Chronic fatigue syndrome and the detrimental application of the 'biopsychosocial model'

'The times they are a changin'' said a Nobel prize winner and that's also a sentiment that seems true when it comes to chronic fatigue syndrome / myalgic encephalomyeltis (CFS/ME) too (see here for example).

Anyone who has followed the tos-and-fros of the PACE trial - the one that suggested that CBT (cognitive behavioural therapy) and GET (graded exercise therapy) might provide some significant relief of symptoms associated with CFS/ME - will probably have heard the quite open claims being made that "the study was bad science." Scientific dirty laundry continues to be aired in public as a result of the focus on the wrongs and rights of PACE and with it, precious money that might well have been used for CFS/ME science has instead seemingly been used in legal disputes.

Outside of the methodological points potentially associated with the PACE trial/results, at the heart of the issue on whether CBT for example, might influence the progression of CFS/ME is the continued idea in some quarters that ME/CFS is part of a spectrum of conditions primarily centred in the domain of the biopsychosocial (BPS) model. Here, the suggestion is that a biological agent or agents act to trigger the condition but thereafter psychological and sociological factors play a major part in 'maintaining' the condition. For many people who suffer (yes, suffer) with ME/CFS the application of the BPS model to their symptoms has been likened to charges of malingering and subsequently many patients feel let down by medicine and indeed, that their symptoms have been trivialised.

The paper by Keith Geraghty & Aneez Esmail [1] puts some scientific flesh on to the idea that continued use of the BPS model applied to CFS/ME might be detrimental to many patients and particularly their interactions with healthcare providers. Including reference to the quite extensive literature suggesting that all-manner of biological factors may be at work on the various experiences of CFS/ME (see here for example), the authors question "whether or not the BPS model generates ‘harms’ for CFS patients." The conclusion: yes, applying the logic of the BPS model during healthcare consultation is probably not doing much for quite a few patients with ME/CFS who are often in real distress and don't really want to be told it's 'all psychological' and treated as such.

This is an important piece of work. Irrespective of your personal viewpoint of what ME/CFS is (and isn't) it tells us that healthcare interactions are important to people diagnosed with the condition and that "an over-emphasis on the 'psycho' (and only then with regard to alleged causation, rather than impact), at the expense of 'bio' and 'social' aspects of their impairments" has done little to either treat or manage or improve symptoms or quality of life for many people. It also tells us to respect the concept that CFS/ME is a heterogeneous condition and perhaps offer some viable alternatives to the BPS model. Not least is the idea that screening for conditions known to influence fatigue (see here) might be a good starting point and then taking things from there.

I do however think it is important that we don't minimise the psychological effects that ME/CFS can have on a person. Sometimes being bed-bound with only limited contact with the 'outside world' trapped in a spiral of fatigue and rest, fatigue and rest is unlikely to do anyone any good. Indeed, when researchers talk about depression and other psychiatric features being potentially over-represented in cases of CFS/ME, I'm not surprised given how severe fatigue and other symptoms can sometimes be. A good physician should be screening for such accompanying issues and offering the appropriate treatment for them, mindful that these are not necessarily a core part of CFS/ME [2].

I get the impression that the BPS model (in its current form [3]) is coming to the end of its reign when applied to a label like CFS/ME on the basis of more research resources being pumped into looking at the biology/biological course of the condition and less emphasis on the psychological 'treatment' of the condition (see here). This perhaps follows a more general trend where psychogenic explanations for physical illness are starting to receive some critical commentary [4] including critically looking at the idea that "psychogenic illnesses are believed to be more responsive to psychological interventions than comparable "organic" illnesses". This is of course, little consolation for those patients with ME/CFS who've had to face the BPS model even in light of contrary indication [5] and perhaps not had the best experience of it. Indeed, I wonder if there will come a point where a formal apology will be issued about the way science and medicine has treated many people with ME/CFS and the sometimes needless suffering that the BPS model in particular, has had on many aspects including the doctor-patient relationship.

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[1] Geraghty KJ. & Esmail A. Chronic fatigue syndrome: is the biopsychosocial model responsible for patient dissatisfaction and harm? Br J Gen Pract. 2016 Aug;66(649):437-8.

[2] Taylor AK. et al. 'It's personal to me': A qualitative study of depression in young people with CFS/ME. Clin Child Psychol Psychiatry. 2016 Oct 14. pii: 1359104516672507.

[3] Maes M. & Twisk FN. Chronic fatigue syndrome: Harvey and Wessely's (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. BMC Med. 2010 Jun 15;8:35.

[4] Wilshire CE. & Ward T. Psychogenic Explanations of Physical Illness: Time to Examine the Evidence. Perspect Psychol Sci. 2016 Sep;11(5):606-631.

[5] Twisk FN. & Maes M. A review on cognitive behavorial therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuro Endocrinol Lett. 2009;30(3):284-99.

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Geraghty KJ, & Esmail A (2016). Chronic fatigue syndrome: is the biopsychosocial model responsible for patient dissatisfaction and harm? The British journal of general practice : the journal of the Royal College of General Practitioners, 66 (649), 437-8 PMID: 27481982

Maternal obesity and offspring autism meta-analysed (again)

Meta-analyses eh? You spend ages waiting for one and two come along in quick succession. Well today I'm posting about yet another meta-analysis of the peer-reviewed scientific literature suggesting that "excessive maternal BMI [body mass index] is associated with an increased ASD [autism spectrum disorder] risk in offspring." [1]

The review by Ying Wang et al follows hot on the heels of the meta-analysis by Li and colleagues [2] (see here for my take) but further looked at "the potential association of different category of BMI including overweight and underweight with ASD risk" among other things. BMI by the way, is a rough and ready way to quantify how much of a person there is according to height and weight. Whilst a useful statistic, it is not without its issues.

After taking into account data from "6 cohort studies and 1 case-control study involving 8,403 cases and 509,167 participants" the authors unsurprisingly came to the same conclusion as Li and colleagues that a higher BMI seems to confer more [relative] risk for offspring autism as an outcome. Authors even included a nice graphic (see here) suggesting something of a dose-response relationship between the two variables (based on data from four of the studies included in their meta-analysis).

What's more to say? Well, 'The maternal body as environment in autism science' returns into the frame and questions about possible mechanisms need to be asked/answered. No, such findings don't mean (a) every mum with a child with autism was overweight or obese before or during pregnancy or (b) every overweight or obese mum will have a child with autism: "Compared with children whose mothers were at normal weight, children born to overweight and obese mothers have a 28% and 36% higher risk of developing ASD, respectively." Such data does however open the door to the idea of foetal programming when it comes to potential offspring outcomes and how elevated BMI as possibly linking to facets of metabolic syndrome for example, might have some role to play for some (see here).

More investigations are indicated.

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[1] Wang Y. et al. Maternal Body Mass Index and Risk of Autism Spectrum Disorders in Offspring: A Meta-analysis. Scientific Reports. 2016; 6: 34248.

[2] Li YM. et al. Association Between Maternal Obesity and Autism Spectrum Disorder in Offspring: A Meta-analysis. J Autism Dev Disord. 2016 Jan;46(1):95-102.

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Wang, Y., Tang, S., Xu, S., Weng, S., & Liu, Z. (2016). Maternal Body Mass Index and Risk of Autism Spectrum Disorders in Offspring: A Meta-analysis Scientific Reports, 6 DOI: 10.1038/srep34248

Atopic dermatitis and the "increased risk of developing ADHD and ASD later in life"

I'm not gonna dwell too much on the findings reported by Lee and colleagues [1] talking about how "toddlers who suffer from AD [atopic dermatitis] at the age younger than 3 years are at a higher risk of developing ADHD [attention-deficit hyperactivity disorder] and ASD [autism spectrum disorder] during later childhood" because science already seems to understand that there may be an important connection between early allergic disease and later offspring behavioural/developmental outcomes (see here for example).

That the Lee data is derived once again from the 'big data' powerhouse that is Taiwan - specifically the National Health Insurance Research Database (NHIRD) - makes the findings that little bit more 'believable' given the numbers and processes involved in collecting said information.

"Children from the AD group with 3 comorbidities together, namely, allergic rhinitis, allergic conjunctivitis, and asthma, had the greatest risk of developing ADHD and ASD." Within statements like that it is getting progressively more difficult to downplay the impact that immune function (or immune response?) might have to quite a few people diagnosed as on the autism spectrum or with ADHD (or both). Further, that for some the 'treatment' of certain allergic symptoms might also impact on behaviour/development (see here and see here for examples) provides an important roadmap for further investigations in this area and the identification of who might be 'best responders' for such intervention (with no medical advice given or intended).

"Pediatricians taking care of toddlers with AD should have knowledge of this increased risk of developing ADHD and ASD later in life, especially when children have certain comorbidities such as allergic rhinitis, allergic conjunctivitis, and asthma." Who would disagree, bearing in mind that the spectrum of potential correlates linked to early life allergy may be pretty wide?

To close, some words of wisdom: "there is no good reason for self-conscious farters to avoid fibre."

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[1] Lee CY. et al. Longitudinal association between early atopic dermatitis and subsequent attention-deficit or autistic disorder: A population-based case-control study. Medicine (Baltimore). 2016 Sep;95(39):e5005.

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Lee CY, Chen MH, Jeng MJ, Hsu JW, Tsai SJ, Bai YM, Hung GY, Yen HJ, Chen TJ, & Su TP (2016). Longitudinal association between early atopic dermatitis and subsequent attention-deficit or autistic disorder: A population-based case-control study. Medicine, 95 (39) PMID: 27684861

Yet more on potential biomarkers and chronic fatigue syndrome

'Thick and fast' is probably the best way that I can describe the flurry of peer-reviewed scientific papers recently appearing (see here and see here for examples) talking about how chronic fatigue syndrome (CFS) (also linked to the diagnosis of myalgic encephalomyelitis, ME) might have some important biological processes attached to it.

Now we can add the findings reported by Federica Ciregia and colleagues [1] (open-access) to the list and their observations that "the identification of biomarkers present in particular subgroups of CFS patients may help in shedding light upon the complex entity of CFS."

The Ciregia paper is open-access but well-worth a few inches of discussion on this blog. Not least because (a) the word 'mitochondria' is part and parcel of the their findings in line with other research in this area, (b) one of the gold standards of analytical chemistry - liquid chromatography mass spectrometry -  was used, and (c) some of the findings are based on a study of twins: "a patient suffering from CFS in comparison with his healthy monozygotic twin." This mirrors other similar published work from this authorship group [2].

So, using a discovery/training and validation approach similar to other biomarker studies in other areas, researchers initially set out to "study the mitochondria extracted from platelets of the twins" using "nano-liquid chromatography electrospray ionization mass spectrometry (nano-LC-MS)." They were looking for evidence of different compounds being presented/expressed in those twins diagnosed with CFS compared with their non-affected twin and eventually came up with 41 proteins - "34 were upregulated in CFS and 7 were downregulated" (see here for the list of compounds).

Using a process called Ingenuity Pathway Analysis (IPA) "to retrieve the known functions of each protein" authors were able to visualise where each compound 'fitted' in terms of specific biological functions. The top three included: "metabolism of isocitric acid..., metabolism of NADH... and metabolism of nucleic-acid component or derivative." Certainly NADH has some 'history' when it comes to CFS/ME (see here).

Then came the validation side of the study where "the most promising biomarkers were validated by western blot [WB] analysis in a big cohort of patients, using whole saliva (WS)." Here some 45 patients diagnosed with CFS ("based on the classification criteria of Fukuda et al") were recruited alongside 45 not-CFS controls and spit samples from all were analysed for "aconitate hydratase (ACON), ATP synthase subunit beta (ATPB) and malate dehydrogenase (MDHM)." Two proteins, ACON and ATPB. were replicated or at least "consistent with the results from nano-LC-MS."

Finally, researchers looked at whether presented clinical features as described in various questionnaires delivered to participants might play a role in the presentation of their biological results. They did see something (see here) - "For each marker, the values were actually higher in the group of patients who had clinical features similar to the ill twin" - but I would be minded to suggest that quite a bit more work is needed before anyone reads too much into this as the results stand.

So, there you have it. A little bit more evidence to suggest that science is edging a little closer to potentially identifying some of the biology behind (or least associated with) at least some CFS (and ME). A little bit more peer-reviewed evidence moving the discussions away from 'psychosomatic' [3] to something a little more testable/analysable with CFS/ME in mind (I'll be coming to the paper by Geraghty & Esmail soon enough on this blog by the way). Independent replication is the next step, onwards to potentially "developing tailored treatments." That bearing in mind, we already have some emerging data in this area too (see here) (with no medical advice given or intended).

And just in case you want yet more potential biomarker research for CFS, here's another paper that has just been published [4]. Thick and fast people, thick and fast.

So, there is a new trailer for Rogue One (A Star Wars story)...

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[1] Ciregia F. et al. Bottom-up proteomics suggests an association between differential expression of mitochondrial proteins and chronic fatigue syndrome. Transl Psychiatry. 2016 Sep 27;6(9):e904.

[2] Ciregia F. et al. A multidisciplinary approach to study a couple of monozygotic twins discordant for the chronic fatigue syndrome: a focus on potential salivary biomarkers. J Transl Med. 2013 Oct 2;11:243.

[3] Geraghty KJ. & Esmail A. Chronic fatigue syndrome: is the biopsychosocial model responsible for patient dissatisfaction and harm? Br J General Practitioners. 2016. Aug 1.

[4] Yamano E. et al. Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles. Scientific Reports. 2016; 6: 34990.

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Ciregia F, Kollipara L, Giusti L, Zahedi RP, Giacomelli C, Mazzoni MR, Giannaccini G, Scarpellini P, Urbani A, Sickmann A, Lucacchini A, & Bazzichi L (2016). Bottom-up proteomics suggests an association between differential expression of mitochondrial proteins and chronic fatigue syndrome. Translational psychiatry, 6 (9) PMID: 27676445

ADHD and conduct disorder long-term

Today I'm once again blogging about peer-reviewed research suggesting that when it comes to the long-term effects of attention-deficit/hyperactivity disorder (ADHD) on a person, there is some pretty solid evidence that addressing symptoms early could "potentially avert a wide range of future adverse outcomes."

The paper making such a conclusion is the one from Holly Erskine and colleagues [1] who conducted a systematic review and meta-analysis pertinent to this topic; also taking into account the potential effects of a diagnosis of conduct disorder (CD) in the long-term. Including nearly 100 studies "linking ADHD and CD with a range of health and psychosocial outcomes" authors were able to say with some degree of confidence that issues with academic achievement, risk of comorbid "mental and substance use disorders", employment prospect likelihood and risk of criminality (i.e. being arrested) were all seemingly linked to a diagnosis of ADHD. Similar findings were also reported for CD. I know this is kind of research is not exactly great PR for ADHD (or CD) but it is nonetheless important.

Accepting that (i) sweeping generalisations about ADHD/CD do no-one any good and (ii) there may be multiple variables attached to the 'adverse' outcomes detailed outside of just diagnosis, there are some important points to be acted upon following the Erskine review. I might for example, advocate the position that academic achievement is a particularly important area when it comes to the symptoms of ADHD (see here) and moves to address the impact of ADHD on education should perhaps be a priority.

Minus any medical and/or clinical advice being dished out on this blog (I don't do that), there are several intervention options that have been discussed in the collected science literature to think about. Medication is one possibility as per what is known about the effectiveness of something like methylphenidate on ADHD signs and symptoms (see here). Sleep training is something else that appears to be quite useful when it comes to [some] ADHD (see here) too and could probably tie into research looking at physical activity levels and ADHD (see here). And then we have the collected literature pointing to dietary elements as possibly showing some connection to some facets of ADHD as per the whole fatty acid story (see here) and even something potentially linked to milk allergy for at least some (see here). This nutrition research building on the almost forgotten studies on a few foods diet and ADHD (see here) for example, which seems to have ground to a shuddering halt in research strategy terms. The list is long and getting longer (immune system, nutritional supplements, etc) of where to look when it comes to potentially important intervention routes for something like ADHD. Discussions with physicians need to be had and further investment in research is needed.

And perhaps one might also be inclined to take more note of the research suggesting that various 'somatic disease' might also be more likely when a diagnosis of ADHD is received [2] and how, for a start, preferential screening might be undertaken?

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[1] Erskine HE. et al. Long-Term Outcomes of Attention-Deficit/Hyperactivity Disorder and Conduct Disorder: A Systematic Review and Meta-Analysis. J Am Acad Child Adolesc Psychiatry. 2016 Oct;55(10):841-50.

[2] Instanes JT. et al. Adult ADHD and Comorbid Somatic Disease: A Systematic Literature Review. J Atten Disord. 2016 Sep 22. pii: 1087054716669589.

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Erskine HE, Norman RE, Ferrari AJ, Chan GC, Copeland WE, Whiteford HA, & Scott JG (2016). Long-Term Outcomes of Attention-Deficit/Hyperactivity Disorder and Conduct Disorder: A Systematic Review and Meta-Analysis. Journal of the American Academy of Child and Adolescent Psychiatry, 55 (10), 841-50 PMID: 27663939

Obesity in adolescent chronic fatigue syndrome (CFS)

"At 13 years, adolescents who had received a diagnosis of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) who were attending specialist CFS/ME services were more than two times more likely to be obese than adolescents in the general population."

At first reading, I wasn't particularly surprised by the findings reported by Norris and colleagues [1] (open-access) drawing on data partly derived from everyone's favourite UK longitudinal birth cohort: ALSPAC (Avon Longitudinal Study of Parents and Children). If one assumes that those suffering (yes, people do suffer from CFS/ME) might not be engaging in an optimal exercise regime nor eating the best of diets one can perhaps see how the condition might be a susceptibility factor for issues with weight. That being said, and after some further thought, the Norris findings might not be something entirely representative of the effects of CFS/ME either given documented cases of malnutrition and sadly, death (see here). Sweeping generalisations are, yet again, not required.

So, the Norris group findings... well, some of the authors are not completely unknown to the idea that eating habits might be perturbed in cases of CFS/ME as per other entries on this blog (see here). This time around ALSPAC data was joined by "data collected from all National Health Service (NHS) paediatric specialist services that participated in the CFS/ME National Outcomes Database (NOD) between August 2004 and October 2014." The aim was to "obtain prevalence estimates for obesity at two time points during adolescence (ages 13 years and 16 years), in three groups of adolescents representing a continuum of CFS/ME severity (healthy population, CFS/ME based on responses to questionnaires and clinically diagnosed CFS/ME)." In case your a little confused, the CFS/ME by questionnaire response group were derived from ALSPAC. The categorisation of obesity or not was made by clinical height and weight measurements from the ALSPAC data but was a little less 'formalised' for the more detailed diagnosis CFS/ME group (in clinic) including measurement "in the clinic or GP surgery or obtained from parental report." Body mass index (BMI) was calculated from said measurements.

Results: well, aside from that opening sentence on 13 year olds, the authors also reported that for those with CFS/ME: "At 16 years, they were more than 4 times more likely to be obese compared to those in the general population." The authors noted that the association between CFS/ME and obesity was 'driven' in the most part by "those attending the specialist services, thus representing those with CFS/ME severe enough to be referred for specialist treatment."

"Health professionals should be aware of this association to encourage appropriate screening for obesity and its possible complications when assessing patients with CFS/ME." I agree with the authors conclusions stemming from their findings but I think a word of caution also needs to be applied too.

For those who've followed the CFS/ME research scene for the past few years, you'll probably already have heard about the PACE trial and the 'suggestion' among other things that graded exercise therapy (GET) might be something to consider "to gradually increase how long you can carry out a physical activity." PACE has stumbled in recent times following a long and drawn out (and expensive) 'battle' to access the data behind the headlines; having already seen a 'downgrading' of effect from some agencies. Now, think to yourself what would be a health professional's response to being presented by a patient who is obese? Change your diet? Maybe do a little more exercise? Hmm...

I'm not saying that young people with CFS/ME who present with weight issues shouldn't be provided with the same appropriate medical advice and care as everyone else with such issues. I'm not saying that every health professional would be prescribing pounding the treadmill or anything related given the quite unique issues associated with CFS/ME. I do however think that set within the research history created partly as a result of initiatives such as the PACE trial, there are sensitivities that need to be observed before sweeping healthcare advice is provided en-masse. That also 'not out-running' a bad diet is gaining some traction is an important point to make as other areas of research could yet be explored bearing in mind how exercise might impact on the gut microbiome of some CFS/ME (see here) for example. That might also includes the gut virome [2] too...

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[1] Norris T. et al. Obesity in adolescents with chronic fatigue syndrome: an observational study. Arch Dis Child. 2016 Sep 21. pii: archdischild-2016-311293.

[2] Giloteaux L. et al. A Pair of Identical Twins Discordant for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Differ in Physiological Parameters and Gut Microbiome Composition. Am J Case Rep. 2016 Oct 10;17:720-729.

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Norris T, Hawton K, Hamilton-Shield J, & Crawley E (2016). Obesity in adolescents with chronic fatigue syndrome: an observational study. Archives of disease in childhood PMID: 27655658