On the question of suicide risk and chronic fatigue syndrome / myalgic encephalomyelitis continued

The paper by Andrew Devendorf and colleagues [1] brought me back to a complicated and sensitive topic previously discussed on this blog (see here) regarding the issue of suicide risk in the context of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, the Devendorf findings provide some potentially important information about the possible reasoning behind suicide risk in the context of ME/CFS: "(1) feeling trapped and (2) loss of self, loss of others, stigma and conflict."

Based on discussions with 29 people diagnosed with ME/CFS "who endorsed suicidal ideation but did not meet depression criteria" researchers, including one Leonard Jason (see here), discussed some of the hows-and-whys of such suicidal ideation. As per the 'did not meet depression criteria' sentiments of the research, this work was less about 'mental health diagnoses affecting suicide risk' and more about how thoughts, feelings and situational factors might play a role. And as per the two variables highlighted by the study - 'feeling trapped' and 'loss of self & others and the stigma and conflict' generated by this incapacitating condition(s), some clear areas for further research and clinical attention emerged.

I've covered the sensitive issue of suicide (risk, ideation, completion) quite a few times on this blog for all-manner of different reasons (see here and see here for examples). In the most part, my musings have been on research into suicide where a specific label/condition/disorder has been diagnosed, and how facets of such labels/conditions/disorders *might* at least partially, 'intrinsically' elevate the risk of suicide ideation or beyond. The Devendorf findings kinda deviate from such 'intrinsic' sentiments, insofar as examining the implications of an acquired physical disability (see here and see here) and the onward the physical (and mental) restrictions of a condition seemingly elevating the risk of suicidality. By saying all that, I'm not making any sweeping generalisations...

I don't think anyone should really be surprised by the Devendorf results. With ME/CFS you have a condition that literally steals life from people; for example, rendering previously fit and active people to sometimes being bed-bound for days and days (or even longer) at a time. Add in a 'boom-bust' pattern of symptoms (see here) and the various 'environmental' effects (to employment, finances, social life, etc) of the condition, and well, I'm often surprised how resilient people with ME/CFS are.

I noted also how the words 'stigma' and 'conflict' were also detailed in the Devendorf study, and what implications this might have for quite a few areas of current research and clinical practice in relation to ME/CFS. I'm thinking specifically about the whole 'biopsychosocial (BPS) thing' that seems to have pervaded ME/CFS thinking down the years (see here), and how psychology in particular, seems to have over-stepped it's usefulness in relation to ME/CFS. It's kind of a coincidence that as I write this post, another article including Keith Geraghty [2] on the authorship list, is published discussing how some ME/CFS patients and patient groups have been labelled as 'militant' (or similar words and phrases) on the basis of them pushing back against medical dogma as a function of their own experiences of BPS-backed 'intervention' for example (see here). Militant is one word that has been used, 'vexatious' is another (see here).

"Participants emphasized that they were not depressed, but felt trapped by the lack of treatments available." This sentence serves to reiterate that suicidality in the context of ME/CFS is perhaps not something that should necessarily be thought of as intrinsic to the condition(s). It emphasises how issues like 'hopelessness' at the state of medical knowledge about ME/CFS, about the lack of biological explanation for the condition, and the lack of intervention options (not BPS guided I might add) may play a role in thoughts and feelings related to suicidality. It also provides another rather pressing reason why less 'psychologising' and more biological science needs to be dedicated to the hows-and-whys of ME/CFS and the search for a cure...

----------

[1] Devendorf AR. et al. Suicidal ideation in non-depressed individuals: The effects of a chronic, misunderstood illness. J Health Psychol. 2018 Jul 1:1359105318785450.

----------

"Due to the definitions of ME and CFS, “ME/CFS” does not exist..."

Today, May 12th, is ME/CFS and Fibromyalgia International Awareness Day, a day to designed to "bring awareness to ME/CFS patients, families, caregivers, and researchers." Keep that terminology in mind...

The quote heading the title of this post - "Due to the definitions of ME and CFS, “ME/CFS” does not exist..." - comes from the viewpoint paper published by Frank Twisk [1]. The report covers an important topic in the realms of chronic fatigue syndrome (CFS) also known as myalgic encephalomyelitis (ME) also known as systemic exertion intolerance disease (SEID) in terms of whether it is appropriate to use such terms of defining the illness in a mixed or interchangeable fashion. Indeed, whether the connections between all those 'also known as' words I just used are actually accurately reflective of current diagnostic descriptions...

It's no secret that science and clinical practice is still coming to grips with some of the fundamentals of CFS, ME and SEID (see here and see here for examples) in terms of what to call it, how to define it and how to test for some of the fundamental diagnostic characteristics (see here). It's also still dealing with things like the definition of recovery (see here), which might seem like common sense (a complete and sustained remission of symptoms) but hasn't been particularly straightforward in this area for quite a few reasons.

Twisk takes the reader through some of the history of the terminology used and, how, whilst there is overlap in the way that ME, CFS and SEID are defined (chronic and long-lasting weakness or fatigue is a commonality), there are also some important differences. Take for example the authors description of the Ramsay criteria for ME and specifically onset: "Illness commonly initiated by respiratory and/or gastrointestinal infection, but an insidious or more dramatic onset following neurological, cardiac, or endocrine disability occurs." This contrasts with the onset criteria for CFS and SEID which basically says little about how symptoms start or come about.

Twisk concludes that: "ME is a neuromuscular disease" and should typically not to be viewed as 'equivalent' to CFS. CFS, he argues, tends to rely heavily on a single mandatory 'chronic fatigue' symptom, something that might intersect with ME but does not go far enough to evoke a full diagnosis of ME. As for SEID, well, trumpeted as being the solution to all the diagnostic confusion, SEID has it's own issues according to Twisk. Not least that it can't serve both masters (ME and CFS) in diagnostic terms. Also important: "SEID case criteria are also applicable to subsets of people with other diseases, for example, Multiple Sclerosis (MS) and lupus; and psychological conditions, for example, major depression." There is the propensity for diagnostic confusion.

I do think that Twisk is on to something with his observations. I know quite a few people who don't like the confusion caused by combination terminology like 'ME/CFS'; often seeing it as conflating two (or even more!) quite different conditions. Add in yet another potentially important variable to such an argument - the addition of chronic disabling fatigue (CDF) as "a proxy for clinically diagnosed CFS/ME" as some authors have (see here) - and things get even more muddled. I daresay a lot of this confusion might also intersect with discussions/debates/arguments as to how far something like the biopsychosical (BPS) model should or rather shouldn't be applied to such fatigue related conditions (see here)...

You want to do something for ME/CFS and Fibromyalgia International Awareness Day? Well, first thing you could do is watch 'Unrest', then follow the #millionsmissing hashtag and then push for more research, biological research...

----------

[1] Twisk FNM. Myalgic Encephalomyelitis, Chronic Fatigue Syndrome, and Systemic Exertion Intolerance Disease: Three Distinct Clinical Entities. Challenges. 2018; 9(1): 19.

---------

On mitochondrial DNA (mtDNA) changes and autism

Mitochondrial issues accompanying some diagnoses of autism have quite a bit of peer-reviewed research backing (see here for example). Not for everyone, but for some people diagnosed with an autism spectrum disorder (ASD), there seems to be something afoot with regards to these 'powerhouses of the cell' that could well impact on various aspects of their lives [1]. Indeed, keep that paper from Poling et al [1] in mind...

Although by no means an expert on mitochondrial issues in any context, I believe that there are a few ways in which mitochondrial dysfunction can manifest. It can present as a secondary disorder for example (see here), where some acquired biochemistry (non-genetic) provides some of the 'answers'. Or it can present as a primary mitochondrial disorder, a genetic condition "confirmed by a known or indisputably pathogenic mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutation" [2], where issues in the genetic code of mitochondria are present.

The recent findings reported by Noémi Ágnes Varga and colleagues [3] focused on that latter route looking at issues with mtDNA in the context of autism. They turned up some rather interesting results...

So: "The aim of the present study was to investigate the presence of the most common pathogenic mtDNA alterations in patients with ASD." Researchers screened 60 children with autism and 60 not-autism controls. One detail stuck out when it came to those controls: "Our control group for mtDNA screening consisted of 60 European adults (26 females and 34 males, median age = 28 years, IQR = 13.75) selected from our biobank." Compared with those participants diagnosed with autism, they were quite a bit older (median age = 7 years vs. median age  = 28 years) and indeed, the gender ratios were a little bit more balanced.

Anyhow: "Mitochondrial deletions were identified in 16.6% (10/60) of our patients with ASD." OK, 'patients' is not exactly the word I would use for participation in such a research project but that shouldn't distract from the findings. Varga et al also provide some further insights into those 10 'participants' with a diagnosis of autism and mtDNA deletion(s) which turned up some other interesting details, such as the finding that various other symptoms presented alongside autism. Quite a few of them were connected to muscle and movement functions (limb and truncal ataxia, hypotonia, dyspraxia) which ties into other independent findings [4]. I also noted the words 'gluten sensitivity' were mentioned in one case, which is guaranteed to perk my professional interest (see here) although I'm still a little unsure of whether this connected to mtDNA issues or not.

Another set of potentially important details were also observed by researchers when comparing those with autism with and without mtDNA deletion(s). Keeping in mind the small numbers falling into that autism with mtDNA deletion(s) category, developmental regression seemed to be an important facet of the clinical profile of this group. Regression of previously acquired skills is something else I've talked about quite a bit on this blog with regards to autism (see here and see here for examples). Going back to that paper by Jon Poling and colleagues [1] that I told you to keep in mind, it's interesting to note the overlap of regression reported by them and also reported by Varga in the context of mitochondrial disorder. And this isn't the only occasion that regression and mitochondrial issues have been talked about in the same breath as autism [5] and even with other potentially important clinical indicators [6]. Correlation is not necessarily causation but...

There are quite a few other details listed in the Varga paper that I'd encourage readers to pursue but I think I've gone on enough about this topic for now. It, yet again, appears that a diagnosis of autism is protective of nothing when it comes to other conditions/diseases/symptoms/labels appearing and perhaps implies that preferential screening for mitochondrial disorder should be more commonplace than it is as and when autism is diagnosed. I'm also inclined to draw your attention to other clinical labels where mitochondrial issues might be relevant for some (see here) albeit not always with genetics in mind (see here). How perhaps investigations need to be carried out looking at any possible intersection between *some* autism and something like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (see here) for example, also in light of other important data (see here). Indeed, I'll be coming to the findings reported by Bilevicute-Ljunger and colleagues [7] on this topic quite soon in a separate post...

----------

[1] Poling JS. et al. Developmental Regression and Mitochondrial Dysfunction in a Child With Autism. J Child Neurology. 2006;21(2):170-172.

[2] Niyazov DM. et al. Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction: Importance of Distinction for Diagnosis and Treatment. Mol Syndromol. 2016 Jul;7(3):122-37.

[3] Varga NA. et al. Mitochondrial dysfunction and autism: comprehensive genetic analyses of children with autism and mtDNA deletion. Behavioral and Brain Functions. 2018. 14: 4.

[4] Ghaoui R. & Sue CM. Movement disorders in mitochondrial disease. J Neurology. 2018. Jan 6.

[5] Rossignol DA. & Frye RE. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry. 2012 Mar;17(3):290-314.

[6] Shoffner J. et al. Fever plus mitochondrial disease could be risk factors for autistic regression. J Child Neurol. 2010 Apr;25(4):429-34.

[7] Bilevicute-Ljunger. I. et al. Patients with chronic fatigue syndrome do not score higher on the Autism-apectrum quotient than healthy controls: comparison with autism spectrum disorder. Scandinavian Journal of Psychology. 2018.

----------

Anxiety prevention meta-analysed and some implications...

"Psychological and/or educational interventions had a small but statistically significant benefit for anxiety prevention in all populations evaluated. Although more studies with larger samples and active comparators are needed, these findings suggest that anxiety prevention programs should be further developed and implemented."

That was the research bottom-line published by Patricia Moreno-Peral and colleagues [1] assessing the collected peer-reviewed literature pertinent to the question: "Are psychological and/or educational preventive interventions for anxiety effective in varied populations?" An accompanying editorial on the Moreno-Peral findings is also worthwhile reading [2].

The methodological name of the game was systematic review and meta-analysis followed by "meta-regression" to boil down data from some 29 studies examining whether "psychological and/or educational interventions are effective in the prevention of anxiety." Said interventions covered some ground but in the most part relied on the use of cognitive behavioral therapy (CBT).

I'm not going to say too much more about the Moreno-Peral findings because I think they speak for themselves. I do however want to make comment on the authors' use of the term 'varied populations' to highlight potential implications for a couple of populations pertinent to this blog: (a) the autism spectrum and (b) those diagnosed with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

Starting with autism, there are two salient points to make: (i) anxiety is pretty rife in relation to autism (see here and see here) and (ii) treating anxiety in relation to autism already has some peer-reviewed science efforts (see here) but little so far has seemingly been done on the point of potentially heading-off clinically relevant anxiety before it takes hold. I say this mindful of the idea that core symptoms linked to autism might be potential 'anxiety-provokers' (see here). Quite a bit more research is needed to ensure that psychological and/or educational interventions for anxiety currently available are specifically tailored to the wants and needs of those on the autism spectrum (including all of the spectrum!) but this area promises quite a bit. It's also worth appreciating that there may be a place for other types of prevention/intervention when it comes to anxiety (see here for example) in the context of autism (see here).

I also mentioned the [careful] application of the Moreno-Peral findings to CFS/ME. Coincidentally at the time of writing this post, I stumbled across the paper by Sarah Stoll and colleagues [3] asking: 'What treatments work for anxiety in children with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)?' The answer, based on the available literature is 'we don't know yet' with the requirement for more investigations.

I tread very carefully in this area based on the fact that whilst anxiety does seem to be part and parcel of some CFS/ME (see here), suggestions about the possible usefulness of something like CBT to manage anxiety have to viewed in the context of CBT still courting controversy as part of the biopsychosocial 'view' of CFS/ME (see here) (something that is relevant to other recent discussions about CFS/ME). Indeed, one might see the Stoll findings in the context that the 'failure' of interventions like CBT in relation to treating core CFS/ME (see here for what I mean by 'failure') is moving some people along to still try and stick with CBT but re-do and re-apply it in the context of treating more peripheral signs and symptoms accompanying CFS/ME such as anxiety. I might be wrong but...

To close, but keeping the CFS/ME link in mind, I once again note a welcomed U-turn from NICE (National Institute for Health and Care Excellence) on the topic of CFS/ME: "The strong message from stakeholders was that the continuing debate about the causes of this condition and the best approach to treatment argued for a review of the current guideline." I've said it before and will say it again: patient-power has driven this reconsideration (see here)...

----------

[1] Moreno-Peral P. et al. Effectiveness of Psychological and/or Educational Interventions in the Prevention of Anxiety. JAMA Psychiatry. 2017. Sept 6.

[2] Hudson JL. Prevention of Anxiety Disorders Across the Lifespan. JAMA Psychiatry. 2017. Sept 6.

[3] Stoll SVE. et al. What treatments work for anxiety in children with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)? Systematic review. BMJ Open. 2017; 7: e015481.

----------

CFS/ME associated with pandemic influenza infection

"Pandemic influenza A (H1N1) infection was associated with a more than two-fold increased risk of CFS/ME [Chronic fatigue syndrome/myalgic encephalomyelitis]."

That was the headline finding from the study by Per Magnus and colleagues [1] looking at whether large population data might provide some clues about 'associated' variables when it comes to the various debilitating conditions headed under the terms CFS/ME.

I'm blogging at a slight disadvantage with regards to the Magnus study because I don't yet have the full-text paper. Looking at the source data - "Using the unique personal identification number assigned to everybody who is registered as resident in Norway" - and observing some notable names on the authorship list, I'm inclined to suspect that this study might have some MoBa undertones (see here) bearing in mind the focus on the "complete Norwegian population" not just pregnant women and their offspring. Indeed, other research from this authorship group provides some further clues about data derivation [2].

Focusing on those specifically diagnosed with CFS/ME - "diagnostic code G93.3 in the International Classification of Diseases, Version 10" researchers calculated hazard ratios (HRs) for CFS/ME "after influenza infection and/or vaccination." A few details emerged including:

• "The incidence rate of CFS/ME was 2.08 per 100,000 person-months at risk." At this point I might direct you towards some details on the difference between incidence and prevalence.
• Influenza infection seemed to confer something of an enhanced risk for CFS/ME as per the finding of an adjusted HR of 2.04 (95% CI: 1.78-2.33). 
• That being said, the authors report "no indication of increased risk of CFS/ME after [pandemic] vaccination." This has potentially important public health implications (see here).
• They conclude by suggesting that such natural infection = increased risk of CFS/ME vs. antigenic stimulation (vaccination) = no increased risk of CFS/ME might indicate "a model whereby symptomatic infection, rather than antigenic stimulation may trigger CFS/ME."

The first thing that struck me about these findings was the 'overlap' noted with a familiar concept to this blog: maternal immune stimulation and offspring outcomes. This is the idea that immune 'stimulation' during critical periods of pregnancy might have the propensity to affect offspring developmental outcomes in a behavioural fashion (see here for example). Two of the big names in this area (Alan Brown and the late Paul Patterson) wrote rather a good review of this area focused on how some of the tools of public health such as vaccination might already be affecting the risk of development/onset of schizophrenia in relation to the maternal immune activation (MIA) model [3] with viruses such as influenza in mind. More detailed work is of course indicated.

Without trying to equate CFS/ME with schizophrenia or any other related label, I do find it interesting that infection and the associated biological response associated with it, might show some 'connection' to CFS/ME in the same/similar way that such biology might also be involved in priming a person for later-life schizophrenia. If we've learned anything about CFS/ME this year aside from it being 'a real illness' (see here if you really needed telling) it is that in amongst the multitude of findings on the condition, there is some really interesting 'immune-related' features coming through (see here). I know the term 'immune-related features' covers a lot of ground but alongside the already tantalising idea that infection is linked to CFS/ME onset (see here) (why else would it be also referred to as post-viral fatigue syndrome), I'm talking about how infection and response to infection might so severely impact on a person and what could be done to potentially prevent it.

Further work is indicated on the basis of the Magnus findings including a focus not just on influenza and CFS/ME but other biological agents such as the really, really interesting prospect of a connection between cases of CFS/ME and acute enterovirus infection [4] for example. Assuming that genetic make-up probably plays an important role in the handling of such viruses in relation to labels like CFS/ME, I'd like to think that research is heading in the right direction to offer viable prevention / treatment options for such devastating disorders bearing in mind the heterogeneity present [5]...

Music: Therapy? - Nowhere.

----------

[1] Magnus P. et al. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine. Vaccine. 2015 Oct 13. pii: S0264-410X(15)01433-4.

[2] Bakken IJ. et al. Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: a population-based registry study from Norway 2008-2012. BMC Med. 2014 Oct 1;12:167.

[3] Brown AS. & Patterson PH. Maternal Infection and Schizophrenia: Implications for Prevention. Schizophrenia Bulletin. 2011;37(2):284-290.

[4] Chia J. et al. Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence. J Clin Pathol. 2010 Feb;63(2):165-8.

[5] Zdunek M. et al. A Cross Cultural Comparison of Disability and Symptomatology Associated with CFS. Int J Psychol Behav Sci. 2015;5(2):98-107.

----------

Magnus P, Gunnes N, Tveito K, Bakken IJ, Ghaderi S, Stoltenberg C, Hornig M, Lipkin WI, Trogstad L, & Håberg SE (2015). Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine. Vaccine PMID: 26475444

Health-related quality of life in CFS/ME

Hvidberg et al (2015) PLoS One. e0132421

Two papers are served up for your reading today. Both provide stark peer-reviewed evidence that when it comes to chronic fatigue syndrome (CFS) / myalgic encephalomyelitis (ME), measures of quality of life (QoL) rank this/these condition(s) as potentially causing great suffering compared with population norms and various other states.

The first paper is by Michael Falk Hvidberg and colleagues [1] (open-access available here) and details response of Danish participants diagnosed with ME/CFS on the EQ-5D-3L "a generic, self-reported questionnaire with five dimensions: 1) mobility; 2) self-care; 3) usual activities; 4) pain/discomfort; and 5) anxiety/depression."

Taking into account various other variables such as gender/sex and education, researchers reported that the "ME/CFS study population is more disabled and socially marginalized than the average population with regards to the subjects of long-term illness, number of illnesses, proportion of disability pensioners and relationships." Further based on the examination of various other data utilising the EQ-5D-3L schedule "the ME/CFS patients of the current study have the lowest, unadjusted EQ-5D-3L measured HRQoL [health-related quality of life] of 20 conditions, thus even worse than multiple sclerosis and stroke." The figure reproduced from the Hvidberg study shows how ME/CFS measures up against those other conditions.

Continuing the theme of of health-related QoL are the results published by Anette Winger and colleagues [2] (open-access available here). Detailing the experiences of some 120 Norwegian adolescents, researchers delivered "The Pediatric Quality of Life Inventory™, 4.0 (PedsQL)" among other things to participants and "39 healthy controls (HC)." They concluded that: "adolescents with CFS have a significantly lower quality of life compared with healthy controls, demonstrated by lower overall HRQOL score and sub-score levels for specific HRQOL domains." Further: "Depressive symptoms were found in both adolescents with CFS and HCs, but the score levels were higher among the adolescents with CFS. The low HRQOL level in the CFS group was not explained by depressive symptoms but by having CFS."

Bearing in mind potential methodological issues such as the relatively small participant numbers included and the reliance on self-report as a measure of QoL (though not necessarily a bad thing when it comes to an individual's perceived quality of life), there are some pretty stark messages to come from this and other peer-reviewed data on this topic.

First and foremost is the idea that a diagnosis of ME/CFS really, really impacts on a person's life. For those suffering (yes, people diagnosed with ME/CFS do suffer) from this disorder, this is not likely to be new news. If you want just one story about how far-reaching the effects of this disorder can be, you can read it here. That a reduction in health-related QoL which follows ME/CFS is likely to be compounded by the 'stigma' built up around the condition(s) should also not be under-estimated. Indeed, only this year (2015) has science really started to put some flesh on the bones that ME/CFS is a 'biological illness' as per the Hornig/Lipkin results (see here) and those from others (see here).

Second, and as per some comment in the Winger results, is the idea that 'school functioning' is an important area that is impacted when it comes to adolescent ME/CFS. To quote: "school functioning was the most affected HRQOL domain, with a score level... substantially lower compared with previous studies on CFS patients." I've covered the idea that ME/CFS might show something of a connection to school attendance before on this blog (see here) and how onset of symptoms during such a critical period of development might be something in need of much greater inspection in terms of improving access to education for those diagnosed.

Finally is the question of what can be done to improve QoL for those diagnosed with ME/CFS. From a biological perspective, I might draw your attention to various discussions on this blog about the ways and means research has tried to intervene to ameliorate symptoms as a possible means to improve QoL (see here and see here for example). With no medical or clinical advice given or intended, science continues to approach the idea that within the spectrum of conditions probably included under the heading(s) of ME/CFS, there may be viable treatment options available [3] assuming further investigations. I might add that one area that particularly interests me is a possible role for enterovirus in at least some ME/CFS [4] and where this could eventually lead in terms of potential intervention(s). Added to this are the various other ways and means that society can help insofar as improving healthcare access, recognising that the risk of various comorbidity might be heightened following a diagnosis (see here) and ensuring that appropriate adjustments are made for a person in terms of finance, education and/or employment and other areas when a diagnosis is eventually made.

In short, more needs to be done to ensure that those diagnosed with ME/CFS are not subject to further health inequality...

----------

[1] Falk Hvidberg M. et al. The Health-Related Quality of Life for Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS). PLoS One. 2015 Jul 6;10(7):e0132421.

[2] Winger A. et al. Health related quality of life in adolescents with chronic fatigue syndrome: a cross-sectional study. Health Qual Life Outcomes. 2015 Jul 3;13(1):96.

[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: 10(7): e0129898.

[4] Chia JK. The role of enterovirus in chronic fatigue syndrome. J Clin Pathol. 2005 Nov;58(11):1126-32

----------

Falk Hvidberg M, Brinth LS, Olesen AV, Petersen KD, & Ehlers L (2015). The Health-Related Quality of Life for Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS). PloS one, 10 (7) PMID: 26147503





Winger A, Kvarstein G, Wyller VB, Ekstedt M, Sulheim D, Fagermoen E, Småstuen MC, & Helseth S (2015). Health related quality of life in adolescents with chronic fatigue syndrome: a cross-sectional study. Health and quality of life outcomes, 13 (1) PMID: 26138694

Physical activity and fitness levels and autism

Although at present having to be slightly more cautious following some recent surgery (general anaesthetic is awesome by the way!), I normally consider myself to be quite an active person. Through previous discussions on this blog covering topics on the positive effects of walking (see here) and the physical+ benefits of the martial arts (see here) I'd like to think that there are quite a few ways and means that the population at large can easily increase their daily physical activity levels. That physical activity might have quite a few knock-on effects for mental health and wellbeing is another angle to which I subscribe.

"'A storm is coming,' Frank says"

With my autism research blogging hat on, I've talked about how quite a bit of the peer-reviewed literature looking at autism and physical activity levels seems to imply 'more to do' when it comes to decreasing sedentary behaviours and getting people up and active (see here). A recent paper from Kiley Tyler and colleagues [1] (open-access) confirms this assertion.

The Tyler paper in open-access but a few pointers might be useful...

• Small groups of children and young adults with autism (n=17) and asymptomatic controls (n=12) were included for study and following an assessment looking at diagnostic and developmental factors were investigated using "a series of physical fitness assessments in aerobic fitness, muscular strength, flexibility, and anthropometric measures (height and weight)". We are also told that: "Physical activity was measured through accelerometry".
• If, like me, measures like aerobic fitness mean very little to you, this particular assessment involved something called the 20-metre multistage shuttle run [2] used to "determine the estimated maximal aerobic power (VO2max) for that individual". Basically, run back and forth across 20m to an ever frequent pinging sound until you can do no more and measure your maximum rate of oxygen consumption. 
• Muscular strength was measured "using a handgrip strength assessment". Reading about this assessment brought to mind some other autism research in this area which I read about recently from Janet Kern and colleagues [3].
• Physical activity levels were assessed using an accelerometer worn over 7 days. 
• Results: well, most of the physical fitness parameters did not significantly differ between the autism and not-autism groups. Strength did come out as reduced in the autism group as per the findings from Kern et al but that's about it. 
• But... physical activity levels were different between the groups across the various gradings describing sedentary, light and moderate activity levels. "Children with ASD spent less time in light, moderate, and moderate-to-vigorous physical activity and spent more time in sedentary behavior when compared to typically developing peers".
• The authors conclude that: "more research is needed on the physical activity determinants specific to children with ASD [autism spectrum disorder]". But also that their results were "encouraging as they indicate that children and youth with an ASD show capacity to meet daily guidelines for physical fitness and activity".

So basically, this particular cohort of children and young adults with autism do not lack the capacity to engage in physical activity but for whatever reason, physical activity levels are down compared to those not in receipt of a diagnosis of autism. I should also say that I summarise this without pointing any fingers of blame.

A quick trawl of some of the related research literature in this area provides one or two clues as to what might be influencing those activity levels. Schenkelberg and colleagues [4] talked about features of the social environment potentially influencing physical activity levels of children with autism. It is perhaps an under-appreciated aspect of the social side of autism that solitary play for example, is probably not going to include any great degree of physical activity as compared to what you might see in shared play with peers for example. Schenkelberg et al kinda hint at this with their observation of no significant differences in physical activity levels between their small group with autism vs. asymptomatic controls when engaged in "organized activity".

I mentioned previously that capacity to engage in physical activity did not seem to be affected in the participants of the Tyler study but one should also not assume this is pertinent to all on the autism spectrum. Motor issues have been talked about previously on this blog (see here) and, as per the findings from Christensen and colleagues [5] there is a growing appreciation that an autism diagnosis might increase the risk for conditions potentially affecting motor function: "The higher frequency of ASD in non-spastic than in spastic subtypes of CP [cerebral palsy] calls for closer examination". Again, something discussed on this blog before (see here). Rather more speculatively, I'm also minded to point you to a gap in the research base looking at something like comorbidity of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS / ME) with autism (see here) as another area to potentially investigate.

Physical inactivity is pretty endemic these days across all walks of life. Autism is not unique in its general relationship to relative inactivity although does seem to rank up there when it comes to the available data [6]. Allied to the data on levels of obesity in cases (see here) and the corresponding issues circling things like eating habits for example (see here), there are some important factors to tackle here to ensure that such physical inactivity does not further 'disable' or disadvantage many people who are perhaps already subject to significant health inequality...

Oh, and just in case you were wondering, it's as easy as 10,000 steps [7].

Music then. Fill My Little World by The Feeling.

----------

[1] Tyler K. et al. Physical Activity and Physical Fitness of School-Aged Children and Youth with Autism Spectrum Disorders. Autism Research and Treatment. 2014; Article ID 312163.

[2] Léger LA. et al. The multistage 20 metre shuttle run test for aerobic fitness. J Sports Sci. 1988 Summer;6(2):93-101.

[3] Kern JK. et al. Handgrip strength in autism spectrum disorder compared with controls. J Strength Cond Res. 2013 Aug;27(8):2277-81.

[4] Schenkelberg MA. et al. Social Environmental Influences on Physical Activity of Children With Autism Spectrum Disorders. J Phys Act Health. 2014 Aug 7. [Epub ahead of print]

[5] Christensen D. et al. Prevalence of cerebral palsy, co-occurring autism spectrum disorders, and motor functioning - Autism and Developmental Disabilities Monitoring Network, USA, 2008. Dev Med Child Neurol. 2014 Jan;56(1):59-65.

[6] Mangerud WL. et al. Physical activity in adolescents with psychiatric disorders and in the general population. Child Adolesc Psychiatry Ment Health. 2014 Jan 22;8(1):2.

[7] LaLonde KB. et al. Increasing physical activity in young adults with autism spectrum disorders. Research in Autism Spectrum Disorders. 2014; 8: 1679-1684.

----------

Tyler, K., MacDonald, M., & Menear, K. (2014). Physical Activity and Physical Fitness of School-Aged Children and Youth with Autism Spectrum Disorders Autism Research and Treatment, 2014, 1-6 DOI: 10.1155/2014/312163

Tick, tick, tick...boom

Despite the very dramatic title of this post, I am not going to be discussing explosives nor even the Will Smith (not forgetting Jazzy Jeff) song which carried such lyrical swagger, but rather a few things related to the small but mighty tick (and no, not that tick either). For those of a squeamish disposition who prefer not to see creepy-crawlies and their various effects on body parts, I would perhaps suggest not clicking on this link (or even worse this link) which describes, in quite some detail, how the tick and its bite is potentially linked to a condition called Lyme disease.

For those who didn't click on the link but are still curious, Lyme disease is an inflammatory disease which occurs when a tick harbouring the bacteria Borrelia burgdorferi bites and transmits said bacteria to humans. The name Lyme comes from the place Lyme, USA where an outbreak of the disease leading to a cluster of cases of juvenile arthritis led to the first comprehensive description. The symptoms can include things like lethargy, fever, headaches, muscle pain and in more serious cases, joint inflammation and changes to behaviour. This last symptom relating to behaviour is a little non-descript although some people have speculated that this could include autistic-like behaviours. Bacteria affecting behaviour also conjours up some interesting links with the many and varied posts made on this blog relating to how external organisms might be able to affect our presented behaviour; but I digress.

Looking on the web, there is quite a lot of interest in a possible connection between Lyme disease and lots of different conditions. Chronic, persistent Lyme disease has found some overlap with conditions such as Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) and fibromyalgia (FM) given the described similarities in symptoms. Indeed, there is some evidence that Lyme disease may co-exist alongside conditions such as FM, although a universally causative relationship has not yet been established. As mentioned, a particular form of arthritis is one of the more serious symptoms associated with Lyme disease but there are a variety of other effects linked to the nervous system for example.

Autism has also been speculatively linked to Lyme disease, although I would perhaps emphasise the 'speculatively' side of things. The evidence for an association is sparse to say the least, and currently non-existent (at least in PubMed listed journals) in terms of data on things like serological co-morbidity and any potential effects on autistic symptoms following infection or treatment for Lyme disease. That being said, the prescribed treatment schedule for Lyme disease utilising antibiotics such as the tetracyclines has found some initial favour in the management of symptoms in autism-linked conditions such as Fragile X syndrome albeit tied into potential effects outside of antimicrobial activity.

Although the data is sparse, there is some common sense reason for looking at the potential involvement of Lyme disease in some cases of autism. As per my comments in previous posts, autism is not protective of developing other conditions/diseases/infections, so one could perhaps see that a child with autism walking in woodland with their parents would be at equal risk of being bitten by a tick as everyone else. Whether or not there would be some increased likelihood of being bitten is not known. Gestational Lyme disease, diagnosed on the presence of anti-Borrelia burgdorferi antibodies, can be associated with adverse neonatal and post-natal outcomes for the infant. This, despite the fact, that pregnancy might actually provide some protective immunological effects. Some of the adverse outcomes described by Nadal and colleagues show some possible connection to autism (hyperbilirubinaemia, hypotonia, macrocephaly) but it is altogether a different thing to say that such outcomes related to autism might be caused by secondary Lyme disease. Further research would perhaps be required.

I appreciate that for some people thinking about ticks and what they could do is spine-tingling stuff. Suffice to say that the risk of getting a tick bite is pretty low assuming that a few precautions are taken, not least keeping away from tick hotspots (long grass off the beaten track where deer may roam).

XMRV marks the spot?

In quite a few posts on this blog, the nature of the relationship between humans and the various smaller organisms which have populated our planet for many millions of years in one form or another, has been explored. Take for example the possible relationship between Toxoplasma gondii and schizophrenia covered in this post, and you can see that there is the potential for an interesting relationship between the human body, mind and various infective agents. The research of course does not say that we are all singularly at the mercy of such external organisms or that somehow free will is just an illusion; merely that our health and functioning might be influenced by lots of different factors, some of which we are only beginning to realise and understand.

My attention in this post is on an area of research which has been speculated to straddle quite a few conditions including autism and the various fatigue-related conditions. Readers might remember a post a few days back where I 'attempted' to look at some of the preliminary research commonalities between autism and chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME). If true, the focus of this post could be a very important commonality - if true.

Xenotropic Murine Leukemia Virus-Related Virus (XMRV) has had quite a bit of exposure in the research (and media) world of late. This retrovirus has been linked to quite a few different conditions, most notably prostate cancer, with some evidence presented for a possible association. I say linked, but be under no illusion that the evidence base is conclusive in this area. Indeed, with regards to prostate cancer, there have been several reports detailing no universal connection between XMRV and such cancer. One of the most recent studies from the CDC no less can be read here and details only a very low prevalence of XMRV in prostate cancer (1.9%). Of course that 1.9% is a reality for 1.9% of prostate cancers, but I think most people would admit that this is quite a small percentage of cases and is certainly not grounds for a universal relationship.

XMRV has perhaps found most controversy in its proposed relationship to CFS/ME. I don't really have the time or space to provide the full story linking the two conditions together so would perhaps refer you to this page for a summary. The paper which first suggested an association is this one published in Science, whereby XMRV was reported in PBMCs of people with CFS (67%) over and above controls (~4%).  The authors suggested that such a significant finding could either be indicative of an aetiological factor for CFS and/or could suggest potential 'treatment' options via the use of anti-retroviral drugs. CFS/ME is no stranger to a possible viral connection: ME has also been known as post-viral fatigue syndrome (PVFS) (not even mentioning the Royal Free incident of 1955). Indeed viral infections including glandular fever and even SARS have also been reported to be associated with symptoms. The subsequent research carried out on XMRV and CFS/ME has not however exactly provided a ringing endorsement for a possible connection between the two, despite some tentative confirmation of aspects related to the original findings. There are numerous papers suggesting no link between ME/CFS and XMRV including this one from the UK and this one from the USA. A good summary of the results so far is here. I am not going to say much more on the XMRV-CFS/ME relationship in this post aside from the fact that the controversy continues. There are various reasons to potentially account for the results obtained and there are many people better qualified than I to offer their informed opinion.

Autism spectrum conditions have also been discussed in connection with XMRV, at least preliminarily. I can't say for sure where and why XMRV was first related to autism but I seem to remember someone at the original study location, the Whittemore-Peterson Institute, suggesting that autism may also show some correlation based on other (unpublished) results. Viral infections accompanying autism have been the topic of some debate down the years with several suggestions put forward for a possible connection (see here and here). There have been some case reports detailing the diagnosis of XMRV infection in autism, but at this stage I cannot confirm whether the same issues potentially related to ME/CFS (i.e. cross-contamination) are applicable or not given the lack of information on testing protocols. The limited published group evidence on any connection between autism and XMRV is pretty categorical: no presence of XMRV in cases of autism (see here and here). As per the mantra of this blog, science is about probabilities not absolutes. In the case of XMRV and autism, I have to say that the data (so far) is quite explicit in the direction of its findings.

The initial interest in XMRV has perhaps abated slightly given the number of studies that have been completed. I think there are a few interesting points to note from this whole issue including the concept of universality (and what it means when potentially assigning a correlate to all or a large proportion of people with often nebulous symptoms), correlation and causation (one does not equal the other - even in those cases where XMRV has been detected, the various data do not yet provide any indication that treating XMRV actually impacts on presented symptoms outside of just reducing viral load) and population differences. Because of the small number of trials specifically looking at autism spectrum conditions, I would perhaps like to see some further data on XMRV and whether issues such as age, geographic population, sub-diagnosis and co-morbidity show any potential effects before drawing a line under the XMRV story and the question of whether XMRV really does mark the spot.

All hail the gut bacteria

'Flash, ah-ahh'. Flash Gordon. You remember him, and that fantastic film in 1980 with the soundtrack by Queen. Max von Sydow played Ming the Merciless who ruled Mongo with a iron fist. 'All hail Ming, Ruler of the Universe' was the chant from his (dis)loyal subjects. Well, Ming might well have been Ruler of the Cosmos, but us humans may very well bow down to another Ruler - or should I say a couple of trillion Rulers - our endogenous gut bacteria.

Despite my previous posts examining a possible relationship between some cases of autism spectrum conditions and 'abnormal' gut bacteria, this post is a little different. Different because it is not looking at gut bacteria in relation to autism per se, but rather some wider research.

Before I start, I want to acknowledge a few sources of information including Emily Deans over at Evolutionary Psychiatry, Maff at the Environmental Illness Resource and the Neurophilosophy blog (I don't want any charges of plagiarism levelled against me).

My attention was turned to two papers published recently on a possible bi-directional relationship between gut bacteria and behaviour in mice. By bi-directional, I mean that gut bacteria could influence behaviour and behaviour could influence gut bacteria. OK I hear you cry, fine if you are a mouse - and you would be absolutely right. But remember that mice are used to build a variety of different models of human functioning including that related to autism (see special edition of the Autism Research journal on mouse models).

Both the papers highlighted have generated quite a bit of discussion on their various implications.
The paper suggesting that behaviour (in this case, stress) can affect gut bacterial populations implies a few things: (a) gut bacterial populations are dynamic and responsive to our psychology and/or behaviour as well as more physiologically-determined variables such as medication or diet, (b) where gastrointestinal conditions are present and potentially tied into gut bacteria (IBS for example), the mechanism for psychosocial stress impinging on symptoms may well be tied in. This last point in particular may have some relevance for specific cases of autism spectrum conditions where stress and arousal seem to be common. Think also to my recent post covering probably the most undesirable therapy ever invented, fecal transplantation and the implications of a comment posted in jest on the EP blog "..if you ever have a fecal transplant, make sure it is from a slender, non-asthmatic, happy person!".

The other paper detailing the effect of gut bacteria (or lack of it) on behaviour seems to tie in with the growing interest in such a relationship related to autism. Remember that study from Richard Sandler and colleagues from 2000 where short-term administration of a powerful antimicrobial acting on gut bacteria (I assume!) led to some short-term positive behavioural changes in children with autism?

As per the ethos of this blog I have tried to tie the work back to autism, but really these papers potentially show some applicability to lots of different areas. ME/CFS perhaps? How about what happens when we try and change/affect our gut bacterial populations? What happens to behaviour?

This paper was published a few years back and tried just that. Using a double-blind, placebo-controlled methodology, the authors looked at what happened to anxiety symptoms in participants with CFS when a probiotic preparation was taken. The results: a rise in the 'good' bacteria (aerobic predominantly) and a decrease in anxiety symptoms when taking the probiotic over the placebo. Let's be straight though. I am not saying that such an intervention will help everyone with every condition. But all these papers tell us that perhaps we should be looking at our gut bacterial populations a little more closely from a research perspective.

All hail the gut bacteria, ruler of OUR Cosmos!

Gluten relations

As this blog develops you will see that I have a bit of a penchant for all things related to diet and particularly gluten. Don't get me wrong; I am not anti-gluten (or anti-casein for that matter); indeed quite the opposite, acknowledging the significant part gluten has had, and continues to play, in feeding our ever increasing populations. I do however believe in 'horses for courses' - what is suitable for one might not necessarily be suitable for another.

For many years I have been struck by the number of people, groups, studies outside of autism who have suggested a possible link between their symptoms (whatever they may be) and their diet - that is what they eat seemed to go hand-in-hand with how they felt or what illness/condition they developed. Diet mediating physical health is of course well-recognised; diet mediating mental health and development is perhaps another story. From the outset I will admit that I am a fan of the notion that correlation does not imply causation; that is just because 2 events occur close together does not necessarily mean that one causes the other. I also however believe that if two events do happen close together, it is the responsibility of science to investigate any possibility of a relationship, if nothing else just to disprove it.

I digress. One of the more interesting conditions where reports of a link between presented symptoms and diet have surfaced was with a group of people who had been diagnosed with myalgic encephalomyelitis (ME) or Chronic Fatigue Syndrome (CFS). First and foremost I will admit that I am not an expert on ME/CFS (add it to the list of my non-expertise). I know a little bit about the symptoms; a little bit about the various hypotheses on aetiology and pathology; and a little bit about the variability and heterogeneity involved (similar to autism). That's it. I have corresponded with a few people who have ME/CFS and got a flavour of how much it impacts on their lives.

My interest in ME/CFS and diet was perked after reading a newspaper article recently. The article described the daughter of quite a famous UK TV personality who has ME and a purported link to gluten. OK it is a newspaper and things tend to get a little sensationalised (to sell more newspapers perhaps?), but it was a very interesting read. The summary is that this young lady struggled with ME for many years, presented also with some other 'somatic' conditions and eventually was led through to the possibility that she could have a problem with gluten. The article mentions coeliac disease (quite extensively) but a connection between the two in this case has been queried. I have since done a little hunting around and found a couple articles suggesting that routine screening for coeliac disease should be carried out in cases of CFS given indications of about 2% of patients presenting with CFS also being endomysial antibody (EMA) positive, whether co-morbid or as an alternate diagnosis to explain fatigue. What I was unable to find was good scientific questioning of what happens to ME/CFS symptoms when those with positive EMAs went on a gluten-free diet, and whether the recent newspaper story suggestive of positive effects potentially outside of coeliac disease has been examined.
 
Set against the recent PACE study published in the Lancet and the various discussions around the trial design and results, it is perhaps timely that the UK Medical Research Council (MRC) have this week set aside funds to conduct further research into ME/CFS. I wonder if anyone will chose to look at the potential connection between diet and ME/CFS?