"contrary to its findings, there is no evidence that graded exercise therapy is effective" for myalgic encephalomyelitis / chronic fatigue syndrome

Things can sometimes move pretty fast in the world of peer-reviewed science. I had originally scheduled this post to appear in November (2018) but there's been some recent 'movement' in this area (see here) so I've decided to publish it now.

The original post is shown below. And below that are a few extra thoughts in light of the reported decision to remove the Larun article (at least for now)...

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The re-analysis paper published by Mark Vink & Alexandra Vink-Niese [1] makes for some really interesting reading. Not only because it adds to other voices in the peer-reviewed domain (see here) questioning the usefulness and safety of the intervention known as graded exercise therapy (GET) 'for' myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but also because it kinda fits in with a narrative suggesting that 'trusted evidence' is almost always open to interpretation (see here).

So, graded exercise therapy (GET) and ME/CFS. I have to say that out of all the interventions / treatments that I've come across down the years that have been indicated for various diagnostic labels, GET is probably one of the most reviled by the population it is supposed to be aimed at. The reasons for such a scenario are multiple and complex, but one of the more vocal arguments seems to be the lack of regard for harm caused by the use of a stepped physical activity schedule on a population whose illness is defined by boom-bust symptom profiles caused by physical exertion. Of particular importance to this line of thinking is the idea that post-exertional malaise (PEM) needs to have a lot more prominence attached to it when it comes to ME/CFS, minus any psychobabble 'deconditioning' chatter or related explanations.

The Vink-Vink-Niese paper is based on a Cochrane review paper of GET published by Lillebeth Larun and colleagues [2]. Yes, the same Cochrane that is going through a bit of turmoil at the moment. The Larun paper concluded a few things such as: "Exercise therapy did not worsen symptoms for people with CFS" and "Moderate‐quality evidence showed exercise therapy was more effective at reducing fatigue compared to ‘passive’ treatment or no treatment." This based on the examination of "eight randomised controlled studies" with "reported data from 1518 participants." To be fair to the Larun review paper, the authors did also mention that: "Serious side effects were rare in all groups, but limited information makes it difficult to draw firm conclusions about the safety of exercise therapy" and "further studies should be carried out to discover what type of exercise is most beneficial for people affected by CFS, which intensity is best, the optimal length, as well as the most beneficial delivery method." This, on the basis that CFS/ME is best described as a heterogeneous condition and accepting that exercise can come in various different forms, some of which might be more applicable than others when it comes to individuals with fatigue-related labels (see here for example) minus any sweeping generalisations.

Some familiar themes crop up in the Vink re-review paper - "Entry score requirements were not sufficiently strict" and "The review used subjective fatigue measured by questionnaires as the primary outcome" - which have quite notably hindered the research in this area. I note also that authors mention about attrition (dropout) rates in the reviewed studies and how, in some studies, over a third of participants placed in exercise conditions withdrew from such investigations. Such statistics will no doubt have an important influence on any final results, as well as providing an important clue that such an intervention might not be sufficiently well tolerated by quite a few [3].

Vink concludes by saying that: "The GET trials reviewed here are inherently biased: use of exercise may attract only the mildly affected and may deter the more disabled patients from participating" and that: "The flaws in the review and the trials... all created a bias in favour of the exercise intervention."

On the basis of their interpretation of the scientific data, I'm in agreement with Vink & Vink-Niese that the evidence base for the universal application of GET to ME/CFS is by no means indicated. You might well say that GET is not universally rolled out for everyone with ME/CFS but, as things currently stand at the time of writing, it is still part of the clinical guidance for the condition(s) here in Blighty (for now) and hence potentially something that can be suggested for anyone diagnosed with ME/CFS. The ethos behind GET also being tied into another biopsychosocial (BPS) favourite - CBT - also makes for a good reason why psychology really shouldn't be let anywhere near such clinical issues, particularly when the evidence against such 'interventions' is seemingly mounting (see here). Indeed, although little comfort to those currently living with ME/CFS, I'm sure one day we'll look back at the whole BPS 'involvement' with ME/CFS and truly say WTF?

And finally, whilst on the topic of 'not listening to your target population' I would also draw your attention to the recent findings from McManimen and colleagues [4] highlighting what could happen when those with ME/CFS face stigma (and dogma). Oh, and because the Cochrane name is part-and-parcel of today's post, I'll also draw your attention to an important message concerning some of their other advice pertinent to CFS...

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What else to add to this post? Well, a quote appearing in that Reuters report on the decision to temporarily withdraw the Larun review suggesting that "the withdrawal decision set a worrying precedent for scientific evidence being over-ridden by the opinions of activists" is, to my mind, inappropriate. Aside from the feedback received regarding the Larun article (see here) the Vink paper for example, is peer-reviewed science and published peer-reviewed science at that. It's not some activist randomly throwing around allegations and the like on social media or blogs(!). It's published peer-reviewed-science that calmly calls into question the conclusions of the original Larun analysis. Indeed, it's part of a trend for serious scientific conversations being held in the peer-reviewed science domain concerning some of the science and clinical practice around ME/CFS (see here). Nothing vexatious.

As I mentioned, given that other Cochrane reviews covering the topic of CFS have also been recently withdrawn [5] (see here for more on the withdrawal notice) it strikes me that Cochrane is perhaps also wisely ensuring that it's previous high standards are maintained and confidence restored in its 'evidence-based' name particularly when it comes to research into ME/CFS. Given also the turbulent few weeks that have just passed (see here) and seemingly, are still continuing (see here) for the 'collaboration', it's also a timely reappraisal that fits the important narrative that ME/CFS is a long-term physical health condition (see here) and not a mental disorder or worse. And intervention options need to recognise this fact...

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[1] Vink M. & Vink-Niese A. Graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective and unsafe. Re-analysis of a Cochrane review. Health Psychology Open. 2018;5(2):2055102918805187.

[2] Larun L. et al. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2016 Jun 24;(6):CD003200.

[3] Cheshire A. et al. Guided graded Exercise Self-help for chronic fatigue syndrome: patient experiences and perceptions. Disabil Rehabil. 2018 Oct 16:1-10.

[4] McManimen SL. et al. Effects of unsupportive social interactions, stigma, and symptoms on patients with myalgic encephalomyelitis and chronic fatigue syndrome. J Community Psychol. 2018 Nov;46(8):959-971.

[5] Adams D. et al. WITHDRAWN: Traditional Chinese medicinal herbs for the treatment of idiopathic chronic fatigue and chronic fatigue syndrome. Cochrane Database Syst Rev. 2018 Oct 15;10:CD006348.

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On Cochrane and 'facts' and 'politics' in evidence-based medicine

The controversy surrounding the reported expulsion of Peter Gøtzsche from the Cochrane Collaboration (or should that just be Cochrane?) is something that I've been following for a few days now (see here). Cochrane, under the heading "Trusted evidence. Informed decisions. Better health", represents one of the premier go-to sources for evidence-based healthcare advice on a range of topics. Some of those topics have been previous fodder for this blog too (see here and see here for examples).

I don't profess to have any unique insight into the various goings-on leading to the reported expulsion of Gøtzsche and resignations of fellow members beyond that which has been discussed in various sections of the science media (see here and see here and see here). From what I gather, things look like they've been 'brewing' for a while with regards to Cochrane and the views and opinions expressed by some of those who are seemingly departing. Such a public spat however, is unlikely to be good for science or evidence-based medicine, and indeed may have some wider implications for some fundamentals of science and science communication...

One of the possible [late] precipitating events mentioned around the Gøtzsche saga was the publication of a quite scathing article by Lars Jørgensen and colleagues [1] (including Gøtzsche as an author) questioning the published results of a recent Cochrane review [2] titled: "Prophylactic vaccination against human papillomaviruses [HPV] to prevent cervical cancer and its precursors". The original review by Marc Arbyn et al garnered media headlines when published (see here) as per conclusions such as: "There is high‐certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and young women aged 15 to 26." A comforting finding by all accounts. Accompanying such efficacy data were other statements made by the authors on the basis of the evidence reviewed that: "The vaccines do not increase the risk of serious adverse events, miscarriage or pregnancy termination."

Jørgensen and colleagues however put forward their [peer-reviewed] view that the Arbyn paper fell short of the expected standards from Cochrane: "We do not find the Cochrane HPV vaccine review to be ‘Trusted evidence’, as it was influenced by reporting bias [3] and biased trial designs." They highlighted several 'issues' with the original review stretching from trial selection for the review, to the assessment of "serious and systemic adverse events" to potential "conflicts of interest." Similar sentiments had been voiced about other Cochrane reviews too that were subsequently pulled from the scientific literature. Feathers were inevitably ruffled (see here) by the Jørgensen paper, even as far as prompting a response from the journal that published the paper [4] about the peer-review process leading to publication of the critique. Things are getting serious when a journal has to defend its publication of a paper.

Without wishing to reduce this saga to any one event, I don't think it would be unreasonable to assume that the Jørgensen paper might have influenced matters quite considerably; perhaps even bringing them to a head. As per involvement on the Boesen paper [5] Gøtzsche is no stranger to calling out Cochrane reviews that seemingly don't make the grade, alongside also voicing opinions on various other matters down the years. To quote: "... in another book, [he] likened the pharmaceutical industry to "organized crime""; such forthright statements stretching back some years are unlikely to have made too many friends in certain circles.

As per the title of this post mentioning the words 'facts' and 'politics', one particular write-up of this saga I think hits the nail on the head. The opinion piece from Trish Greenhalgh [6] presents the two sides to this 'dispute': on the one hand is that the “crisis” is "philosophical (relating to the nature of facts)" and on the other, "political (relating to organisational governance)." The philosophical side of things is pretty evident as per the publication of the Jørgensen paper as a counter to the Arbyn paper. Greenhalgh mentions about how "Gøtzsche might be classified as an evidence-based medicine purist" given his views and sizeable contribution to various "statements on how to undertake and publish research." In this respect, his published views on the original Arbyn paper (and similarly in other reviews) seem to detail scientific standards not being met, or at least not being met to his and his co-authors standards. And certainly on points such as access to trial results and data, he's seemingly not alone in his concern (see here).

On the political side of things, well, at the time of writing we just don't know enough to reasonably comment. Greenhalgh mentions that: "The political explanation for Cochrane’s crisis relates to the tension between governing an organisation and respecting individual members’ academic freedom to express dissent." The fact that such dissent has over the years covered various important public health topics - "cast doubts about the safety of a vaccine against human papillomavirus (HPV), a cause of cervical cancer, and says psychiatry has “gone astray” by coercing patients into taking medication, such as antidepressants, they don’t want to use and that cause “brain damage” over the long run" - is likely to have really stretched those organisational relationships with Gøtzsche. Not least because immunisation and antidepressant use reflect important pillars of modern public healthcare and, historically, uptake of such medicines is very, very susceptible to differences in scientific views, opinions and beyond.

As to the idea mentioned by Greenhalgh that: "We should cut it [Cochrane] some slack while it gets its house in order", I'm not exactly sure how it's going to approach this 'house in order' requirement and what this means for the future credibility of Cochrane. Based solely on the 'facts' side of this saga, it strikes me that organisations like Cochrane actually need people like Peter Gøtzsche and their "evidence-based medicine purist" beliefs. They need them in order to critically (really critically) boil down the ever-growing research literature into scientifically sound statements for public and policy consumption without fear or favour. Minus such voices, it's more likely that evidence-based messages originating from such initiatives are perhaps going to be weakened, which in turn means that population healthcare is potentially going to suffer. Moreover, I assume also that just because Gøtzsche is reportedly not part of Cochrane any more does not mean that he won't be heard from again in the peer-reviewed domain...

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[1] Jørgensen L. et al. The Cochrane HPV vaccine review was incomplete and ignored important evidence of bias. BMJ Evidence-Based Medicine. 2018. July 27.

[2] Arbyn M. et al. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database Syst Rev. 2018 May 9;5:CD009069.

[3] Jørgensen L. et al. Index of the human papillomavirus (HPV) vaccine industry clinical study programmes and non-industry funded studies: a necessary basis to address reporting bias in a systematic review. Syst Rev. 2018 Jan 18;7(1):8.

[4] Heneghan C. & Onakpoya I. Editors’ response to concerns over the publication of the Cochrane HPV vaccine review was incomplete and ignored important evidence of bias. BMJ Evidence-Based Medicine. 2018. Sept 12.

[5] Boesen K. et al. The Cochrane Collaboration withdraws a review on methylphenidate for adults with attention deficit hyperactivity disorder. Evid Based Med. 2017 Aug;22(4):143-147.

[6] Greenhalgh T. The Cochrane Collaboration—what crisis? BMJ. 2018. Sept 17.

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"weak evidence that EIBI may be an effective behavioral treatment for some children with ASD"

Today I bring to your attention the 'Cochrane does...' findings reported by Brian Reichow and colleagues [1] which concluded that: "There is weak evidence that EIBI [early intensive behavioral intervention] may be an effective behavioral treatment for some children with ASD [autism spectrum disorder]."

The Cochrane in the term 'Cochrane does...' refers to the Cochrane Database of Systematic Reviews, an important resource that provides systematic reviews on various aspects of healthcare that help inform practice and policy. I've talked about them a few times previously on this blog (see here and see here). EIBI - "a treatment based on the principles of applied behavior analysis" - is something that has been part and parcel of the autism research scene for many years. It aims to 'target' the early presentation of autism in both severity and "functional behaviors and skills" among other things; in the context to 'modify' the presentation of autism and "lessen the impact of symptoms on children's functioning."

The Reichow review found five studies that examined EIBI in the context of autism or autism spectrum disorder (ASD) and included over 200 children. They concluded that: (a) "No adverse effects were reported across studies" following the important tenet: first, do no harm, (b) there was "weak evidence that children receiving the EIBI treatment performed better than children in the comparison groups after about two years of treatment on scales of adaptive behavior, intelligence tests, expressive language (spoken language), and receptive language (the ability to understand what is said)", and (c) "Differences were not found for the severity of autism symptoms or a child's problem behavior."

Although the overall key message from authors was one that: "The evidence supports the use of EIBI for some children with ASD", the authors caution that the evidence base in this area remains weak. They mention that: "only a small number of children were involved in the studies, and only one study had an optimum design in which children were randomly assigned to treatment groups." There is a requirement for more [longitudinal] investigation following more 'rigourous' methodological designs.

I've always been in two minds about the usefulness of EIBI and autism, and indeed, early behavioural intervention in general. Yes, infants and young children are always going to be reactive to the behaviour of those around them, but the inference that the course of autism can be universally and significantly 'affected' by [various] structured programs of this type, has always been a challenge to me (see here). I've been particularly worried about headlines reporting that something like 'super-parenting' could potentially affect the presentation of autism (yes, someone did actually say that) and the connotations stemming from them. I also have concerns coming from a perspective that the behavioural presentation of autism probably comes about for various reasons in various people; some of them are likely linked to biology, as per the examples of various inborn errors of metabolism manifesting autism (see here) and autism presentation following viral or bacterial infection (see here and see here). In such cases, it strikes me that one perhaps needs to look at the biology first rather than the presented (secondary) symptoms in a sort of 'catch-up' manner. I know that last sentence is likely not to sit well with some people who follow the sweeping generalisation that autism is innate and immutable, but there are some good examples in the peer-reviewed research literature on well-controlled intervention studies of this type (see here and see here). And yes, there needs to be more longitudinal follow-up in these areas too...

I'm not totally poo-pooing the idea of EIBI in the context of autism, but rather, would wish to see greater long-term, controlled evidence before grand sweeping generalisations and big headlines are made. A better focus on 'sub-groups' might also be quite useful when it comes to possible best- and non-responders [2] to the various interventions put forward with autism in mind...

To close, a crow with a Yorkshire accent. This is what the internet was made for.

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[1] Reichow B. et al. Early intensive behavioral intervention (EIBI) for young children with autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2018 May 9;5:CD009260.

[2] Paynter J. et al. Differential outcome subgroups in children with autism spectrum disorder attending early intervention. J Intellect Disabil Res. 2018 May 23.

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Cochrane does methylphenidate for ADHD

'Cochrane does' in the title of this post refers to the Cochrane Library and the sterling work that is done by the Cochrane Reviews to analyse the collected peer-reviewed evidence on various aspects of health and wellbeing and provide a sort of 'state of the evidence' address. It's something that has graced this blog before (see here).

This time around attention has turned to the paper by Ole Jakob Storebø and colleagues [1] (open-access) who started with the objective to: "assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD [attention-deficit hyperactivity disorder]." Methylphenidate, more readily known by the brand names Concerta or Ritalin is one of the management tools of choice for some people diagnosed with ADHD as part of a suite of stimulant medicines indicated for the condition. As what can happen with quite a few medicines in the medicinal chest, methylphenidate is also becoming a nootropic of choice in these days of so-called cognitive enhancers or smart drugs and particularly with reference to the academic rat race that many people find themselves in.

The paper from Storebø et al surveyed the peer-reviewed research literature on the topic of methylphenidate (MPH) and ADHD up to February of this year (2015) identifying some 185 trials: "randomised controlled trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD." They concluded that there was some evidence that MPH was a useful medicine for improving things like teacher-rated ADHD scores and parent-reported quality of life among children and young adults with ADHD. Serious, life-threatening side-effects were also fairly rare based on the data inspected. Good news indeed.

But... as per some other write-up of the study findings (see here), the picture was not universally rosy when it came to MPH use and ADHD in the research literature. So: "The most common non-serious adverse events were sleep problems and decreased appetite. Children in the methylphenidate group were at 60% greater risk for trouble sleeping/sleep problems..., and 266% greater risk for decreased appetite... than children in the control group." Such findings even within the context of requiring better designed trials to assess MPH, are slightly worrying and are perhaps the reasons why the BBC headline on this study read: "Experts call for caution over Ritalin." Other recent research has also come to similar conclusions [2].

Bearing in mind my oft-cited caveats on this blog about not giving anything that looks, sounds or smells like clinical advice, I have a few things to add to the Storebø report based on my reading of some of the research literature in this area. First and foremost is the fact that outside of something like MPH (and a few other medicines) science and medicine have not got a great deal of other therapeutic options to offer when ADHD is diagnosed. Yes, behavioural interventions can be implemented; indeed, even something like sleep interventions have been discussed with ADHD in mind (see here). But surprisingly little else is available unless one considers that some of the more 'complementary' interventions might also be useful for some (see here).

Second, as per quite a bit of professional opinion these days, childhood developmental disorders such as ADHD really need to be tackled in the younger years in view of the 'risks' attached to their perpetuation into adulthood. Take for example the emerging research suggesting that ADHD might 'prime' for something like psychosis or schizophrenia in later years (see here) (albeit with other important variables potentially playing a role) and one has a taste of what future enhanced risks might be associated with the label. Even some of the authors from the current Cochrane review have some previous research form in this area [3]. This also covers other more societal risks too (see here).

Finally is the idea that whilst no-one particularly likes the idea that children and young adults are being dispensed quite powerful medicines, things like MPH with appropriate medicines management, can make a real difference to people's lives. With my autism research blogging hat on and acknowledging how autism and ADHD show some significant 'overlapping' (see here) the peer-reviewed research confirms such 'positive effects' [4] at least for some. And yes, we need to know more about who the potential best and non-responders are likely to be.

Further research is of course indicated in this area including that related to the mechanism of effect from something like MPH (see here). As part of a suite of intervention options for labels like ADHD (including something as simple as promoting physical activity), MPH continues to have a place subject to the idea that the use of such medication should be treated as a time-limited experiment with an N=1 and appropriate monitoring for side-effects.

Music: Where's Your Car Debbie - Slaves.

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[1] Storebø OJ. et al. Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). Cochrane Database of Systematic Reviews. 2015; Issue 11. Art. No.: CD009885.

[2] Kidwell KM. et al. Stimulant Medications and Sleep for Youth With ADHD: A Meta-analysis. Pediatrics. 2015 Nov 23. pii: peds.2015-1708.

[3] Storebø OJ. & Simonsen E. The Association Between ADHD and Antisocial Personality Disorder (ASPD): A Review. J Atten Disord. 2013 Nov 27.

[4] Posey DJ. et al. Positive effects of methylphenidate on inattention and hyperactivity in pervasive developmental disorders: an analysis of secondary measures. Biol Psychiatry. 2007 Feb 15;61(4):538-44.

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Storebø OJ, Ramstad E, Krogh HB, Nilausen TD, Skoog M, Holmskov M, Rosendal S, Groth C, Magnusson FL, Moreira-Maia CR, Gillies D, Buch Rasmussen K, Gauci D, Zwi M, Kirubakaran R, Forsbøl B, Simonsen E, & Gluud C (2015). Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD). The Cochrane database of systematic reviews, 11 PMID: 26599576