Saturday 29 December 2018

2018 autism research review on Questioning Answers

So, once again it's time for my annual 'what was hot in autism research this year' roundup. As in previous years (see here), 2018 was a year packed with all sorts of weird (see here) and wonderful (see here) research and research-based discussions. Some important key themes emerged and/or continued to be discussed that I'd like to bring to your attention.

So...

1. Autism does not typically appear in a diagnostic vacuum.

Last year (2017) I predicted that we'd see a lot more (research) recognition that autism rarely appears in some sort of diagnostic vacuum, be that in relation to behavioural and psychiatric labels or more somatic diagnoses. I'd like to think that I was roughly right, as various papers were published pertinent to this topic. A few articles that were covered on this blog included:


There's still a way to go in this area. Various questions need answering such as whether 'comorbidity' is the factually correct word to use in some contexts [1] or whether, in some circumstances, various *issues* might actually be more 'core' to the presentation of autism. Y'know, something like what Mildred Creak talked about with regards to anxiety and autism for example [2] quite a few years ago albeit with some different terminology. This also has some important implications, not least for how such *comorbid* issues are to be managed if connected to core autistic features alongside the pitfalls of self-diagnosis.

2. The (estimated) prevalence of autism.

The autism numbers game features prominently every year. In 2018 it was particularly notable as a result of the United States CDC releasing their 'once every two year estimates of autism in 8-year olds' report. A few posts covered this and other research including:


The net result of all this research is that whilst it's pretty difficult to say exactly how many people have been diagnosed with autism or an autism spectrum disorder (ASD) in any particular population at any particular time, the estimates continue to flood in. And the bottom line seems to be: the 'growth' in the (estimated) numbers is seemingly still continuing at a pace and science should continue to be asking 'why'? (see here and see here for examples). Policymakers likewise should also continue planning and ensuring that money, resources and services are available to all who need them.

3. The autisms (plural). 

The autisms. Y'know, the idea that within the huge heterogeneity that is covered by the label 'autism' or 'ASD', there may be lots of different 'types' of autism and/or pathways to the diagnosis. It's a topic that continues to be explored in the peer-reviewed research arena. Some examples this year include:


And you'll perhaps have noted that among some of that research, words like 'actionable metabolic tests' have been used indicating that observable behaviour might eventually not be the only variable when it comes to diagnosing autism. Indeed, I'll be blogging about this more early in the New Year based on further study [3]...

4. The ICF core sets for autism.

I've talked quite a bit on this blog in 2018 about the development of the ICF core sets for autism. This initiative has an important purpose: "To capture [the] complex melange of functioning experiences beyond the diagnosis, the ICF offers a tool to describe the lived experience of a person with ASD in a comprehensive and standardized way." And progress was seemingly made in 2018 and long should it continue:


5. Other news, views and progress.

Because there were a myriad of other research papers published in 2018 and discussed on this blog, I've included a few other posts that might be an interesting read for some. It's a mixed bag of science, news and ideas, but hopefully you can see that autism research continues at a pace in various different directions.


As to my prediction of 'where next?' for autism research in 2019, well, I'm hoping that the topic of nutritional deficiency and autism might receive quite a bit more 'interest' given the quite worrying data that is emerging on the topic of scurvy and autism for example (see here and see here and see here). It's not exactly difficult research to undertake, and given what nutritional deficiency can mean for some folk (yes, things like physical pain and discomfort), I'd suggest that it should be made a research priority. Perhaps add it to the autism research list?

And finally as always, Happy New Year. I hope you'll visit and enjoy this blog again in 2019 - you know that you're always welcome!

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[1] Rubenstein E. & Bishop-Fitzpatrick L. A Matter of Time: The Necessity of Temporal Language in Research on Health Conditions that Present with Autism Spectrum Disorder. Autism Res. 2018 Sep 5.

[2] Evans B. How autism became autism: The radical transformation of a central concept of child development in Britain. Hist Human Sci. 2013;26(3):3-31.

[3] Barone R. et al. A Subset of Patients With Autism Spectrum Disorders Show a Distinctive Metabolic Profile by Dried Blood Spot Analyses. Front Psychiatry. 2018;9:636.

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Friday 28 December 2018

"Psychotic experiences are important clinical markers of risk for future suicidal behavior"

The quote titling this post - "Psychotic experiences are important clinical markers of risk for future suicidal behavior" - comes from the systematic review and meta-analysis findings reported by Kathryn Yates and colleagues [1].

Authors posed the research question: "Are psychotic experiences associated with an increased risk of later suicidal ideation, suicide attempt, and/or suicide death?" and looked to the existing peer-reviewed research literature to try and answer it. Based on the combined results from ten studies that "reported on 84 285 participants from 12 different samples and 23 countries" and met the inclusion criteria of their review, Yates et al made some important conclusions.

"Individuals who reported psychotic experiences had an increase in the odds of future suicidal ideation (5 articles; n = 56 191; odds ratio [OR], 2.39 [95% CI,1.62-3.51]), future suicide attempt (8 articles; n = 66 967; OR, 3.15 [95% CI, 2.23-4.45]), and future suicide death (1 article; n = 15 049; OR, 4.39 [95% CI, 1.63-11.78])." These are important statistics. They translate into some important details insofar as "individuals who reported PEs [psychotic experiences] had 2-fold increased odds of subsequent suicidal ideation, 3-fold increased odds of subsequent suicide attempt, and 4-fold increased odds of subsequent suicide death." Some further nifty statistical analysis from the authors looking into something called the population-attributable fraction (PAF), defined as "the proportion of incidents in the population that are attributable to the risk factor", suggested that the percentage figure for "PEs for suicide attempts and suicide deaths combined was 24.7%." That is also something rather important.

Should anyone be surprised by these results? Well, yes and no. Yes, because the magnitude of the association between PEs and suicidal behaviours was probably a lot more pronounced than many would have perhaps expected. No, because other literature has talked about psychosis in depression for example, as being potentially important to the development and presentation of suicidal behaviour (see here). Having said all that, I will reiterate that suicidal behaviours are very complicated.

Aside from the important issue of potentially expanding screening for suicidal behaviours when PEs are present, there are other factors to consider. Not least that: "The mechanisms explaining the association between PEs and suicidal behavior are potentially manifold." I was particularly interested in one theory put forward by the authors, suggesting that: "In the context of high stress and poorer communication skills, this might adversely affect the individual’s ability to formulate logical plans to manage perceived challenges and instead increase the likelihood of turning to suicide." Such an idea is based on other findings observing that there may be cognitive 'challenges' accompanying PEs that may impair problem-solving skills. Y'know, not having the skills to stop molehills from turning into mountains? Perhaps further research in this area might also turn to looking at some of the underlying biology behind such issues as well as the psychology. How, for example, inflammatory processes and the immune system *might* show some important involvement (see here and see here) for at least some people? One future avenue of research attention at least.

The data from Yates and colleagues is particularly poignant at the time of writing this post as the US CDC release figures suggesting that suicide mortality in the United States has climbed and climbed and climbed over the past few decades (see here). Again, the reasons are probably going to be complicated but that shouldn't stop people from continually asking 'why?' and 'what can we do about them?'

I close this post with some important contact details should anyone need someone to talk to (see here)...

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[1] Yates K. et al. Association of Psychotic Experiences With Subsequent Risk of Suicidal Ideation, Suicide Attempts, and Suicide Deaths. JAMA Psychiatry. 2018. Nov 28.

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Thursday 27 December 2018

Pioglitazone for autism?


Enjoyed Christmas? Welcome back. Onward...

"Pioglitazone is well-tolerated and shows a potential signal in measures of social withdrawal, repetitive, and externalizing behaviors."

So said the findings reported by Lucia Capano and colleagues [1] (open-access) describing preliminary efforts to "elucidate the maximum tolerated dose, safety, preliminary evidence of efficacy, and appropriate outcome measures in autistic children ages 5–12 years old" taking the hypoglycemic medicine called pioglitazone. The results obtained from this phase II pilot study - "a 16-week prospective cohort, single blind, single arm, 2-week placebo run-in, dose-finding study of pioglitazone" - suggest that further research on this medicine in the context of autism is warranted.

Capano et al provide quite a lot of information about the whys-and-wherefores of pioglitazone use in the context of autism. They talk about immune system 'issues' and inflammation being no strangers to autism research. They talk about various findings in relation to immune signalling and autism, drawing on data from several investigations that have looked at compounds like the cytokines and chemokines. Pioglitazone fits into this story by way of it being "an agonist of peroxisome proliferator activated receptor (PPAR)-ϒ." Activation of PPAR-ϒ leads to "insulin sensitization and enhances glucose metabolism." It also seemingly has an anti-inflammatory role to play too. Through the use of  pioglitazone ramping up the action of PPAR-ϒ, so researchers opined that this could be useful for some people diagnosed with autism where immune system and behaviour might meet...

Unlike other trials of pioglitazone in the context of autism [2], the Capano study was more exploratory than 'gold-standard' in it's design. It did however include both behavioural and biological components, where various behavioural outcome measures were included alongside the describing of various "research bloodwork" that included various cytokines ("IL1-β, IL-10, and TNF-α in plasma; IL-6 in serum") that have been discussed in other studies with autism in mind (see here for example).

Alongside those initial results mentioned in the opening sentence of this post, there are a few other important points to make. So: "Overall, pioglitazone was well tolerated." Welcome news indeed. Researchers also noted that: "There were no serious adverse events (SAEs) in any of the doses within the range tested (0.25 mg/kg, 0.5 mg/kg, and 0.75 mg/kg)." This is important in the context that all medicines have the propensity for 'adverse effects' for some people, and pioglitazone is no different. Given also the focus on medication and weight gain in the context of autism (see here for example), it's a bit of relief to see that, for the study period at least, authors reported that: "BMI [body mass indexdid not change significantly during the study."

I'm not going to go to heavily into the behavioural changes noted over the study period on this occasion, because these are preliminary and one has to be careful with any interpretation. I do however want to mention some of the biological results; namely: "Significant changes with treatment occurred with both IL-6 and IL-10" and "IL-1β and TNF-α did not change significantly with treatment." The authors note that the IL-6 and IL-10 findings - "decreasing IL-6 and increasing IL-10" - were "consistent with the known effect of PPAR-gamma agonists like pioglitazone." This is an interesting finding.

Cumulatively, such results suggest that quite a bit more research focus is needed on pioglitazone in the context of [some] autism. But for now, it looks quite promising (again [3])...

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[1] Capano L. et al. A pilot dose finding study of pioglitazone in autistic children. Molecular Autism. 2018; 9: 59.

[2] Ghaleiha A. et al. A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: Effects on aberrant behavior in children with autism. Psychiatry Res. 2015 Sep 30;229(1-2):181-7.

[3] Boris M. et al. Effect of pioglitazone treatment on behavioral symptoms in autistic children. J Neuroinflammation. 2007;4:3.

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Saturday 22 December 2018

"Hyperopia, astigmatism, and strabismus seem to be independently associated with ADHD"

The findings reported by Charlotte Reimelt and colleagues [1] provide the brief blogging fodder today and the observation that following their analysis: "all examined forms of refractive error and strabismus showed an association with ADHD [attention-deficit hyperactivity disorder]."

Refractive error (e.g. near and far sightedness) and strabismus (squint) are not uncommon eye/vision issues among the general population. I've previously talked on this blog about such issues being potentially over-represented among certain diagnostic labels (see here) but up until now I don't think I've talked about such issues with ADHD in mind. I have discussed visual impairment and ADHD (see here) but not these specific eye issues.

Drawing on data derived from "the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) study (N = 13,488)", researchers observed "an increased risk for ADHD in children with hyperopia, astigmatism, and strabismus compared with the control group." They also make a case for further research in this area.

Obviously the oft-used tenet 'correlation is not the same as causation' comes into play here. It means that we have to be quite careful not to say that such eye/visions are a *cause* of ADHD or vice-verse because that has not been proven by such data. The Reimelt findings do however imply that preferential screening for such eye conditions when a diagnosis of ADHD is received might be a good idea. They also imply that preferential screening for ADHD and/or related behavioural issues, might also be a good idea as and when such eye/vision conditions are also detected.

So, Merry Christmas and as is typical, Kirsty MacColl and The Pogues. And just in case you thought 'drunk tanks' were a thing of the past, think again...

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[1] Reimelt C. et al. The Underestimated Role of Refractive Error (Hyperopia, Myopia, and Astigmatism) and Strabismus in Children With ADHD. J Atten Disord. 2018 Oct 29:1087054718808599.

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Friday 21 December 2018

Knowledge, attitude and stigma in relation to autism

A mash-up post for you today, as two papers are brought to the blogging table. The first paper by Sheri Stronach and colleagues [1] set out to "explore autism understanding and stigma among university students, and general community members recruited at a state fair." The second paper by Eilidh Cage and colleagues [2] wanted to examine "knowledge, openness and dehumanising attitudes of non-autistic people towards autistic people." Although the language used in the two papers is slightly different (i.e. 'dehumanising attitudes') the goals were pretty much the same: how much does the general public understand about autism and what are the perceptions of the label?

Stronach et al reported results based on the completion of the Autism Stigma and Knowledge Questionnaire (ASK-Q) by almost 500 people. Their combined results suggested that their cohort showed: "relatively high levels of autism knowledge and low levels of stigma." Ergo, awareness of autism seemed to be quite good and people were generally very accepting of autistic people.

Cage et al reported results based on a slightly smaller sample, albeit including over 350 participants. We are told that participants "completed a survey measuring autism openness, knowledge and experience, along with a measure of dehumanisation." Their results indicated that "knowledge of autism was comparable to past research" and that "females were more open towards autism." But things were not completely rosy in the Cage study as researchers found evidence for "dehumanisation, with a particular denial of 'human uniqueness' traits." Ergo, autism awareness is again pretty good, but more needs to be done in this area.

Minus any sweeping generalisations and judgements from little ole' me, I think it's important to frame some of this work in the context of other work from some of the authors on the topic of autism. I speak particularly of the Cage results, and how elements of this authorship group have previously expressed an 'inclination' to the whole social model of disability (see here) as being relevant to autism based on their other work [3]. The social model of disability by the way, opines that "people are disabled by barriers in society, not by their impairment or difference." Of course there is some truth in this idea as there are in many theories/hypotheses. The problem is however, when one assumes that society is the only barrier, and then potentially becomes blinded to the very real disability that a label is described and defined by. The fact also that the social model of disability is put forward as a counter to the medical model of disability is also a little unhelpful, and perhaps encourages some 'either or' thinking rather than looking at a potential mixture of influences and effects.

The comment about a 'denial of 'human uniqueness' traits' mentioned in the Cage study is also pertinent to other discussions/arguments in the context of autism. I speak about the term 'neurodiversity' which is often used to denote "a notion of neurological difference across humanity akin to the variation we see in plants and animals in biodiversity" and how such a term has grown in popularity over the years. One might see the Cage results as perhaps providing evidence that the notion of neurological diversity still has some way to go when it comes to the inclusion of autism under the heading, and indeed, making more progress towards illustrating just how heterogeneous the autism spectrum really is.

And finally, without trying to get too immersed in the implications of the Cage results in particular, that mention of 'human uniqueness' could also be viewed as another nail in the coffin for a problematic term used in some autism circles: neurotypical. And how, with all the complexity of the human brain and/or central nervous system, the term neurotypical is a still, very much, a scientific nonsense (see here)...

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[1] Stronach S. et al. Brief Report: Autism Knowledge and Stigma in University and Community Samples. J Autism Dev Disord. 2018 Nov 21.

[2] Cage E. et al. Understanding, attitudes and dehumanisation towards autistic people. Autism. 2018 Nov 21:1362361318811290.

[3] Cage E. et al. Experiences of Autism Acceptance and Mental Health in Autistic Adults. J Autism Dev Disord. 2018 Feb;48(2):473-484.

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Thursday 20 December 2018

1 in 5 adults with autism diagnosed with non-affective psychotic disorder (NAPD) before the age of 35?

The quote heading this post - "1 in 5 adults with autism diagnosed with non-affective psychotic disorder (NAPD) before the age of 35?" - comes from the findings reported by Schalbroeck and colleagues [1] continuing a research theme from this authorship group [2] on how autism rarely appears in some sort of diagnostic vacuum.

Relying on longitudinal data from the Netherlands ("from Dutch psychiatric case registers"), authors sought to capitalise on their previous findings from Sweden to "to assess the risk of NAPD or BD [bipolar disorder] among individuals with ASD [autism spectrum disorder], and compared the results to those obtained for the Dutch population in earlier studies." NAPD in this case refers to a grouping of labels covering schizophrenia, delusional disorder and acute and transient psychotic disorder. Bipolar disorder was previously called manic depression, reflecting mood swings between depression and mania. Both labels have some research history when it comes to autism (see here and see here for examples).

Based on the longitudinal analysis of participant records in the thousands, over 17,000, all diagnosed with ASD, researchers set about calculating the risk of NAPD and BD in their cohort. They observed that: "Of the individuals with ASD, 23.50%... were diagnosed with NAPD and 3.79%... with BD before age 35 years." Such percentages contrasted with general population figures of 0.9% and 0.1% for NAPD and BD respectively. Further study based on around 8,000 people "diagnosed with ASD before age 16 years" also showed elevated levels of NAPD and BD being diagnosed before 25 years of age (1.8% and 0.5% respectively) compared with general population figures (0.6% and 0.1%); albeit to a lesser extent.

Aside from concluding that the risk of NAPD and BD in relation to autism "is likely not the result of diagnostic or selection bias", the Schalbroeck findings reiterate again that autism seemingly rarely exists in some sort of diagnostic vacuum (see here). They reiterate that psychiatric comorbidity, some of which can often be both serious and quality-of-life destroying, is not uncommon in the context of the label of autism. They also reiterate that timely screening, diagnosis and yes, treatment for such comorbidity, are basic human rights that are as relevant to someone with autism as they are to someone not on the autism spectrum.

Oh, and given the quite significant overlap between autism and such psychiatric comorbidity, it is perhaps all the more reason to keep on studying a group where autistic and psychiatric issues seemingly were but are no more (see here)...

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[1] Schalbroeck R. et al. Risk of non-affective psychotic disorder or bipolar disorder in autism spectrum disorder: a longitudinal register-based study in the Netherlands. Psychol Med. 2018 Nov 21:1-8.

[2] Selten JP. et al. Risks for nonaffective psychotic disorder and bipolar disorder in young people with autism spectrum disorder: a population-based study. JAMA Psychiatry. 2015 May;72(5):483-9.

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Wednesday 19 December 2018

Scurvy in a child with autism following a ketogenic diet

"We report a case of a 5-year-old patient with autism, who presented with scurvy secondary to the dietary restrictions of a ketogenic diet."

That was the aim of the paper by Syed Amir Ahmad and colleagues [1] who continue an important theme in autism research and clinical practice circles pertinent to the seeming over-representation of illnesses of malnutrition in relation to autism (see here).

The 'value added' bit to the Ahmad findings is the observation that scurvy - a disease caused by insufficient vitamin C in the diet - was seemingly present as a result of "the dietary restrictions of a ketogenic diet" (where a ketogenic diet represents a high fat, low carbohydrate eating schedule). I assume said diet was put in place in light of some previous research suggesting that a ketogenic diet (KD) may be 'useful' for some children on the autism spectrum (see here and see here) from a behavioural perspective or where indicated following the detection of an inborn error of metabolism for example.

Scurvy is something of a pet topic on this blog (see here and see here). Described as a rare disease, the growing [research] literature on autism and scurvy indicates that it is perhaps not as rare as many people think or would like it to be. One of the big issues in this area is that more screening needs to be done for scurvy in relation to a diagnosis of autism, particularly when children (and adults) on the autism spectrum might have a limited or restricted diet (see here).

"This case emphasizes the importance of vitamin supplements in patients consuming a special diet." I wholeheartedly agree with that conclusion made by the authors. I say this in the context that supplementation with various vitamins, minerals and nutrients where autism is present and a 'special diet' is being followed is already a good idea (see here). The fact that some of those nutrients being supplemented might themselves have an 'effect' of on the behaviour of some children (see here and see here for examples) is also something important to mention.

the bottom line: screen and keep screening for health issues like scurvy when autism is diagnosed.

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[1] Ahmad SA. et al. Florid Scurvy in an Autistic Child on a Ketogenic Diet. Pediatr Emerg Care. 2018 Nov 19.

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Tuesday 18 December 2018

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

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

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

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

'Nuff said.

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

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Monday 17 December 2018

Buspirone for anxiety accompanying autism?

OK, before heading into the findings reported by Tolga Atilla Ceranoglu and colleagues [1] talking about the *potential* usefulness of the anxiolytic medicine called buspirone in the context of autism, I feel I should reiterate my oft-cited blogging caveat that no medical or clinical advice is given or intended. It's particularly important in this case because (a) anxiety accompanying autism is a really, really important issue (see here), and (b) I don't want anyone to assume that I'm giving any 'quick fix advice' on this topic. I'm not.

The Ceranoglu paper represents a "retrospective chart review" where the files of some 31 youth diagnosed with an autism spectrum disorder (ASD) who were treated with buspirone were analysed. We are told that: "Effectiveness was assessed through the Clinical Global Impressions Scale (CGI) severity (CGI-S) and improvement (CGI-I) scores noted by the treating clinician." The words 'high-functioning' are also used in the Ceranoglu paper; I assume to denote a cohort of young people who were verbal and had a good level of 'adaptive behaviour skills'. As I've said before, I'm not totally sold on the idea of 'high' and 'low' functioning in the context of autism but readily recognise that there are few alternative descriptions at present. The reliance on such a 'high-functioning' cohort probably also ties into other work with anxiety and autism in mind (see here).

Researchers report that use of buspirone "for an average duration of 272 ± 125 days" coincided with some important scores using the CGI. So: "Significant improvement in anxiety symptoms... was observed in 58% and mild improvement... in 29% of the HF-ASD patients who received buspirone treatment." The important issue of adverse side-effects is also covered in the Ceranoglu paper as we are told that: "Buspirone was well tolerated with no adverse events reported by the majority of participants, with the exception of two subjects who developed treatment emergent adverse events (activation and mood lability)."

A quick trawl of the available peer-reviewed literature on the topic of buspirone and autism reveals that there's quite a bit of history (see here). Anxiety is already part-and-parcel of that research history, in line with the clinical indication for buspirone, but I also note other studies [2] talking about its possible usefulness in the context of other, more traditionally core autistic behaviours too.

Insofar as the question of 'where next?' for buspirone and anxiety and autism, well, Ceranoglu et al also provide an answer: "Further research with prospective and randomized-controlled trials is necessary." I agree with this on the basis that, whilst we know that anxiety is very much over-represented when it comes to autism, conversations need to turn to what can be done about such a quality-of-life-draining issue, on the basis that clinically indicated 'talk therapy' may not be right for everyone (see here)...

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[1] Ceranoglu TA. et al. A Retrospective Chart Review of Buspirone for the Treatment of Anxiety in Psychiatrically Referred Youth with High-Functioning Autism Spectrum Disorder. J Child Adolesc Psychopharmacol. 2018 Nov 16.

[2] Chugani DC. et al. Efficacy of Low-Dose Buspirone for Restricted and Repetitive Behavior in Young Children with Autism Spectrum Disorder: A Randomized Trial. J Pediatr. 2016 Mar;170:45-53.e1-4.

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Friday 14 December 2018

Estimated one in 69 children aged 8 years old with autism (not one in 68) in 2012

"On June 5, 2018, the authors informed MMWR [Morbidity & Mortality Weekly Report] about a number of inadvertent errors throughout the report that resulted from reporting of autism spectrum disorder cases among persons who did not live in the geographic surveillance area."

So said a brief note [1] recently listed in the CDC Morbidity & Mortality Weekly Report (MMWR) concerning an important article published in 2016 [2] that described the estimated autism prevalence rate in the United States in 2012 for children aged 8 years old.

The original paper by Deborah Christensen and colleagues [2] was fodder for this blog at the time of publication (see here), with their estimated figures for 2012 (one in 68) showing a potential plateauing of the autism estimated prevalence rate in the US (see here for some discussion on the previous figures for 2010). The 'plateau' proved to be short-lived; as more recent figures published this year (2018) for the surveillance year 2014 once again showed the continuation of the upward trend (see here) in the childhood autism prevalence rate, now up to an estimated 1 in 59 children. Other figures have suggested even 1 in 59 is likely an understatement (see here).

Christensen and colleagues have republished their 2016 paper [3] showing 'where they went wrong'. It's not a wildly different article from their original publication and to a large extent, does not alter the underlying figures in any hugely significant way: 'one in 68' is replaced by 'one in 69'. Looking at the tables accompanying the Christensen republication, I was first drawn to Table 2 showing the: "Estimated prevalence* of autism spectrum disorder [ASD] among 1,000 children aged 8 years, by sex —Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012." Under the column labelled "Total no. with ASD" it looks like a few participating States had corrections. Arkansas in particular stood out; their total going from 170 with ASD down to 125. Their estimated autism prevalence subsequently dropped from 12 per 1,000 children (aged 8) to 8.8 per 1,000. Other States showed a correction in the opposite direction. New Jersey (which has had an important role to play in the CDC estimates) showed a slight increase (of 3 children) in their "Total no. with ASD" similar also to Missouri.

There's little more to say about the Christensen correction aside from reiterating that: (a) the CDC statistics citing figures like 'one in 69' or more recently 'one in 59' are estimates, and (b) how and what data you include for counting is going to have an important bearing on what (estimated) prevalence rate you arrive at. By saying all that, I've not changed my view that we are witnessing something of at least a partial 'real' increase in cases of autism (see here and see here and see here) as older 'better awareness' and 'diagnostic substitution' arguments become less and less relevant as the numbers (estimated) climb ever higher. And aside from keeping on asking 'why?' the powers-that-be should be putting a lot more money and resources into the services that will inevitably be required, to ensure that children and adults on the autism spectrum aren't (societal) disadvantaged by their diagnosis.

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[1] No authors listed. Correction and Republication: Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. MMWR Morb Mortal Wkly Rep. 2018 Nov 16;67(45):1279.

[2] Christensen DL. et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years--Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. MMWR Surveill Summ. 2016 Apr 1;65(3):1-23.

[3] Christensen DL. et al. PPrevalence and characteristics of autism spectrum disorder among children aged 8 years — Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2012. MMWR Surveill Summ. 2018 Nov 16;65(13):1-23.

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Thursday 13 December 2018

Middle ear infection and autism (again)

"Autism was more common in children who had had an otitis media infection or who had been treated with antibiotics."

Minus any sweeping generalisations, that was the conclusion reached in the study by Theresa Wimberley and colleagues [1] continuing some important research themes (see here and see here) examining any "interplay among otitis media, antibiotics, and the subsequent risk of developing autism."

Just in case you don't already know, otitis media infection refers to an infection of the middle ear that "causes inflammation (redness and swelling) and a build-up of fluid behind the eardrum." Aside from the use of painkillers, the seriousness of certain otitis media infections can sometimes mean that antibiotics are prescribed to combat any underlying bacterial infection or even in some cases, grommets inserted as treatment.

Wimberley et al report results based on "the entire Danish population", well, over three-quarters of a million children "followed from birth (January 1, 1997 to December 31, 2008) until December 31, 2012." They calculated various 'risk of autism' statistics as a function of a previous medical diagnosis of otitis media and "antibiotic prescriptions redeemed at Danish pharmacies." Yes folks, yet again those big data Scandinavian population registries have been used to good research effect.

Results: "The absolute risk of autism before age 10 was increased among children with otitis media (1.2% for females and 3.3% for males) and in children who had redeemed an antibiotic prescription (0.6% and 2.7% for females and males) compared to children without a history of otitis media and antibiotics usage (0.4% for females and 1.9% for males)." Researchers also reported finding "little evidence of a synergistic effect between otitis media infections and treatment with antibiotics" despite them being over-represented in relation to autism. They also caution that cause-and-effect cannot be inferred from their observational results.

What more can one say about the Wimberley findings? Well, echoing the idea that correlation is not the same thing as causation, I'd say that there is quite a bit more research to do on this topic. Further investigations are required into the possible mechanisms through which autism may manifest at least partially as a result of a history of ear infection (or indeed vice-versa). Mention of antibiotics also brings in areas of additional research interest such as the gut microbiome and what antimicrobials might 'be doing' to the trillions of passengers that are carried in the deepest, darkest recesses of the human body. I'm also minded to suggest that alongside antibiotic use to potentially treat infections like otitis media, researchers might also want to focus in on other medicines that might be accessed in such case such as over-the-counter pain relief in light of other *associations* that have been made (see here).

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[1] Wimberley T. et al. Otitis media, antibiotics, and risk of autism spectrum disorder. Autism Res. 2018 Oct 3.

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Wednesday 12 December 2018

Elevated zonulin levels in ADHD = more hyperactivity and "impairment of social functioning"

"Children with ADHD [attention-deficit hyperactivity disorderhad higher serum zonulin levels and were more impaired in social functioning compared to controls."

So said the findings reported by Gonca Özyurt and colleagues [1] exploring a topic quite close to my research heart, zonulin and the assumption that "the level of zonulin increases when intestinal permeability is impaired."

Before heading further into the Özyurt findings, I'll perhaps refer you to some of my previous musings on the topic of zonulin (see here) and the hows-and-whys of this potentially important compound. It's rooted in the idea that intestinal permeability is perhaps rather more than it should be in some people with some labels (see here) and this *could* have some important implications for biochemistry and beyond; particularly the notion of a 'gut-brain' relationship (see here).

Özyurt et al examined zonulin in the context of attention deficit hyperactivity disorder (ADHD) based on the idea that: "Zonulin has been shown to be associated with social impairment in children with autism spectrum disorder" but such functions (and other attention-related behaviours) have not yet been looked at with ADHD in mind. Based on the examination of serum zonulin levels in some 40 kids diagnosed with ADHD and a similar number of not-ADHD controls, analysed via "enzyme-linked immunosorbent assay", researchers reported that: "Children with ADHD had higher serum zonulin levels and were more impaired in social functioning compared to controls." Also: "The level of zonulin was independently predicted with hyperactivity symptoms and SRS [Social Responsiveness Scalescores in regression analysis."

Bearing in mind that the Özyurt study was a fairly small scale study that utilised a methodology that has its critics (see here), I'm cautiously interested in the presented findings. I don't want to say anything further about this at the present time; aside that is, from the need for quite a bit more data on this potentially interesting relationship...

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[1] Özyurt G. et al. Increased zonulin is associated with hyperactivity and social dysfunctions in children with attention deficit hyperactivity disorder. Compr Psychiatry. 2018 Oct 29;87:138-142.

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Tuesday 11 December 2018

Gut symptoms are important for 'psychiatric outcomes' in autism

"Individuals with autism spectrum disorder (ASD) are at heightened risk of psychiatric comorbidities across the lifespan, including elevated rates of internalizing, externalizing, and self-injurious behaviors." And: "Gastrointestinal (GI) conditions are of particular interest, as they are prevalent among those with ASD, may share genetic or neurobiological etiologies with the core features of ASD, and are linked with psychiatric difficulties in the general population."

Putting the issue of 'psychiatric comorbidities' and 'gastrointestinal (GI) conditions' together are the results of the findings reported by Emily Neuhaus and colleagues [1] who concluded that: "the presence and quantity of GI symptoms should be considered when evaluating psychiatric and behavioral concerns among children with ASD." Importantly too, they talk about how 'alleviating' accompanying bowel issues in the context of autism *might* also have some important influences on some of those psychiatric issues.

The starting point for Neuhaus and colleagues was a recognition that autism does not exist in some sort of diagnostic vacuum. This means that various 'comorbid' conditions/labels seem to be over-represented when it comes to autism, covering the behavioural/psychiatric (see here) and also the somatic (see here). The authors specifically zoomed in on GI symptoms because they've mentioned over and over and over again as being part-and-parcel of quite a few instances of autism (see here). Marrying the psychiatric and gastrointestinal together, they had two aims: "First, we sought to document the prevalence and variety of GI concerns within a large, well-characterized sample of children and adolescents with ASD. Second, we sought to understand relationships between ASD symptoms and GI concerns over and above the effects of psychosocial factors."

So, authors "draw on data from nearly 2,800 children and adolescents with ASD within the Simons Simplex Collection" pertinent to their aims and objectives. The Simons Simplex Collection (SSC) is no stranger to autism research for various reasons (see here and see here). Importantly too, the SSC is not stranger to specifically looking at GI issues in relation to autism (see here). They reported that: "Consistent with previous literature, families in the SSC frequently reported that their child with ASD had significant GI symptoms" to the tune of over one third of their sample experiencing at least one GI symptom.

Looking at their types of psychiatric symptoms - "internalizing, externalizing, and self-injurious behaviors" - they observed "evidence of unique variance associated with GI symptoms across all three measures of psychiatric symptoms we examined." This didn't mean that GI symptoms were 'the' [singular] cause of those psychiatric/behavioural issues; merely that the presence of such physical symptoms should be considered as one possible factor alongside things like "ASD symptoms, verbal IQ, adaptive behavior, family income." Given that something like self-injurious behaviour (SIB) can be pretty hard-hitting in terms of effects on the person and the people around them (see here), the idea that GI issues might be 'in the mix' alongside "more ASD symptoms, lower adaptive behavior, lower income" should not be ignored. To quote again: "levels of GI symptoms accounted for unique variance in psychiatric outcomes over and above these other factors, linking increased GI problems with increased psychiatric symptoms in children with ASD."

There is a further scheme of work to be followed in this important area.

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[1] Neuhaus E. et al. Gastrointestinal and Psychiatric Symptoms Among Children and Adolescents With Autism Spectrum Disorder. Front. Psychiatry. 2018. Oct 22.

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Monday 10 December 2018

"the incidence of ADHD, ASD, and DD significantly increased after TBI events in early childhood"

TBI mentioned in the title of this post refers to traumatic brain injury, and represents the 'target variable' examined by Hsuan-Kan Chang and colleagues [1] in the context of rates of "attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and developmental delay (DD)."

Consistent with various other research published by this authorship group, the fantastic but sadly now defunct National Health Insurance Research Database (NHIRD) in Taiwan was the resource used by Chang et al in pursuit of their research goal. And the participant numbers under study reflected the use of the NHIRD: "A total of 7,801 and 31,204 children were enrolled in the TBI and control cohorts, respectively."

As well as instances of TBI being listed in the NHIRD "from 1998-2008", researchers also had access to "the incidence of subsequent ADHD, ASD, or DD (according to ICD-9 criteria)." They observed that: "The TBI cohort exhibited a higher incidence of subsequent ADHD, ASD, or DD than the controls" and that said developmental diagnoses tended to be made "at a younger age compared with the controls" (non-TBI controls). They concluded that TBI seemed to increase the risk of each developmental diagnosis and that "severe TBI, repeated TBI events, and TBI at a younger age" were all (variably) potentially important factors for the labels.

This is interesting and thought-provoking research. It does require some 'treading carefully' sentiments; not least with the idea that within the huge heterogeneity and variability of labels such as ADHD and autism (ASD), TBI *might* be a route or part of a possible route towards a diagnosis. Whilst not discounting the idea that sub-clinical signs and symptoms of developmental disorders could actually put someone at greater risk for TBI (see here for example), the possibility that TBI 'might lead to' a developmental diagnosis should not be shied away from. Indeed, other independent findings might also be important (see here). I say that mentioning that TBI is a general term that says nothing about the reason for the injury, the type of injury or what specific part of the brain may be affected. If one however takes autism as an example, it's not beyond the realms of possibility that certain TBIs could 'mimic' effects seen in other examples of 'acquired autism' where brain injury is part-and-parcel of the clinical picture (see here and see here). Indeed, similar sentiments have been expressed in relation to ADHD too (see here).

Whatever the relationship and mechanisms involved, the Chang findings imply that further investigations are needed in this area. Also, far greater efforts need to go into first preventing and then managing TBI...

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[1] Chang HK. et al. Traumatic Brain Injury in Early Childhood and Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder: A Nationwide Longitudinal Study. J Clin Psychiatry. 2018 Oct 16;79(6). pii: 17m11857.

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Saturday 8 December 2018

"Anti-Candida albicans IgG antibodies in children with autism spectrum disorders"

The quote titling this post - "Anti-Candida albicans IgG antibodies in children with autism spectrum disorders" - reflects the title of the paper by Paul Ashwood & Heather Hughes [1] who set out to "determine if children with ASD [autism spectrum disorder] exhibit elevations in antibodies that target C. albicans, indicating current or previous overgrowth of this fungal species." Such work is based on the still developing idea that "individuals with ASD have significant aberrations in the composition of their gut microbiota, known as dysbiosis" and part of that dysbiosis might also stretch to fungal as well as bacterial species.

Candida albicans also known as C. albicans is described as a 'opportunistic pathogenic yeast' quite readily observed in quite a large proportion of 'healthy adults'. For most people, this yeast does not cause any issues. On occasion however, C. albicans can lead to problems, particularly among those who are described as 'immunocompromised'. This is not the first time that C. albicans has been examined in the context of autism. Granted, the studies so far have been relatively small scale [2] and in requirement of follow-up [3] but this topic is no stranger to the peer-reviewed science literature. The Ashwood & Hughes paper should also be viewed in the context of other science discussions from this authorship group [4]; indeed several [5].

So: "We measured anti-C. albicans immunoglobulin (IgG) in plasma from eighty children enrolled in the UC Davis MIND Institute CHARGE study." IgG antibodies, represent 'immune status' with regards to a history of encountering specific pathogens. So, being positive to "anti-C. albicans immunoglobulin (IgG)" means that someone has been exposed to C. albicans at some point in their lifetime and retained something of an 'immune memory' to it. This subsequently means that your immune system is 'primed' in case that specific pathogen is encountered once again.

Results: "Plasma anti-C. albicans antibody positivity was found in 36.5% (19/52) of children with ASD. Anti-C. albicans antibodies in typically developing controls was (14.3%; 4/28)." I'm sure that you can see the disparity between the groups, bearing in mind that this was not an 'all-or-nothing' finding in relation to the separation of the groups. I should also mention that researchers also reported that gastrointestinal (GI) symptoms, also examined in this cohort, did not seemingly play a role in C. albicans antibody positivity.

Where next for this area of investigation? Well, alongside perhaps taking these results into consideration with other findings from this research group (see here), the authors mention that "exploring fungal composition within the gut as well as metabolic byproducts of yeast species such as d-arabinitol and ethanol, and identifying associations these might have with behaviors in ASD" could be one direction. In light of other independent research (see here), I'd say that was a sensible next step to take.

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[1] Ashwood P. & Hughes HK. Brief Report: Anti-Candida albicans IgG antibodies in children with autism spectrum disorders. Front. Psychiatry. 2018. Nov 26.

[2] Ekiel A. et al. Intestinal microflora of autistic children. Med Dosw Mikrobiol. 2010;62(3):237-43.

[3] Iovene MR. et al. Intestinal Dysbiosis and Yeast Isolation in Stool of Subjects with Autism Spectrum Disorders. Mycopathologia. 2017 Apr;182(3-4):349-363.

[4] Hughes HK. et al. The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders. Curr Neurol Neurosci Rep. 2018 Sep 24;18(11):81.

[5] Hughes HK. et al. Immune Dysfunction and Autoimmunity as Pathological Mechanisms in Autism Spectrum Disorders. Front. Cell. Neurosci. 2018.

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Friday 7 December 2018

"hold promise as cross-cultural key indicators for autism"

The quote heading this post - "hold promise as cross-cultural key indicators for autism" - comes from the paper by Sophie Carruthers and colleagues [1] which "aimed to identify the items on the Autism Spectrum Quotient (AQ)-Child that are most predictive of an autism diagnosis among children aged 4–9 years across samples from India, Japan and the UK." Attempting to fill quite an important 'hole' in the use of the go-to 'are you autistic' screener, authors set out to look at the presentation of autistic traits across three different countries, all with some quite different cultural perspectives and contexts.

The Carruthers paper is open-access so doesn't need too many grand discussions from me. The basics: "parent-reported AQ-Child data from India (73 children with an autism diagnosis and 81 neurotypical children), Japan (116 children with autism and 190 neurotypical children) and the UK (488 children with autism and 532 neurotypical children)" was the source material. Once again I'll mention how the term neurotypical is a misnomer (see here); it's use in this paper is all the more surprising given that one of the authors wrote an editorial paper [2] mentioning how "there is no single way for a brain to be normal, as there are many ways for the brain to be wired up and reach adulthood." Oh well.

Results: from the collected data, researchers were able to undertake various statistical analyses. Pertinent to the quote titling this post were some important findings "identified to be universal key indicators" across the different countries and cultures. These were: "In a social group, s/he can easily keep track of several different people’s conversations; s/he enjoys social chit-chat; s/he knows how to tell if someone listening to him/her is getting bored; s/he is good at social chit-chat and s/he finds it difficult to work out people’s intentions." Alongside, various other indicators were rated as "performed excellently or acceptably" across the three different country groups.

The conclusion: "Cross-cultural overlap in the items most predictive of an autism diagnosis supports the general notion of universality in autistic traits whilst also highlighting that there can be cultural differences associated with certain autistic traits." I'd like to see more research done in this area. Quite a few years ago I posed the question 'Is autism the same all over the world?' (see here) and well, I don't have a good answer despite the Carruthers and other results. Obviously such a question needs also to be wrapped in the idea that the plural 'autisms' also exert an effect (see here) and take into account other factors such as comorbidity (if that is the right word). It should also perhaps appreciate that whilst the AQ is undoubtedly 'picking up' something, it might not just exclusively be autism or autistic traits (see here and see here)...

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[1] Carruthers S. et al. A cross-cultural study of autistic traits across India, Japan and the UK. Molecular Autism 2018; 9:52.

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Thursday 6 December 2018

On autism and exposure to fragranced consumer products

The findings reported by Anne Steinemann [1] tap into an important issue seemingly relevant to many people diagnosed with autism or an autism spectrum disorder (ASD): exposure to various fragranced products such as air fresheners, deodorants and perfumes can seemingly cause various adverse physiological reactions. I know to some people this might not seem like particularly groundbreaking research, but when you read that almost 60% of autistic adults have been reporting "lost workdays or lost a job, in the past year, due to fragranced product exposure in the workplace" it kinda turns into something a lot more important.

Steinemann reports results across various different geographical cohorts pertinent to "the effects of fragranced products on autistic individuals ages 18–65 in the United States, Australia, and United Kingdom." This was a questionnaire-based study, a "web-based" survey, "part of the SSI [Survey Sampling Internationalweb-based panel." The numbers included for study are in the thousands, with some 4% reporting "medically diagnosed autism" upon which the Steinemann study is based.

The conclusion: "83.7% report adverse health effects from fragranced products." Said effects included "migraine headaches (42.9%), neurological problems (34.3%), respiratory problems (44.7%), and asthma attacks (35.9%)." Further: "Health problems can be severe, with 74.1% of these effects considered potentially disabling under legislation in each country."

As you can perhaps see, exposure to fragranced products is potentially an important issue for many people on the autism spectrum. The Steinemann results are based on discussions with adults (18-65 years) but I daresay there may be much to see with younger cohorts too. I'd also be interested to see whether issues like comorbidity potentially over-represented alongside autism might also exert something of an important effect too.

Solutions? Well, I don't think it's too much to ask if public and workplaces could perhaps look at some of their spaces with a view to reducing their use of fragranced products. If for example, this means cutting back on things like those automated air fresheners that periodically squirt out a cloud of smelly stuff, I'm pretty sure quite a few more people - more than just autistic people - would benefit. Indeed, with all the focus on 'autism hours' these days, I wonder if this could be something to add to the list of being 'autism-friendly'? As for personal scented products and the like, well, if you know that you're going to be interacting with autistic people who might be particularly sensitive to fragrances, how about giving those scented products a miss for that day? I promise that you will still smell OK. I don't think these are unreasonable requests.

Then the next question: why? Why do such symptoms come about and what are the biological mechanism through which such 'sensitivity' occurs? Well, it appears that Steinemann has some research history when it comes to fragrances and autism [2] albeit looking at "the neuromodifications of three selected fragrances on male and female human fetal brain neurons." Oxytocin and arginine vasopressin were the molecular targets in that study. Whether there may be more to see from these compounds in relation to fragrance sensitivity in adults is a question to ask. Such issues also perhaps overlap with other research talking about olfaction and autism (see here and see here). I'm also minded to point readers in the direction of another condition/set of symptoms that could be relevant: multiple chemical sensitivity (MCS). Yes, yes, I know that MCS is disputed in some quarters, even to the point of mentioning the word 'psychosomatic' on some occasions [3], but it strikes me that such high rates of 'fragrance intolerance' in relation to autism *could* also be tied into the presentation of MCS. And such high numbers reporting such an intolerance is probably not just 'all in the mind'.

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[1] Steinemann A. Fragranced consumer products: effects on autistic adults in the United States, Australia, and United Kingdom. Air Quality, Atmosphere & Health. 2018; 10: 1137-1142.

[2] Sealey LA. et al. Environmental factors may contribute to autism development and male bias: Effects of fragrances on developing neurons. Environ Res. 2015 Oct;142:731-8.

[3] Jimenez XF. et al. Polyallergy (Multiple Chemical Sensitivity) is Associated with Excessive Healthcare Utilization, Greater Psychotropic Use, and Greater Mental Health/Functional Somatic Syndrome Disorder Diagnoses: A Large Cohort Retrospective Study. Psychosomatics. 2018 Aug 2. pii: S0033-3182(18)30418-3.

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Wednesday 5 December 2018

Cannabis treatment and autism

"This preliminary study supports [the] feasibility of CBD [cannabidiol]-based cannabis trials in children with ASD [autism spectrum disorder]."

That was the research bottom-line suggested by Adi Aran and colleagues [1] following their retrospective study of some "60 children with ASD and severe behavioral problems" who were given cannabidiol (CBD)-rich cannabis. They report that nearly two-thirds of parents/caregivers of those children in receipt of CBD-rich cannabis observed "much improved or very much improved" behaviour on the Caregiver Global Impression of Change scale, "a 7-point, caregiver rated scale, designed to assess how much the child's symptoms have improved (‘No change’, ‘Slightly improved’, ‘Much improved’, or ‘Very much improved’), or worsened (‘Slightly worse’, ‘Much worse’, or ‘Very much worse’) relative to the baseline state."

Cannabidol (CBD) is a component of cannabis. Distinct from tetrahydrocannabinol (THC) in terms of chemical arrangement, CBD is still thought to have some psychoactive properties, although perhaps not as 'detrimental' as THC [2]. Cannabis and CBD have been fairly big news lately as a consequence of the legalisation of such compounds for specific medicinal uses here in Blighty (see here).

Aran et al report findings suggesting that further controlled research is required in this area. They observed that among their 60 children (50 boys and 10 girls with an average age of 12 and 10 years respectively) taking on average between 4-5 "drugs for behavioral problems", quite a high proportion were still being treated with cannabis "≥ 6 months from treatment onset." Perhaps also importantly, a third of children received less medications or lower dosage of medication following their "cannabis treatment."

I will however add in a word or two of caution following the Aran observations. First, although there is a lot of discussion and hype around the use of medicinal cannabis and various diagnoses / conditions / labels, one still has to remember that this is a drug, and a drug of abuse at that. This mirrors the chatter about another substance of abuse being potentially indicated in the context of autism (see here). Aran et al also talked about some adverse effects noted in their cohort ("sleep disturbances (14%) irritability (9%) and loss of appetite (9%)") including: "One girl who used higher tetrahydrocannabinol [THC] had a transient serious psychotic event which required treatment with an antipsychotic." Others have also independently warned about medical cannabis use [3] citing ASD as one example. What this information imply is that alongside any potential studies of cannabis or specific compounds derived from cannabis with autism in mind, one needs to also keep a focus on the potential downsides to its use as well as any positives...

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[1] Aran A. et al. Brief Report: Cannabidiol-Rich Cannabis in Children with Autism Spectrum Disorder and Severe Behavioral Problems-A Retrospective Feasibility Study. J Autism Dev Disord. 2018 Oct 31.

[2] Pierre JM. et al. Cannabis-induced psychosis associated with high potency "wax dabs". Schizophr Res. 2016 Apr;172(1-3):211-2.

[3] Bou Khalil R. Why Is It Important to Protect Children with Mental Disorders from Medical Cannabis? J Dev Behav Pediatr. 2015 Nov-Dec;36(9):766.

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