'Physical signs' to aid the diagnosis of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)?

I have to say that I wasn't completely au fait with the Perrin technique mentioned in the article by Lucy Hives and colleagues [1] or the exploration of whether "the five physical signs of the Perrin technique can assist in the screening of patients with CFS/ME, which could then subsequently lead to quicker treatment" but I was interested.

Interested because CFS/ME remains a condition diagnosed on the basis of observable symptoms. As a result, it is still subject to quite a few 'debates' on what the best fitting criteria might be (see here). Anything that might potentially help that diagnostic position is therefore welcomed. Indeed, anything that might provide something approaching an objective diagnosis could potentially open up a whole new world of treatment and intervention...

Accepting that talk of 'Perrin's point' "lymphatic drainage" and "the principle that toxins within fluid in the brain or spine column do not drain away as they should" are probably not everyone's cup of 'science' tea, the authors set about testing the Perrin technique for potentially diagnosing CFS/ME. Also whether "newly trained allied health professional (AHP) with no prior experience of CFS/ME" had the same diagnostic accuracy as more expert AHP. I'm not actually sure what specific disciplines those AHPs were actually following, but looking at the text - "One had 10 years of experience of using the Perrin technique and working with patients with CFS/ME (experienced AHP)" - and the affiliations of the authorship list (see here) - it looks to me like something between physiotherapy and osteopathy as a rough guess.

Approaching 100 participants were recruited for study - "52 patients with CFS/ME and 42 non-CFS/ME controls" - all adults and for those diagnosed with CFS/ME, all with "a prior formal diagnosis of CFS/ME at a National Health Service (NHS) hospital specialised clinic" and displaying various core features of CFS/ME (i.e. persistent fatigue and "the fatigue should feel worse after physical activity"). I note that they also required "a clear starting point to the fatigue." Assessments - "standard clinical neurological and rheumatological" - were also carried out and CFS/ME diagnosis was pitted (blind) against the Perrin technique. Indeed: "A priori, the Perrin technique required all five symptoms to be present for a patient to be diagnosed as CFS/ME." Not to copy too much text from the Hives paper, the five symptoms were: "(1) postural/mechanical disturbances of the thoracic spine... ; (2) breast varicosities... ; (3) tender Perrin’s point... ; (4) tender coeliac plexus... ; and (5) dampened cranial flow."

How did the Perrin technique do? Well, not bad at all: "Results show that, on average, the experienced AHP was most accurate (86%) at correctly diagnosing participants. This was followed by the newly trained who correctly diagnosed 77% and the physician who correctly diagnosed 69% of participants." I reiterate that the clinical team were "blinded to the groupings" (whether or not they were seeing a patient with CFS/ME or not).

Hives et al also provide some data on the specificity and sensitivity of the Perrin technique in relation to CFS/ME diagnosis, as well as some initial chatter about whether all the five symptoms together represent the most efficient grouping. They concluded that: "accuracy for both AHPs, overall, is highest when using only tests of tender coeliac plexus and postural/mechanical disturbance of the thoracic spine" potentially suggesting that "not all of the five physical signs may be necessary."

Whilst pretty interesting results, there is a need for further independent replication before anyone gets too excited about a possible objective test for CFS/ME. The authors similarly note that this was a straight 'yes you're diagnosed with ME/CFS' vs 'no diagnosis of CFS/ME' but also in future need to take into account other conditions potentially overlapping with CFS/ME such as fibromyalgia (FM) and whether the diagnostic waters are still so clear with such comparisons in mind. As I've mentioned in other posts (see here), the tendency in some quarters to conflate CFS/ME with 'chronic fatigue' also perhaps needs some further investigation too.

Still, there are reasons to be optimistic about the Hives findings. How, even alongside more traditional ways and means of diagnosing CFS/ME, the Perrin technique (in whatever form) *might* serve as a useful accompaniment to aiding the diagnostic process and perhaps even further distancing CFS/ME from the whole biopsychosocial model of disease (see here)...

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[1] Hives L. et al. Can physical assessment techniques aid diagnosis in people with chronic fatigue syndrome/myalgic encephalomyelitis? A diagnostic accuracy study. BMJ Open. 2017; 7: e017521.

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Methylphenidate as a 'suicide risk reducing agent' in ADHD: implications for other labels?

Don't get me wrong, I'm not falling hook, line and sinker for the findings reported by Sophie Hsin-Yi Liang and colleagues [1] observing that "among ADHD [attention-deficit hyperactivity disorder] youths, reduction of suicide risk was observed in patients prescribed MPH [methylphenidate] for duration 90 days and longer."

I've read too much on how complex something like suicide - ideation, attempts and completion - is to ever believe that there is some single magical answer to universally reducing or eliminating suicidal behaviours and the wide-ranging effects they have. Yes, there are some compounds that have a pretty good evidence base for being an 'anti-suicidal agent' (see here) but even with something like lithium, further investigations are required on their universal applicability and important details like their cost-benefit ratio.

Having said all that, I am drawn to the findings reported by Liang et al for a few very good reasons. First, is the continued reliance on 'big data' Taiwan and the use of the National Health Insurance Research Database (NHIRD) as a research resource. Second, is the continued focus on suicide and possible factors/predictors of suicide based on examination of NHIRD data [2]. Third, is the idea that "rates of suicide ideation, self-injury and suicide attempts are significantly increased in untreated ADHD populations" and how something like MPH use potentially (positively) affecting ADHD symptoms might have other effects. Finally, there is also the tantalising prospect that other conditions/labels where ADHD might be over-represented where also alongside there is a growing focus on suicidal behaviours, the Liang findings might also be relevant...

So what did Liang and colleagues do and find? Well looking at the records of some 85,000 children and young people where ADHD was diagnosed, researchers looked for evidence of recorded suicide attempts as a function of whether MPH was being used or not (where "MPH is the only stimulant approved for the treatment of ADHD in Taiwan"). They found that "100 (0.1%) youths met the criteria for suicide attempts during the surveillance period" and perhaps a little contrary: "37 (0.2%) in the group without any MPH use and 63 (0.1%) in the group with MPH use."

But the devil is in the detail, as authors then factored in a few pertinent, potentially confounding variables (gender, age, other diagnoses, other medication) and length of time of taking MPH (1-90 days, 91-180 days, over 180 days) into models of risk. They concluded that there was actually a 'risk reducing effect' from MPH use following such analyses: "We observed a 59% suicide attempt risk reduction among ADHD youths prescribed between 90 and 180 days and a 72% risk reduction in those prescribed more than 180 days of MPH."

This is not the first time that MPH use for ADHD and suicide risk has been discussed in the peer-reviewed science literature. The paper by Man and colleagues [3] talked about how the incidence of suicide went up before and at the beginning of MPH initiation in their cohort of around 25,000 children and young adults, but importantly risk "returned to baseline levels during continuation of methylphenidate treatment." They account for their findings by suggesting that: "The observed higher risk of suicide attempts before treatment may reflect emerging psychiatric symptoms that trigger medical consultations that result in a decision to begin ADHD treatment." I put this in the context that ADHD does seem to be a risk factor for various other psychiatric diagnoses (see here and see here). Other independent data [4] has also talked about "a potential protective effect of drugs for ADHD on suicidal behaviour, particularly for stimulant drugs." There seems to be a case for MPH as potentially affecting [some] suicide risk in relation to [some] ADHD...

I want to now take you back to the title of this post, and specifically the 'implications for other labels?' bit. How ADHD and specifically, MPH use for ADHD symptoms, might offer some important 'lessons' for conditions where for example ADHD is over-represented as a comorbidity. Of course I speak of autism and autism spectrum disorder (ASD) where it is fast becoming accepted that the risk of receiving a diagnosis of ADHD is pretty significantly heightened (see here). Alongside, quite a lot of attention is also being paid to the issue of suicide risk and autism (see here) and specifically, what factors might predispose to an elevated risk of suicide in cases of autism (see here) (hint: it's probably not all just down to depression or indeed, any one factor in isolation). Adding in the Liang findings to autism is, I think, quite a sensible thing to do. No, it's not about shifting 'blame' for suicidal behaviours from one label to the next, but instead realising that for some people on the autism spectrum, ADHD does present an additional 'feature' and such a feature might very well carry with it some increased risk for suicidal behaviours. The other strand of evidence that is probably relevant to this is the idea that the risk of various psychiatric diagnoses seem also to be elevated alongside a diagnosis of autism. The prospect therefore that MPH used to manage ADHD occurring alongside autism might reduce any risk of suicidal behaviours is something that requires quite a bit more investigation.

And while I'm mentioning MPH in the context of [some] autism, the recent Ccohrane review of MPH for kids and young people diagnosed with autism [5] suggests something quite positive when it comes to issues such as "symptoms of hyperactivity and possibly inattention" (albeit with more research required)...

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[1] Liang SHY. et al. Suicide risk reduction in youths with attention-deficit/hyperactivity disorder prescribed methylphenidate: A Taiwan nationwide population-based cohort study. Research in Developmental Disabilities. 2018; 72: 96-105.

[2] Lin YW. et al. Influential Factors for and Outcomes of Hospitalized Patients with Suicide-Related Behaviors: A National Record Study in Taiwan from 1997-2010. PLoS One. 2016 Feb 22;11(2):e0149559.

[3] Man KKC. et al. Association of Risk of Suicide Attempts With Methylphenidate Treatment. JAMA Psychiatry. 2017 Oct 1;74(10):1048-1055.

[4] Chen Q. et al. Drug treatment for attention-deficit/hyperactivity disorder and suicidal behaviour: register based study. BMJ. 2014 Jun 18;348:g3769.

[5] Sturman N. et al. Methylphenidate for children and adolescents with autism spectrum disorder. Cochrane Database Syst Rev. 2017 Nov 21;11:CD011144.

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Is the word 'comorbid' accurate when describing emotional and behavioural issues occurring alongside autism?

The findings reported by Per Normann Andersen and colleagues [1] observing that: "The amount of autism symptoms and degree of attention problems at baseline significantly predicted EBP [emotional and behavioral problems] at follow-up" potentially taps into a wider discussion in the context of autism.

EBP refers to feeling "anxious/depressed, withdrawn/depressed, somatic complaints, social problems, thought problems, attention problems, rule-breaking behavior, and aggressive behavior." The wider discussion is framed around a question on whether use of the term 'comorbid' - comorbid EBP for example - is accurate when it comes to such 'issues' appearing alongside the core features of autism? Should instead we be thinking and talking about comorbid issues/symptoms such as depression and anxiety as being something rather more central to at least 'some' autism? Y'know, is there a lot more than just the the triad/dyad of core features for some at least?

It's a discussion that has emerged before on this blog (see here and see here) and continues in the peer-reviewed science arena [2]. It has some potentially profound implications for things like autistic identity, the distinction between autism as a developmental condition as opposed to a psychiatric disorder, talk about the 'disabling aspects' of autism (and 'where they potentially come from') and the often polarised topic of intervention specifically 'for autism'...

Andersen et al report results based on analysis of children and adolescent diagnosed with autism - 'high-functioning' autism (HFA) (their term not mine) - where "levels of EBP, autism symptoms, inattention problems, and verbal IQ" were assessed at baseline and 2 years later.  The aim was to see whether symptoms such as autism "can predict EBP 2 years later."

Interestingly, the authors opted for the use of the Autism Spectrum Screening Questionnaire (ASSQ) as one of their study instruments, [partly] devised by a researcher who I have a lot of time for on this blog (see here) and his equally pertinent concept of ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations). This was complemented by "the Schedule for Affective Disorders and Schizophrenia for School Age Children/Present and Lifetime version-2009 (K-SADS-PL)" covering questions on possible "affective disorders, psychotic disorders, anxiety disorders, behavioral disorders (ADHD), substance abuse disorders, eating disorders, tic disorders and ASD [autism spectrum disorder]" and the ADHD rating scale IV among others research tools.

Results: "the level of autism symptoms at baseline were the best predictor of EBP in our group of children with HFA." The authors also observed that "attention problems had an independent impact on EBP" but noted that whilst autism and attention issues correlated at baseline, the role of attentional issues on EBP was "considerably less compared to the level of autism symptoms." Authors also stated that verbal IQ did not seemingly predict EBP, which is perhaps at odds with other independent research on a similar topic (see here). They conclude by suggesting that "interventions aimed at improving ASD symptoms may positively affect the prevalence of EBP in children with HFA."

Of course the Andersen study was not perfect and one has to be careful not to extrapolate too much. As the authors note, their study: "focused on symptoms of autism and attention, and we cannot generalize these findings to those with ASD and clinical diagnoses of ADHD" representing one important limitation. They add that their focus on those with an IQ above 70 and their investigating a very 'male-orientated' sample group also limited the generalisability of their findings to the entire autism spectrum; particularly some of the 'under-studied' people of the autism spectrum (see here). And before you mention it, yes, IQ still needs quite a bit more research work done on it when it comes to autism...

Nevertheless, I believe that these findings do add to an increasingly vocal peer-reviewed research evidence base suggesting that the term 'comorbidity' might not be the most 'useful' description when it comes to chatter about a range of labels/conditions/symptoms that are seemingly over-represented in relation to autism. Indeed, as per more historical mentions - yes, Mildred Creak yet again - set within the context of the plural 'autisms' (see here), many issues described today as 'comorbid' may eventually turn out to be rather more central to [some] autism...

The idea also discussed by Andersen et al about 'intervening' in/on the traditional 'core symptoms' of autism as potentially 'offsetting' some of the effects of those EBP is, no doubt, going to be a bit of a hot potato. We do have a few other examples showing how a reduction/dissipation of core autism symptoms does seem to impact on 'comorbid' signs and symptoms as per some of the discussions on the term 'optimal outcome' (see here). In the example recorded by Gillberg et al [3] observing that "The minority of the AS [Asperger syndrome] group who no longer met criteria for a full diagnosis of an autism spectrum disorder were usually free of current psychiatric comorbidity", we see how there could be quite a bit more to a diagnosis of autism (AS) than has traditionally been recognised. Other research from Andersen and colleagues [4] talking about the same cohort as being discussed today with depression and autism presentation again in mind likewise adds to such 'intervening' sentiments.

I have one final point to make just in case the idea of intervening does not sit well with some: if one assumes that something like depression is in fact, a core part of some autism and could be 'modified' by intervention(s) targeting core autism symptoms, there is a potentially important impact to be made on one of the primary issues affecting the autistic population: risk of suicide. I say that on the basis that depression or related psychiatric disorder (see here) is an all-too-frequent companion when it comes to suicidal behaviour(s) and therefore represents a potentially modifiable variable. Exactly how and where intervention on core autism symptoms is done is another question for another day; also bearing in mind that 'current' core autism symptoms themselves, might be an important risk factors when it comes to suicidal thoughts/behaviours (see here).

Lots more research is indicated, minus hype and minus too much politics...

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[1] Andersen PN. et al. Severity of Autism Symptoms and Degree of Attentional Difficulties Predicts Emotional and Behavioral Problems in Children with High-Functioning Autism; a Two-Year Follow-up Study. Frontiers in Psychology. 2017; 8: 2004.

[2] Nah Y-H. et al. Brief Report: Screening Adults with Autism Spectrum Disorder for Anxiety and Depression. J Autism Dev Disord. 2017. Dec 2.

[3] Gillberg IC. et al. Boys with Asperger Syndrome Grow Up: Psychiatric and Neurodevelopmental Disorders 20 Years After Initial Diagnosis. J Autism Dev Disord. 2016 Jan;46(1):74-82.

[4] Andersen PN. et al. Associations Among Symptoms of Autism, Symptoms of Depression and Executive Functions in Children with High-Functioning Autism: A 2 Year Follow-Up Study. J Autism Dev Disord. 2015 Aug;45(8):2497-507.

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Vitamin D for schizophrenia? No but...

The results published by Amir Krivoy and colleagues [1] talking about "no significant effect of vitamin D on psychotic, depressive or metabolic parameters" in a cohort of people diagnosed with schizophrenia, make for interesting reading.

Interesting, not only because authors reported very little effect of supplementation on the symptoms of schizophrenia, but also because such 'negative' findings kinda follow a theme in vitamin D - psychiatric research circles: low levels of vitamin D (insufficiency and/or deficiency) being associated with a condition (see here) yet little [experimental] evidence that supplementation does anything more than correct the vitamin D availability issues (see here for another example). Certainly the quite significant speculation that vitamin D might have lots and lots of 'extra-bone' related actions do not yet seem to have been borne out by the currently available experimental data in this area...

Krivoy et al describe the methodology and results of their "eight-week, randomized, double-blind, placebo-controlled clinical trial" focused on some 47 patients "age between 18 and 65 years old, diagnosis of schizophrenia according to DSM-IV-TR criteria confirmed by two senior psychiatrists, treated with clozapine for at least 18 weeks and being on a stable clozapine dose for at least four weeks prior to enrollment, serum 25(OH) vitamin D level below 75 nmol/L (30 ng/ml) and total severity of psychopathology score, as measured by the Positive and Negative Symptom Scale (PANSS) total score above 70." Vitamin D supplementation - 14,000 IU [international units] per week - was pitted against a placebo formulation, although I can't seem to find what exactly the placebo contained (N=24 vs. N=23 respectively). Various outcome measures were used to determine any effect or not.

Results: as per the opening line of this post, there was little to see between the vitamin D and placebo receiving groups when compared on the basis of PANSS scores. Both groups showed a trend towards a decreasing total and sub-scale psychopathology scores over the course of the experimental period indicative of some modest improvement in psychiatric symptoms. At the same time, authors report that vitamin D levels did change amongst those in receipt of the vitamin D supplement: "The 25(OH) vitamin D serum levels increased significantly in the drug group... while essentially unchanged in the placebo group" so we can be pretty sure that there was both compliance with the experimental regime and that vitamin levels were increasing in the supplemented group as expected.

There was one small 'ray of hope' when it came to supplementation that has been hinted at in the research literature previously: "A beneficial effect of vitamin D supplementation was noted on cognitive performance, as reflected in an increase in MoCA [Montreal Cognitive Assessment] total score." I say 'hinted at' because although it is a little premature to talk about vitamin D as a nootropic (cognitive enhancer), there is evidence that low levels of the stuff *might* under certain circumstances, negatively affect certain cognitive abilities (see here for example). Whether supplementation with vitamin D is a more general cognitive 'affector' remains to be seen but the Krivoy results suggest further inspection is indicated.

There is more to do in this area before the vitamin D - schizophrenia link is branded completely spurious. The authors mention the relatively small sample sizes included for study and how the nature of schizophrenia as a condition potentially means that "patients with extreme presentation are less likely to consent to participate in a randomized controlled trial due to their paranoid and suspicious attitudes" as being something important. It's also interesting that at least one of the supplemented participants seemed to show little response to vitamin D in a physiological levels sense: "This patient, despite attending all assessments and dosing visits, showed vitamin D level of 22 nmol/L at baseline and 17 nmol/L at endpoint due to unclear reasons." Assuming that vitamin D testing was accurate i.e. using something like mass spectrometric methods over older, potentially less reliable assays (see here) I wonder if there could be other components required in future studies in this area, such as also looking at the genetics of vitamin D metabolism as per other, unrelated research (see here).

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[1] Krivoy A. et al. Vitamin D Supplementation in Chronic Schizophrenia Patients Treated with Clozapine: A Randomized, Double-Blind, Placebo-controlled Clinical Trial. EBioMedicine. 2017. Nov 29.

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US National Health Interview Survey (NHIS) on autism rates and beyond

The US National Center for Health Statistics (NCHS) has recently released a data brief [1] covering the topic of diagnosed developmental disabilities and specifically: "the latest prevalence estimates for diagnosed autism spectrum disorder, intellectual disability, and other developmental delay among children aged 3–17 years from the 2014–2016 National Health Interview Survey (NHIS)."

The figures show a number of trends in relation to various diagnoses; not least that the prevalence of autism spectrum disorder (ASD) rose year on year between 2014 and 2016, albeit not significantly. In 2014, the percentage of positive responses to the question: "Has a doctor or health professional ever told you that [sample child] had Autism, Asperger’s disorder, pervasive developmental disorder, or autism spectrum disorder?" was 2.24%; in 2015 it was 2.41% and in 2016 it was 2.76%. I might add that we already knew what the 2014 data showed given other publications (see here).

When it came to the categorisation of developmental disability - "A composite measure of children with a diagnosis of autism spectrum disorder, intellectual disability, or any other developmental delay" - the figures were rather more significant. So: "During 2014–2016, the prevalence of children aged 3–17 years who had ever been diagnosed with a developmental disability increased from 5.76% to 6.99%." The categorisation 'other developmental delay' seemed to be the main driver of the [statistically significant] increase in that composite measure (2014: 3.57%; 2015: 3.56%; 2016: 4.55%).

There are a few additional details to mention about the report by Benjamin Zablotsky and colleagues. Boys, yet again, were the over-represented group when it came to all and total categories and race/ethnicity seemed to show some important differences such as a typically lower percentage estimate being present for most diagnoses in Hispanic children compared to other groups.

What can we make of these recent statistics? Well, it's pretty evident that, for whatever reason(s), there is still an upward trend when it comes to a diagnosis of autism and various other developmental labels. It's worthwhile pointing out that the current report used "a more restrictive definition for a developmental disability that does not include conditions such as attention-deficit/hyperactivity disorder or learning disabilities" so the figures might also not be entirely reflective of the 2014-2016 situation. I also had a question in mind about what the difference was between 'intellectual disability' (shown) and 'learning disability' (not shown) given their interchangeable meaning at least here in Blighty (see here).

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[1] Zablotsky B. et al. Estimated prevalence of children with diagnosed developmental disabilities in the United States, 2014–2016. NCHS Data Brief, no 291. Hyattsville, MD: National
Center for Health Statistics. 2017

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"a pooled ASD prevalence of 6.3% in individuals with epilepsy"

The quote heading this short-ish post came from the findings reported by Lauren Strasser and colleagues [1] who systematically reviewed and meta-analysed the collected data pertinent to "the prevalence and risk factors for autism spectrum disorder (ASD) in epilepsy."

Bearing in mind that epilepsy is quite a comprehensive term, authors estimated that some 6-7% of those diagnosed with epilepsy or a condition manifesting epilepsy will also present with an ASD. Further that specific types of epilepsy might confer a specific risk for ASD: "When divided by type, the risks of ASD for general epilepsy, infantile spasms, focal seizures, and Dravet syndrome were 4.7%, 19.9%, 41.9%, and 47.4% respectively."

The relationship between autism and epilepsy has been known about for many years (see here). We know for example, that age and intellectual functioning level play a role in the risk of developing epilepsy in the context of autism but are careful with sweeping generalisations (see here). We also know that a growing number of genetic conditions manifest both as autism or autistic traits and epilepsy (see here for example). We even have 'colliding' research areas talking about options for treating some 'difficult to treat' cases of epilepsy as perhaps also impacting on some of the features of autism too (see here) (with no medical or clinical advice given or intended).

What's also being recognised a little more in the peer-reviewed research literature and beyond is that being diagnosed with certain types of epilepsy also potentially impacts on the risk of autism or ASD also being diagnosed or presenting with 'significant' autistic traits (see here and see here). This to me has quite a few important implications, not least that this data "may help clinicians in early screening and diagnosis of ASD in this population." It also cements the relationship between autism and epilepsy / epilepsy and autism and further asks whether for some people at least, 'comorbidity' in relation to the presence of both terms should be replaced with something rather more core and fundamental?

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[1] Strasser L. et al. Prevalence and risk factors for autism spectrum disorder in epilepsy: a systematic review and meta-analysis. Dev Med Child Neurol. 2017 Nov 9.

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