Post-Exertional Malaise (PEM) in ME/CFS: what do patients say about it?

"The findings of this survey suggest that there are key domains of this symptom, including triggers, symptom onset, and duration, which have often not been comprehensively assessed in a previous PEM [post-exertional malaise] instrument."

So said the findings reported by Carly Holtzman and colleagues [1] (open-access available here) examining (yet again and yet again) an important part of the clinical profile of the conditions known as myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS): post-exertional malaise or PEM.

Although still the source of some debate (see here), PEM basically refers to "a worsening of ME/CFS symptoms after minimal physical or mental exertion." Some authors have used other words to describe PEM - "payback" is one of them - but the sentiments remain the same: a physiological (and psychological) 'cost' following exertion. And said exertion does not necessarily have to be over-exertion either.

In light of the 'confusion' around PEM, Holtzman et al decided on a rather sensible course of action: "to try to develop a comprehensive measure [of PEM] with active collaboration of the patient community." This follows other independent research that has reaped the rewards of asking patients suffering with ME/CFS (yes, suffering) about their experience of their illness (see here for example). To do this, one of the rather famous authors on the Holtzman paper - Leonard Jason - started some conversations with various other patients who were unhappy with some of the descriptions of PEM that were being bounced around. Joined by Holtzman, things took off with regards to a questionnaire that was developed with PEM in mind [2] as we are told that: "comments and items received helped shape each new revision of the questionnaire."

"A survey was ultimately developed and was subsequently completed by 1534 members of the patient community."

Findings? Well, first and foremost "94.4% reported being diagnosed by a medical doctor." Nearly three-quarters of participants reported 'symptom exacerbation' immediately following exertion. Nine out of ten participants "had experienced delayed onset after exertion." As to the triggers of PEM, well, "basic activities of daily living" was a big one, as was "emotional events (88.3%), noise (85.5%), and sensory overload (83.6%)." What sorts of symptoms were experienced? So: "reduced stamina and/or functional capacity (99.4%), physical fatigue (98.9%), cognitive exhaustion (97.4%), problems thinking (97.4%), unrefreshing sleep (95.0%), muscle pain (87.9%), insomnia (87.3%), muscle weakness/instability (87.3%), temperature dysregulation (86.9%), and flu-like symptoms (86.6%)." Quite a few. How long did PEM last for? An average of 3-6 days (that's days) and in some cases, an awful lot longer. Also: "67.1% of the sample had experienced a “crash” that never resolved." Most participants who answered the survey also felt that it pretty well reflected their experience of PEM.

There's quite a bit more to do in this area in terms of developing said questionnaire and hopefully putting more flesh on the descriptive bones of PEM. I'm also inclined to suggest that as well as describing PEM and how it is experienced by those diagnosed with ME/CFS, science needs to do a lot more on the biology of PEM and what could potentially help (yet again, minus the psychobabble). Still, 'asking patients' continues to be an important theme in ME/CFS research...

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[1] Holtzman CS. et al. Assessment of Post-Exertional Malaise (PEM) in Patients with Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS): A Patient-Driven Survey. Diagnostics (Basel). 2019 Mar 2;9(1). pii: E26.

[2] Jason LA. et al. The development of an instrument to assess post-exertional malaise in patients with myalgic encephalomyelitis and chronic fatigue syndrome. J Health Psychol. 2018 Oct 24:1359105318805819.

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"PEM, cognitive impairment, and orthostatic intolerance as core symptoms of pediatric ME/CFS"

There were a few rather familiar aspects to the study results published by Maria Roma and colleagues [1] investigating health-related quality of life (HRQOL) in relation to myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).

Familiar because HRQOL was found to be "substantially lower in an ambulatory population of adolescents and young adults with ME/CFS than for healthy controls in North America" in the Roma study, in keeping with other studies looking at this important parameter (see here). Familiar also because PEM - post-exertional malaise - was found to be something really quite important to ME / CFS, again in line with other findings (see here for example). But don't think that the Roma findings aren't important, they are. Indeed, with mention of something called orthostatic intolerance in the context of CFS / ME, they provide some further directions for investigation.

So: "We enrolled 55 consecutive ME/CFS patients (46 F) aged 10–23 years." They all "satisfied the 1994 International Chronic Fatigue Syndrome Study Group criteria" (also called the Fukuda criteria). Importantly too: "Individuals with primary depression who were referred by psychiatrists for evaluation of chronic fatigue were excluded, but those who had developed depression sometime after the onset of ME/CFS were included." See those words 'developed depression... after the onset of ME/CFS'. Control participants (n=55) - asymptomatic and in good health - were also included for study. Quite a large battery of questionnaires and schedules were delivered to participants covering HRQOL and quite a bit more including fatigue and depression. Researchers also asked a few questions about "the type of onset for ME/CFS" as well as items pertinent to the IOM (United States Institute of Medicine) criteria for ME/CFS. Lots to see.

And indeed, the results were pretty revealing. Yes, HRQOL was lower - significantly lower - in the ME/CFS group, as talk about a percentage of those with ME/CFS having to change from regular schooling "to part-time schooling... [or] home tutoring" tells you everything you need to know (yet again). Also: "A novel finding of this study is the correlation of impairment in HRQOL with the frequency of PEM, at least for an ambulatory population with ME/CFS." PEM, or 'payback' as another study categorised it as (see here), is starting to get the clinical and research attention that it truly deserves. Researchers specifically mention how "as the frequency of PEM increased, the mean PedsQL [Pediatric Quality of Life Inventory] score fell and the mean FDI [Functional Disability Inventory] score increased, consistent with a significant association of PEM with worse overall function." Need I say anymore?

And then back to orthostatic intolerance (i.e. the "development of symptoms when standing upright which are relieved when reclining"). Researchers considered this present in participants if "(a) self-reported lightheadedness occurred at least several times per week, (b) there was a history of recurrent syncope in the presence of a structurally normal heart, considered consistent with NMH [neurally mediated hypotension]... or (c) previous upright tilt testing or a passive standing testing (performed in patients not being treated with medications for orthostatic intolerance) had confirmed the presence of NMH or POTS [postural tachycardia syndrome]." And present it was in 96% of participants. So much so that authors decided that with orthostatic intolerance being one of the core diagnostic criteria for the IOM diagnostic criteria for ME/CFS, 85% of their participants hit the diagnostic thresholds based on that scheme. Important stuff.

This takes us neatly back to the quote titling this post: "PEM, cognitive impairment, and orthostatic intolerance as core symptoms of pediatric ME/CFS." And perhaps a change is coming to research and clinical practice in this area. Having said that, change is going to be quite difficult for some groups it seems [2] as words like: "Parental representations could contribute to fatigue maintenance" still appear in the peer-reviewed science literature with CFS/ME in mind...

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[1] Roma M. et al. Impaired Health-Related Quality of Life in Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Impact of Core Symptoms. Front. Pediatr. 2019. Feb 15.

[2] Loades ME. et al. Perfectionism and beliefs about emotions in adolescents with chronic fatigue syndrome and their parents: a preliminary investigation in a case control study nested within a cohort. Psychol Health. 2019 Mar 1:1-17.

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"Fatigue, fluctuation and payback were described by all adolescents with CFS/ME in this study"

The quote titling this post - "Fatigue, fluctuation and payback were described by all adolescents with CFS/ME in this study" - comes from the findings reported by Roxanne Parslow and colleagues [1] during their study designed "to explore outcomes important in paediatric chronic fatigue syndrome/myalgic encephalopathy (CFS/ME) and what improvements in fatigue and disability are key."

Indeed, this latest study seems to follow a theme of looking at the personal experiences of CFS/ME [2] by members of this authorship team, potentially onward to the development of a PROM (Patient Reported Outcome Measure) [3] specifically with children and adolescents in mind. If this was a goal, I wondered if perhaps this *could* also be linked to some other work from some of the Parslow paper authors that has also been previously discussed on this blog too (see here)?

I specifically wanted to talk about this paper because of the word 'payback' and it's particular use to mean an "increase in fatigue and symptoms following activity." Mentioning it only twice in their article (one of those occasions being the use of a reference), I think the authors mean post-exertional malaise (PEM) (see here and see here for more discussion of this concept). They however, seemed a little reluctant to use that term. In answering one of the reviewers of their paper prior to acceptance for publication, the authors did say: "Payback is defined as a core symptom in NHS guidance, and is used in the clinical setting." They also clarified how "the term ‘payback’ was used instead of exhaustion."

No mind, based on interviews with "21 adolescents and their parents (20 mothers and 2 fathers)", most adolescents being female with a mean age of around 14 years, several key themes emerged. To reiterate: "All adolescents with CFS/ME report fatigue, a natural fluctuation of the condition, as well as an increase in fatigue and symptoms after activity (payback)." Several sub-themes also emerged from such reporting including how: "Adolescents and parents reflected on how CFS/ME naturally fluctuates" and "Adolescents and parents recognised patterns of good and bad days" and "Adolescents were limited in the amount of time they could spend on activities, which ranged from minutes, ‘5 min’ to hours, ‘an hour at the most’." These aren't exactly novel findings by any means but it's always useful to see them described in the peer-reviewed research domain.

Heading back to that 'payback' issue, researchers mention how their results are "consistent with previous research where children described the intensity of symptoms fluctuating as well as ‘overextension’ making it worse, resulting in ‘paying the price’." Accepting that such payback or PEM or 'payback exhaustion resulting in fatigue and other symptoms following activity' if you prefer, is widely present in CFS/ME (albeit individual and 'variable' in nature), one might see the Parslow results perhaps as further justification for being slightly critical of the use of something like graded exercise therapy (GET) in relation to CFS/ME (see here). GET relies on the assumption that increasing or grading in physical activity will eventually 'help' facets of CFS/ME. Unfortunately, whilst still expounded in some circles, there is accumulating (peer-reviewed) evidence that many patients with CFS/ME experience GET as more of a hindrance rather than a help for their symptoms (see here). Indeed, allied to terms like 'deconditioning' as part of suite of 'psychobabble' that seems to have enveloped CFS/ME down the years, the idea that CFS/ME is something that can be just 'exercised out of' seems to have been a truly damaging policy that has not seemingly served many patients particularly well.

The Parslow findings are revealing and add something further to the idea that an overhaul of current thinking on CFS/ME in children and adults is perhaps required (see here). Obviously the results are small-scale and require some follow-up, but listening to patients and their parents/caregivers and their collected experiences is a good idea in my book; particularly when it comes to a group of conditions like CFS/ME that have seen more than their fair share of 'assumptions' down the years.

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[1] Parslow RM. et al. Adolescent’s descriptions of fatigue, fluctuation and payback in chronic fatigue syndrome/myalgic encephalopathy (CFS/ME): interviews with adolescents and parents. BMJ Paediatr Open. 2018;2(1):e000281.

[2] Parslow RM. et al. Children's experiences of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review and meta-ethnography of qualitative studies. BMJ Open. 2017 Jan 13;7(1):e012633.

[3] Parslow RM. et al. Important factors to consider when treating children with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): perspectives of health professionals from specialist services. BMC Pediatr. 2017 Feb 1;17(1):43.

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The DePaul Symptom Questionnaire for chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME)

It's another short descriptive post today as I bring the paper by Len Jason & Madison Sunnquist [1] to your attention charting "the development of the DePaul Symptom Questionnaire (DSQ) to assess symptoms of the major chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME) case definitions."

I say this is a descriptive post because the Jason/Sunnquist paper provides some important technical details about the DSQ and its evolution; all from a research group who seem to be pretty clued into ME/CFS and its very wide range of clinical presentation (see here).

There are some important aspects included in the paper; not least a focus on the issue of post-exertional malaise (PEM), something which has been a real focus to these researchers (see here). The other very welcomed side to the Jason/Sunnquist paper are the various links to the DSQ derivatives all provided free of charge.

'Nuff said.

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[1] Jason LA. & Sunnquist M. The Development of the DePaul Symptom Questionnaire: Original, Expanded, Brief, and Pediatric Versions. Front Pediatr. 2018;6:330.

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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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More welcome research on post-exertional malaise (PEM) in ME/CFS

The findings reported by Lily Chu and colleagues [1] provide the blogging fodder today, and some further welcome research into the concept of post-extertional malaise (PEM) in the context of chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME).

PEM represents a cardinal feature of CFS/ME, where physical exertion - whether covering exercise or even just daily activities - brings about a period of (even more) exhaustion, weakness and fatigue. As per my previous discussion of the paper by McManimen and colleagues [2], there's still some ambiguity when it comes to clinically defining PEM (and indeed, whether the word 'malaise' covers the range of symptoms that the term includes). What is clear however is that PEM is real and can be absolutely disabling.

The Chu study, including the name Jose Montoya on the authorship list, set out to "describe symptoms associated with and the time course of PEM." Authors designed an online survey "asking subjects about the history and course of their ME/CFS" that asked a few questions about PEM. This included: "1) What symptoms, if any, are triggered or worsened by physical or mental activity?; 2) What symptoms are triggered or worsened by emotional distress?; 3) How soon usually after starting mental or physical exertion does your illness begin to worsen?; and 4) If you feel worse after activities, how long does this worsening usually last?" They also describe how they were careful not to actually use the word 'PEM' during the course of their research in order to "try to decrease the chances that subjects already diagnosed with ME/CFS would automatically answer our question based on their knowledge of or preconceived notions about PEM." Smart move.

Results: some 150 people as part of something called the MGEISD (Genetic Expression and Immune System Dynamics) study responded to the survey. While some of the participants were formally diagnosed with ME/CFS, the cohort also included those "waiting to be seen at the clinic, members of online ME/CFS forums, and participants of local ME/CFS support groups." Although all were telephone screened to see "if they fitted Fukuda 1994 CFS criteria" one does need to be a little careful with describing such a process as providing anything approaching a 'homogeneous' group.

"Most subjects (N = 129, 90%) experienced PEM with both physical/ cognitive exertion and emotional distress." There didn't seem to be any specific 'rules' in terms of the connection between the 'stressor' and onset of PEM, although around 40% of participants reported experiencing PEM within 24 hours. This was however subject to quite some variation. Symptoms reported in relation to the PEM questionnaire items were also variable. Fatigue is up there as one would expect, but also things like sleeping issues and headache were noted. Around 40% of participants also reported on a constellation of PEM symptoms: fatigue, sleep disturbance, pain and "at least one immune-related symptom."

What is becoming a little clearer from this and other research is that (a) PEM or whatever you want to call it is a real issue for many people diagnosed with CFS/ME and (b) the symptoms of PEM are not necessarily uniform in either character or timescale (onset, duration, etc.) What's still missing? Well, biology is still missing from quite a lot of the PEM literature; biology in terms of what PEM looks like on a physiological level and whether there may be something that can be done to alleviate it at a biological level aside from resting up (often for days at a time). I've talked about this before on this blog, in terms of biologically characterising PEM and how, for example, it might look in terms of defining recovery from ME/CFS (see here). To that end, lots more investigation in this area is implied...

And while on the topic of ME/CFS, I'll draw your attention to the paper by Karfakis [3] talking about the "biopolitics of CFS/ME." Yes, there has been and continues to be lots of that, including the phrase: "CFS/ME is an illness trapped between medicine and psychology". Discuss in 500 words.

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[1] Chu L. et al. Deconstructing post-exertional malaise in myalgic encephalomyelitis/ chronic fatigue syndrome: A patient-centered, cross-sectional survey. PLoS One. 2018 Jun 1;13(6):e0197811.

[2] McManimen SL. et al. Deconstructing post-exertional malaise: An exploratory factor analysis. Journal of health psychology. August 2016:1359105316664139.

[3] Karfakis N. The biopolitics of CFS/ME. Stud Hist Philos Biol Biomed Sci. 2018 Jun 8. pii: S1369-8486(17)30070-5.

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'Premature telomere attrition' and chronic fatigue syndrome

I'm always a little cautious these days when I hear any disease/condition/label linked to telomeres. These biological aglets (the plastic tips at the end of shoelaces) are quite wonderful bits of genetic engineering found at the ends of chromosomes, and serve an important protective biological function. The trouble is that, as with various other areas of science, a whole slew of articles has linked [prematurely] shorted telomeres to this, that and t'other and it has subsequently become a bit confusing as to what effects are 'real' and which ones might be more coincidental or spurious...

I cautiously then approach the findings reported by Mangalathu Rajeevan and colleagues [1] and their observations of a "significant association of ME/CFS [myalgic encephalomyelitis/chronic fatigue syndrome] with premature telomere attrition that is largely moderated by female subjects < 45 years old." Given that ME/CFS has already been subject to spurious preliminary findings not-so-long-ago (see here), such associations need to be treated cautiously.

Rajeevan et al started with the hypothesis that "ME/CFS is associated with accelerated aging and that shorter telomeres will serve as a marker of this association." While it is certainly true that ME/CFS produces some debilitating symptoms that are not a million miles away from something like extreme ageing, I've not yet heard too many people talk about the condition(s) in the context of such ageing. That's not to say it might not be a good comparator; just that it's not commonly referenced in this context. The addition of the word 'immunosenescence' by the authors, describing how the immune system gradually wanes with advancing age, is also perhaps pertinent to ME/CFS, bearing in mind what science is starting to discover about immune function in the context of ME/CFS (see here for example) and also what something like physical activity *might* do for immunosenescence (see here). I also cautiously use the word 'burnout' when it comes to the immunological picture emerging for at least some ME/CFS but it could be relevant...

With a total participant group numbering 639 participants (adults, mostly female) including "64 CFS, 77 CFS-X [CFS but with exclusionary conditions], 302 ISF [unexplained chronic illness with insufficient symptoms/fatigue to meet all of the criteria for CFS] (with and without exclusionary conditions), and 196 NF [non-fatigued] without exclusionary conditions", the authors describe relative telomere length (T/S ratio) and other physiological data parameters. Some of the other parameters reported on were "HDL cholesterol (mg/dL), triglycerides (mg/dL), fasting glucose (mg/dL), insulin (µIU/mL), C-reactive protein (CRP, mg/dL), and albumin (g/dL)."

Results: "This study demonstrates a significant association of ME/CFS with premature telomere attrition." I've already mentioned how this finding was "largely moderated by female subjects < 45 years old"; taking into account other data that has observed that in a general population sense, females tend to have longer telomeres when compared with age-matched males. This sex-related general trend was not however observed among the fatigue group participants. The telomere attrition differences reported also survived when other potential confounders were included in the statistical mix. This included: "age, sex, body mass index, waist–hip ratio, post-exertional malaise and education attainment." Ergo, telomere length and attrition probably needs further study with CFS/ME in mind. That might also include some focus on telomerase activity too.

Another result reported on by Rajeevan and colleagues also caught my eye: "mean CRP level in CFS-X and CFS groups being 93% greater than in NF group." CRP denoting levels of C-reactive protein, is a pentraxin that is elevated in response to inflammation. I note that inflammation as characterised by various inflammatory markers has been described in some cases of ME/CFS [2] but surprisingly little seems to have been done with CRP specifically in mind [3]. Maybe the Rajeevan results will also spur on a little more investigation to rectify this issues too.

The authors conclude that their telomere results combined with evidence of inflammation (low-grade inflammation) and "metabolic decline/mitochondrial dysfunction" (see here) "provide multiple levels of support to include ME/CFS to the list of conditions associated with accelerated aging that could be triggered by genetic, epigenetic, infection, stress or other environmental factors." At the current time, and subject to further studies being undertaken, I would struggle to disagree with such a conclusion. The next important question: what can be done about reversing this accelerated/premature ageing?

And while on the topic of biological research starting to take its [rightful] place in the context of ME/CFS, I'll direct you to some observations from someone diagnosed with the condition...

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[1] Rajeevan M. et al. Association of chronic fatigue syndrome with premature telomere attrition. Journal of Translational Medicine. 2018; 16: 44.

[2] Maes M. et al. Evidence for inflammation and activation of cell-mediated immunity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): increased interleukin-1, tumor necrosis factor-α, PMN-elastase, lysozyme and neopterin. J Affect Disord. 2012 Feb;136(3):933-9.

[3] Spence VA. et al. Low-grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome. Clin Sci (Lond). 2008 Apr;114(8):561-6.

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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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"patients with CFS/ME do not exhibit insufficient concentrations of circulating total 25(OH)D"

The title heading this post comes from the findings reported by Kate Earl and colleagues [1] (open-access available here), where '25(OH)D' refers to calcifediol, a compound typically used to estimate how much vitamin D is present in the body and CFS/ME refers to Chronic Fatigue Syndrome / Myalgic Encephalomyelitis.

After assaying some 92 people with CFS/ME and an almost equal number of 'age-matched healthy controls' (HCs) for plasma total 25(OH)D and individual vitamin D metabolites - "25(OH)D2 and 25(OH)D3" - researchers concluded that vitamin D deficiency was not rife in their cohort. Indeed we are told that: "total 25(OH)D was significantly higher (p=0.001) in serum of patients with CFS/ME compared with HCs (60.2 and 47.3 nmol/L, respectively)." The authors were also able to report that vitamin D supplementation by the CFS/ME group seemed to be a primary reason for their findings.

There are a few important strengths to the Earl results that are worth mentioning. Not least that vitamin D metabolites were measured by mass spectrometric methods similar to other independent research occasions (see here for example). Mass spectrometry seems to have quite a few advantages over other methods of vitamin D analysis; now labelled as a gold-standard technique. Added to their use of a deuterated standard ("hexadeuterated (OH)D3") and one has some degree of confidence in the analytical results; albeit, as the authors acknowledge: "that only the main marker of vitamin D status, that is, 25(OH)D, was measured" and how "there is a need to assess all of the vitamin D metabolites" of which there are quite a few [2].

At first glance, the Earl findings seem pretty unremarkable. Supplementation with vitamin D, as everyone is being encouraged to do these days (see here), means higher levels of circulating vitamin D. I would be surprised if they didn't. This is also not the first time that vitamin D levels in relation to CFS/ME have been talked about in the peer-reviewed domain either (see here) albeit not always with the same results but again with that caveat about supplementation in mind.

Given however that a measure of fatigue - "the Chalder Fatigue Questionnaire" - was also included for all participants in the Earl study, and how nothing very much seemed to be present when looking at any connection between fatigue scores and vitamin D status, this provides a possible clue that vitamin D is probably not a big player specifically in relation to the presentation of fatigue in most cases of CFS/ME. Such a questionnaire does not rule out other potential associations (e.g. post-exertional malaise, PEM) nor that other, potential comorbidity appearing alongside CFS/ME might not have a stronger vitamin D link (see here for example). But for now, it adds to the literature (see here) casting doubt on any direct role for vitamin D in relation to CFS/ME.

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[1] Earl KE. et al. Vitamin D status in chronic fatigue syndrome/myalgic encephalomyelitis: a cohort study from the North-West of England. BMJ Open. 2017 Nov 8;7(11):e015296.

[2] Abu Kassim NS. et al. Simultaneous determination of 12 vitamin D compounds in human serum using online sample preparation and liquid chromatography-tandem mass spectrometry. J Chromatogr A. 2017 Dec 6. pii: S0021-9673(17)31772-7.

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'Childhood adversity' and chronic fatigue syndrome: comorbidity might count...

"The data suggests that previous studies showing a relationship between childhood adversity and CFS [chronic fatigue syndrome] may be attributable to the confounding effects of co-morbid or misdiagnosed depressive disorder."

So said the findings reported by James Clark and colleagues [1], inviting a 'rethink' about the suggested role of childhood adversity when it comes to CFS. Childhood adversity can cover quite a bit of clinical ground but typically includes things like interpersonal loss (death or separation from a loved one), parental maladjustment, maltreatment and other health or social 'mountains to climb' [2]. Clark et al relied on the use of the Childhood Trauma Questionnaire (CTQ) for their study, which focuses more specifically on things like abuse and neglect in childhood over and above loss or those other social and health-related variables like poverty and ill-health.

Said questionnaire was delivered to over 50 people diagnosed with CFS who importantly had "depression comprehensively excluded" from their clinical picture. Compared with CTQ responses from a smaller - "did not meet criteria for a psychiatric disorder" - control group, authors found little to separate the CFS and control groups. They concluded that whilst there was a small increased risk of CTQ defined adversity being linked to CFS, "much of this risk is mediated by the concomitant development of major depression."

This is rather interesting work. Obviously, we need more independent research to see if such trends hold water following replication, but there may be some important implications.

First, is the whole idea that childhood trauma might be a risk factor for CFS [3]. For those who've followed the ups-and-downs of certain 'biopsychosocial' discussions with CFS in mind (see here), the Clark results represent a bit of a blow to the fluffy psychological thinking that CFS is somehow some kind of 'response' to such adverse events. I'm not saying that childhood adversity can't potentially manifest as a psychiatric disorder (whether contributory in whole or in part) but this latest data perhaps fits with other observations [4] where confounding by "comorbid psychopathology" is to be more typically assumed in the context of CFS. I might also add that CFS is NOT a psychiatric disorder just in case you didn't know...

A second point to make is in relation to how CFS and something like depression are probably linked but not necessarily 'centrally' linked. I've touched upon this before on this blog (see here), where depression can most definitely be part of the clinical picture with CFS in mind [5] but one should not assume that depression is either causative of, or specifically inter-related to the aetiology or pathology of CFS. If, for example, having been a previously active person you are struck down with a condition that blights your life for years and years and potentially leaves you bed bound for extended periods of time, one could argue that your risk of developing something like depression or depressive symptoms is probably going to be elevated. Add in other issues such as loneliness for example, and the risk becomes heightened. A case in point is this piece and the quote: "Every night I’d have these incredibly kinetic dreams. I was flying or running up mountains. I’d wake up in the morning and realise that I was still in the same bedroom, and many mornings felt really disappointed that I was still alive." The crux of the matter is that depression in such a case is a 'reactive' scenario and needs to be treated independently; also evidenced by the fact that not everyone with CFS will suffer with depression [6]...

Finally, I also want to mention the difference between CFS and 'chronic fatigue' as being something potentially important. As noted on other blogging occasions (see here) there has been a tendency among certain researchers to use the term 'chronic fatigue' and this has also extended to research looking at "childhood psychological factors" too [7]. I'm not here to question findings that suggest that "children whose mothers experience anxiety and/or depression between pregnancy and child's age 6 years have an increased risk of developing chronic disabling fatigue in early adolescence" (bearing in mind correlation is not the same as causation), just that 'chronic disabling fatigue' is not necessarily the same as CFS and hence one should not assume the same overlap might pertain. One of the key differences to consider is PEM - post-extertional malaise; an integral component of CFS and something that needs a lot more recognition in the research and clinical literature in general.

I'm going to reiterate the opening sentence to this post from the Clark paper to end things: "The data suggests that previous studies showing a relationship between childhood adversity and CFS may be attributable to the confounding effects of co-morbid or misdiagnosed depressive disorder." Just in case. And also that the continuing focus on potential psychological/psychiatric 'explanations' for CFS is too often at the expense of some rather more concrete science that is emerging (see here) at least for some (see here)...

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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] Kessler RC. et al. Childhood adversities and adult psychopathology in the WHO World Mental Health Surveys. Br J Psychiatry. 2010 Nov;197(5):378-85.

[3] Heim C. et al. Early adverse experience and risk for chronic fatigue syndrome: results from a population-based study. Arch Gen Psychiatry. 2006 Nov;63(11):1258-66.

[4] Clark C. et al. Premorbid risk markers for chronic fatigue syndrome in the 1958 British birth cohort. Br J Psychiatry. 2011 Oct;199(4):323-9.

[5] Loades ME. et al. The presence of co-morbid mental health problems in a cohort of adolescents with chronic fatigue syndrome. Clin Child Psychol Psychiatry. 2017 Oct 1:1359104517736357.

[6] Daniels J. et al. Anxiety and depression in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): Examining the incidence of health anxiety in CFS/ME. Psychol Psychother. 2017 Sep;90(3):502-509.

[7] Collin SM. et al. Maternal and childhood psychological factors predict chronic disabling fatigue at age 13 years. J Adolesc Health. 2015 Feb;56(2):181-7.

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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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Post-exertional malaise (PEM) in CFS might mean more than one thing

"The results suggest that post-exertional malaise [PEM] is composed of two empirically different experiences, one for generalized fatigue and one for muscle-specific fatigue."

So said the findings reported by Stephanie McManimen and colleagues [1] looking at one of the most common and debilitating aspects of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and how rough-and-ready generalised descriptions often do little to reveal the complexities of this particular symptom.

The research group at the centre of this new paper based at DePaul University under the stewardship of Leonard Jason have some previous interest in this facet of ME/CFS as per other recent publications [2] talking about the trials and tribulations of defining PEM. Once again, the very multiple and very complicated ways that CFS/ME is currently diagnosed (see here for example) comes into play as the wording used to define PEM seems to count in terms of who is more or less likely to display this symptom. I might also add that even the words 'post-exertional malaise' have been subject to question and redefinition as per the use of the term PENE (Postexertional neuroimmune exhaustion) [3].

In their latest paper, McManimen et al set out to "discern whether post-exertional malaise is a unified construct or whether it is composed of two smaller constructs, muscle fatigue and generalized fatigue." As per the opening sentence of this post, researchers came down on the side of PEM meaning more than one thing, and with it the possibility of further revisions being required to the criteria to define this concept. Indeed, going back to yet another paper from this group [4] researchers suggested that several composite items might better define PEM over just one question: "Dead, heavy feeling that occurs quickly after starting to exercise; Next day soreness or fatigue after non-strenuous, everyday activities; Mentally tired after the slightest effort; Physically drained or sick after mild activity; and Minimum exercise makes you physically tired." Words, in a diagnostic sense, need to be used accurately.

And finally, whilst on the topic of CFS/ME, there have been some further developments around the science of CBT and graded exercise...

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[1] McManimen SL. et al. Deconstructing post-exertional malaise: An exploratory factor analysis. J Health Psychol. 2016 Aug 24. pii: 1359105316664139.

[2] Jason LA.  et al. Problems in Defining Post-Exertional Malaise. Journal of prevention & intervention in the community. 2015;43(1):20-31.

[3] Carruthers BM. et al. Myalgic encephalomyelitis: International Consensus Criteria. Journal of Internal Medicine. 2011;270(4):327-338.

[4] Jason LA. et al. Fatigue Scales and Chronic Fatigue Syndrome: Issues of Sensitivity and Specificity. Disabil Stud Q. 2011 Winter;31(1). pii: 1375.

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McManimen SL, Sunnquist ML, & Jason LA (2016). Deconstructing post-exertional malaise: An exploratory factor analysis. Journal of health psychology PMID: 27557649