Monday, 22 October 2018

"Omega-3 polyunsaturated fatty acid treatment for anxiety might be effective in clinical settings"

Today I present the findings of yet another systematic review and meta-analysis as per the publication from Kuan-Pin Su and colleagues [1] that concluded: "omega-3 PUFAs [polyunsaturated fatty acids] might help to reduce the symptoms of clinical anxiety." A finding that may have some quite profound implications for lots and lots of different diagnoses/conditions/labels where anxiety seems to be particularly over-represented and life-draining (see here and see here for examples).

So, the starting hypothesis was that "omega-3 PUFAs might have anxiolytic effects in patients with significant anxiety- and fear-related symptoms." Various studies, both in animals and humans, have implicated fatty acids in 'emotional states', particularly the so-called 'good fatty acids' including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The authors reported that "there have been no systematic reviews of this topic to date" so decided to remedy the situation.

Trawling through various repositories and databases of peer-reviewed science, they searched for relevant science on the topic of fatty acid supplementation and anxiety measurement. From little over a hundred possible science articles, they whittled the numbers down to 19 studies including over 1200 participants "with omega-3 PUFA treatment (mean age, 43.7 years; mean female proportion, 55.0%; mean omega-3 PUFA dosage, 1605.7 mg/d)" and "1037 participants without omega-3 PUFA treatment (mean age, 40.6 years; mean female proportion, 55.0%)." Taking into account that some studies (most) included a placebo element to their design, different dosages and formulations of PUFAs were used and that various different tools and schedules were used to 'measure anxiety', there were some boiled-down messages to emerge.

First: "The overall findings revealed modest anxiolytic effects of omega-3 PUFAs in individuals with various neuropsychiatric or major physical illnesses." That's not to say that every study was 'positive' in terms of PUFA effects on anxiety, but generally speaking the evidence tended to side more with an effect rather than no effect. Second, dose and formulation seemed to matter: "Participants treated with a daily dose of 2000 mg or more of omega-3 PUFAs showed a significantly greater association of treatment with reduced anxiety symptoms." Third: "the association of omega-3 PUFA treatment with reduced anxiety symptoms was significantly stronger in subgroups with specific clinical diagnoses than in subgroups without specific clinical conditions." So the effect of PUFA supplementation was stronger in those with a clinical diagnosis of something like anxiety than those who didn't have one.

Downsides? Well, there are of course limitations to the data included in the Su study; for example, "the significant heterogeneity among the included studies... with potential influence by some outlier studies" and these should not be underestimated. I'm also minded to bring in the [still emerging] issue that meta-analyses are only as good as the data that they are based on (see here and see here for examples). And I'd also mention that side-effects are something not discussed too heavily in the Su study but one shouldn't assume that just because we're talking about a fish oil so this is somehow side-effect free for everyone...

Given the low cost of fatty acid supplements and their wide, very wide, availability, the Su results provide some pretty good support to suggest that 'giving it a go' could be an option for at least some people diagnosed with an anxiety disorder. Please don't however take that as me giving anyone medical or clinical advice; I'm merely following what the results say and the media coverage that has followed (see here).

And since we're on the topic of food and mood, I note the recent meta-analysis from Camille Lassale and colleagues [2] suggesting that "adhering to a healthy diet, in particular a traditional Mediterranean diet, or avoiding a pro-inflammatory diet appears to confer some protection against depression in observational studies" has been garnering news headlines (see here). These studies combined suggest that diet might have an important effect of mood and well being. Now, where have I heard that before (see here)...?

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[1] Su K-P. et al. Association of Use of Omega-3 Polyunsaturated Fatty Acids With Changes in Severity of Anxiety Symptoms. JAMA Network Open. 2018;1(5):e182327.

[2] Lassale C. et al. Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of observational studies. Molecular Psychiatry. 2018. Sept 26.

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Friday, 19 October 2018

Helminthic Trichuris Suis Ova vs. placebo for repetitive behaviours in adult autism

The trial results published by Eric Hollander and colleagues [1] were not entirely unexpected. I had previously mentioned their study on the "use of the immunomodulator Trichuris Suis Ova (TSO)" with autism in mind in another post (see here) but, at that time, still awaited the peer-reviewed publication version to appear. I wait no longer.

OK, Trichuris suis (T. suis) is a parasite. It makes its home in the deepest, darkest recesses of other creatures, apparently also having the rather important evolutionary advantage of being able to stay in egg form for quite a long time 'awaiting ingestion'. But just before you turn away John Hurt style (no, I'm not going to link to the 'chest-buster' scene), this particular parasite might not be 'all bad'. I'm specifically talking about some preliminary data suggesting that T. suis *might* have some important immunological effects [2] when ingested in a controlled manner under certain clinical circumstances.

Hollander et al took things one stage further by their insinuation of a link between use of an "immunomodulator" such as T. suis and their study to determine "the effect sizes for TSO vs. placebo on repetitive behaviors, irritability and global functioning in adults with ASD [autism spectrum disorder]." And just before you question the idea that immune function might be something important to some overt behaviour(s), there is other research out there discussing the possibility of such an effect (see here and see here) specifically with autism in mind.

"A 28-week double-blind, randomized two-period crossover study of TSO vs. placebo in 10 ASD adults, ages 17 to 35, was completed, with a 4-week washout between each 12-week period." This was a 'gold-standard' trial design albeit with a very, very small participant group who represented only a specific 'part' of the autism spectrum [3]. The trial was also registered for all to see the proposed hows-and-whys (see here) including the detail: "Have a personal or family history of allergies" as part of the inclusion criteria.

Results: "Differences between treatment groups did not reach statistical significance." This is an important point highlighting how use of T. suis ("the eggs of intestinal helminthes (trichuris suis ova) administered as 2500 ova doses every two weeks") did not translate into statistically significant group differences across measures looking at the social communication aspects of autism for example. I say this bearing in mind that the Hollander study was a cross-over trial too.

But... "Large effect sizes for improvement in repetitive behaviors (d = 1.0), restricted interests (d = 0.82), rigidity (d = 0.79), and irritability (d = 0.78) were observed after 12 weeks of treatment." What this means is that when comparing participants using T. suis vs. their baseline measurements, they seemed to do better on the T. suis portion of the trial across various different types of behaviour. Importantly too we are told that "TSO had only minimal, non-serious side effects" bearing in mind this included various gastrointestinal (GI) side-effects (and knowing that GI issues are already 'a thing' when it comes to autism).

So, there we have it. The results of the first (small scale) clinical trial using Trichuris Suis Ova (TSO) helminthic style with autism in mind. Obviously a lot more research is required before this type of intervention goes anything like 'mainstream'. Alongside there is also the 'acceptability' factor to consider: how many people would actually want to ingest a parasite such as T. suis? Indeed, one of the next courses of study is perhaps to see 'why' such helminthic therapy has the effect that it has on behaviour, and whether such an effect can be replicated in a medicine or other formulation rather than ingesting a parasite?

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[1] Hollander E. et al. Randomized Crossover Feasibility Trial of Helminthic Trichuris Suis Ova vs. Placebo for Repetitive Behaviors in Adult Autism Spectrum Disorder. World J Biol Psychiatry. 2018 Sep 19:1-25.

[2] Jouvin MH. & Kinet JP. Trichuris suis ova: testing a helminth-based therapy as an extension of the hygiene hypothesis. J Allergy Clin Immunol. 2012 Jul;130(1):3-10.

[3] Hollander E. et al. Trichuris Suis Ova (TSO) as an immune-inflammatory treatment for repetitive behaviors in ASD. European Neuropsychopharmacology. 2016; 26: 891.

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Thursday, 18 October 2018

"contrary to its findings, there is no evidence that graded exercise therapy is effective" for myalgic encephalomyelitis / chronic fatigue syndrome


Things can sometimes move pretty fast in the world of peer-reviewed science. I had originally scheduled this post to appear in November (2018) but there's been some recent 'movement' in this area (see here) so I've decided to publish it now.

The original post is shown below. And below that are a few extra thoughts in light of the reported decision to remove the Larun article (at least for now)...

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The re-analysis paper published by Mark Vink & Alexandra Vink-Niese [1] makes for some really interesting reading. Not only because it adds to other voices in the peer-reviewed domain (see here) questioning the usefulness and safety of the intervention known as graded exercise therapy (GET) 'for' myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but also because it kinda fits in with a narrative suggesting that 'trusted evidence' is almost always open to interpretation (see here).

So, graded exercise therapy (GET) and ME/CFS. I have to say that out of all the interventions / treatments that I've come across down the years that have been indicated for various diagnostic labels, GET is probably one of the most reviled by the population it is supposed to be aimed at. The reasons for such a scenario are multiple and complex, but one of the more vocal arguments seems to be the lack of regard for harm caused by the use of a stepped physical activity schedule on a population whose illness is defined by boom-bust symptom profiles caused by physical exertion. Of particular importance to this line of thinking is the idea that post-exertional malaise (PEM) needs to have a lot more prominence attached to it when it comes to ME/CFS, minus any psychobabble 'deconditioning' chatter or related explanations.

The Vink-Vink-Niese paper is based on a Cochrane review paper of GET published by Lillebeth Larun and colleagues [2]. Yes, the same Cochrane that is going through a bit of turmoil at the moment. The Larun paper concluded a few things such as: "Exercise therapy did not worsen symptoms for people with CFS" and "Moderate‐quality evidence showed exercise therapy was more effective at reducing fatigue compared to ‘passive’ treatment or no treatment." This based on the examination of "eight randomised controlled studies" with "reported data from 1518 participants." To be fair to the Larun review paper, the authors did also mention that: "Serious side effects were rare in all groups, but limited information makes it difficult to draw firm conclusions about the safety of exercise therapy" and "further studies should be carried out to discover what type of exercise is most beneficial for people affected by CFS, which intensity is best, the optimal length, as well as the most beneficial delivery method." This, on the basis that CFS/ME is best described as a heterogeneous condition and accepting that exercise can come in various different forms, some of which might be more applicable than others when it comes to individuals with fatigue-related labels (see here for example) minus any sweeping generalisations.

Some familiar themes crop up in the Vink re-review paper - "Entry score requirements were not sufficiently strict" and "The review used subjective fatigue measured by questionnaires as the primary outcome" - which have quite notably hindered the research in this area. I note also that authors mention about attrition (dropout) rates in the reviewed studies and how, in some studies, over a third of participants placed in exercise conditions withdrew from such investigations. Such statistics will no doubt have an important influence on any final results, as well as providing an important clue that such an intervention might not be sufficiently well tolerated by quite a few [3].

Vink concludes by saying that: "The GET trials reviewed here are inherently biased: use of exercise may attract only the mildly affected and may deter the more disabled patients from participating" and that: "The flaws in the review and the trials... all created a bias in favour of the exercise intervention."

On the basis of their interpretation of the scientific data, I'm in agreement with Vink & Vink-Niese that the evidence base for the universal application of GET to ME/CFS is by no means indicated. You might well say that GET is not universally rolled out for everyone with ME/CFS but, as things currently stand at the time of writing, it is still part of the clinical guidance for the condition(s) here in Blighty (for now) and hence potentially something that can be suggested for anyone diagnosed with ME/CFS. The ethos behind GET also being tied into another biopsychosocial (BPS) favourite - CBT - also makes for a good reason why psychology really shouldn't be let anywhere near such clinical issues, particularly when the evidence against such 'interventions' is seemingly mounting (see here). Indeed, although little comfort to those currently living with ME/CFS, I'm sure one day we'll look back at the whole BPS 'involvement' with ME/CFS and truly say WTF?

And finally, whilst on the topic of 'not listening to your target population' I would also draw your attention to the recent findings from McManimen and colleagues [4] highlighting what could happen when those with ME/CFS face stigma (and dogma). Oh, and because the Cochrane name is part-and-parcel of today's post, I'll also draw your attention to an important message concerning some of their other advice pertinent to CFS...

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What else to add to this post? Well, a quote appearing in that Reuters report on the decision to temporarily withdraw the Larun review suggesting that "the withdrawal decision set a worrying precedent for scientific evidence being over-ridden by the opinions of activists" is, to my mind, inappropriate. Aside from the feedback received regarding the Larun article (see here) the Vink paper for example, is peer-reviewed science and published peer-reviewed science at that. It's not some activist randomly throwing around allegations and the like on social media or blogs(!). It's published peer-reviewed-science that calmly calls into question the conclusions of the original Larun analysis. Indeed, it's part of a trend for serious scientific conversations being held in the peer-reviewed science domain concerning some of the science and clinical practice around ME/CFS (see here). Nothing vexatious.

As I mentioned, given that other Cochrane reviews covering the topic of CFS have also been recently withdrawn [5] (see here for more on the withdrawal notice) it strikes me that Cochrane is perhaps also wisely ensuring that it's previous high standards are maintained and confidence restored in its 'evidence-based' name particularly when it comes to research into ME/CFS. Given also the turbulent few weeks that have just passed (see here) and seemingly, are still continuing (see here) for the 'collaboration', it's also a timely reappraisal that fits the important narrative that ME/CFS is a long-term physical health condition (see here) and not a mental disorder or worse. And intervention options need to recognise this fact...

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[1] Vink M. & Vink-Niese A. Graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective and unsafe. Re-analysis of a Cochrane review. Health Psychology Open. 2018;5(2):2055102918805187.

[2] Larun L. et al. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2016 Jun 24;(6):CD003200.

[3] Cheshire A. et al. Guided graded Exercise Self-help for chronic fatigue syndrome: patient experiences and perceptions. Disabil Rehabil. 2018 Oct 16:1-10.

[4] McManimen SL. et al. Effects of unsupportive social interactions, stigma, and symptoms on patients with myalgic encephalomyelitis and chronic fatigue syndrome. J Community Psychol. 2018 Nov;46(8):959-971.

[5] Adams D. et al. WITHDRAWN: Traditional Chinese medicinal herbs for the treatment of idiopathic chronic fatigue and chronic fatigue syndrome. Cochrane Database Syst Rev. 2018 Oct 15;10:CD006348.

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Wednesday, 17 October 2018

"maternal pre-pregnancy obesity is associated with autism-like behaviors in offspring"

The results reported by Kandice Varcin and colleagues [1] concluding that "maternal pre-pregnancy obesity is associated with autism-like behaviors in offspring" continue and extend a research theme (see here and see here). A research theme that highlights a potentially important relationship between maternal weight (and/or related parameters) and offspring development across various, potentially intertwined, variables (see here).

Including the notable name of Andrew Whitehouse on the authorship team (see here and see here for some examples of his other research), researchers set about to explore whether "pre-pregnancy weight was related to autistic-like traits among offspring not diagnosed with ASD [autism spectrum disorder]." I added the bold highlight to the word 'not' to emphasise how this work was set slightly apart from the other research that has observed an *association* between maternal weight before or during pregnancy and a risk of a formal diagnosis of autism in offspring. Pregnant women in their second trimester of pregnancy were recruited and "had their height measured." They also "reported their pre-pregnancy weight" which combined with the height measurements to give the measure known as the body mass index (BMI). And also: "At 19-20 years of age, 1238 offspring of these women completed a measure of autistic-like traits, the Autism-Spectrum Quotient (AQ)." Keep those issues in mind for now.

Results: "Regression analyses identified a positive association between increasing maternal pre-pregnancy BMI and increasing AQ Total Score amongst offspring; this association was maintained even after controlling for a range of variables including maternal/obstetric factors (age at conception, education, smoking, alcohol consumption, hypertensive diseases, diabetes, threatened abortion), paternal BMI at pregnancy, and child factors (parity, sex)." Sorry for the large quote, but the authors said it better than I ever could. Authors also reported that those women defined as being obese before pregnancy, according to their BMI measurement, were quite a bit more likely to "have offspring with high scores (≥26) on the AQ." This then lead them to conclude that "maternal pre-pregnancy obesity is associated with autism-like behaviors in offspring."

Caveats? Well, yes, a few. Height measured in the second trimester but participants "reported their pre-pregnancy weight"? I can see a few complications there in terms of accuracy of recall and perhaps the possibility of some bias creeping in. Having said that, many mums-to-be do have records of their weight during that 'special time' and some probably before as part of their regular clinical care or just as a result of how health conscious everyone is being these days. That and the fact that most people roughly know their typical weight (outside of pregnancy).

But also the AQ... the AQ. Regular readers probably already know that I have some qualms about the AQ and it's 'specificity' when it comes to autism and autistic traits (see here and see here). I know it's often seen as one of the internet's premier 'are you autistic?' instruments, but sometimes I think it's done more harm than good by way of it's probable link to the rise and rise of the 'self diagnosis' (see here) for example. I could go on about this, but I won't. Instead I'll just mention that 'autism-like' behaviours as judged by the AQ is probably the correct phrase to use in the context of the Varcin paper. Indeed, one might easily suggest that in a non-clinical population, AQ might also be tapping into other labels and traits [2]: "Higher AQ scores were associated with higher scores of loneliness, social anxiety, depression, and anxiety, as well as with lower scores of quality of life (QoL)." So unless one accepts that depression and/or anxiety might potentially be core features of autism (see here and see here), AQ might be picking up other things other than autism.

Still, I can't argue with the *association* talked about by Varcin et al, and what it might mean for the quite spectacular rise and rise in the numbers of people being diagnosed with an autism spectrum disorder (see here). No, not by any means the only factor to account for the increase in diagnoses, but potentially an important part of the story...

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[1] Varcin KJ. et al. Maternal pre-pregnancy weight and autistic-like traits among offspring in the general population. Autism Res. 2018 Sep 19.

[2] Reed P. et al. Loneliness and Social Anxiety Mediate the Relationship between Autism Quotient and Quality of Life in University Students. Journal of Developmental and Physical Disabilities. 2016; 28: 723-733.

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Tuesday, 16 October 2018

Prevalence of autism in preterm infants meta-analysed

"The prevalence of ASD [autism spectrum disorder] is significantly high in the preterm population. Adequate resources are needed to improve the outcomes of these children."

So said the findings reported by Sachin Agrawal and colleagues [1] who present the results of yet another meta-analysis with autism in mind; yet again on a topic that has filled quite a few peer-reviewed science column inches (see here and see here for examples).

'Preterm' typically refers to babies who are born alive but before completing the usual 37 weeks of gestation. It is further sub-categorised into extremely (less than 28 weeks), very (born between 28 and 32 weeks gestation) and moderate-to-late (born between 32 and 37 weeks gestation) preterm. The risk of a wide variety of 'adverse' outcomes seems to be significantly heightened following preterm birth, covering both physical (somatic) and psychological/developmental domains. Outside of the very final outcome that is early mortality, longer-term issues, particularly associated with brain development occurring outside of the womb, have been a feature of several results. Autism has also been mentioned in this context (see here).

Agrawal et al set about analysing the data pertinent to autism risk and preterm birth. They talk about the scenario of a 'perfect storm' whereby "whatever initiates the preterm birth process might also initiate abnormal pathways of brain development" as being potentially pertinent to autism. Covering the research literature up to May 2017, some 18 studies including over 3300 preterm infants were included for analysis. They specifically included studies that utilised known diagnostic tests for autism or ASD (ADOS, ADI, DAWBA) rather than those that used only "ASD screening tools" and looked up the cumulative prevalence rate for autism.

Results: 7%. That was the overall autism prevalence rate among preterm infants included in the various studies analysed. There was quite a bit of variation across the studies and the prevalence figure fluctuated to some degree as and when children with disabilities were included or not, but the 7% figure seemed to be an accurate one. Authors also put the 7% figure into some 'real world' perspective too: "This equates to ∼900 000 additional children each year who will develop ASD given that globally ∼15 million infants are born preterm (before 37 weeks’ gestation), of whom 13 million survive." Kinda takes your breath away doesn't it?

A couple of other important details are worthwhile mentioning too. So: "Our meta-regression analysis revealed no significant association between gestational age, birth weight, and prevalence of ASD in preterm infants." This doesn't totally rule out such factors as exerting an effect, but...

What else to say? Well preferential screening for autism or ASD in cases of preterm birth could be indicated. The allocation of further research resources into how and why preterm birth occurs could also be useful, focusing on how and why the infant brain seems to be so sensitive to maturation outside of mum's body. And then in relation to all those 'we don't know what causes autism' sentiments that continue to be expressed, well, add prematurity to the growing list of strong possibilities (see here and see here for other examples).

Oh and minus any medical or clinical advice being given or intended, it appears that nutrition, particularly omega-3 fatty acid levels, *might* play 'some' role in some preterm births [2] with some intriguing possibilities for supplementation (minus sweeping generalisations)...

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[1] Agrawal S. et al. Prevalence of Autism Spectrum Disorder in Preterm Infants: A Meta-analysis. Pediatrics. 2018 Aug 3. pii: e20180134.

[2] Olsen SF. et al. Plasma Concentrations of Long Chain N-3 Fatty Acids in Early and Mid-Pregnancy and Risk of Early Preterm Birth. EBioMedicine. 2018 Aug 2. pii: S2352-3964(18)30252-4.

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Monday, 15 October 2018

Autism research really needs to study the prevalence and treatment of scurvy in autism

The results published by Melinda Saavedra and colleagues [1] describing another case report where scurvy was [eventually] diagnosed as appearing alongside autism represents yet another 'call to action' on this topic.

I've covered this issue quite a few times before on this blog (see here and see here and see here), and quite frankly it's reached the point where autism research really needs to step up and formally study the prevalence of scurvy in relation to autism. Indeed given the almost universal reports of medical science not initially recognising that scurvy can be no stranger to autism, the time has also come to "announce [to] the pediatrician and other professionals dedicated to primary health care about scurvy as a potential consequence of restrictive diets in children with autism spectrum disorders."

This time around the clinical focus was on a 4 year old boy who was brought to clinical attention as a result of "hip pain and refusal to walk, associated with petechiae and bruising of the lower limbs." The clues were all there that scurvy could be a cause of such symptoms, but it was only when it was revealed that the child had "selective feeding habit" that the penny seemed to finally drop. Indeed: "Levels of Vitamin C in blood were measured and without waiting for results he started treatment with 300 mg per day of ascorbic acid." Lo and behold, his vitamin C results were found to be low, and vitamin C supplementation eventually did the trick. Of vital importance, the pain associated with scurvy also showed improvement and he was discharged from clinical care with a maintenance dose of vitamin C and some nutritional advice.

'Selective feeding patterns', 'picky eating' or whatever you want to call it, is an issue that is not stranger to autism (see here). It's reasonable to assume that where such feeding issues continue into the longer-term, and dependent on what foods are consumed as part of such a restrictive pattern, there are likely to be biological consequences for the person concerned as a function of what nutritional inadequacies follow. Indeed, I daresay that such a pattern follows what is being noticed in connection with other food-related conditions in the longer term (see here). Set in this context, a lot more research and importantly, clinical practice, needs to focus on the hows-and-whys of such behaviours and their remediation. There is no longer any excuse for allowing diseases of the past such as scurvy and also others like rickets, to plague the children of today, vulnerable children of today, where healthy food in most parts of the world, is not in short supply.

Oh, and bear in mind that 'picky eating' might not be the only reason why scurvy might appear alongside autism [2]. We need lots more data.

And also, as I write this [3]...

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[1] Saavedra MJ. et al. Scurvy due to restrictive diet in a child with autism spectrum disorder: case report. Arch Argent Pediatr. 2018 Oct 1;116(5):e684-e687

[2] Hasan Al-Breiki S. et al. Scurvy as the tip of the iceberg. Journal of Dermatology & Dermatologic Surgery. 2014; 18: 46-48.

[3] Caldwell KJ. et al. Child With Autism and a Limp. Ann Emerg Med. 2018 Oct;72(4):493-495.

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Saturday, 13 October 2018

Regressive vs. non-regressive autism: limited chemical differences noted

The paper published by Antonio Gomez-Fernandez and colleagues [1] examining whether or not there may be some potentially important biological differences as a function of reported regression vs. no regression in autism provides the blogging fodder today. Not for the first time has the immune system and 'regressive autism' been mentioned in the peer-reviewed science literature (see here and see here), but the current work focuses on the examination of various immune system and other related compounds: in a seemingly well-defined cohort: "Analyses of plasma molecules, such as cathepsin, IL1β, IL6, IL8, MPO, RANTES, MCP, BDNF, PAI NCAM, sICAM, sVCAM and NGF."

"Fifty-four children (45 males and nine females) aged 2-6, who were diagnosed with ASD [autism spectrum disorder], and a control group of 54 typically-developing children of similar ages were selected." Authors relied on quite an extensive battery of assessments looking at behaviour, alongside their use of the DSM-5 diagnostic criteria for autism (see here). Also accompanying physical examination "with a special emphasis on neurological and nutritional status", authors garnered blood samples from participants (overnight fasting) for their immune system and related functioning evaluations.

"The group of ASD children was further divided into two subgroups based on the presence or absence of neurodevelopmental regression during the first two years of life, which was assessed using a five-item questionnaire following the guidelines used by the Autism Diagnostic Interview-Revised (ADI-R) for the evaluation of this process." The ADI-R has been previously discussed on this blog in relation to regression in autism (see here). And just in case you might not be totally convinced that regression can be part of a pathway to autism, here's some more evidence for you (see here)...

Results: "there were 20 children included in the AMR [neurodevelopmental regression] subgroup and 32 in the ANMR [without neurodevelopmental regression] subgroup; two children could not be classified in these subgroups because they were adoptees, allocated by a national adoption agency." Bearing in mind that we cannot rule out any recruitment bias that might have leaned towards including those with regressive autism on the Gomez-Fernandez study, the figure of approaching 40% of their cohort showing such a regressive profile is notable. I'd also draw your attention to the finding that the behavioural profile for the regressive group (AMR) was also significantly different from the non-regressive group (ANMR) insofar as perhaps painting a picture of greater [group] autism severity...

Interestingly, the study did not show too many immune system and other compound differences between those diagnosed with autism and the asymptomatic (for autism) control group. So: "No differences were found between the two groups in terms of the cytokine and adhesion molecule levels studied, except for NGF [nerve growth factor], in which the group of ASD children was found to have twice the plasma levels compared to the control group." NGF is no stranger to autism research, and other studies have come to a similar conclusion [2].

When it came to examining results based on comparing the regressive (AMR) and non-regressive (ANMR) groupings, things got slightly more interesting but again no complicated pattern of difference was noted. So, for the ANMR (non regression) grouping: "lower plasma levels of the NCAM adhesion molecule were detected compared to the levels in the AMR subgroup and the control group. This ANMR group also exhibited higher NGF levels than the typically-developing children, which could indicate an alteration in neuronal development." Again, adhesion molecules have been mentioned in other autism research (see here).

"In conclusion, the results of this study show that there is not a typical profile for the expression of relevant plasma cytokines, adhesion molecules or growth factors in children with ASD compared with that in typically-developing children." OK, there are caveats to the phrasing used by the authors; not least that the participant numbers were quite small in the Gomez-Fernandez study and the idea that within the very heterogeneous autism spectrum, there may be smaller groupings (phenotypes) that perhaps show a tendency to greater immune system and related 'issues' (see here). But there are also some strengths attached to the Gomez-Fernandez study; not least the study "benefits from a careful selection of children of similar ages, as well as the complete diagnosis of ASD with multiple tests, clinical follow-up and associated complementary tests."

Questions still remain. Perhaps an important one is the question around why some children show a regressive pattern of behaviour as part of their path to a diagnosis of autism? Yes, issues such as infection do seem to be part-and-parcel of the clinical profile for some (see here and see here for examples) and perhaps more detailed focus is required in such areas. But much like a group showing the opposite of regressive autism - those who seemed to 'grow out' of autism - currently thought to include as many as one in ten (see here), a wider range of biological as well as psychometric measures are required to help pick out potentially important mechanisms pertinent to the idea that autism is not necessarily 'hard-wired' for all...

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[1] Gomez-Fernandez A. et al. Children With Autism Spectrum Disorder With Regression Exhibit a Different Profile in Plasma Cytokines and Adhesion Molecules Compared to Children Without Such Regression. Front. Pediatr. 2018. September 26.

[2] Dinçel N. et al. Serum nerve growth factor levels in autistic children in Turkish population: a preliminary study. Indian J Med Res. 2013 Dec;138(6):900-3.

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