötthet”, del 3.

UPPDATERING 25 jan: Nytt inlägg med ytterligare vetenskaplig fakta som motbevisar desinformationen, ME är inte “trötthet”, del 4.

 

Publicerat i: Osorterat