Nighttime body movements and autism

I was rather interested in the findings reported by Nobushige Naito and colleagues [1] talking about how atypical body movements during the night seemed to be more frequently observed in children diagnosed with an autism spectrum disorder (ASD) compared to not-autism controls. Interested because, sleep is a long-running 'issue' in relation to autism (see here) and because, researchers relied on the use of actigraphy in their study: "a movement-based index measured by an accelerometer" rather than just second-hand observational questioning.

So: "Seventeen TD [typically developing] children and 17 children with ASD participated in this study (5 to 8 years old)." Importantly (see here) we are told that: "Considering the frequent co-occurrence of ASD and ADHD [attention-deficit hyperactivity disorder] symptoms, we did not exclude ASD patients with ADHD symptoms." Authors relied on data from a waistband accelerometer worn by participants over at least 3 nights. Using a waistband was seen as preferable to the more typical wristband. Data was collected and analysed. It included something called a movement index (MI): "the ratio of the body movement period in 20 minutes was calculated continuously for 9 hours using the sliding window method."

Results: "a higher rate of body movement 2 to 3 hours after the first onset of body stillness was more prominent in children with ASD than in TD children." Importantly authors also mention how the objective data provided by the waistband accelerometer showed a different "time course of body movements during night in young children with ASD" despite parents/carers reporting no "apparent" problems with sleeping. They also talk some of the differences in body movements seen in those children with ASD potentially *related* to some awake behaviours - "a lower social ability and more frequent maladaptive behaviour."

The Naito results represent a good start at looking at these important behaviours. I'm a little bit hesitant to go all-in with the suggestion from the authors that "atypical nocturnal body movement could be an ASD state and trait marker in young children with ASD" but can see the importance of further investigations in this area.

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[1] Naito N. et al. Atypical body movements during night in young children with autism spectrum disorder: a pilot study. Sci Rep. 2019 May 6;9(1):6999.

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"to [try and] advance the understanding of potential mechanisms underlying insomnia in adults with ASD"

The paper by Vanessa Hohn and colleagues [1] (open-access available here) provides the blogging fodder today and their findings in relation to the presence of insomnia as a "common source of distress in adults with autism spectrum disorder (ASD)."

Insomnia is essentially a regular problem in getting to sleep. It has a myriad of 'causes' ranging from uncomfortable sleeping conditions (bed, noise, temperature) to the influence of things like stress, depression and anxiety. Insomnia is no joke. Outside of the potential wide-ranging effects on physical and mental health [2] it puts a person at some heightened risk of all-manner of adverse outcomes [3].

As part of a suite of sleeping-related problems, insomnia is also no stranger to diagnostic labels like autism. With autism in mind, sleep problems that begin in childhood are pretty likely to carry over to adulthood. Nobody knows the precise reason(s) why those on the autism spectrum are more likely to experience sleep problems including insomnia. Some have speculated that the presence of autistic traits may be a risk factor for such sleeping issues (see here) but there is currently little detail regarding the bridge from core autism features to sleep problems. Others have observed an *association* between the presence of other somatic issues occurring alongside autism and sleep problems (see here and see here) but again, further clarity is needed on the hows-and-whys of any relationship and, importantly, what can be done to alleviate such issues.

Hohn et al started with the premise that: "Two characteristics of ASD could be relevant to insomnia complaints by hampering the entrainment of a circadian sleep-wake rhythm." They specifically talk about examining the link between sensory responsiveness and social skills in the context of insomnia in adults with ASD.

"Data were obtained from the Netherlands Autism Register (NAR), which is a longitudinal register including approximately 2000 individuals with ASD." Some 630 participants with autism were included for study, where "individual responses given to three measures of interest during an online survey in 2015 were analyzed." Those 'measures' were the Insomnia Severity Index (ISI), the Sensory Perception Quotient and the Autism Spectrum Quotient-28. The combined data were analysed.

Results: bearing in mind that this was a study exclusively including self-report from participants with autism - with no non-autistic control group - and one that relied on a single temporal snapshot of insomnia symptoms, one has to be a little careful with the findings. So: "The mean ISI score in the present sample was 9.50 (SD = 6.01), which is indicative of subthreshold insomnia and higher than means reported for the general population ranging between 1 and 7... but lower than values obtained from insomnia patients ranging between 17 and 20." Further, about half of participants scored in the "absence of insomnia" category with only around 20% of the group recording either moderate or severe insomnia. This tells us that, again according to self-report (and not using actigraphy for example), insomnia was not necessarily a widespread issue in this cohort but present in a not-significant number: about 1 in 5 people.

Next: "Primary analyses revealed that each of the covariates had a significant impact on the ISI total score." What this means is that biological sex, gender and medication use potentially played a role in insomnia. Women participating in the study tended to score higher on the ISI than men, and those aged 45-65 also seemingly showed more of a tendency towards insomnia. I don't think anyone would be really surprised with the idea that age and insomnia might be connected [4].

Some further statistical analysis of their results led researchers to opine on: "positive associations of insomnia severity with general and visual sensory hyper-reactivity and with impairment of social skills." I'm not too au fait with the specifics of the statistical modelling technique used by the authors - hierarchical multiple linear regression analyses (HMLR) - but can see what they did and how they did it, including "controlling for confounding effects of covariates" such as "medication, biological sex, intelligence, and age" (as previously mentioned). That being said, I'll draw your attention to some other conclusions reached by the authors: "The rather small effect sizes reported in the present study suggest that other factors not assessed in this study contribute to the emergence and persistence of sleep problems in adults with ASD."

The Hohn study does add something to the literature on sleep difficulties being experienced by quite a few people (children and adults) on the autism spectrum. I'm not overly convinced that they've stumbled upon evidence that core autistic features such as social skills problems and sensory issues are necessarily central to insomnia in their cohort but am willing to concede that they might play a role. Personally, I'd be inclined to go back to that data on 'comorbid' issues like gastrointestinal (GI) problems (see here) or breathing issues like apnoea (see here) as being something to explore further; also with the assumption that such issues are potentially 'treatable' and could have an important knock-on effect for something like insomnia and other sleep issues with autism in mind...

Oh, and don't forget the molecular handyperson that is melatonin and it's potential role in all of this (see here and see here). That and other potential avenues of research/clinical interest (see here)...

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[1] Hohn VD. et al. Insomnia Severity in Adults with Autism Spectrum Disorder is Associated with sensory Hyper-Reactivity and Social Skill Impairment. J Autism Dev Disord. 2019 Feb 9.

[2] Fernandez-Mendoza J. & Vgontzas AN. Insomnia and its impact on physical and mental health. Curr Psychiatry Rep. 2013;15(12):418.

[3] Garbarino S. et al. Insomnia is associated with road accidents. Further evidence from a study on truck drivers. PLoS One. 2017;12(10):e0187256.

[4] Foley DJ. et al. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep. 1995 Jul;18(6):425-32.

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PACE trial for chronic fatigue syndrome (still) being put through its paces: a reply

I'm bringing the paper published by Michael Sharpe and colleagues [1] to your attention today in the interest of balance and peer-reviewed 'right to reply'.

The Sharpe paper concerns the PACE trial, the study which reported that "when added to specialist medical care, cognitive behaviour therapy and graded exercise therapy were more effective in improving both fatigue and physical function in participants with CFS [chronic fatigue syndrome], than both adaptive pacing therapy and specialised medical care alone."

Anyone with a little bit of knowledge about the PACE trial will know that it's a 'contentious' topic within CFS (and ME, myalgic encephalomyelitis) circles. Indeed, the Sharpe paper comes about as a direct result of a reanalysis paper (see here) which reported findings raising "serious concerns about the robustness of the claims made about the efficacy of CBT [cognitive behavioural therapy] and GET [graded exercise therapy]" in the context of CFS/ME. 'Serious concerns' is putting it mildly considering how others have described the PACE trial and some of its tenets (see here).

Sharpe et al, who were authors listed on the original PACE trial paper [2], have had to defend their work/findings before in the peer-reviewed realm (see here). Same as before, the name Carolyn Wilshire is addressed and her teams reanalysis of the PACE trial data [3]. Said data was, I might add, (partially) released only following intervention from the Information Commissioners Office (ICO) here in Blighty (see here). More recent events have similarly reiterated that 'access to raw study data' is something that CFS/ME researchers perhaps need to bear in mind at study conception (see here).

I'm not going to clinically dissect the Sharpe paper in this post because (a) 'interpretation' forms quite a bit of the reply to the Wilshire reanalysis, and (b) your opinion on the scientific quality of the Sharpe reply is most likely going to be shaped by where you stand in terms of the whole CBT/GET for CFS/ME discussion. Indeed, a peer-reviewer of the Sharpe paper also said as much (see here). What I will comment on is how the Wilshire reanalysis paper and the more recent Sharpe reply to the reanalysis paper might further inform research more generally with CFS/ME in mind.

Oh, and it's probably just a coincidence that the Sharpe paper comes out only days after a news headline reads "Online activists are silencing us, scientists say" talking about a familiar topic.

So:

• Point 1: Design a good trial analysis plan and stick to it. From my 'outsider looking in' perspective, the changes made to "the scoring of the pre-specified outcomes" regarding fatigue and physical functioning in the PACE trial, however innocent they might have been, have created tension. Lots of tension. Such changes, whether agreed by "Trial Data Monitoring and Steering Committees" or not, can be construed in various different ways. It's better not to make such changes in the first place.
• Point 2: If you are going to study something like physical functioning in relation to CFS/ME, don't just rely on things like questionnaires and Likert scales; use actigraphy too. Self-report is always a good thing but I've never understood why, with the wide range of cost-effective technology out there (available I believe, even in the early 2000s), wearable trackers such as pedometers or similar were not also utilised during such studies (see here). If you're spending £5 million on a trial, a few quid for some pedometers is not exactly going to break the bank and will inevitably bring some further quality data to the table.
• Point 3: Recovery. As per other discussions (see here), most people would characterise recovery as a complete remission of symptoms and/or return to typical functioning. If you're not going to use this description, don't use the word recovery. Use something else instead. Indeed, use 'partial remission' or 'improvement' if you need to but don't call anything less than the complete remission of symptoms 'recovery'.
• Point 4: Long-term outcomes. It's probably best to avoid any sweeping statements after the arms of a trial - a "randomised trial" not necessarily a "randomised controlled trial" according to Wilshire et al - have been completed. More so when you're measuring such long-term outcomes via a postal question minus any objective measure(s) (see point 2). It's probably also a good idea to ask patients about their quality of life too and whether that has changed (see here).
• Point 5: Even if your paper states in no uncertain terms that: "The effectiveness of behavioural treatments does not imply that the condition is psychological in nature" the use of something like CBT for CFS/ME implies that you probably think there is a substantial psychological 'component' to the condition. This is compounded when you're for example, a Professor of Psychological Medicine. If you were pitting CBT in particular against a specific pharmacological or biological intervention 'for CFS/ME' (see here for example), I'd be more inclined to see your view in a more 'rounded sense'. Indeed, if you were to study one or two biological parameters as well as behavioural ones looking for any change following intervention, you might convince more people that psychology is not the primary line you take. And whilst on the topic of psychology and CFS/ME, it's probably also best not to use 'psychobabble' terms like 'deconditioning' in your research. Such terms are pretty much scientifically untestable and, given the recent discussions about the legacy of some adherents to something like psychosomatic research (see here), is likely to be consigned to the scientific dustbin as some later point.

I think I've covered the main points as I see them. Please feel free to agree/disagree as you wish.

End of Line.

Addition: 26 March 2019. Not quite 'End of Line' it seems, as a reply to a reply to a reply emerges [4]. Peer reviewed science is far from slow...

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[1] Sharpe M. et al. The PACE trial of treatments for chronic fatigue syndrome: a response to WILSHIRE et al. BMC Psychology. 2019; 7: 15.

[2] White PD. et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011; 377(9768):823-36.

[3] Wilshire CE. et al. Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychology. 2018; 6: 6.

[4] Wilshire CE. & Kindlon T. Response: Sharpe, Goldsmith and Chalder fail to restore confidence in the PACE trial findings. BMC Psychology. 2019; 7: 19.

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"A 4-Day Mindfulness-Based Cognitive Behavioral Intervention Program for CFS/ME" but...

I did um-and-ah about whether I should blog about the findings reported by Bjarte Stubhaug and colleagues [1] observing that "a brief, concentrated treatment program for CFS/ME might be highly beneficial."

The reasoning behind my reticence was primarily to do with the study design whereby "a 4-day group intervention program, comprised by education, cognitive group therapy sessions, mindfulness sessions, physical activity and writing sessions, within a context of cognitive behavioral therapy, mindfulness, acceptance and commitment model" was delivered to over 300 people diagnosed with Chronic Fatigue Syndrome/Myalgic Encephalopathy (CFS/ME) and self-report results plotted "1 week before and 1 week after the intervention program, and at 3 months and 1 year after the intervention" without any control group or any kind of blinding. Even the researchers themselves wrote that their study design make "conclusion of the actual effect of the treatment program [in part or whole] and its impact on the clinical course through the follow-up period difficult." But, here I am...

As you can see from the picture accompanying this post, others are also just a little bit critical of the Stubhaug paper and findings. Although I can't speak for anyone else, I imagine some of the 'criticism' of the study and results rightly follows on from the methodology employed by the authors. I did also wonder if some feeling might also be there because of the subject matter, and specifically, the continuing idea in some quarters that the application of the biopsychosocial (BPS) model to CFS/ME should carry weight. To quote from the authors: "The therapeutic rationale behind the program was to increase the medical knowledge and interpretation of bodily distress, challenge and modify dysfunctional illness perceptions as well as illness behavior, and through acceptance and commitment strategies contribute to behavioral change and clinical improvement." Sounds about as BPS as you can get I reckon.

Focusing for now on the methodological and related side of the Stubhaug paper, the starting point for the study was the authors' observation that: "The most promising treatment so far seem to be cognitive-behavioral treatment programs... and graded exercise." Just before anyone gets angry about this, authors do also highlight how "the effectiveness of interventions and robustness of findings are continuously being questioned" in this area. Yes, yes they are being questioned (see here and see here for examples) and by lots and lots of different people. Nonetheless, researchers decided to test whether their 4-day program, encompassing quite a few elements, might impact on some of the signs and symptoms of CFS/ME in their cohort. Said program included education: an "introduction to stress medicine with focus on physiological and psychological stress", cognitive group therapy, mindfulness and writing experience ("patients were instructed to write for 15 min about positive experiences and emotions"). They also talk about the use of "daily walking sessions of 60–90 min, in low to moderate pace" which, considering other research (see here), sounds pretty 'full on' to me, in light of some of principal issues that define CFS/ME (see here).

Relying on self-report measures such as the Chalder Fatigue Scale and the Short Form Health Survey-36 (SF-36), researchers reported their results as per the timescales already mentioned. The picture that emerged was a fairly positive one as various statistically significant group changes (improvements) were noted across the testing sessions, even when taking into account different ways of diagnosing CFS and across the various instruments used. Most participants also said that they were pretty satisfied with the intervention program and the service they received. In short, the study met it's aims quite successfully.

But... not to pour cold water on the findings, one cannot forget about the 'open study' shortcomings of the study design. So on top of what has already been mentioned: "Many patients with CFS/ME tend to be critical to biopsychosocial interventions, and possibly most of these patients did not accept referral to the clinic, contributing to the possible selection bias." I'd say that this was another quite important *issue* that faced the Stubhaug study. The authors go on to note that their results "clearly represent a CFS population, albeit not representing the total body of CFS/ME patients" so perhaps clarifying the caution needed in this area of science specifically around any sweeping generalisations. And as an example: "At 1 year follow-up, half of the patients completing assessments (56%) still report levels of fatigue representing substantial fatigue." Such an intervention is therefore no panacea for CFS/ME.

What else? Well, the continued focus on subjective questionnaires over and above more objective measures is also apparent in the Stubhaug findings (see here). As I've mentioned on more than one occasion, it's perfectly acceptable to ask patients how they are feeling and about related issues like quality of life for example (see here). But when it comes to a condition or set of conditions like ME/CFS defined by fatigue and other symptoms that very much impact on core issues such as activity, it strikes me that one should really include an objective measure of activity if one wants to study it in its entirety. So yes, actigraphy would have been a good feature to see in this study (with before and after results). Even a pedometer costing a few quid, used a few times a week over a number of different weeks would be something at least. And once again, how about also including some biological parameters into such studies too? Y'know, just on the off-chance that things like mindfulness, minus any grand sweeping claims, for example, could have possible biological effects too [2]?

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[1] Stubhaug B. et al. A 4-Day Mindfulness-Based Cognitive Behavioral Intervention Program for CFS/ME. An Open Study, With 1-Year Follow-Up. Front Psychiatry. 2018;9:720.

[2] Hoge EA. et al. The effect of mindfulness meditation training on biological acute stress responses in generalized anxiety disorder. Psychiatry Res. 2018 Apr;262:328-332.

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Subclinical autistic traits affecting adolescent sleep patterns?

There was something rather intriguing about the results published by Liisa Salmela and colleagues [1] (open-access available here) observing that: "Elevated levels of autistic traits were significantly associated with shorter weekday sleep duration" in a cohort of adolescents from Helsinki in Finland. The fact that researchers also concluded that "autistic traits remained an independent predictor of short sleep duration when comorbid psychiatric symptoms were controlled for" added to the intrigue.

I was impressed with some elements of the Salmela study; notably the use of actigraphy as an objective measure of sleep accompanying self-report data derived from the Pittsburgh Sleep Quality Index (PSQI). The fact that actigraphs were worn "continuously for an average of 8.36 nights (SD = 1.76; range 4–17)" also meant that researchers had access to quite a bit of data from their 150+ participant study group when it came to activity cycles covering sleep.

What was the measure of autistic traits used I hear you ask? Well, we are told that: "Autistic traits were assessed using the Autism Spectrum Quotient (AQ)" which is an OK measure I suppose, although not without some shortcomings in terms of what is being specifically measured (see here). I should also mention that for the most part, the Salmela study was a study of non-autistic adolescents (two participants were reported to have "scored at or above the clinical cut-off score of 32" on the AQ).

"Continuous autistic traits significantly predicted weekday total sleep time" and "having elevated autistic traits as measured by AQ (Autism Spectrum Quotient) increased the risk for short sleep duration." Mindful that correlation is not necessarily the same as causation, details were important to the Salmela findings as we are also told that (a) as a group, boys tended to score higher on the AQ and (b) again as a group "boys had significantly shorter weekday total sleep time" than girls. It's perhaps no surprise therefore that: "Sex had a statistically significant main effect (p = 0.032) on total sleep time."

Next question: why? Why should autistic traits potentially "increase the risk for short sleep duration in a general adolescent population"? Is there something about the presentation of autistic traits that affects sleep either through psychological/cognitive processes or more physiological processes? Well, those are questions that still need answering. And alongside we seem to have yet another example where core autistic features may very well impact on so-called comorbid issues to add to the collection (see here and see here). This also has potential implications for intervention too...

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[1] Salmela L. et al. Autistic traits and sleep in typically developing adolescents. Sleep Med. 2018 Oct 29;54:164-171.

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A short-term aquatic exercise intervention for (some) individuals with CFS/ME?

I have to say that I did um-and-ah about whether or not to make this blog entry on the results published by Suzanne Broadbent and colleagues [1]. In it, researchers talked about the use of "a short-term aquatic exercise programme" with a small group of women diagnosed with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

My 'in two minds' state was because the words 'exercise as intervention' and 'CFS/ME' have a rather poor history both in research and clinical terms; as proposals like 'graded exercise therapy' (GET) have the ability to invoke some rather adverse memories and reports for some/many people (see here and see here). As you can see, I did in the end decide that science should be seen and heard, even if it might be a tad uncomfortable. As hopefully you'll see, the Broadbent results might even provide some much needed focus in the area of activity and exercise with CFS/ME in mind minus any sweeping generalisations and psychobabble explanations which have typically followed such research.

Before progressing through their paper, it is worth mentioning that some of the authors on this most recent paper have some 'research form' when it comes to looking at exercise in the context of CFS/ME. Yes, there is mention of the words 'graded exercise' [2] in previous publications, but interestingly this is wrapped in the context of "immune system dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)" and their looking at various biological aspects of exercise [3] with an immune system slant to it. This is not your regular 'de-conditioning' thinking...

Aquatic exercise was the name of the research game on this most recent occasion, and an open trial detailing various physiological and behavioural measures pre- and post-use of "an initial 20-min aquatic exercise session then two self-paced 20-min sessions per week for 4 weeks" with 11 women. As you can already see, this was not a controlled trial and there was no comparison group used; just an initial research foray looking at whether their fairly brief water-based exercise program might produce some meaningful results or not. I assume that the authors were conscious that water-based exercise has some advantages over er, not water-based activity, in relation to impact (aquatic exercise is typically termed 'low impact) and also strength-building (water resistance is much greater than air resistance). I might also add that others have been following the development of this trial with some interest (see here).

'First, do no harm' is a primary tenet in all of medicine, and on the basis of "no reports of symptom exacerbation" in their small participant cohort, the authors can tick an important item of their research checklist on this occasion. Alongside, authors detail results based on various physiological parameters: "6 min Walk Test (6MWT), perceived exertion (RPE), hand grip strength, Sit-to-Stand, Sit-Reach test, Apley's shoulder test" as well as monitoring heart rate after each session. There's even mention of "24- and 48-h post-session tiredness/pain scores" which, I assume, could be stretched to mean looking at aspects of an important symptom: post-extertional malaise (PEM). And on that basis the authors reported that many of those physiological parameters did show changes between pre- and post-intervention in relation to things like grip strength, the 6MWT and also pain ("24-h post-test tiredness and pain decreased"). Ergo, aquatic exercise was seemingly well-tolerated in their small participant group and further - more scientifically 'stronger' - investigations are perhaps indicated to substantiate this finding.

When I first tweeted about the Broadbent article, it did create some discussion (see here). I wasn't surprised by this given the nature of the trial and some of the references to other peer-reviewed research made by authors. It's not easy to put into words how much damage has been done by the widespread (universal?) advocacy of something like GET when it comes to ME/CFS. Suffice to say that for many people with CFS/ME, any study that mentions 'exercise' as an intervention is likely to be met with a degree of scepticism. Once bitten and all that. And I also note the words "raising the possibility that there could be future lawsuits from ME patients whose condition has worsened from the treatment" have recently been mentioned in relation to GET...

But I do think there is more research to be done in this area on the back of the Broadbent results. Minus hype, sweeping generalisation and again importantly without any 'psychological theory' input, further analysis of the physiological effects of exercise on those with ME/CFS is a must, particularly with something like PEM in mind. No, I'm not advocating research practices that unethically put people with CFS/ME onto exercise regimes, but rather smaller research steps starting, for example, with the greater use of actigraphy on a day-to-day basis. It's been a real point of contention that actigraphy - the (objective) study of rest and activity cycles - has not been more incorporated into CFS/ME research (see here). Particularly, when discussions about 'recovery' from ME/CFS have been prominent in many quarters (see here) seemingly without mention of objective ways and means of establishing parameters of such recovery. I'd also suggest that the authors' previous work on immune function following exercise could also be applied to further aquatic exercise research too...

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[1] Broadbent S. et al. Effects of a short-term aquatic exercise intervention on symptoms and exercise capacity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis: a pilot study. Eur J Appl Physiol. 2018 Jun 19.

[2] Broadbent S. & Coutts R. Intermittent and graded exercise effects on NK cell degranulation markers LAMP-1/LAMP-2 and CD8+CD38+ in chronic fatigue syndrome/myalgic encephalomyelitis. Physiol Rep. 2017 Mar;5(5). pii: e13091.

[3] Broadbent S. & Coutts R. Graded versus Intermittent Exercise Effects on Lymphocytes in Chronic Fatigue Syndrome. Med Sci Sports Exerc. 2016 Sep;48(9):1655-63.

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Shocker alert: gut problems in autism impact on sleep (again)

"Increased odds of sleep problems were most frequently associated with gastrointestinal distress (GID) and non-verbal IQ (NVIQ), followed by male sex and age."

That was one of the findings reported by Ann Johansson and colleagues [1] who set out to examine "the relationship between sleep problems and characteristics of children with ASD [autism spectrum disorder] in a large, nationwide sample." Mention of the words 'Simons Simplex Collection' in the Johansson article provides a clue as to the source population examined in this study and some of the hows-and-whys of the research. From what I also understand, this paper is part of a doctoral thesis by Johansson looking at some of the possible genetics of sleep with autism in mind (see here). Indeed, if one scrolls to page 70 of the thesis, one finds the study in question...

The Simons Simplex Collection Sleep Interview (SSCSI) was the instrument of choice for assessing sleep issues. This is a short parent-report questionnaire that includes both a composite score for total sleep issues and subscale scores for things like 'sleep duration issues'. Alongside, GID was classified "if they were reported (yes/no) to have bloating/excess gas, celiac disease, constipation, diarrhea, ulcers, gastroesophageal reflux disease, inflammatory bowel disease (Crohn’s disease, ulcerative colitis), irritable bowel syndrome, abdominal pain, unusual stools, vomiting, and/or other GID." Throw in scores on the ADOS "used to measure ASD severity" and crunch the data...

I've inserted the word 'again' into the title of this post because this is not the first time that functional gastrointestinal issues 'over-represented' in autism have been connected to sleep issues (see here). This time around, researchers mention that over 40% of their cohort (2000+ children) "were categorized as having mild or moderate/severe sleep problems" according to their SSCSI composite score. 'Difficulty falling asleep' seemed to be one of the more frequently reported issues. GID - gastrointestinal distress - was the strongest factor linked to sleep issues (odds ratio = 2.79), again based on the SSCSI composite score for sleep issues. There were other combinations of symptoms potentially linking to sleep noted by the authors but I'm minded to put them to one side for now.

Caveats? Well, one big caveat sticks out: the reliance on parent-reported responses to a questionnaire about sleep without any reference to objective measures of sleep. I've gone on and on (and on) about the use of actigraphy when it comes to sleep research relating to various diagnostic labels (see here and see here for examples) and well, keep coming to the same conclusion about a strong requirement for such objective measures on sleep-wake cycles. I appreciate that there may be some 'consumer resistance' to wearing a wristband for example, to measure activity and rest cycles (see here), but surely someone, somewhere can engineer something when kids don't want to wear such gadgets? Insofar as the classification of GID also relying on parental report, I'm a little kinder to this because the evidence is pretty good for suggesting that parents might be tuned into what is typical and what is not typical from a functional bowel habits perspective in their offspring (see here)...

No mind, the results do accord with other independent data on how gut issues present in autism can seemingly have some far-reaching effects. As to 'how', well, I would always start with the obvious explanation: pain and discomfort caused by bowel issues affecting sleep, and then work back from there. Indeed, as if I need to say it again, bowel issues (both functional and more pathological) are truly 'over-represented' when it comes to a diagnosis of autism (see here) and science and clinical practice really need to do a lot more to tackle such issues as and when they are reported/detected...

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[1] Johansson AEE. et al. Characteristics of sleep in children with autism spectrum disorders from the Simons Simplex Collection. Research in Autism Spectrum Disorders. 2018; 53: 18-30.

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Do childhood sleep issues "have a causal role" in 'chronic disabling fatigue' in adolescence?

There's those words again: 'chronic disabling fatigue' or CDF, being used as a proxy for chronic fatigue syndrome (CFS, also known as 'ME') as per the findings reported by Simon Collin and colleagues [1].

Elements of this authorship group seem to be using CDF quite a bit (see here and see here) in their various research studies, and I have to say it's starting to get a little confusing (see here). I'll come back to my thoughts on the term CDF in a moment...

On this research occasion, Collin et al set out to explore whether "sleep might be a causal risk factor for CFS/ME" (or should that just be CDF) on the basis that sleep issues have been reported in that context previously [2]. Once again, "data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort" was the research source material, and researchers were specifically looking at: "sleep patterns of children aged 6 months to 11 years, who were subsequently classified as having (or not having) 'chronic disabling fatigue'... between the ages 13 and 18 years." Sleep duration was quite a big element to this study.

So yeah, shorter night-time sleep duration from 6 months to 11 years of age did seem to show some connection to CDF. To quote: "The odds of CDF at age 13 years were 39% lower... for each additional hour of night-time sleep at age nine years, and the odds of CDF at age 16 years were 51% lower... for each additional hour of night-time sleep at age 11 years." This and a few other observations led authors to conclude that sleep abnormalities might have a role to play in relation to CFS/ME (sorry, CDF).

I have to say however, that I'm not particularly impressed with these findings. I say that on the basis that one set of variables (sleep) are being *correlated* with another later variable (CDF) and well, correlation does not necessarily equal causation. As per other work from this authorship group [2], they've also previously suggested that level of physical activity *might* also correlate with CFS/ME (sorry CDF) albeit with a reduced timescale between the variables. This dual research based on the same cohort I assume, kinda disqualifies any one variable from being related to CDF. Assuming that is, that sleep and physical activity are not somehow connected...

And then there's the issue of how sleep duration was measured in the latest Collin paper: "The sleep durations in our study were obtained from parents’ (mostly mothers’) answers to questions about the child’s usual bedtime and waking time, rather than from data collected in a sleep/wake diary or by actigraphy." So, they basically asked what time children went to bed and what time they woke up. There's nothing wrong with asking such questions but likewise there is little to confirm that children actually closed their eyes and nodded off the minute they went to bed and/or woke up the minute of parental report on waking. Anyone who has children knows that this is 'optimistic' at best (and indeed, takes no account of things like duration of night waking or quality of sleep for examples). The lack of use of actigraphy - that fabulous wearable tech that allows us to objectively chart sleep and activity cycles - is a real problem for elements of CFS/ME research (see here), and is something that is getting harder and harder to overlook. This includes the lack of use in this particular research study too.

Then, back to CDF. CDF basically comes about because we are told that "children in [the] study were not examined by a physician" when it comes to CFS/ME. Further: "CDF at ages 13 and 16 years was defined as fatigue (feeling tired or lacking in energy) of >6 months’ duration that was associated with absence from full-time school or that had prevented the child from taking part in activities ‘quite a lot’ or ‘a great deal’, excluding fatigue possibly associated with sport, snoring, and other illnesses." So fatigue is a primary symptom. But how can you exclude fatigue associated 'other illnesses'? Did the authors for example, screen for something like fatigue due to mitochondrial issues or disorders (see here)? No, they didn't appear to. Similarly there is no mention as far as I can see of another primary symptom of CFS/ME: post-exertional malaise (PEM). Important too was another quote from the authors: "Our definition of CDF did not exclude children with comorbid depressive symptoms." I'll say little more on this topic.

So, again, unfortunately I have to say that I'm left unimpressed by these latest findings from Collin and colleagues. And once again, I have to point out that CDF whilst described as "a proxy for chronic fatigue syndrome/ME" is not necessarily CFS or ME (and indeed, neither it seems, could it be both).

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[1] Collin SM. et al. Childhood sleep and adolescent chronic fatigue syndrome (CFS/ME): evidence of associations in a UK birth cohort. Sleep Med. 2018 Jun;46:26-36.

[2] Collin SM. et al. Physical activity at age 11 years and chronic disabling fatigue at ages 13 and 16 years in a UK birth cohort. Arch Dis Child. 2018 Jun;103(6):586-591.

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Immunoadsorption and ME/CFS: observations from a small proof of concept study

Immunoadsorption refers to "an alternative blood purification technique... used to eliminate pathogenic antibodies." I'll freely admit that I don't know an awful lot about this procedure, so approach the findings reported by Carmen Scheibenbogen and colleagues [1] with a degree of naivety with regards to 'usefulness' and also important issues such as safety.

Authors report preliminary findings from their 'proof of concept' study, using immunoadsorption (IA) on a small group of adults (N=10) diagnosed with Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS / ME) who also presented with "infection-triggered disease onset, disease severity according to the Bell scale of ≤ 50 of 100, and elevated levels of ß2 antibodies." The Bell scale by the way, seems to refer to a scale developed by David Bell with scores ranging from 0 to 100 to denote fatigue symptoms, post-exertional malaise (PEM) and 'ability to work full-time'. A lower score denotes more severe symptoms. The description "elevated levels of ß2 antibodies" refers to antibodies against ß2 adrenergic receptors; receptors which are found throughout the body and are involved in various biological tasks including smooth muscle relaxation and regulating certain cardiac functions. As the authors note: "Antibodies to ß2... receptors had been reported in various other diseases including dilatative cardiomyopathy, postural tachycardia, regional pain syndrome, Alzheimer, Sjögren’s syndrome, asthma and others." The 'antibodies' bit implies that the body is failing to recognise these receptors as 'self' and instead wrongly mounts an immune response against them.

Scheibenbogen et al mention that during their other studies on ME/CFS [2] they noted "a sustained decline of pretreatment elevated ß2 antibody levels in clinical responders to rituximab treatment." The rituximab bit refers to some initially encouraging results [3] from the use of this treatment that, unfortunately, do not seem to have weathered more rigorous scientific scrutiny (see here). Authors further hypothesised that IA might be a route to "removing autoantibodies" and specifically those "elevated antibodies against β2."

Results: "Prior to IA all patients had elevated antibodies against β2, in addition 7 patients against ß1 adrenergic receptors and 6 patients against both M3 and M4 acetylcholine receptors." Autoantibodies in many of the participants included for study went beyond just those against β2.

Following quite a few cycles of IA - "IA was conducted in 5 cycles on days 1–3 and 6–7 with 2 to 2.5-fold plasma volume filtered" - authors reported that: "Levels of ß2 adrenergic antibodies were low to undetectable in 9 of 10 patients." This is kinda what would be expected following IA (bearing also in mind that: "After the 5th IA cycle all patients received 25 g IgG i.v." also known as IVIG).

Insofar as the clinical course of participants' presented symptoms, well, it was a bit of a mixed bag. So: "A rapid improvement of several symptoms was reported by 7 of these 9 patients during IA. However, none of the patients completely recovered and 5 patients had worsening of fatigue towards the end of treatment despite improvement of other symptoms." I'm happy to report that the authors did utilise the wonderful technology headed under the term actigraphy (activity monitoring) as per their assessing participants step counts "by a Vivofit activity tracker." Such objective activity monitoring is sadly lacking from many other studies on ME/CFS (see here for example). Again however, the step counts reflect an initial 'good start' for IA followed by a not-so-good finish...

"Taken together, this pilot study provides evidence that IA can effectively remove ß2 and M3/M4 autoantibodies in CFS/ME and can result in rapid moderate to marked symptom improvement." I wouldn't disagree with the authors' conclusions but would perhaps suggest that the current results as they stand don't yet provide authoritative evidence for a beneficial effect of IM in the longer term. More [controlled] study is required.

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[1] Scheibenbogen C. et al. Immunoadsorption to remove ß2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME. PLoS One. 2018 Mar 15;13(3):e0193672.

[2] Loebel M. et al. Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain, Behavior, and Immunity. 2016; 52: 32-39.

[3] Fluge Ø. et al. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. PLoS One. 2015 Jul 1;10(7):e0129898.

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Is early adolescent physical activity protective against later "chronic disabling fatigue"?

TIE fighter crossing the moon?

One particular detail in the recent paper by Simon Collin and colleagues [1] (open-access available here) talking about higher physical activity potentially being *protective* against subsequent adolescent 'fatigue', immediately caught my attention: "CDF [chronic disabling fatigue], a proxy for clinically diagnosed CFS/ME [chronic fatigue syndrome/myalgic encephalomyelitis]."

This is not the first time that this authorship group have used the term CDF and seen it's use 'merging' into meaning something close to or like CFS/ME (see here) and I doubt that it will be the last. Far be it from me to put myself forward as some sort of expert on diagnosing CFS/ME - I'm not - but CDF as representing a proxy for CFS/ME does not mean that CDF is the same as CFS/ME. And that's also bearing in mind that the issue of diagnosis of CFS/ME is still the topic of lots and lots of (continuing) discussion (see here)...

Keeping all that in mind, I do want to briefly talk about the new paper from Collin et al. The Avon Longitudinal Study of Parents and Children (ALSPAC) was, once again, the data source for their findings, and yet again, this was a study looking at adolescent and young adults. The aim of the study was to: "investigate whether levels and patterns of physical activity at age 11 years are associated with ‘chronic disabling fatigue’... at ages 13 and 16 years."

A strength of the Collin research is that authors looked at more than just subjective 'how much exercise did you do' questionnaire via their use of actigraphy. So: "All ALSPAC children who attended research clinics at age 11 years... were asked to wear an Actigraph AM7164 2.2 accelerometer (Actigraph LLC, Fort Walton Beach, Florida, USA) for 7 days." Further: "Data from children who had worn the accelerometer for at least 10 hours a day for at least 3 days were considered valid" and from such data various calculations were made in terms of sedentary time, total physical activity and the proportion of "moderate-to-vigorous physical activity." Such data was analysed in the context of CDF measurements at ages 13 and 16 using methods previously described in their other research [2].

Results: "Children who had CDF at age 13 years had lower levels of physical activity at age 11 years." The authors translated this into various stats including: "For each additional 1% of monitored time spent in moderate-to-vigorous activity, the odds of CDF were reduced by 16%" and "Each additional hour of sedentary time per day was associated with 35% higher odds of CDF."

But just before anyone thinks that pushing children off the sofa and into some moderate-to-vigorous exercise in early adolescence is some kind of magical shield protecting against CDF, a few words of caution from the authors might also be important. Namely: "the lower levels of physical activity at age 11 years [may be] a consequence of chronic fatigue which is already present or developing and which persists until the child is 13 years old." In other words, there could be an alternative explanation for the lower physical activity (PA) levels *causing* chronic disabling fatigue; those who didn't do much PA were already developing and manifesting CDF...

"The main limitation of our study is that children were not assessed by a doctor, which is why we describe our outcome as ‘chronic disabling fatigue’, a proxy for CFS/ME." Yup, no arguments there; also reiterating why one needs to be quite careful about the terminology used around CFS/ME. The suggestions that lower physical activity might show a *correlation* with CDF also needs to be carefully handled given some continuing conversations about 'exercise therapy' in the context of CFS/ME (see here) and in particular, what various patients have been reporting from interventions in this area (see here)...

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[1] Collin SM. et al. Physical activity at age 11 years and chronic disabling fatigue at ages 13 and 16 years in a UK birth cohort. Arch Dis Child. 2018 Jan 30. pii: archdischild-2017-314138.

[2] Norris T. et al. Natural course of chronic fatigue syndrome/myalgic encephalomyelitis in adolescents. Arch Dis Child. 2017 Jun;102(6):522-528.

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"specific microorganisms interact with some ME/CFS symptoms" and intervention could follow?

The quote titling this post: "specific microorganisms interact with some ME/CFS symptoms" and intervention could follow? comes in part from the findings reported by Amy Wallis and colleagues [1]. They reported that, following an open-label study design including 44 eligible patients diagnosed with ME/CFS [myalgic encephalomyelitis/chronic fatigue syndrome], a few potentially important details emerged. Not least that: "antimicrobial and probiotic treatment showed concurrent reduction in enteric Streptococcus counts and improvement in some neurological symptoms." Mmm...

The authors on the Wallis paper have some research form in this area [2] (see here for a previous blogging take on this work) talking about how use of a antibiotic - erythromycin (400 mg) - delivered over a 6-day period seemed to have some important effects on "gram-positive faecal Streptococcus" and also, for some, a positive impact on sleep quality. The caveat being once again, that this was another open-trial so potentially liable to various confounding variables. Still, there was one particularly positive thing to see in this previous trial, the use of actigraphy to collect objective data on sleep-wake cycles (something sadly lacking from various other studies of ME/CFS).

This latest time around it was all about comparing "the treatment response of male and female ME/CFS patients using a combined antibiotic and probiotic intervention aimed at reducing Streptococcus." The trial was registered (see here) and indeed, prospectively registered. The focus was on "sleep, mood and cognitive symptoms" also taking into account sex/gender as a potentially important variable. Alongside the use of an antibiotic, this time researchers also introduced a probiotic into the study protocol on alternate weeks - "Two capsules of Pro4-50 d-lactate free multistrain probiotic." As well as sleep continuing to be a focus for study, a battery of other parameters were also studied over the 4-week period of study covering various aspects of cognition ("word memory, story memory, spatial working memory, visual learning, verbal fluency, processing speed, cognitive flexibility and planning"), fatigue ("General Fatigue subscale from the Multidimensional Fatigue Inventory, MFI-20") and interestingly, 'brain fog'.

Results: the first thing that struck me about the Wallis results was the fact that the attrition (drop-out) rate was zero. Accepting that this was a rather short study, every participant (27 females and 17 males) completed the study protocol and had full results. That's not bad at all. It also makes statistical analyses sooo much easier.

Next, despite the authors reporting that "some sleep" parameters seemed to show some positive changes following the intervention, I'm minded to point out a key statement made in their text: "The primary outcome for sleep, actigraphic sleep efficiency, revealed similar mean scores at baseline... and post... with a small effect estimate... indicating no change in objective measurement of sleep efficiency." Given the 'open trial' nature of the experiment being described combined with the short experimental time, one therefore needs to be cautious about other, more self-report observations included for study. Cautious but not necessarily dismissive.

Then: "Streptococcus count was the only microbial variable that showed a large effect for time... with a reduction from baseline... to post." This is perhaps not unexpected given the use of an antibiotic that targets that specific type of bacteria. That being said, not everyone on the study showed the same 'direction' of effect, as per the statement: "individual variability of treatment response was highlighted by the proportion of participants who increased in Streptococcus counts at post." I guess this might imply that things are complicated when it comes to bacteria and antimicrobial use. Like just about every other medicine in use these days, not everyone will show the same clinical response to the same medicine.

Finally, bearing in mind an important aim of the Wallis study to undertake "sex comparisons", the results pretty much suggested that things are not so clear-cut when it comes to ME/CFS. So: "Analysis of the change in scores from baseline to post for male and female subgroups (sex-time interactions) revealed no large effects and thus did not support a sex-specific response to the treatment."

What we have with the Wallis paper and results is a well-described study, albeit with an inherent issue: the use of an open-label trial. I'm not saying there isn't value in such results; merely that one needs to be cautious about any findings produced (this comes from someone who has used similar trial designs). I might also add that whilst the authors talk about "Change in mean scores for all clinical outcomes (sleep, mood, cognitive and other) [that] were in the direction of improvement at post-intervention" this is not the same as statistically significant findings no matter what your views are on the current system employed. When joined to that open-label study design employed, such 'in the right direction' views needs to be kept to a minimum without further, more controlled investigations, to back them up...

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[1] Wallis A. et al. Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons. Journal of Translational Medicine. 2018; 16: 24.

[2] Jackson ML. et al. Sleep quality and the treatment of intestinal microbiota imbalance in Chronic Fatigue Syndrome: A pilot study. Sleep Science. 2015;8(3):124-133.

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FITNET-NHS (Fatigue In Teenagers on the interNET in the NHS) - a trial protocol and some questions...

FITNET-NHS (Fatigue In Teenagers on the interNET in the NHS) is an initiative discussed in a recent study protocol paper published by Sarah Baos and colleagues [1]. It continues a research interest based on previous published results from a trial undertaken in the Netherlands by Sanne Nijhof and colleagues [2] looking at a possible intervention option for adolescents with chronic fatigue syndrome (CFS) (also referred to as myalgic encephalomyelitis, ME by some).

Said intervention option - Fatigue In Teenagers on the interNET (FITNET) - is "a web-based cognitive-behavioural treatment accessible to patients and both parents, based on the existing face-to-face CBT [cognitive behaviour therapy] protocol for adolescents developed by the ECCF [Expert Centre for Chronic Fatigue (Radboud University Nijmegen Medical Centre, ECCF)]." The previous Nijhof findings concluded that: "FITNET offers a readily accessible and highly effective treatment for adolescents with chronic fatigue syndrome" on the basis of previous (registered) trial results.

The recent Baos paper detailing 'what researchers are going to do' is looking to build on the previous Nijhof findings to determine whether "it is effective in the National Health Service (NHS) or if it is cost-effective." Alongside the descriptions offered by Baos et al, trial authors have also prospectively registered their intention to undertake this study (see here).

I don't want to recite all the study details described by Baos et al (the paper is open-access) but I do think a few points are worth noting and a few questions perhaps need to be asked. I say this on the basis that mention of the letters/words CBT in the context of CFS/ME has some 'history' (see here and see here for a part of that history). Also, at the time of writing this post, some of the premises for implementing the FITNET-NHS trial are also subject to 're-inspection' (see here) in light of fairly recent changes to official CFS/ME management guidance in countries outside of the UK (see here)...

Anyhow, point 1: "This is an RCT comparing FITNET-NHS with Activity Management for paediatric CFS/ME." RCT means randomised-controlled trial and means participants (planned 700+ aged 11-17 years old) will be randomly placed in either the treatment arm of the study or the 'activity management' control group. Actually, the authors mention another important detail in respect of the study progression: "An internal pilot study will be conducted with continuation of the trial based on achieving defined criteria." What this means is that certain criteria need to be met before the trial progresses, following a sort of pseudo-adaptive design. The stop criteria we are told are: "(1) the recruitment rate is substantially below target during the last 6 months of the internal pilot study and if the qualitative data suggests that we cannot improve recruitment by changing recruitment methods or (2) the qualitative data suggests that the interventions are not acceptable to participants." I've talked about recruitment rates in relation to trials run by some of the Baos authors before on this blog (see here). In terms of 'acceptability' of the interventions, well, the findings from Geraghty and colleagues [3] perhaps need airing in line with some of the history around the use of CBT in the context of CFS/ME. Will all of this affect recruitment rates? We'll see.

Point 2: Activity management (the comparator). There are various elements - mandatory, flexible, prohibited - that such activity management will include. Prohibited elements, I think, mean that specialist therapists cannot discuss in detail things like "feelings, beliefs and how they change" nor "feelings and their relationship with behaviour." Mandatory elements by contrast include finding a baseline level of activity, "to record time spent each day doing high-energy cognitive activities" and importantly: "Increasing activity by 10–20% each week." Yes, this is an active comparator that looks like it is expecting quite an increase in activity over the duration of the study. I think they call this graded exercise therapy (GET). All of this will be delivered on-line and participants will "receive treatment for 3 to 6 months." As you can see, things like recording activity levels (the ActiveME app is mentioned) is going to be predominantly (exclusively?) done via "paper/electronic diaries." I'm a little cautious of this method, and once again (see here) need to question why more objective activity trackers such as the wonderful technologies headed under the title of actigraphy are not being fully utilised with CFS/ME research in mind (see here for another example). Given also that the primary outcome measure is: "Disability measured using the Physical Function Scale (SF-36-PFS) at 6 months after randomisation", surely such actigraphic data would provide a really sound comparator to such subjective scoring?

Point 3: There are a range of secondary outcomes listed by Boas and colleagues in relation to measuring any effects from intervention and/or comparator. I am happy to see that quality of life (QoL) will be measured via use of the EQ-5D-Y (EuroQoL health-related quality of life questionnaire, Youth version) given some chatter about this previously (see here and see here). But there are some things missing from such an outcome line-up; a primary one seems to be that although fatigue and physical function is kinda (see above) mentioned in an analysis sense, more specific facets of CFS/ME are not seemingly being addressed such as PEM (post-exertional malaise). I note from the study website for example, the authors talk about how "fatigue and other symptoms get worse after exertion" suggesting that they know all about PEM. The question then: why not try and test for it and importantly, assess it before and after intervention? OK, I know that measuring PEM is still more of an art rather than a science [4], but I wonder if it would have been helpful for researchers to also potentially think about examining biochemistry for example, as well as psychology and behaviour throughout their study to aid some further investigation in this important area. Y'know things like immune function for example [5] which seems to be an area of research rising (see here) and could add something extra when it comes to sub-grouping among the CFS/ME population? Oh, and just in case you were thinking 'eh?' when it comes to me talking about CBT potentially affecting immune function, have a look at another trial protocol from Schakel and colleagues [6] and the measures they want to use/are using as part of their study "to investigate the effects of a psychological intervention on self-reported and physiological health outcomes in response to immune and psychophysiological challenges."

Point 4: Safety. I am happy to see that safety of the intervention(s) is also discussed in the Boas paper. To quote for example: "We will define a serious deterioration in health as: (1) clinician-reported serious deterioration in health, (2) a decrease of ≥ 20 in SF-36-PFS between baseline and 3, 6 or 12 months or scores of ‘much’ or ‘very much’ worse on the Clinical Global Impression Scale or (3) withdrawal from treatment because of feeling worse." Good news indeed, and I assume this covers the comparator arm of the study too. What is perhaps missing from such study safety features however, is a little more detail on what screening will be carried out before participants are allowed on to the study in order to reduce/minimise any potential adverse events or even worse, include those who really shouldn't be included in such a study ('first, do no harm'). So: "Young people will be excluded if any of the following apply: (1) they are not disabled by fatigue (defined in eligibility screening), (2) their fatigue is due to another cause, (3) they are unable to complete video calls or FITNET-NHS online chapters or (4) they report pregnancy at assessment." Under 'their fatigue is due to another cause' I'm a little unsure about what this might mean. Does this for example, infer that all potential participants will be screened for mitochondrial disease in light of other data suggesting overlap with cases of CFS/ME (see here) and a possible/probably connection with some fatigue-related symptoms? How is one able to rule out so many potential causes of fatigue other than CFS? As to the idea that there may be those 'unable to complete video calls or FITNET-NHS chapters', well, I imagine that excludes those who might be at a more severe presentation stage of their illness? This then introduces the issue of representativeness of any trial results subsequently obtained...

I applaud the authors for communicating as much as they did about their intentions to conduct this trial. More research groups need to do this both inside and outside the realms of CFS/ME to make replication easier and allow old farts like me to scrutinise and comment from on high. Relying solely on the cold, objective science in this often contentious area, I can also see the rationale behind their running this trial and the urgent need to improve quality of life for many, many young (and older) people diagnosed with CFS/ME.

But... as things stand with the protocol, particularly the distinct lack of using widely available objective measures to provide data on activity levels, I can't also see how this study is going to significantly add to the existing research base nor wider discussions about the use of something like CBT in the context of CFS/ME. I say that also acknowledging that the original FITNET trial is not without criticism [7], including a section that was titled 'The Actometer Results' that perhaps should be renamed 'What happened to the Actometer Results' given "the results were not reported and the reason for this was not given." One also needs look at the masses of discussions on the PACE trial (see here for example) that included CBT as part of an intervention package, to see how the biopsychosocial (BPS) model on which such research rest is, at best, disliked by many suffering with CFS/ME (see here). Said discussions now even reaching the House of elected officials here in Blighty (see here). The glaring lack of any biochemical measures also accompanying this new study adds to the feeling that despite recognition from the authors that "common symptoms in children and young people are unrefreshing sleep, problems with memory and concentration, headaches, nausea (feeling sick), dizziness, muscle and joint pain, and sore throats" psychosomatic ideas still prevail regarding the nature of such symptoms and the continuing rationale for studying CBT in the context of CFS/ME.

I'll hopefully come back to this topic as and when any study results are forthcoming ("Overall trial end date 30/10/2021").

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[1] Baos S. et al. Investigating the effectiveness and cost-effectiveness of FITNET-NHS (Fatigue In Teenagers on the interNET in the NHS) compared to Activity Management to treat paediatric chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME): protocol for a randomised controlled trial. Trials. 2018; 19: 136.

[2] Nijhof SL. et al. Effectiveness of internet-based cognitive behavioural treatment for adolescents with chronic fatigue syndrome (FITNET): a randomised controlled trial. Lancet. 2012 Apr 14;379(9824):1412-8.

[3] Geraghty K. et al. Myalgic encephalomyelitis/chronic fatigue syndrome patients' reports of symptom changes following cognitive behavioural therapy, graded exercise therapy and pacing treatments: Analysis of a primary survey compared with secondary surveys. J Health Psychol. 2017 Aug 1:1359105317726152.

[4] McManimen SL. & Jason LA. Differences in ME and CFS Symptomology in Patients with Normal and Abnormal Exercise Test Results. International journal of neurology and neurotherapy. 2017; 4(1): 066.

[5] Nijs J. et al. Unravelling the nature of postexertional malaise in myalgic encephalomyelitis⁄chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1b. J Intern Med. 2010 Apr;267(4):418-35.

[6] Schakel L. et al. The effects of a psychological intervention directed at optimizing immune function: study protocol for a randomized controlled trial. Trials. 2017 May 26;18(1):243.

[7] Ghatineh S. & Vink M. FITNET's Internet-Based Cognitive Behavioural Therapy Is Ineffective and May Impede Natural Recovery in Adolescents with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. A Review. Behav Sci (Basel). 2017 Aug 11;7(3). pii: E52.

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What does 'recovery from myalgic encephalomyelitis / chronic fatigue syndrome' look like?

The title of this post reflects the material included in the paper by Andrew Devendorf and colleagues [1] who sought "an operationalised definition of recovery from myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) for research and practice."

Although perhaps at first sight being a rather simple question to answer - Q: What does recovery look like in relation to ME/CFS? A: Complete remission of symptoms -  there's a lot more behind such a query than you might expect. I'm particularly thinking about how 'recovery' has been a real source of discussion/debate/argument (delete as appropriate) in the context of ME/CFS in recent 'PACE' times (see here and see here).

Ten experts on ME/CFS were quizzed about their views specifically on recovery from the condition(s). As probably expected: "Physicians conceptualised recovery as complete symptom remission and a return to premorbid functioning (adjusted for with age)." No surprises there then. Insofar as the term 'significant improvement', experts also quite sensibly reported that this should be 'operationalised' as "a substantial reduction in symptoms with considerable functional gains, where patients may operate in daily life but still must cope or be treated." Again, not really that earth-shattering to be honest.

'Recovery' in the context of ME/CFS has been discussed in the peer-reviewed domain before [2] with views to "recommend a consistent definition that captures a broad-based return to health with assessments of both fatigue and function as well as the patient's perceptions of his/her recovery status." Although not everyone agreed with all that was said by Adamowicz and colleagues [3], there  is a general consensus that recovery represents an absolute term where 'complete symptom remission' is the important feature. Everything else outside of recovery falls into 'a spectrum of improvement' (substantial, significant, so-so, etc) through to no change or even potential symptom worsening.

The task facing ME/CFS research and practice now: how best to measure the recovery / non-recovery spectrum? I agree that questionnaires about fatigue and (very) important clinical signs like post-exertional malaise (PEM) need to be part and parcel of such measurements. As with any condition that is [currently] diagnosed solely on the basis of presented symptoms with no genetic or biological test yet able to distinguish cases from not-cases, questionnaires and interviews are always going to be important in terms of how symptoms change/evolve over time either naturally or as a result of some specific intervention(s). But research and practice really need more than that; they need some objectivity too...

So, physical activity levels: well, I've often gone on (and on!) about the great potential of actigraphy in the context of several research areas. You want data on rest and activity cycles for a condition characterised by rest and activity cycles? There's plenty of technology out there in the marketplace to measure such cycles and associated measures that could be used in a complementary fashion (see here). How do you define 'recovery' based on such data? Well, typically (at the moment where such tech are still relatively new) there probably won't be 'before and after' data as noted in other examples of such tech use (see here) so a reliance of general population data is the next best thing. Yes, by doing so we're moving from individual data to more generalised data as a comparator, but when such generalised data runs into the thousands or even millions of people (see here for one example) you can start to build up a picture based on 'expected' physical activity levels taking into account sex/gender, age and other important variables. The important point is that one element of recovery in CFS/ME is going to be a restoration of physical activity levels (and perhaps even sleep cycles?) and there are easy ways to measure that minus any subjectivity issues potentially included in questionnaires or interviews. I say all of that acknowledging that levels of typical day-to-day tasks such as work, shopping, socialising and other pastimes/activities which generally require physical exertion can also be to some extent ascertained via a questionnaire.

PEM? I'm not so sure about how to measure this outside of some limited research in this area [4] talking about a "change in complement C4a level and the increase in pain and fatigue 24 h following the self-paced, physiologically limited exercise support the use of C4a as a marker for postexertional malaise in people with ME⁄CFS." Complement C4a by the way, is something of a 'mediator of local inflammatory processes' and has cropped up on this blog before (see here). In light of other work also suggesting that PEM might have cognitive effects [5] too, I'm sure a little more scientific inquiry could bring together a suite of fairly cost-effective ways and means to objectively measure PEM both in terms of biology and also cognitive prowess. Yes, there are details to be worked out but...

Other things to be included in recovery criteria? Well, it depends on whether you're going to go down the sole 'core' symptoms pathway or going to include elements that may potentially be more peripheral [6] yet still impact on notions of recovery in CFS/ME (hyperacuity anyone?). That's not my call I'm afraid, although given what has been discussed with regards to health-related quality of life and ME/CFS (see here), the addition of something like the EQ-5D-3L to any protocol might not also go amiss as part of any measurement of recovery with CFS/ME in mind...

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[1] Devendorf AR. et al. Defining and measuring recovery from myalgic encephalomyelitis and chronic fatigue syndrome: the physician perspective. Disabil Rehabil. 2017 Oct 5:1-8.

[2] Adamowicz JL. et al. Defining recovery in chronic fatigue syndrome: a critical review. Qual Life Res. 2014 Nov;23(9):2407-16.

[3] Twisk FN. A definition of recovery in myalgic encephalomyelitis and chronic fatigue syndrome should be based upon objective measures. Qual Life Res. 2014 Nov;23(9):2417-8.

[4] Nijs J. et al. Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1beta. J Intern Med. 2010 Apr;267(4):418-35.

[5] Cook DB. et al. Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Brain, Behavior, and Immunity. 2017; 62: 87-99.

[6] Whiteley P.  et al. Correlates of Overlapping Fatigue Syndromes. Journal of Nutritional & Environmental Medicine. 2004; 14: 247-259.

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