A science-based medicine skeptic struggles with his as-yet medically unexplained pain and resists alternative quack treatments

Paul: “For three years I kept my faith that relief had to be just around the corner, but my disappointment is now as chronic as my pain. Hope has become a distraction.”

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Chronic pain and tragic irony…

Paul: “For three years I kept my faith that relief had to be just around the corner, but my disappointment is now as chronic as my pain. Hope has become a distraction.”

Paul Ingraham is quite important in the Science-Based Skeptics movement and in my becoming involved in it. He emailed me after a long spell without contact. He wanted to explain how he had been out of touch. His life had been devastated by as-yet medically unexplained pain and other mysterious symptoms.

Paul  modestly describes himself at his blog site as “a health writer in Vancouver, Canada, best known for my work debunking common myths about treating common pain problems on PainScience.com. I actually make a living doing that. On this blog, I just mess around.  ~ Paul Ingraham (@painsci, Facebook).”

Some of Paul’s posts at his own blog site

massage

on fire

stretching

Paul’s Big Self-Help Tutorials for Pain Problems are solidly tied to the best peer-reviewed evidence.

Detailed, readable tutorials about common stubborn pain problems & injuries, like back pain or runner’s knee.

Many common painful problems are often misunderstood, misdiagnosed, and mistreated. Made for patients, but strong enough for professionals, these book-length tutorials are crammed with tips, tricks, and insights about what works, what doesn’t, and why. No miracle cures are for sale here — just sensible information, scientifically current, backed up by hundreds of free articles and a huge pain and injury science bibliography.

 

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Paul offered me invaluable assistance and support when I began blogging at the prestigious Science Based Medicine. See for instance, my:

Systematic Review claims acupuncture as effective as antidepressants: Part 1: Checking the past literature

And

Is acupuncture as effective as antidepressants? Part 2. Blinding readers who try to get an answer

I have not consistently blogged there, because my topics don’t always fit. Whenever I do blog there, I learn a lot from  the wealth of thoughtful comments I received.

I have great respect for Science Based Medicine’s authoritative, well documented and evidence-based analyses. I highly recommend the blog for those who are looking for sophistication  delivered in a way that an intelligent lay person could understand.

What’s the difference between Sciencebased medicine (SBM) versus evidence-based medicine (EBM)?

I get some puzzlement every time I bring up this important distinction – Bloggers at SBM frequently make a distinction between science-based- and evidence-based- medicine. They offer careful analyses of unproven treatments like acupuncture and homeopathy. Proponents of these treatment increasingly sell them as evidence-based, citing randomized trials that do not involve an active treatment. The illusion of efficacy is often created by the positive expectations and mysterious rituals with which these treatments are delivered. Comparison treatments in these studies often lack this boost, particularly when tested in in unblinded comparisons.

The SBM bloggers like to point out that there are no plausible tested scientific mechanisms by which these treatments might conceivably work. The name of  blog,  Science-Based Medicine calls  attention to their higher standards for considering treatments efficacious: to be considered science based medicine, they have to be proven as effective as evidence-based active treatments, and have to have a mechanism beyond nonspecific, placebo effects.

Paul Ingram reappears from a disappearance.

Paul mysteriously disappeared for a while. Now he’s reemerged with a tale that is getting a lot of attention. He gave me permission to blog about excerpts. I enclose a link to the full story that I strongly recommend.

Paul Ingram title

http://www.paulingraham.com/chronic-pain-tragic-irony.html

A decade ago I devoted myself to helping people with chronic pain, and now it’s time to face my ironic new reality: I have serious unexplained chronic pain myself. It may never stop, and I need to start learning to live with it rather than trying to fix it.

I have always been “prone” to aches and pains, and that’s why I became a massage therapist and then moved on to publishing PainScience.com. But that tendency was a pain puppy humping my leg compared to the Cerberus of suffering that’s mauling me now. I’ve graduated to the pain big leagues.

For three years I kept my faith that relief had to be just around the corner, but my disappointment is now as chronic as my pain. Hope has become a distraction. I’ve been like a blind man waiting for my sight to return instead of learning braille. It’s acceptance time.

Paul describes how is pain drove him into hiding.

… why I’ve become one of those irritating people who answers every invitation with a “maybe” and bails on half the things I commit to. I never know what I’m going to be able to cope with on a given day until it’s right in front of me.

He struggled to define the problem:

Mostly widespread soreness and joint pain like the early stages of the flu, a parade of agonizing hot spots that are always on the verge of breaking my spirit, and a lot of sickly fatigue. All of which is easily provoked by exercise.

But there was a dizzying array of other symptoms…

Any diagnosis would be simply a label, not an explanation.

Nothing turned up in a few phases of medical investigation in 2015 and 2016. My “MS hug” is not caused by MS. My thunderclap headaches are not brain bleeds. My tremors are not Parkinsonian. I am not deficient in vitamins B or D. There is no tumour lurking in my chest or skull, nor any markers of inflammation in my blood. My heart beats as steadily as an atomic clock, and my nerves conduct impulses like champs.

Paul was not seriously tempted by alternative and complementary medicine

I am not tempted to try alternative medicine. The best of alt-med is arguably not alternative at all — e.g. nutrition, mindfulness, relaxation, massage, and so on — and the rest of what alt-med offers ranges from dubious at best to insane bollocks at the worst. You can’t fool a magician with his own tricks, and you can’t give false hope to an alt-med apostate like me: I’ve seen how the sausage is made, and I feel no surge of false hope when someone tells me (and they have) “it’s all coming from your jaw, you should see this guy in Seattle, he’s a Level 17 TMJ Epic Master, namaste.” Most of what sounds promising to the layperson just sounds like a line of bull to me.

Fascinating how many people clearly think Paul’s story was almost identical to their own.

All these seemingly “identical” cases have got me pondering: syndromes consist of non-specific symptoms by definition, and batches of such symptoms will always seem more similar than they actually are… because blurry pictures look more alike than sharp and clear ones. Non-specific symptoms are generalized biological reactions to adversity. Anxiety can cause any of them, and so can cancer. Any complex cases without pathognomic (specific, defining) symptoms are bound to have extensive overlap of their non-specific symptoms.

There are many ways to be sick, and relatively few ways to feel bad.

Do check out his full blog post. http://www.paulingraham.com/chronic-pain-tragic-irony.html

Flawed meta-analysis reveals just how limited the evidence is mapping meditation into specific regions of the brain

The article put meaningless, but reassuring effect sizes into the literature where these numbers will be widely and uncritically cited.

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“The only totally incontrovertible conclusion is that much work remains to be done…”.

lit up brain not in telegraph article PNG

Authors of a systematic review and meta-analysis of functional neuroanatomical studies (fMRI and PET) of meditation were exceptionally frank in acknowledging problems relating the practice of meditation to differences in specific regions of the brain. However, they did not adequately deal with problems hiding in plain sight. These problems should have discouraged integration of this literature into a meta-analysis and the authors’ expressing the strength of the association between meditation and the brain in terms of a small set of moderate effect sizes.

The article put meaningless, but reassuring effect sizes into the literature where these numbers will be widely and uncritically cited.

An amazing set of overly small studies with evidence that null findings are being suppressed.

Many in the multibillion mindfulness industry are naive or simply indifferent to what constitutes quality evidence. Their false confidence that “meditation changes the brain*” can be bolstered by selective quotes from this review seemingly claiming that the associations are well-established and practically significant. Readers who are more sophisticated may nonetheless be mislead by this review, unless they read beyond the abstract and with appropriate skepticism.

Read on. I suspect you will be surprised as I was about the small quantity and poor quality of the literature relating the practice of meditation to specific areas of the brain. The colored pictures of the brain widely used to illustrate discussions of meditation are premature and misleading.

As noted in another article :

Brightly coloured brain scans are a media favourite as they are both attractive to the eye and apparently easy to understand but in reality they represent some of the most complex scientific information we have. They are not maps of activity but maps of the outcome of complex statistical comparisons of blood flow that unevenly relate to actual brain function. This is a problem that scientists are painfully aware of but it is often glossed over when the results get into the press.

The article is

Fox KC, Dixon ML, Nijeboer S, Girn M, Floman JL, Lifshitz M, Ellamil M, Sedlmeier P, Christoff K. Functional neuroanatomy of meditation: A review and meta-analysis of 78 functional neuroimaging investigations. Neuroscience & Biobehavioral Reviews. 2016 Jun 30;65:208-28.

Abstract.

Keep in mind how few readers go beyond an abstract in forming an impression of what an article shows. More readers “know” what the meta analysis found solely based on their reading the abstract , relative to the fewer people who read both the article and the supplementary material).

Meditation is a family of mental practices that encompasses a wide array of techniques employing distinctive mental strategies. We systematically reviewed 78 functional neuroimaging (fMRI and PET) studies of meditation, and used activation likelihood estimation to meta-analyze 257 peak foci from 31 experiments involving 527 participants. We found reliably dissociable patterns of brain activation and deactivation for four common styles of meditation (focused attention, mantra recitation, open monitoring, and compassion/loving-kindness), and suggestive differences for three others (visualization, sense-withdrawal, and non-dual awareness practices). Overall, dissociable activation patterns are congruent with the psychological and behavioral aims of each practice. Some brain areas are recruited consistently across multiple techniques—including insula, pre/supplementary motor cortices, dorsal anterior cingulate cortex, and frontopolar cortex—but convergence is the exception rather than the rule. A preliminary effect-size meta-analysis found medium effects for both activations (d = 0.59) and deactivations (d = −0.74), suggesting potential practical significance. Our meta-analysis supports the neurophysiological dissociability of meditation practices, but also raises many methodological concerns and suggests avenues for future research.

The positive claims in the abstract

“…Found reliably dissociable patterns of brain activation and deactivation for four common styles of meditation.”

“Dissociable activation patterns are congruent with the psychological and behavioral aims of each practice.”

“Some brain areas are recruited consistently across multiple techniques”

“A preliminary effect-size meta-analysis found medium effects for both activations (d = 0.59) and deactivations (d = −0.74), suggesting potential practical significance.”

“Our meta-analysis supports the neurophysiological dissociability of meditation practices…”

 And hedges and qualifications in the abstract

“Convergence is the exception rather than the rule”

“[Our meta-analysis] also raises many methodological concerns and suggests avenues for future research.

Why was this systematic review and meta-analysis undertaken now?

A figure provided in the article showed a rapid accumulation of studies of mindfulness in the brain in the past few years, with over 100 studies now available.

However, the authors systematic search yielded “78 functional neuroimaging (fMRI and PET) studies of meditation, and used activation likelihood estimation to meta-analyze 257 peak foci from 31 experiments involving 527 participants.” About a third of the studies identified in a search provided usable data.

What did the authors want to accomplish?

Taken together, our central aims were to: (i) comprehensively review and meta-analyze the existing functional neuroimaging studies of meditation (using the meta-analytic method known as activation likelihood estimation, or ALE), and compare consistencies in brain activation and deactivation both within and across psychologically distinct meditation techniques; (ii) examine the magnitude of the effects that characterize these activation patterns, and address whether they suggest any practical significance; and (iii) articulate the various methodological challenges facing the emerging field of contemplative neuroscience (Caspi and Burleson, 2005; Thompson, 2009; Davidson, 2010; Davidson and Kaszniak, 2015), particularly with respect to functional neuroimaging studies of meditation.

Said elsewhere in the article:

Our central hypothesis was a simple one: meditation practices distinct at the psychological level (Ψ) may be accompanied by dissociable activation patterns at the neurophysiological level (Φ). Such a model describes a ‘one-to-many’ isomorphism between mind and brain: a particular psychological state or process is expected to have many neurophysiological correlates from which, ideally, a consistent pattern can be discerned (Cacioppo and Tassinary, 1990).

The assumption is meditating versus not-meditating brains should be characterized by  distinct, observable neurophysiological pattern. There should also be distinct, enduring changes in the brain in people who have been practicing meditation for some time.

I would wager that many meditation enthusiasts believe that links to specific regions are already well established. Confronted with evidence to the contrary, they would suggest that links between the experience of meditating and changes in the brain are predictable and are waiting to be found. It is that kind of confidence that leads to the significance chasing and confirmatory bias currently infecting this literature.

Types of meditation available for study

Quantitative analyses focused on four types of meditation. Additional terms of meditation did not have sufficient studies and so were examined qualitatively. Some studies of the four provided within-group effect size, whereas other studies provided between-group effect sizes.

Focused attention (7 studies)

Directing attention to one specific object (e.g., the breath or a mantra) while monitoring and disengaging from extraneous thoughts or stimuli (Harvey, 1990, Hanh, 1991, Kabat-Zinn, 2005, Lutz et al., 2008b, Wangyal and Turner, 2011).

Mantra recitation (8 studies)

Repetition of a sound, word, or sentence (spoken aloud or silently in one’s head) with the goals of calming the mind, maintaining focus, and avoiding mind-wandering.

Open monitoring (10 studies)

Bringing attention to the present moment and impartially observing all mental contents (thoughts, emotions, sensations, etc.) as they naturally arise and subside.

Loving-kindness/compassion (6 studies)

L-K involves:

Generating feelings of kindness, love, and joy toward themselves, then progressively extend these feelings to imagined loved ones, acquaintances, strangers, enemies, and eventually all living beings (Harvey, 1990, Kabat_Zinn, 2005, Lutz et al., 2008a).

Similar but not identical, compassion meditation

Takes this practice a step further: practitioners imagine the physical and/or psychological suffering of others (ranging from loved ones to all humanity) and cultivate compassionate attitudes and responses to this suffering.

In addition to these four types of meditation, three others can be identified, but so far have only limited studies of the brain: Visualization, Sense-withdrawal and Non-dual awareness practices.

A dog’s breakfast: A table of the included studies quickly reveals a meta-analysis in deep trouble

studies included

This is not a suitable collection of studies to enter into a meta-analysis with any expectation that a meaningful, generalizable effect size will be obtained.

Most studies (14) furnish only pre-post, within-group effects for mindfulness practiced by long time practitioners. Of these 14 studies, there are two outliers with 20 and 31 practitioners. Otherwise the sample size ranges from 4 to 14.

There are 11 studies furnishing between-group comparisons between experienced and novice meditators. The number of participants in the smaller cell is key for the power of between-group effect sizes, not the overall sample size. In these 11 studies, this ranged from 10 to 22.

It is well-known that one should not combine within- and between- group effect sizes in meta analysis.  Pre-/post-within-group differences capture not only the effects of the active ingredients of an intervention, but nonspecific effects of the conditions under which data are gathered, including regression to the mean. These within-group differences will typically overestimate between-group differences. Adding a  comparison group and calculating between-group differences has the potential for  controlling nonspecific effects, if the comparison condition is appropriate.

The effect sizes based on between-group differences in these studies have their own problems as estimates of the effects of meditation on the brain. Participants were not randomized to the groups, but were selected because they were already either experienced or novice meditators. Yet these two groups could differ on a lot of variables that cannot be controlled: meditation could be confounded with other lifestyle variables: sleeping better or having a better diet. There might be pre-existing differences in the brain that made it easier for the experienced meditators to have committed to long term practice. The authors acknowledge these problems late in the article, but they do so only after discussing the effect sizes they obtained as having substantive importance.

There is good reason to be skeptical that these poorly controlled between-group differences are directly comparable to whatever changes would occur in experienced meditators’ brains in the course of practicing meditation.

It has been widely appreciated that neuroimaging studies are typically grossly underpowered, and that the result is low reproducibility of findings. Having too few participants in a  study will likely yield false negatives because of an inability to achieve the effects needed to obtain significant findings. Small sample size means a stronger association is needed to be significant.

Yet, what positive findings (i.e., significant) are obtained will of necessity be larger likely to be exaggerated and not reproducible with a larger sample.

Another problem with such small cell sizes is that it cannot be assumed that effects are due to one or more participants’ differences in brain size or anatomy. One or a small subgroup of outliers could drive all significant findings in an already small sample. The assumption that statistical techniques can smooth these interindividual differences depends on having much larger samples.

It has been noted elsewhere:

Brains are different so the measure in corresponding voxels across subjects may not sample comparable information.

How did the samples get so small? Neuroanatomical studies are expensive, but why did Lazar et al (2000) have 5 rather 6 participants, or only the 4 participants that Davanger et had? Were from some participants dropped after a peeking at the data? Were studies compromised by authors not being able to recruit intended numbers of participants and having to relax entry criteria? What selection bias is there in these small samples? We just don’t know.

I am reminded of all the contentious debate that has occurred when psychoanalysts insisted on mixing uncontrolled case-series with randomized trials in the same meta-analyses of psychotherapy. My colleagues and I showed this introduces great distortion  into the literature . Undoubtedly, the same is occurring in these studies of meditation, but there is so much else wrong with this meta analysis.

The authors acknowledge that in calculating effect sizes, they combined studies measuring cerebral blood flow (positron emission tomography; PET) and blood oxygenation level (functional magnetic resonance imaging; fMRI). Furthermore, the meta-analyses combined studies that varied in the experimental tasks for which neuroanatomical data were obtained.

One problem is that even studies examining a similar form of meditation might be comparing a meditation practice to very different baseline or comparison tasks and conditions. However, collapsing across numerous different baselines or control conditions is a common (in fact, usually inevitable) practice in meta_analyses of functional neuroimaging studies…

So, there are other important sources of heterogeneity between these studies.

Generic_forest_plot
A generic forest plot. This article did not provide one.

It’s a pity that the authors did not provide a forest plot [How to read  a forest plot.]  graphically showing the confidence intervals around the effect sizes being entered into the meta-analysis.

But the authors did provide a funnel plot that I found shocking. [Recommendations for examining and interpreting funnel plot] I have never seen one like, except when someone has constructed an artificial funnel plot to make a point.

funnel plot

Notice two things about this funnel plot. Rather than a smooth, unbroken distribution, studies with effect sizes between -.45 and +.45 are entirely missing. Studies with smaller sample sizes have the largest effect sizes, whereas the smallest effect sizes all come from the larger samples.

For me, this adds to the overwhelming evidence there is something gone wrong in this literature and any effect sizes should be ignored. There must have been considerable suppression of null findings so large effects from smaller studies will not generalize. Yet, the authors find the differences between small and larger sample studies encouraging

This suggests, encouragingly, that despite potential publication bias or inflationary bias due to neuroimaging analysis methods, nonetheless studies with larger samples tend to converge on similar and more reasonable (medium) effect sizes. Although such a conclusion is tentative, the results to date (Fig. 6) suggest that a sample size of approximately n = 25 is sufficient to reliably produce effect sizes that accord with those reported in studies with much larger samples (up to n = 46).

I and others have long argued that studies of this small sample size in evaluating psychotherapy should be left as pilot feasibility studies and not used to generate effect sizes. I think the same logic applies to this literature.

Distinctive patterns of regional activation and deactivation

The first part of the results section is devoted to studies examining particular forms of meditation. Seeing the apparent consistency of results, one needs to keep in mind the small number of studies being examined and the considerable differences among them. For instance, results presented for focused attention combine three between-group comparisons with four within-group studies. Focused attention includes both pre-post meditation differences from experienced Tibetan Buddhist practitioners to differences between novice and experienced practitioners of mindfulness-based stress reduction (MBSR). In almost all cases, meaningful statistically significant differences are found in both activation and deactivation regions that would make a lot of sense in terms of the functions that are known to be associated with them. There is not much noting of anomalous brain regions being identified by significant effects There is a high ratio of significant findings to number of participants comparisons. There is little discussion of anomalies.

Meta-analysis of focused attention studies resulted in 2 significant clusters of activation, both in prefrontal cortex (Table 3;Fig. 2). Activations were observed in regions associated with the voluntary regulation of thought and action, including the premotor cortex (BA 6; Fig. 2b) and dorsal anterior cingulate cortex (BA24; Fig. 2a). Slightly sub-threshold clusters were also observed in the dorsolateral prefrontal cortex (BA 8/9; Fig. 2c) and left midinsula (BA 13; Fig. 2e); we display these somewhat sub-threshod results here because of the obvious interest of these findings in practices that involve top-down focusing of attention, typically focused on respiration. We also observed clusters of deactivation in regions associated with episodic memory and conceptual processing, including the ventral posterior cingulate cortex (BA 31; Fig. 2d)and left inferior parietal lobule (BA 39; Fig. 2f).

How can such meaningful, practically significant findings obtains when so many conditions mitigate against finding them? John Ioannidis once remarked that in hot areas of research, consistency of positive findings from small studies often reflects only the strength of bias with which they are sought. The strength of findings will decrease when larger, more methodologically sophisticated studies become available, conducted by investigators who are less committed to having to get confirmation.

The article concludes:

Many have understandably viewed the nascent neuroscience of meditation with skepticism (Andresen, 2000; Horgan, 2004), burecent years have seen an increasing number of high-quality, controlled studies that are suitable for inclusion in meta-analyses and that can advance our cumulative knowledge of the neural basis of various meditation practices (Tang et al., 2015). With nearly a hundred functional neuroimaging studies of meditation now reported, we can conclude with some confidence that different practices show relatively distinct patterns of brain activity, and that the magnitude of associated effects on brain function may have some practical significance. The only totally incontrovertible conclusion, however, is that much work remains to be done to confirm and build upon these initial findings.

“Increasing number of high-quality, controlled studies that are suitable for inclusion in meta-analyses” ?…” “Conclude with some confidence…? “Relatively distinct patterns”?… “Some practical significance”?

In all of this premature enthusiasm about findings relating the practice of meditation to activation of particular regions of the brain and deactivation of others, we should not lose track of some other issues.

Although the authors talk about mapping one-to-one relationships between psychological states and regions of the brain, none of the studies would be of sufficient size to document some relationships, given the expected size of the relationship, based on what is typically found between psychological states and other biological variables.

Many differences between techniques could be artifactual –due to the technique altering breathing, involving verbalization, or focused attention. Observed differences in the brain regions activated and deactivated might simply reflect these differences without them being related to psychological functioning.

Even if the association were found, it would be a long way to establishing that the association reflected a causal mechanism, rather than simply being correlational or even artifactual. Think of the analogy of discovering a relationship between the amount of sweat while exercising in concluding that any weight loss was due to sweating it out.

We still have not established that meditation has more psychological and physical health benefits than other active interventions with presumably different mechanisms. After lots of studies, we still don’t know whether mindfulness meditation is anything more than a placebo. While I was finishing up this blog post, I came across a new study:

The limited prosocial effects of meditation: A systematic review and meta-analysis. 

Although we found a moderate increase in prosociality following meditation, further analysis indicated that this effect was qualified by two factors: type of prosociality and methodological quality. Meditation interventions had an effect on compassion and empathy, but not on aggression, connectedness or prejudice. We further found that compassion levels only increased under two conditions: when the teacher in the meditation intervention was a co-author in the published study; and when the study employed a passive (waiting list) control group but not an active one. Contrary to popular beliefs that meditation will lead to prosocial changes, the results of this meta-analysis showed that the effects of meditation on prosociality were qualified by the type of prosociality and methodological quality of the study. We conclude by highlighting a number of biases and theoretical problems that need addressing to improve quality of research in this area. [Emphasis added].

 

 

 

When psychotherapy trials have multiple flaws…

Multiple flaws pose more threats to the validity of psychotherapy studies than would be inferred when the individual flaws are considered independently.

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Multiple flaws pose more threats to the validity of psychotherapy studies than would be inferred when the individual flaws are considered independently.

We can learn to spot features of psychotherapy trials that are likely to lead to exaggerated claims of efficacy for treatments or claims that will not generalize beyond the sample that is being studied in a particular clinical trial. We can look to the adequacy of sample size, and spot what Cochrane collaboration has defined as risk of bias in their handy assessment tool.

We can look at the case-mix in the particular sites where patients were recruited.  We can examine the adequacy of diagnostic criteria that were used for entering patients to a trial. We can examine how blinded the trial was in terms of whoever assigned patients to particular conditions, but also what the patients, the treatment providers, and their evaluaters knew which condition to which particular patients were assigned.

And so on. But what about combinations of these factors?

We typically do not pay enough attention multiple flaws in the same trial. I include myself among the guilty. We may suspect that flaws are seldom simply additive in their effect, but we don’t consider whether they may be even synergism in the negative effects on the validity of a trial. As we will see in this analysis of a clinical trial, multiple flaws can provide more threats to the validity trial than what we might infer when the individual flaws are considered independently.

The particular paper we are probing is described in its discussion section as the “largest RCT to date testing the efficacy of group CBT for patients with CFS.” It also takes on added importance because two of the authors, Gijs Bleijenberg and Hans Knoop, are considered leading experts in the Netherlands. The treatment protocol was developed over time by the Dutch Expert Centre for Chronic Fatigue (NKCV, http://www.nkcv.nl; Knoop and Bleijenberg, 2010). Moreover, these senior authors dismiss any criticism and even ridicule critics. This study is cited as support for their overall assessment of their own work.  Gijs Bleijenberg claims:

Cognitive behavioural therapy is still an effective treatment, even the preferential treatment for chronic fatigue syndrome.

But

Not everybody endorses these conclusions, however their objections are mostly baseless.

Spoiler alert

This is a long read blog post. I will offer a summary for those who don’t want to read through it, but who still want the gist of what I will be saying. However, as always, I encourage readers to be skeptical of what I say and to look to my evidence and arguments and decide for themselves.

Authors of this trial stacked the deck to demonstrate that their treatment is effective. They are striving to support the extraordinary claim that group cognitive behavior therapy fosters not only better adaptation, but actually recovery from what is internationally considered a physical condition.

There are some obvious features of the study that contribute to the likelihood of a positive effect, but these features need to be considered collectively, in combination, to appreciate the strength of this effort to guarantee positive results.

This study represents the perfect storm of design features that operate synergistically:

perfect storm

 Referral bias – Trial conducted in a single specialized treatment setting known for advocating psychological factors maintaining physical illness.

Strong self-selection bias of a minority of patients enrolling in the trial seeking a treatment they otherwise cannot get.

Broad, overinclusive diagnostic criteria for entry into the trial.

Active treatment condition carry strong message how patients should respond to outcome assessment with improvement.

An unblinded trial with a waitlist control lacking the nonspecific elements (placebo) that confound the active treatment.

Subjective self-report outcomes.

Specifying a clinically significant improvement that required only that a primary outcome be less than needed for entry into the trial

Deliberate exclusion of relevant objective outcomes.

Avoidance of any recording of negative effects.

Despite the prestige attached to this trial in Europe, the US Agency for Healthcare Research and Quality (AHRQ) excludes this trial from providing evidence for its database of treatments for chronic fatigue syndrome/myalgic encephalomyelitis. We will see why in this post.

factsThe take away message: Although not many psychotherapy trials incorporate all of these factors, most trials have some. We should be more sensitive to when multiple factors occur in the same trial, like bias in the site for patient recruitment; lacking of blinding; lack of balance between active treatment and control condition in terms of nonspecific factors, and subjective self-report measures.

The article reporting the trial is

Wiborg JF, van Bussel J, van Dijk A, Bleijenberg G, Knoop H. Randomised controlled trial of cognitive behaviour therapy delivered in groups of patients with chronic fatigue syndrome. Psychotherapy and Psychosomatics. 2015;84(6):368-76.

Unfortunately, the article is currently behind a pay wall. Perhaps readers could contact the corresponding author Hans.knoop@radboudumc.nl  and request a PDF.

The abstract

Background: Meta-analyses have been inconclusive about the efficacy of cognitive behaviour therapies (CBTs) delivered in groups of patients with chronic fatigue syndrome (CFS) due to a lack of adequate studies. Methods: We conducted a pragmatic randomised controlled trial with 204 adult CFS patients from our routine clinical practice who were willing to receive group therapy. Patients were equally allocated to therapy groups of 8 patients and 2 therapists, 4 patients and 1 therapist or a waiting list control condition. Primary analysis was based on the intention-to-treat principle and compared the intervention group (n = 136) with the waiting list condition (n = 68). The study was open label. Results: Thirty-four (17%) patients were lost to follow-up during the course of the trial. Missing data were imputed using mean proportions of improvement based on the outcome scores of similar patients with a second assessment. Large and significant improvement in favour of the intervention group was found on fatigue severity (effect size = 1.1) and overall impairment (effect size = 0.9) at the second assessment. Physical functioning and psychological distress improved moderately (effect size = 0.5). Treatment effects remained significant in sensitivity and per-protocol analyses. Subgroup analysis revealed that the effects of the intervention also remained significant when both group sizes (i.e. 4 and 8 patients) were compared separately with the waiting list condition. Conclusions: CBT can be effectively delivered in groups of CFS patients. Group size does not seem to affect the general efficacy of the intervention which is of importance for settings in which large treatment groups are not feasible due to limited referral

The trial registration

http://www.isrctn.com/ISRCTN15823716

Who was enrolled into the trial?

Who gets into a psychotherapy trial is a function of the particular treatment setting of the study, the diagnostic criteria for entry, and patient preferences for getting their care through a trial, rather than what is being routinely provided in that setting.

 We need to pay particular attention to when patients enter psychotherapy trials hoping they will receive a treatment they prefer and not to be assigned to the other condition. Patients may be in a clinical trial for the betterment of science, but in some settings, they are willing to enroll because of a probability of getting treatment they otherwise could not get. This in turn also affects the evaluation of both the condition in which they get the preferred treatment, but also their evaluation of the condition in which they are denied it. Simply put, they register being pleased with what they wanted or not being pleased if they did not get what they wanted.

The setting is relevant to evaluating who was enrolled in a trial.

The authors’ own outpatient clinic at the Radboud University Medical Center was the site of the study. The group has an international reputation for promoting the biopsychosocial model, in which psychological factors are assumed to be the decisive factor in maintaining somatic complaints.

All patients were referred to our outpatient clinic for the management of chronic fatigue.

There is thus a clear referral bias  or case-mix bias but we are not provided a ready basis for quantifying it or even estimating its effects.

The diagnostic criteria.

The article states:

In accordance with the US Center for Disease Control [9], CFS was defined as severe and unexplained fatigue which lasts for at least 6 months and which is accompanied by substantial impairment in functioning and 4 or more additional complaints such as pain or concentration problems.

Actually, the US Center for Disease Control would now reject this trial because these entry criteria are considered obsolete, overinclusive, and not sufficiently exclusive of other conditions that might be associated with chronic fatigue.*

There is a real paradigm shift happening in America. Both the 2015 IOM Report and the Centers for Disease Control and Prevention (CDC) website emphasize Post Exertional Malaise and getting more ill after any effort with M.E. CBT is no longer recommended by the CDC as treatment.

cdc criteriaThe only mandatory symptom for inclusion in this study is fatigue lasting 6 months. Most properly, this trial targets chronic fatigue [period] and not the condition, chronic fatigue syndrome.

Current US CDC recommendations  (See box  7-1 from the IoM document, above) for diagnosis require postexertional malaise for a diagnosis of myalgic encephalomyelitis (ME). See below.

pemPatients meeting the current American criteria for ME would be eligible for enrollment in this trial, but it’s unclear what proportion of the patients enrolled actually met the American criteria. Because of the over-inclusiveness of the entry diagnostic criteria, it is doubtful whether the results would generalize to American sample. A look at patient flow into the study will be informative.

Patient flow

Let’s look at what is said in the text, but also in the chart depicting patient flow into the trial for any self-selection that might be revealed.

In total, 485 adult patients were diagnosed with CFS during the inclusion period at our clinic (fig. 1). One hundred and fifty-seven patients were excluded from the trial because they declined treatment at our clinic, were already asked to participate in research incompatible with inclusion (e.g. research focusing on individual CBT for CFS) or had a clinical reason for exclusion (i.e. they received specifically tailored interventions because they were already unsuccessfully treated with individual CBT for CFS outside our clinic or were between 18 and 21 years of age and the family had to be involved in the therapy). Of the 328 patients who were asked to engage in group therapy, 99 (30%) patients indicated that they were unwilling to receive group therapy. In 25 patients, the reason for refusal was not recorded. Two hundred and four patients were randomly allocated to one of the three trial conditions. Baseline characteristics of the study sample are presented in table 1. In total, 34 (17%) patients were lost to follow-up. Of the remaining 170 patients, 1 patient had incomplete primary outcome data and 6 patients had incomplete secondary outcome data.

flow chart

We see that the investigators invited two thirds of patients attending the clinic to enroll in the trial. Of these, 41% refused. We don’t know the reason for some of the refusals, but almost a third of the patients approached declined because they did not want group therapy. The authors left being able to randomize 42% of patients coming to the clinic or less than two thirds of patients they actually asked. Of these patients, a little more than two thirds received the treatment to which were randomized and were available for follow-up.

These patients receiving treatment to which they were randomized and who were available for follow-up are self-selected minority of the patients coming to the clinic. This self-selection process likely reduced the proportion of patients with myalgic encephalomyelitis. It is estimated that 25% of patients meeting the American criteria a housebound and 75% are unable to work. It’s reasonably to infer that patients being the full criteria would opt out of a treatment that require regular attendance of a group session.

The trial is biased to ambulatory patients with fatigue and not ME. Their fatigue is likely due to some combinations of factors such as multiple co-morbidities, as-yet-undiagnosed medical conditions, drug interactions, and the common mild and subsyndromal  anxiety and depressive symptoms that characterize primary care populations.

The treatment being evaluated

Group cognitive behavior therapy for chronic fatigue syndrome, either delivered in a small (4 patients and 1 therapist) or larger (8 patients and 2 therapists) group format.

The intervention consisted of 14 group sessions of 2 h within a period of 6 months followed by a second assessment. Before the intervention started, patients were introduced to their group therapist in an individual session. The intervention was based on previous work of our research group [4,13] and included personal goal setting, fixing sleep-wake cycles, reducing the focus on bodily symptoms, a systematic challenge of fatigue-related beliefs, regulation and gradual increase in activities, and accomplishment of personal goals. A formal exercise programme was not part of the intervention.

Patients received a workbook with the content of the therapy. During sessions, patients were explicitly invited to give feedback about fatigue-related cognitions and behaviours to fellow patients. This aspect was introduced to facilitate a pro-active attitude and to avoid misperceptions of the sessions as support group meetings which have been shown to be insufficient for the treatment of CFS.

And note:

In contrast to our previous work [4], we communicated recovery in terms of fatigue and disabilities as general goal of the intervention.

Some impressions of the intensity of this treatment. This is a rather intensive treatment with patients having considerable opportunities for interactions with providers. This factor alone distinguishes being assigned to the intervention group versus being left in the wait list control group and could prove powerful. It will be difficult to distinguish intensity of contact from any content or active ingredients of the therapy.

I’ll leave for another time a fuller discussion of the extent to which what was labeled as cognitive behavior therapy in this study is consistent with cognitive therapy as practiced by Aaron Beck and other leaders of the field. However, a few comments are warranted. What is offered in this trial does not sound like cognitive therapy as Americans practice it. What is often in this trial seems emphasize challenging beliefs, pushing patients to get more active, along with psychoeducational activities. I don’t see indications of the supportive, collaborative relationship in which patients are encouraged to work on what they want to work on, engage in outside activities (homework assignments) and get feedback.

What is missing in this treatment is what Beck calls collaborative empiricism, “a systemic process of therapist and patient working together to establish common goals in treatment, has been found to be one of the primary change agents in cognitive-behavioral therapy (CBT).”

Importantly, in Beck’s approach, the therapist does not assume cognitive distortions on the part of the patient. Rather, in collaboration with the patient, the therapist introduces alternatives to the interpretations that the patient has been making and encourages the patient to consider the difference. In contrast, rather than eliciting goal statements from patients, therapist in this study imposes the goal of increased activity. Therapists in this study also seem ready to impose their views that the patients’ fatigue-related beliefs are maladaptive.

The treatment offered in this trial is complex, with multiple components making multiple assumptions that seem quite different from what is called cognitive therapy or cognitive behavioral therapy in the US.

The authors’ communication of recovery from fatigue and disability seems a radical departure not only from cognitive behavior therapy for anxiety and depression and pain, but for cognitive behavior therapy offered for adaptation to acute and chronic physical illnesses. We will return to this “communication” later.

The control group

Patients not randomized to group CBT were placed on a waiting list.

Think about it! What do patients think about having gotten involved in all the inconvenience and burden of a clinical trial in hope that they would get treatment and then being assigned to the control group with just waiting? Not only are they going to be disappointed and register that in their subjective evaluations of the outcome assessments patients may worry about jeopardizing the right to the treatment they are waiting for if they overly endorse positive outcomes. There is a potential for  nocebo effect , compounding the placebo effect of assignment to the CBT active treatment groups.

What are informative comparisons between active treatments and  control conditions?

We need to ask more often what inclusion of a control group accomplishes for the evaluation of a psychotherapy. In doing so, we need to keep in mind that psychotherapies do not have effect sizes, only comparisons of psychotherapies and control condition have effect sizes.

A pre-post evaluation of psychotherapy from baseline to follow-up includes the effects of any active ingredient in the psychotherapy, a host of nonspecific (placebo) factors, and any changes that would’ve occurred in the absence of the intervention. These include regression to the mean– patients are more likely to enter a clinical trial now, rather than later or previously, if there has been exacerbation of their symptoms.

So, a proper comparison/control condition includes everything that the patients randomized to the intervention group get except for the active treatment. Ideally, the intervention and the comparison/control group are equivalent on all these factors, except the active ingredient of the intervention.

That is clearly not what is happening in this trial. Patients randomized to the intervention group get the intervention, the added intensity and frequency of contact with professionals that the intervention provides, and all the support that goes with it; and the positive expectations that come with getting a therapy that they wanted.

Attempts to evaluate the group CBT versus the wait-list control group involved confounding the active ingredients of the CBT and all these nonspecific effects. The deck is clearly being stacked in favor of CBT.

This may be a randomized trial, but properly speaking, this is not a randomized controlled trial, because the comparison group does not control for nonspecific factors, which are imbalanced.

The unblinded nature of the trial

In RCTs of psychotropic drugs, the ideal is to compare the psychotropic drug to an inert pill placebo with providers, patients, and evaluate being blinded as to whether the patients received psychotropic drug or the comparison pill.

While it is difficult to achieve a comparable level of blindness and a psychotherapy trial, more of an effort to achieve blindness is desirable. For instance, in this trial, the authors took pains to distinguish the CBT from what would’ve happened in a support group. A much more adequate comparison would therefore be CBT versus either a professional or peer-led support group with equivalent amounts of contact time. Further blinding would be possible if patients were told only two forms of group therapy were being compared. If that was the information available to patients contemplating consenting to the trial, it wouldn’t have been so obvious from the outset to the patients being randomly assigned that one group was preferable to the other.

Subjective self-report outcomes.

The primary outcomes for the trial were the fatigue subscale of the Checklist Individual Strength;  the physical functioning subscale of the Short Health Survey 36 (SF-36); and overall impairment as measured by the Sickness Impact Profile (SIP).

Realistically, self-report outcomes are often all that is available in many psychotherapy trials. Commonly these are self-report assessments of anxiety and depressive symptoms, although these may be supplemented by interviewer-based assessments. We don’t have objective biomarkers with which to evaluate psychotherapy.

These three self-report measures are relatively nonspecific, particularly in a population that is not characterized by ME. Self-reported fatigue in a primary care population lacks discriminative validity with respect to pain, anxiety and depressive symptoms, and general demoralization.  The measures are susceptible to receipt of support and re-moralization, as well as gratitude for obtaining a treatment that was sought.

Self-report entry criteria include a score 35 or higher on the fatigue severity subscale. Yet, a score of less than 35 on this scale at follow up is part of what is defined as a clinically significant improvement with a composite score from combined self-report measures.

We know from medical trials that differences can be observed with subjective self-report measures that will not be found with objective measures. Thus, mildly asthmatic patients will fail to distinguish in their subjective self-reports between [  between the effective inhalant albuterol, an inert inhalant, and sham acupuncture, but will rate improvement better than getting no intervention.  However,  there will be a strong advantage over the other three conditions with an objective measure, maximum forced expiratory volume in 1 second (FEV1) as assessed  with spirometry.

The suppression of objective outcome measures

We cannot let these the authors of this trial off the hook in their dependence on subjective self-report outcomes. They are instructing patients that recovery is the goal, which implies that it is an attainable goal. We can reasonably be skeptical about acclaim of recovery based on changes in self-report measures. Were the patients actually able to exercise? What was their exercise capacity, as objectively measured? Did they return to work?

These authors have included such objective measurements in past studies, but not included them as primary outcomes, nor, even in some cases, reported them in the main paper reporting the trial.

Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010 Jan 5:1

The senior authors’ review fails to mention their three studies using actigraphy that did not find effects for CBT. I am unaware of any studies that did find enduring effects.

Perhaps this is what they mean when they say the protocol has been developed over time – they removed what they found to be threats to the findings that they wanted to claim.

Dismissing of any need to consider negative effects of treatment

Most psychotherapy fail to assess any adverse effects of treatment, but this is usually done discretely, without mention. In contrast, this article states

Potential harms of the intervention were not assessed. Previous research has shown that cognitive behavioural interventions for CFS are safe and unlikely to produce detrimental effects.

Patients who meet stringent criteria for ME would be put at risk for pressure to exert themselves. By definition they are vulnerable to postexertional malaise (PEM). Any trail of this nature needs to assess that risk. Maybe no adverse effects would be found. If that were so, it would strongly indicate the absence of patients with appropriate diagnoses.

Timing of assessment of outcomes varied between intervention and control group.

I at first did not believe what I was reading when I encountered this statement in the results section.

The mean time between baseline and second assessment was 6.2 months (SD = 0.9) in the control condition and 12.0 months (SD = 2.4) in the intervention group. This difference in assessment duration was significant (p < 0.001) and was mainly due to the fact that the start of the therapy groups had to be frequently postponed because of an irregular patient flow and limited treatment capacities for group therapy at our clinic. In accordance with the treatment manual, the second assessment was postponed until the fourteenth group session was accomplished. The mean time between the last group session and the second assessment was 3.3 weeks (SD = 3.5).

So, outcomes were assessed for the intervention group shortly after completion of therapy, when nonspecific (placebo) effects would be stronger, but a mean of six months later than for patients assigned to the control condition.

Post-hoc statistical controls are not sufficient to rescue the study from this important group difference, and it compounds other problems in the study.

Take away lessons

Pay more attention to how limitations any clinical trial may compound each other in terms of the trial provide exaggerated estimates of the effects of treatment or the generalizability of the results to other settings.

Be careful of loose diagnostic criteria because a trial may not generalize to the same criteria being applied in settings that are different either in terms of patient population of the availability of different treatments. This is particularly important when a treatment setting has a bias in referrals and only a minority of patients being invited to participate in the trial actually agree and are enrolled.

Ask questions about just what information is obtained in comparing active treatment group and the study to its control/comparison. For start, just what is being controlled and how might that affect the estimates of the effectiveness of the active treatment?

Pay particular attention to the potent combination of the trial being unblinded, a weak comparision/control, and an active treatment that is not otherwise available to patients.

Note

*The means of determining whether the six months of fatigue might be accounted for by other medical factors was specific to the setting. Note that a review of medical records for sufficient for an unknown proportion of patients, with no further examination or medical tests.

The Department of Internal Medicine at the Radboud University Medical Center assessed the medical examination status of all patients and decided whether patients had been sufficiently examined by a medical doctor to rule out relevant medical explanations for the complaints. If patients had not been sufficiently examined, they were seen for standard medical tests at the Department of Internal Medicine prior to referral to our outpatient clinic. In accordance with recommendations by the Centers for Disease Control, sufficient medical examination included evaluation of somatic parameters that may provide evidence for a plausible somatic explanation for prolonged fatigue [for a list, see [9]. When abnormalities were detected in these tests, additional tests were made based on the judgement of the clinician of the Department of Internal Medicine who ultimately decided about the appropriateness of referral to our clinic. Trained therapists at our clinic ruled out psychiatric comorbidity as potential explanation for the complaints in unstructured clinical interviews.

workup

Accompanied suicide: A Swedish woman with myalgic encephalomyelitis/chronic fatigue syndrome chooses death over further suffering

“I felt it was important to write it and have it published to explain why I personally had to take this step, and hopefully illuminate why so many ME/CFS patients consider or commit suicide.”

Anne-ÖrtegrenAnne Örtegren has circulating  in the patient community a farewell post to follow her recent death, which she chose over further suffering.

“As you understand, this blog post has taken me many months to put together. It is a long text to read too, I know. But I felt it was important to write it and have it published to explain why I personally had to take this step, and hopefully illuminate why so many ME/CFS patients consider or commit suicide.

“And most importantly: to elucidate that this circumstance can be changed! But that will take devoted, resolute, real action from all of those responsible for the state of ME/CFS care, ME/CFS research and dissemination of information about the disease. Sadly, this responsibility has been mishandled for decades. To allow ME/CFS patients some hope on the horizon, key people in all countries must step up and act.”

Her last message is well worth the long read. I just want to start by dispelling a few issues with excerpts from Anne’s post.

Anne’s choice was not a matter of being clinically depressed.

As for most other ME/CFS patients who have chosen suicide, depression is not the cause of my choice. Though I have been suffering massively for many years, I am not depressed. I still have all my will and my motivation. I still laugh and see the funny side of things, I still enjoy doing whatever small activities I can manage. I am still hugely interested in the world around me – my loved ones and all that goes on in their lives, the society, the world (what is happening in human rights issues? how can we solve the climate change crisis?) During these 16 years, I have never felt any lack of motivation. On the contrary, I have consistently fought for solutions with the goal to get myself better and help all ME/CFS patients get better. There are so many things I want to do, I have a lot to live for. If I could only regain some functioning, quieten down the torture a bit and be able to tolerate clothes and a normal environment, I have such a long list of things I would love to do with my life!

Anne’s choice was not hasty, but occurred after much deliberation and a consultation.

This is not a rash decision. It has been processed for many years, in my head, in conversations with family and friends, in discussion with one of my doctors, and a few years ago in the long procedure of requesting accompanied suicide. The clinic in Switzerland requires an extensive process to ensure that the patient is chronically ill, lives with unendurable pain or suffering, and has no realistic hope of relief. They require a number of medical records as well as consultations with specialized doctors.

For me, and I believe for many other ME/CFS patients, this end is obviously not what we wanted, but it was the best solution to an extremely difficult situation and preferable to even more suffering. It was not hasty choice, but one that matured over a long period of time.

a remarkable life
Anne had a remarkable life ahead of her – until ME/CFS hit

The three main reasons Anne cites for her decision (elaborated below in in her post).

  1. Unbearable suffering
  2. No realistic way out of the suffering
  3. The lack of a safety net, meaning potential colossal increase in suffering when the next setback or medical incident occurs

Farewell – A Last Post from Anne Örtegren

Nobody can say that I didn’t put up enough of a fight.

For 16 years I have battled increasingly severe ME/CFS. My condition has steadily deteriorated and new additional medical problems have regularly appeared, making it ever more difficult to endure and make it through the day (and night).

Throughout this time, I have invested almost every bit of my tiny energy in the fight for treatment for us ME/CFS patients. Severely ill, I have advocated from my bedroom for research and establishment of biomedical ME/CFS clinics to get us proper health care. All the while, I have worked hard to find something which would improve my own health. I have researched all possible treatment options, got in contact with international experts and methodically tried out every medication, supplement and regimen suggested.

Sadly, for all the work done, we still don’t have adequately sized specialized biomedical care for ME/CFS patients here in Stockholm, Sweden – or hardly anywhere on the planet. We still don’t have in-patient hospital units adapted to the needs of the severely ill ME/CFS patients. Funding levels for biomedical ME/CFS research remain ridiculously low in all countries and the erroneous psychosocial model which has caused me and others so much harm is still making headway.

And sadly, for me personally things have gone from bad to worse to unbearable. I am now mostly bedbound and constantly tortured by ME/CFS symptoms. I also suffer greatly from a number of additional medical problems, the most severe being a systematic hyper-reactivity in the form of burning skin combined with an immunological/allergic reaction. This is triggered by so many things that it has become impossible to create an adapted environment. Some of you have followed my struggle to find clothes and bed linen I can tolerate. Lately, I am simply running out. I no longer have clothes I can wear without my skin “burning up” and my body going into an allergic state.

This means I no longer see a way out from this solitary ME/CFS prison and its constant torture. I can no longer even do damage control, and my body is at the end of its rope. Therefore, I have gone through a long and thorough process involving several medical assessments to be able to choose a peaceful way out: I have received a preliminary green light for accompanied suicide through a clinic in Switzerland.

When you read this I am at rest, free from suffering at last. I have written this post to explain why I had to take this drastic step. Many ME/CFS patients have found it necessary to make the same decision, and I want to speak up for us, as I think my reasons may be similar to those of many others with the same sad destiny.

These reasons can be summed up in three headers: unbearable suffering; no realistic way out of the suffering; and the lack of a safety net, meaning potential colossal increase in suffering when the next setback or medical incident occurs.

Important note

Before I write more about these reasons, I want to stress something important. As for most other ME/CFS patients who have chosen suicide, depression is not the cause of my choice. Though I have been suffering massively for many years, I am not depressed. I still have all my will and my motivation. I still laugh and see the funny side of things, I still enjoy doing whatever small activities I can manage. I am still hugely interested in the world around me – my loved ones and all that goes on in their lives, the society, the world (what is happening in human rights issues? how can we solve the climate change crisis?) During these 16 years, I have never felt any lack of motivation. On the contrary, I have consistently fought for solutions with the goal to get myself better and help all ME/CFS patients get better. There are so many things I want to do, I have a lot to live for. If I could only regain some functioning, quieten down the torture a bit and be able to tolerate clothes and a normal environment, I have such a long list of things I would love to do with my life!

Three main reasons

So depression is not the reason for my decision to terminate my life. The reasons are the following:

  1. Unbearable suffering

Many of us severely ill ME/CFS patients are hovering at the border of unbearable suffering. We are constantly plagued by intense symptoms, we endure high-impact every-minute physical suffering 24 hours a day, year after year. I see it as a prison sentence with torture. I am homebound and mostly bedbound – there is the prison. I constantly suffer from excruciating symptoms: The worst flu you ever had. Sore throat, bronchi hurting with every breath. Complete exhaustion, almost zero energy, a body that weighs a tonne and sometimes won’t even move. Muscle weakness, dizziness, great difficulties standing up. Sensory overload causing severe suffering from the brain and nervous system. Massive pain in muscles, painful inflammations in muscle attachments. Intensely burning skin. A feeling of having been run over by a bus, twice, with every cell screaming. This has got to be called torture.

It would be easier to handle if there were breaks, breathing spaces. But with severe ME/CFS there is no minute during the day when one is comfortable. My body is a war zone with constant firing attacks. There is no rest, no respite. Every move of every day is a mountain-climb. Every night is a challenge, since there is no easy sleep to rescue me from the torture. I always just have to try to get through the night. And then get through the next day.

It would also be easier if there were distractions. Like many patients with severe ME/CFS I am unable to listen to music, radio, podcasts or audio books, or to watch TV. I can only read for short bouts of time, and use the computer for even shorter moments. I am too ill to manage more than rare visits or phone calls from my family and friends, and sadly unable to live with someone. This solitary confinement aspect of ME/CFS is devastating and it is understandable that ME/CFS has been described as the “living death disease”.

For me personally, the situation has turned into an emergency not least due to my horrific symptom of burning skin linked to immunological/allergic reactions. This appeared six years into my ME/CFS, when I was struck by what seemed like a complete collapse of the bodily systems controlling immune system, allergic pathways, temperature control, skin and peripheral nerves. I had long had trouble with urticaria, hyperreactive skin and allergies, but at this point a violent reaction occurred and my skin completely lost tolerance. I started having massively burning skin, severe urticaria and constant cold sweats and shivers (these reactions reminded me of the first stages of the anaphylactic shock I once had, then due to heat allergy).

Since then, for ten long years, my skin has been burning. It is an intense pain. I have been unable to tolerate almost all kinds of clothes and bed linen as well as heat, sun, chemicals and other everyday things. These all trigger the burning skin and the freezing/shivering reaction into a state of extreme pain and suffering. Imagine being badly sunburnt and then being forced to live under a constant scalding sun – no relief in sight.

At first I managed to find a certain textile fabric which I could tolerate, but then this went out of production, and in spite of years of negotiations with the textile industry it has, strangely, proven impossible to recreate that specific weave. This has meant that as my clothes have been wearing out, I have been approaching the point where I will no longer have clothes and bed linen that are tolerable to my skin. It has also become increasingly difficult to adapt the rest of my living environment so as to not trigger the reaction and worsen the symptoms. Now that I am running out of clothes and sheets, ahead of me has lain a situation with constant burning skin and an allergic state of shivering/cold sweats and massive suffering. This would have been absolutely unbearable.

For 16 years I have had to manage an ever-increasing load of suffering and problems. They now add up to a situation which is simply no longer sustainable.

  1. No realistic way out of the suffering

A very important factor is the lack of realistic hope for relief in the future. It is possible for a person to bear a lot of suffering, as long as it is time-limited. But the combination of massive suffering and a lack of rational hope for remission or recovery is devastating.

Think about the temporary agony of a violent case of gastric flu. Picture how you are feeling those horrible days when you are lying on the bathroom floor between attacks of diarrhoea and vomiting. This is something we all have to live through at times, but we know it will be over in a few days. If someone told you at that point: “you will have to live with this for the rest of your life”, I am sure you would agree that it wouldn’t feel feasible. It is unimaginable to cope with a whole life with the body in that insufferable state every day, year after year. The level of unbearableness in severe ME/CFS is the same.

If we knew there were relief on the horizon, it would be possible to endure severe ME/CFS and all the additional medical problems, even for a long time, I think. The point is that there has to be a limit, the suffering must not feel endless.

One vital aspect here is of course that patients need to feel that the ME/CFS field is being taken forward. Sadly, we haven’t been granted this feeling – see my previous blogs relating to this here and here.

Another imperative issue is the drug intolerance that I and many others with ME/CFS suffer from. I have tried every possible treatment, but most of them have just given me side-effects, many of which have been irreversible. My stomach has become increasingly dysfunctional, so for the past few years any new drugs have caused immediate diarrhoea. One supplement triggered massive inflammation in my entire urinary tract, which has since persisted. The list of such occurrences of major deterioration caused by different drugs/treatments is long, and with time my reactions have become increasingly violent. I now have to conclude that my sensitivity to medication is so severe that realistically it is very hard for me to tolerate drugs or supplements.

This has two crucial meanings for many of us severely ill ME/CFS patients: There is no way of relieving our symptoms. And even if treatments appear in the future, with our sensitivity of medication any drug will carry a great risk of irreversible side-effects producing even more suffering. This means that even in the case of a real effort finally being made to bring biomedical research into ME/CFS up to levels on par with that of other diseases, and possible treatments being made accessible, for some of us it is unlikely that we would be able to benefit. Considering our extreme sensitivity to medication, one could say it’s hard to have realistic hope of recovery or relief for us.

In the past couple of years I, being desperate, have challenged the massive side-effect risk and tried one of the treatments being researched in regards to ME/CFS. But I received it late in the disease process, and it was a gamble. I needed it to have an almost miraculous effect: a quick positive response which eliminated many symptoms – most of all I needed it to stop my skin from burning and reacting, so I could tolerate the clothes and bed linen produced today. I have been quickly running out of clothes and sheets, so I was gambling with high odds for a quick and extensive response. Sadly, I wasn’t a responder. I have also tried medication for Mast Cell Activation Disorder and a low-histamine diet, but my burning skin hasn’t abated. Since I am now running out of clothes and sheets, all that was before me was constant burning hell.

  1. The lack of a safety net, meaning potential colossal increase in suffering when the next setback or medical incident occurs

The third factor is the insight that the risk for further deterioration and increased suffering is high.

Many of us severely ill ME/CFS patients are already in a situation which is unbearable. On top of this, it is very likely that in the future things will get even worse. If we look at some of our symptoms in isolation, examples in my case could be my back and neck pain, we would need to strengthen muscles to prevent them from getting worse. But for all ME/CFS patients, the characteristic symptom of Post-Exertional Malaise (PEM) with flare-ups of our disease when we attempt even small activities, is hugely problematic. Whenever we try to ignore the PEM issue and push through, we immediately crash and become much sicker. We might go from being able to at least get up and eat, to being completely bedbound, until the PEM has subsided. Sometimes, it doesn’t subside, and we find ourselves irreversibly deteriorated, at a new, even lower baseline level, with no way of improving.

PEM is not something that you can work around.

For me, new medical complications also continue to arise, and I have no way of amending them. I already need surgery for one existing problem, and it is likely that it will be needed for other issues in the future, but surgery or hospital care is not feasible for several reasons:

One is that my body seems to lack repairing mechanisms. Previous biopsies have not healed properly, so my doctor is doubtful about my ability to recover after surgery.

Another, more general and hugely critical, is that with severe ME/CFS it is impossible to tolerate normal hospital care. For ME/CFS patients the sensory overload problem and the extremely low energy levels mean that a normal hospital environment causes major deterioration. The sensory input that comes with shared rooms, people coming and going, bright lights, noise, etc, escalates our disease. We are already in such fragile states that a push in the wrong direction is catastrophic. For me, with my burning skin issue, there is also the issue of not tolerating the mattresses, pillows, textile fabrics, etc used in a hospital.

Just imagine the effects of a hospital stay for me: It would trigger my already severe ME/CFS into new depths – likely I would become completely bedbound and unable to tolerate any light or noise. The skin hyperreactivity would, within a few hours, trigger my body into an insufferable state of burning skin and agonizing immune-allergic reactions, which would then be impossible to reverse. My family, my doctor and I agree: I must never be admitted to a hospital, since there is no end to how much worse that would ma

Many ME/CFS patients have experienced irreversible deterioration due to hospitalization. We also know that the understanding of ME/CFS is extremely low or non-existent in most hospitals, and we hear about ME/CFS patients being forced into environments or activities which make them much worse. I am aware of only two places in the world with specially adjusted hospital units for severe ME/CFS, Oslo, Norway, and Gold Coast, Australia. We would need such units in every city around the

It is extreme to be this severely ill, have so many medical complications arise continually and know this: There is no feasible access to hospital care for me. There are no tolerable medications to use when things get worse or other medical problems set in. As a severely ill ME/CFS patient I have no safety net at all. There is simply no end to how bad things can get with severe ME/CFS.

Coping skills – important but not enough

I realize that when people hear about my decision to terminate my life, they will wonder about my coping skills. I have written about this before and I want to mention the issue here too:

While it was extremely hard at the beginning to accept chronic illness, I have over the years developed a large degree of acceptance and pretty good coping skills. I have learnt to accept tight limits and appreciate small qualities of life. I have learnt to cope with massive amounts of pain and suffering and still find bright spots. With the level of acceptance I have come to now, I would have been content even with relatively small improvements and a very limited life. If, hypothetically, the physical suffering could be taken out of the equation, I would have been able to live contentedly even though my life continued to be restricted to my small apartment and include very little activity. Unlike most people I could find such a tiny life bearable and even happy. But I am not able to cope with these high levels of constant physical suffering.

In short, to sum up my level of acceptance as well as my limit: I can take the prison and the extreme limitations – but I can no longer take the torture. And I cannot live with clothes that constantly trigger my burning skin.

Not alone – and not a rash decision

In spite of being unable to see friends or family for more than rare and brief visits, and in spite of having limited capacity for phone conversations, I still have a circle of loved ones. My friends and family all understand my current situation and they accept and support my choice. While they do not want me to leave, they also do not want me to suffer anymore.

This is not a rash decision. It has been processed for many years, in my head, in conversations with family and friends, in discussion with one of my doctors, and a few years ago in the long procedure of requesting accompanied suicide. The clinic in Switzerland requires an extensive process to ensure that the patient is chronically ill, lives with unendurable pain or suffering, and has no realistic hope of relief. They require a number of medical records as well as consultations with specialized doctors.

For me, and I believe for many other ME/CFS patients, this end is obviously not what we wanted, but it was the best solution to an extremely difficult situation and preferable to even more suffering. It was not hasty choice, but one that matured over a long period of time.

A plea to decision makers – Give ME/CFS patients a future!

As you understand, this blog post has taken me many months to put together. It is a long text to read too, I know. But I felt it was important to write it and have it published to explain why I personally had to take this step, and hopefully illuminate why so many ME/CFS patients consider or commit suicide.

And most importantly: to elucidate that this circumstance can be changed! But that will take devoted, resolute, real action from all of those responsible for the state of ME/CFS care, ME/CFS research and dissemination of information about the disease. Sadly, this responsibility has been mishandled for decades. To allow ME/CFS patients some hope on the horizon, key people in all countries must step up and act.

If you are a decision maker, here is what you urgently need to do: You need to bring funding for biomedical ME/CFS research up so it’s on par with comparable diseases (as an example, in the US that would mean $188 million per year). You need to make sure there are dedicated hospital care units for ME/CFS inpatients in every city around the world. You need to establish specialist biomedical care available to all ME/CFS patients; it should be as natural as RA patients having access to a rheumatologist or cancer patients to an oncologist. You need to give ME/CFS patients a future.

Please listen to these words of Jen Brea, which sum up the situation in the US, but are applicable to almost every country:

“The NIH says it won’t fund ME research because no one wants to study it. Yet they reject the applications of the world class scientists who are committed to advancing the field. Meanwhile, HHS has an advisory committee whose sole purpose seems to be making recommendations that are rarely adopted. There are no drugs in the pipeline at the FDA yet the FDA won’t approve the one drug, Ampligen, that can have Lazarus-like effects in some patients. Meanwhile, the CDC continues to educate doctors using information that we (patients) all know is inaccurate or incomplete.”

Like Jen Brea, I want a number of people from these agencies, and equivalent agencies in Sweden and all other countries, to stand up and take responsibility. To say: “ME! I am going to change things because that is my job.”

And lastly

Lastly, I would like to end this by linking to this public comment from a US agency meeting (CFSAC). It seems to have been taken off the HHS site, but I found it in the Google Read version of the book “Lighting Up a Hidden World: CFS and ME” by Valerie Free. It includes testimony from two very eloquent ME patients and it says it all. I thank these ME patients for expressing so well what we are experiencing.

PS.

My previous blog posts:

From International Traveler to 43 Square Meters: An ME/CFS Story From Sweden

Coping With ME/CFS Will Always Be Hard – But There are Ways of Making It A Little Easier

The Underfinanced ME/CFS Research Field Pt I: The Facts – Plus “What Can We Do?

The Underfinanced ME/CFS Research Field Pt II: Why it Takes 20 Years to Get 1 Year’s Research Done

My Swedish ME/CFS newsletters, distributed via e-mail to 2700 physicians, researchers, CMOs, politicians and medical journalists:

https://mecfsnyheter.se/

Take care of each other.

Love, Anne

 

low level funding
Relative to other diseases the NIH has provided pennies for ME/CFS research …but that does not mean progress is not being made

 

Photos are from Anne’s blog posts which are linked above.

The PACE PLOS One data will not be released and the article won’t be retracted

PLOS One has bought into discredited arguments about patient consent forms not allowing sharing of anonymized data. PLOS One is no longer at the vanguard of open science through routine data sharing.

mind the brain logo

Two years have passed since I requested release of the PLOS One PACE data, eight months since the Expression of Concern was posted. What can we expect?

expression of concern-page-0

9 dot problem
Solving the 9-dot problem involves paying attention and thinking outside the box.

If we spot some usually unrecognized connections, we can see the PLOS One editors are biased towards the PACE investigators, favoring them over other stakeholders in whether the data are released as promised..

Spoiler: The PLOS One Senior Editors completed the pre-specified process of deciding what to do about the data not being shared.  They took no action. Months later the Senior Editors reopened the process and invited one of PACE investigators Trudy Chalder’s outspoken co-authors to help them reconsider.

A lot of us weren’t cynical enough to notice.

International trends will continue toward making uploading data into publicly accessible repositories a requirement for publication. PLOS One has slowed down by buying into discredited arguments about patient consent forms not allowing sharing of anonymized data.

PLOS One is no longer at the vanguard of open science through routine data sharing.

The expression of concern

actual display of expression of concern on PLOS article
Actual Expression of Concern on display on PLOS One article.

The editors’ section of the Expression of Concern ends with:

In spite of requests to the authors and Queen Mary University of London, we have not yet received confirmation that an institutional process compatible with the existing PLOS data policy at the time has been developed or implemented for the independent evaluation of requests for data from this study. We conclude that the lack of resolution towards release of the dataset is not in line with the journal’s editorial policy and we are thus issuing this Expression of Concern to alert readers about the concerns raised about this article.

This is followed by the PACE investigators’ response:

Statement from the authors

We disagree with the Expression of Concern about our health economic paper that PLOS ONE has issued and do not accept that it is justified. We believe that data should be made available and have shared data from the PACE trial with other researchers previously, in line with our data sharing policy. This is consistent with the data sharing policies of Queen Mary University of London, and the Medical Research Council, which funded the trial. The policy allows for the sharing of data with other researchers, so long as safeguards are agreed regarding confidentiality of the data and consent as specified by the Research Ethics Committee (REC). We have also pointed out to PLOS ONE that our policy includes an independent appeal process, if a request is declined, so this policy is consistent with the journal’s policy when the paper was published.

During negotiations with the journal over these matters, we have sought further guidance from the PACE trial REC. They have advised that public release, even of anonymised data, is not appropriate. As a consequence, we are unable to publish the individual patient data requested by the journal. However, we have offered to provide key summarised data, sufficient to provide an independent re-analysis of our main findings, so long as it is consistent with the REC decision, on the PLOS ONE website. As such we are surprised by and question the decision by the journal to issue this Expression of Concern.

Check out my critique of their claim to have shared data from the PACE trial with other researchers-

Don’t bother to apply: PACE investigators issue guidance for researchers requesting access to data.

Nothing_to_DeclareConflict of interest: Nothing to declare?

 The PACE authors were thus given an extraordinary opportunity to undermine the editors’ Expression of Concern.

It is just as extraordinary that there is no disclosure of conflict of interest. After all, it is their paper is receiving expression of concern because of the authors’ failure to provide data as promised.

In contrast, when the PLOS One editors placed a discreet Editors Note in 2015 in the comment section of the article about the data not being shared when requested, it carried a COI declaration:

Competing interests declared: PLOS ONE Staff

That COI aroused the curiosity of Retraction Watch who asked PLOS One:

We weren’t sure what the last line was referring to, so contacted Executive Editor Veronique Kiermer. She told us that staff sometimes include their byline under “competing interests,” so the authorship is immediately clear to readers who may be scanning a series of comments.

Commentary from Retraction Watch

PLOS upgrades flag on controversial PACE chronic fatigue syndrome trial; authors “surprised”

Notable excerpts:

A spokesperson for PLOS told us this is the first time the journal has included a statement from the authors in an EOC:

This has been a complex case involving many stakeholders and we wanted to document the different aspects of the case in a fair manner.

And

We asked if the journal plans to retract the paper if the authors fail to provide what it’s asked for; the spokesperson explained:

At this time, PLOS stands by its Expression of Concern. For now, we have exhausted the options to make the data available in accordance with our policy at the time, but PLOS still seeks a positive outcome to this case for all parties. It is our intention to update this notice when a mechanism is established that allows concerns about the article’s analyses to be addressed while protecting patient privacy. PLOS has not given the authors a deadline.

Note: “PLOS did not given the authors a deadline.”

One of the readers who has requested the data is James Coyne, a psychologist at the University Medical Center, Groningen, who submitted his request 18 months ago (and wrote about it on the PLOS blog site). Although some of the data have been released (to one person under the Freedom of Information Act), it’s not nearly enough to conduct an analysis, Coyne told us:

This small data set does not allow recalculation of original primary outcomes but did allow recalculation of recovery data. Release of the PLOS data is crucial for a better understanding of what went on in that trial. That’s why the investigators are fighting so hard.

Eventually, Coyne began suggesting to PLOS that he would organize public protests and scientific meetings attended by journal representatives.

I think it is the most significant issue in psychotherapy today, in terms of data sharing. It’s a flagrant violation of international standards.

The Retraction Watch article cited a 2015 STAT article that was written by Retraction Watch co-founders Ivan Oransky and Adam Marcus. That article was sympathetic to my request:

If the information Coyne is seeking is harmful and distressing to the staff of the university — and that’s the university’s claim, not ours — that’s only because the information is in fact harmful and distressing. In other words, revealing that you have nothing to hide is much less embarrassing than revealing that you’re hiding something.

The STAT article also said:

To be clear, Coyne’s not asking for sex tapes or pictures of lab workers taking bong hits. He’s asking for raw data so that he can evaluate whether what a group of scientists reported in print is in fact what those data show. It’s called replication, and as Richard Smith, former editor of The BMJ (and a member of our board of directors), put it last week, the refusal goes “against basic scientific principles.” But, unfortunately, stubborn researchers and institutions have used legal roadblocks before to prevent scrutiny of science.

The PLOS One Editors’ blog  post.

The Expression of Concern was accompanied by a blog post from PLOS Iratxe Puebla, Managing Editor for PLOS ONE and Joerg Heber, Editor-in-Chief on May 2, 2017

Data sharing in clinical research: challenges and open opportunities

Since we feel we have exhausted the options to make the data available responsibly, and considering the questions that were raised about the validity of the article’s conclusions, we have decided to post an Expression of Concern [5] to alert readers that the data are not available in line with the journal’s editorial policy. It is our intention to update this notice when a mechanism is established that allows concerns about the article’s analyses to be addressed while protecting patient privacy.

This statement seems to suggest that the ball is in the PACE investigators’ court and that PLOS One editors are prepared to wait. But reading the rest of the blog post, it becomes apparent that PLOS One is wavering on the data sharing policy

Current challenges and opportunities ahead

During our follow up it became clear that there is little consensus of opinion on the sharing of this particular dataset. Experts from the Data Advisory Board whom we consulted expressed different views on the stringency of the journal reaction. Overall they agreed on the need to consider the risk to confidentiality of the trial participants and on the relevance of developing mechanisms for consideration of data requests by an independent body or committee. Interestingly, the ruling of the FOI Tribunal also indicated that the vote did not reflect a consensus among all committee members.

Fact checking the PLOS One’s Editors’ blog and a rebuttal

John Peter fact checked  the PLOS One editors’ blog. It came up short on a number of points.

“Interestingly, the ruling of the FOI Tribunal also indicated that the vote did not reflect a consensus among all committee members.”

This line is misleading and reveals either ignorance or misunderstanding of the decision in Matthees.

The Information Tribunal (IT) is not a committee. It is part of the courts system of England and Wales.

…the IT’s decisions may be appealed to a higher court. As QMUL chose not to exercise this right but to opt instead to accept the decision, then clearly it considered there were no grounds for appeal. The decision stands in its entirety and applies without condition or caveat.

And

The court had two decisions to make:

First, could and should trial data be released and if so what test should apply to determine whether particular data should be made public? Second, when that test is applied to this particular set of data, do they meet that test?

The unanimous decision on the first question was very clear: there is no legal or ethical consideration which prevents release; release is permitted by the consent forms; there is a strong public interest in the release; making data available advances legitimate scientific debate; and the data should be released.

The test set by this unanimous decision was simple: whether data can be anonymized. Furthermore, again unanimously, the Tribunal stated that the test for anonymization is not absolute. It is whether the risk of identification is reasonably likely, not whether it is remote, and whether patients can be identified without prior knowledge, specialist knowledge or equipment, or resort to criminality.

It was on applying this test to the data requested, on whether they could be properly anonymized, that the IT reached a majority decision.

On the principles, on how these decisions should be made, on the test which should be applied and on the nature of that test, the court was unanimous.

It should also be noted that to share data which have not been anonymized would be in breach of the Data Protection Act. QMUL has shared these data with other researchers. QMUL should either report itself to the Information Commissioner’s Office or accept that the data can be anonymized. In which case, the unanimous decision of the IT is very clear: the data should be shared.

PLOS ONE should apply the IT decision and its own regulations and demand the data be shared or the paper retracted.

Data Advisory Board

The Editors’ blog referred to “Experts from the Data Advisory Board.. express[ing] different views on the stringency of the journal reaction.”

That was a source of puzzlement for me. Established procedures make no provision for an advisory board as part of the process or any appeal.

A Google Search clarified. I had been to this page a number of times before and did not remember seeing this statement. There is no date or any indication it was added after the rest of the statement.

PLOS has formed an external board of advisors across many fields of research published in PLOS journals. This board will work with us to develop community standards for data sharing across various fields, provide input and advice on especially complex data-sharing situations submitted to the journals, define data-sharing compliance, and proactively work to refine our policy. If you have any questions or feedback, we welcome you to write to us at data@plos.org.

The availability of data from reanalysis and independent probing has lots of stakeholders. Independent investigators, policymakers, and patients all have a stake. I don’t recognize the names on this list and see no indication that consumers affected by what is reported in clinical and health services papers have role in making decisions about the release of data. But one name stands out.

Who is Malcolm Macleod and what is he doing in this decision-making process?

Malcolm Macleod is quoted in the Science Media Centre reaction to the PACEgate special issue:

 Expert reaction to Journal of Health Psychology’s Special Issue on The PACE Trial

Prof. Malcolm Macleod, Professor of Neurology and Translational Neuroscience, University of Edinburgh, said:

“The PACE trial, while not perfect, provides far and away the best evidence for the effectiveness of any intervention for chronic fatigue; and certainly is more robust than any of the other research cited. Reading the criticisms, I was struck by how little actual meat there is in them; and wondered where some of the authors came from. In fact, one of them lists as an institution a research centre (Soerabaja Research Center) which only seems to exist as an affiliation on papers he wrote criticising the PACE trial.

“Their main criticisms seem to revolve around the primary outcome was changed halfway through the trial: there are lots of reasons this can happen, some justifiable and others not; the main think is whether it was done without knowledge of the outcomes already accumulated in the trial and before data lock – which is what was done here.

“So I don’t think there is really a story here, apart from a group of authors, some of doubtful provenance, kicking up dust about a study which has a few minor wrinkles (as all do) but still provides information reliable enough to shape practice. If you substitute ‘CFS’ for ‘autism’ and ‘PACE trial’ for ‘vaccination’ you see a familiar pattern…”

The declaration of interest is revealing in what it says and what it does not say.

Prof. MacLeod: “Prof Sharpe used to have an office next to my wife’s; and I sit on the PLoS Data board that considered what to do about one of their other studies.

The declaration fails to reveal a recent publication co-authored by Macleod and Trudy  Chalder.

Wu S, Mead G, Macleod M, Chalder T. Model of understanding fatigue after stroke. Stroke. 2015 Mar 1;46(3):893-8.

This press release comes from an organization strongly committed to the protection of the PACE trial from independent scrutiny. The SMC even organized a letter writing campaign headed by Peter White to petition Parliament to exclude universities for Freedom of Information Act requests. Of course, that will effectively block request for data.

Why would the PLOS One editors involved such a person to reconsider what been a decision in favor of releasing the data?

Connect the dots.

Trends will continue toward making uploading data into publicly accessible repositories a requirement for publication. PLOS One has bought into discredited arguments about patient consent forms not allowing sharing of anonymized data. PLOS One is no longer at the vanguard of open science through routine data sharing.

Better days: When PLOS Blogs honored my post about fatal flaws in the PACE chronic fatigue syndrome follow-up study (2015)

The back story on my receiving this honor was that PLOS Blogs only days before had shut down the blog site because of complaints from someone associated with the PACE trial. I was asked to resign. I refused. PLOS Blogs relented when I said it would be a publicity disaster for PLOS Blogs.

mind the brain logoThe back story on my receiving this honor was that PLOS Blogs only days before had shut down the blog site because of complaints from someone associated with the PACE trial. I was asked to resign. I refused. PLOS Blogs relented when I said it would be a publicity disaster for PLOS Blogs.

screen shot 11th most accessedA Facebook memory of what I was posting two years ago reminded me of better days when PLOS Blogs honored my post about the PACE trial.

Your Top 15 in ’15: Most popular on PLOS BLOGS Network

I was included in a list of the most popular blog posts in a network that received over 2.3 million visitors reading more than 600 new posts. [It is curious that the sixth and seventh most popular posts were omitted from this list, but that’s another story]

I was mentioned for number 11:

11) Uninterpretable: Fatal flaws in PACE Chronic Fatigue Syndrome follow-up study Mind the Brain 10/29/15

Investigating and sharing potential errors in scientific methods and findings, particularly involving psychological research, is the primary reason Clinical Health Psychologist (and PLOS ONE AE) Jim Coyne blogs on Mind the Brain and elsewhere. This closely followed post is one such example.

Earlier decisions by the investigator group preclude valid long-term follow-up evaluation of CBT for chronic fatigue syndrome (CFS). At the outset, let me say that I’m skeptical whether we can hold the PACE investigators responsible… Read more

The back story was that only days before, I had gotten complaints from readers of Mind the Brain who found they were blocked from leaving comments at my blog site. I checked and found that I couldn’t even access the blog as an author.

I immediately emailed Victoria Costello and asked her what it happened. We agreed to talk by telephone, even though it was already late night where I was in Philadelphia. She was in the San Francisco PLOS office.

In the telephone conversation,  I was reminded me that there were some topics about which was not supposed to blog. Senior management at PLOS found me in violation of that prohibition and wanted me to stop blogging.

As is often the case with communication with the senior management of PLOS, no specifics had been given.  There was no formal notice or disclosure about what topics I couldn’t blog or who had complained. And there had been no warning when my access to the blog site was cut. Anything that I might say publicly could be met with a plausible denial.

I reminded Victoria that I had never received any formal specification about what I could blog nor from whom the complaint hand come. There had been a vague communication from her about not blogging about certain topics. I knew that complaints from either Gabrielle Oettingen or her family members had led to request the blog about the flaws in her book,  Rethinking Positive Thinking . That was easy to do because I was not planning another post about that dreadful self-help book.  Any other prohibition was left so vague that had no idea that I couldn’t blog about the PACE trial. I had known that the authors of the British Psychological Society’s Understanding Psychosis were quite upset with what I had said in heavily accessed blog posts. Maybe that was the source of the other prohibition, but no one made that clear. And I wasn’t sure I wanted to honor it, anyway.

I pressed Victoria Costello for details. She said an editor had complained. When I asked if it was Richard Horton, she paused and mumbled something that I took as an affirmative. Victoria then suggested that  it would be best for the blog network and myself if we had a mutually agreed-upon parting of ways. I told her that I would probably publicly comment that the breakup was not mutual and it would be a publicity disaster for the blog.

igagged_jpg-scaled500Why I was even blogging for PLOS Blogs? Victoria Costello had recruited me over after I expressed discontent with the censorship that I was receiving at Psychology Today. The PT editors there had complained that some of my blogging about antidepressants might discourage ads from pharmaceutical companies for which they depended for revenue. The editors had insisted on  the right to approve my posts before I uploaded them. In inviting me to PLOS Blogs, Victoria told me that she too was a refugee from blogging at Psychology Today.  I wouldn’t have to worry about restrictions on what I could say at Mind the Brain, beyond avoiding libel.

I ended the conversation accepting the prohibition about blogging about the PACE trial. This is was despite disagreeing with the rationale that it would be a conflict of interest for me to blog about it after requesting the data from the PLOS One paper.

Since then, I repeatedly requested that the PLOS management acknowledge the prohibition on my blogging or at least put it in writing. My request was met with repeated refusals from Managing Editor Iratxe Puebla, who always cited my conflict of interest.

In early 2017, I began publicly tweeting about the issue, stimulating some curiosity others about whether there was a prohibition. InJuly 2017, the entire Mind the Brain site, not just my blog, was shut.

In early 2018, I will provide more backstory on that shutdown and dispute what was said in the blog post below. And more about the collusion between PLOS One senior management and the PACE investigators in the data not being available 2 years after I requested it.

Message for Mind the Brain readers from PLOSBLOGS

blank plos blogs thumb nail
This strange thumbnail is the default for when no preferred image is provided. It could indicate the haste with which this blog was posted.

Posted July 31, 2017 by Victoria Costello in Uncategorized

After five years and over a hundred posts, PLOSBLOGS is retiring its psychology blog, Mind the Brain, from our PLOS-hosted blog network. By mutual agreement with the primary Mind the Brain blogger, James Coyne, Professor Coyne will retain the name of this blog and will take his archive of posts for reuse on his independent website, http://www.coyneoftherealm.com.

According to PLOSBLOGS’ policy for all our retired (inactive) blogs, any and all original posts published on Mind the Brain will retain their PLOS web addresses as intact urls, so links made previously from other sites will not be broken. In addition, PLOS will supply the archive of his posts directly to Prof Coyne so that he may repost them anywhere he may wish.

PLOS honors James Coyne’s voice as an important one in peer-to-peer scientific criticism. As discussed with Professor Coyne in recent days, after careful consideration PLOSBLOGS has concluded that it does not have the staff resources required to vet the sources, claims and tone contained in his posts, to assure they are aligned with our PLOSBLOGS Community Guidelines. This has lead us to the conclusion that Professor Coyne and his content would be better served on his own independent blog platform. We wish James Coyne the best with his future blogging.

—Victoria Costello, Senior Editor, PLOSBLOGS & Communities

Bollocks!

Is Donald Trump suffering from Pick’s Disease (frontotemporal dementia)?

Changing the conversation about Donald Trump’s fitness for office from whether he has a personality disorder to whether he has an organic brain disorder.

mind the brain logoChanging the conversation about Donald Trump’s fitness for office from whether he has a personality disorder to whether he has an organic brain disorder.

Trump.jpgFor a long while there has been an ongoing debate about whether Donald Trump suffers from a personality disorder that might contribute to his being unfit the President of the United States. Psychiatrists have ethical constraints in what they say because of the so-called Goldwater rule, barring them from commenting on the mental health of political figures that they have not personally  interviewed.

I am a clinical psychologist, not a psychiatrist. I feel the need to speak out that the behavior of Donald Trump is abnormal and we should caution against normalizing it. The problem with settling on his behavior being simply that of a bad person or con man is it doesn’t prepare us for just how erratic his behavior can be.

I’ll refrain from making a formal psychiatric diagnosis. I actually think that in clinical practice, a lot of mental health professionals too casually make diagnoses of personality disorders for patients (or privately, even for colleagues) they find difficult or annoying.  If they ever gave these people a structured interview,  I suspect they would be found to fall  below the threshold for any particular personality disorder.

Changing the conversation

But now an article in Stat has changed the conversation to whether Donald Trump suffers from personality disorder to whether he is developing an organic brain disorder.

I’m a brain specialist. I think Trump should be tested for a degenerative brain disease

When President Trump slurred his words during a news conference this week, some Trump watchers speculated that he was having a stroke. I watched the clip and, as a physician who specializes in brain function and disability, I don’t think a stroke was behind the slurred words. But having evaluated the chief executive’s remarkable behavior through my clinical lens for almost a year, I do believe he is displaying signs that could indicate a degenerative brain disorder.

As the president’s demeanor and unusual decisions raise the potential for military conflict in two regions of the world, the questions surrounding his mental competence have become urgent and demand investigation.

And

I see worrisome symptoms that fall into three main categories: problems with language and executive function; problems with social cognition and behavior; and problems with memory, attention, and concentration. None of these are symptoms of being a bad or mean person. Nor do they require spelunking into the depths of his psyche to understand. Instead, they raise concern for a neurocognitive disease process in the same sense that wheezing raises the alarm for asthma.

In addition to being a medical journalist, the author Ford Vox of the article is a neurorehabilitation physician who is board-certified physical medicine and rehabilitation physician with additional subspecialty board certification in brain injury medicine.

I was alerted by the possibility of a diagnosis of frontotemporal dementia by a tweet by Barney Carroll. He is a senior psychiatrist whom I have come to trust as a mentor on social media, even though we’ve never overlapped in the same department at the same time.

barney forget psychnoanalysis

And then there was this tweet about the Stat story, but I could judge its credibility because I did not know the tweeter or her source:

trump's disease

I followed up with a Google search and came across an article from August 2016, before the election:

Finally figured out Trump’s medical diagnosis after watching this:

It’s called Pick’s Disease, or frontotemporal dementia

Look at the symptoms, all of these which fit Trump quite closely:

  • Impulsivity and poor judgment
  • Extreme restlessness (early stages)
  • Overeating or drinking to excess
  • Sexual exhibitionism or promiscuity
  • Decline in function at work and home
  • Repetitive or obsessive behavior

And especially these, listed earlier in the article:

Excess protein build-up causes the frontal and temporal lobes of the brain, which control speech and personality, to slowly atrophy. 

Then I followed up with more Google searches, hitting MedLine Plus,  the website maintained by the National Institutes of Health’s Web site for patients and their families and friends and produced by the National Library of Medicine.

Pick disease

Pick disease is a rare form of dementia that is similar to Alzheimer disease, except that it tends to affect only certain areas of the brain.

Causes

People with Pick disease have abnormal substances (called Pick bodies and Pick cells) inside nerve cells in the damaged areas of the brain.

Pick bodies and Pick cells contain an abnormal form of a protein called tau. This protein is found in all nerve cells. But some people with Pick disease have an abnormal amount or type of this protein.

The exact cause of the abnormal form of the protein is unknown. Many different abnormal genes have been found that can cause Pick disease. Some cases of Pick disease are passed down through families.

Pick disease is rare. It can occur in people as young as 20. But it usually begins between ages 40 and 60. The average age at which it begins is 54.

Symptoms

The disease gets worse slowly. Tissues in parts of the brain shrink over time. Symptoms such as behavior changes, speech difficulty, and problems thinking occur slowly and get worse.

Early personality changes can help doctors tell Pick disease apart from Alzheimer disease. (Memory loss is often the main, and earliest, symptom of Alzheimer disease.)

People with Pick disease tend to behave the wrong way in different social settings. The changes in behavior continue to get worse and are often one of the most disturbing symptoms of the disease. Some persons have more difficulty with decision making, complex tasks, or language (trouble finding or understanding words or writing).

The website notes

A brain biopsy is the only test that can confirm the diagnosis.

However, some alternative diagnoses can be ruled out:

Your doctor might order tests to help rule out other causes of dementia, including dementia due to metabolic causes. Pick disease is diagnosed based on symptoms and results of tests, including:

Assessment of the mind and behavior (neuropsychological assessment)

Brain MRI

Electroencephalogram (EEG)

Examination of the brain and nervous system (neurological exam)

Examination of the fluid around the central nervous system (cerebrospinal fluid) after a lumbar puncture

Head CT scan

Tests of sensation, thinking and reasoning (cognitive function), and motor function

Back to Ford Vox in his Stats article:

In Trump’s case, we have no relevant testing to review. His personal physician issued a thoroughly unsatisfying letter before the election that didn’t contain much in the way of hard data. That’s a situation many people want to correct via an independent medical panel that can objectively evaluate the president’s fitness to serve. But the prospects for getting Congress to use the 25th Amendment in this way seem poor at the moment.

What we do have are a growing array of signs and symptoms displayed in public for all to see. It’s time to discuss these issues in a clinical context, even if this is a very atypical form of examination. It’s all we have. And even if the president has a physical exam early next year and releases the records, as announced by the White House, what he really needs is thorough cognitive testing.

So?

Before biting the bullet, I also spoke with Dr. Dennis Agliano, who chairs the AMA’s Council on Ethical and Judicial Affairs, the panel that wrote the new ethical guidance. He advised me to be careful: “You can get yourself into hot water, since there are people who like Trump, and they may submit a complaint to the AMA,” the Tampa otolaryngologist told me. Ultimately, he reassured me that I should just do what I think is right.

Which is warn the president that he needs to be evaluated for a brain disease.

Good luck, Dr Vox, but at least we have a reasonable hypothesis on the table. As Barney Carroll says “Time will tell.”

slurred speech