Cannabis treatment and autism continued

Consider this post talking about the findings reported by Lihi Bar-Lev Schleider and colleagues [1] on the topic of "the epidemiology of ASD [autism spectrum disorder] patients receiving medical cannabis treatment and to describe its safety and efficacy" an extension of other discussions on this blog (see here). Indeed, similar to the paper from Adi Aran et al [2] the name of research game was to look at 'real life experiences' of medicinal cannabis use 'for autism' in Israel (where medicinal cannabis use has been approved for some groups). I foresee this research area growing in months to come...

The focus of the Bar-Lev Schleider paper was CBD - cannabidiol - once again, a component of cannabis distinct from another compound, tetrahydrocannabinol (THC), which is described as being "the principal psychoactive constituent of cannabis." I say the focus was on CBD, but authors mention how: "The treatment in majority of the patients was based on cannabis oil containing 30% CBD and 1.5% THC."

Researchers relied on data "prospectively collected as part of the treatment program of 188 ASD patients treated with medical cannabis between 2015 and 2017." Said participants were an average age of around 13 years old, mostly male and all diagnosed with autism or ASD "in accordance with the accepted practice in Israel." Epilepsy was also mentioned in about 15% of cases, which is interesting in light of the increasing (media) focus on the use of medical cannabis 'for' certain types of epilepsy.

Results: I'm not entirely sure how outcomes with regards to safety and efficacy were actually collected. What I mean by this is that authors describe the use of "the global assessment approach" which meant asking questions like "How would you rate the general effect of cannabis on your child condition?" to participants' parents, but don't seemingly provide details on any specific validated questionnaires used. You might well ask if any such questionnaires exist at the moment with reference to the use of medicinal cannabis, but this doesn't really help matters. Bearing such an issue in mind, researchers reported that: "After six months of treatment 82.4% of patients (155) were in active treatment and 60.0% (93) have been assessed; 28 patients (30.1%) reported a significant improvement, 50 (53.7%) moderate, 6 (6.4%) slight and 8 (8.6%) had no change in their condition." 'Improvement in what?' you might ask. Well, various classes of behaviour are described including those implicated in daily activity - sleep, concentration on daily tasks - among other things. The authors also commented on how medicinal cannabis also seemed to have positively impacted on the occurrence of seizures too: "The improved symptoms at 6 months included seizures, of the 13 patients on an active treatment at six months 11 patients (84.6%) reported disappearances of the symptoms and two patients reported improvement."

And then to another important issue to consider when examining any kind of medicinal product: the presence of (adverse) side-effects. In this respect, we are told: "The most common side effects, reported at six months by 23 patients (25.2%, with at least one side effect) were: restlessness (6 patients, 6.6%), sleepiness (3, 3.2%), psychoactive effect (3, 3.2%), increased appetite (3, 3.2%), digestion problems (3, 3.2%), dry mouth (2, 2.2%) and lack of appetite (2, 2.2%)." Although most of these seem quite minor side-effects, it's still important to recognise them and the distress that they might bring particularly when 'digestion problems' *might* very well compound some already over-represented gastrointestinal (GI) issues already talked about with autism in mind (see here).

"Cannabis as a treatment for autism spectrum disorders patients appears to be well-tolerated, safe and seemingly effective option to relieve symptoms." That's the conclusion reached by Bar-Lev Schleider and colleagues on the basis of their findings. They do note how their results are based on "an observational study with no control group and therefore no causality between cannabis therapy and improvement in patients’ wellbeing can be established" which is important. Important too is the need for further discussions about the ethics of using something like medicinal cannabis in the context of autism [3] and then, if further hurdles are overcome, discussions about the hows-and-whys of a clinical trial or two. Indeed, speaking of clinical trials (see here)...

And as I write this [4] there's more, lots more [5]...

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[1] Bar-Lev Schleider  L. et al. Real life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy. Scientific Reports. 2019: 9.

[2] 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.

[3] Duvall SW. et al. Ethical Implications for Providers Regarding Cannabis Use in Children With Autism Spectrum Disorders. Pediatrics. 2019 Jan 4. pii: e20180558.

[4] Barchel D. et al. Oral Cannabidiol Use in Children With Autism Spectrum Disorder to Treat Related Symptoms and Co-morbidities. Front Pharmacol. 2019 Jan 9;9:1521.

[5] Aran A. et al. Lower circulating endocannabinoid levels in children with autism spectrum disorder. Molecular Autism. 2019; 10:2.

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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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One more time... (roughly) 1 in 40 children with parent-reported autism in the US

Consider this short post an extension of another recent entry on this blog talking about new data observing that the estimated autism prevalence rate (parent-reported) is around 1 in 40 children in the United States (US) (see here). That entry was based on the paper by Michael Kogan and colleagues [1] and their examination of data "using the 2016 National Survey of Children's Health (NSCH)" initiative.

Enter then another piece of research published little over a week after the Kogan study from Guifeng Xu and colleagues [2] which concluded that: "In a large, nationwide, population-based study, the estimated prevalence of ever-diagnosed ASD [autism spectrum disorder] was 2.79% among US children in 2016." In case you were wondering, 2.79% or 2.8% roughly translates as 1 in 36 children. Xu and colleagues, I might add, are no strangers to prevalence studies on childhood neurodevelopmental disorders (see here and see here).

Both these studies have attracted some media attention (see here and see here) mainly because they show a prevalence rate quite a bit higher than the recent CDC (estimated) autism prevalence figures - 1 in 59 8-year olds - published earlier this year (2018) (see here). Those media reports also seem to make quite a big deal of the 'parent-reported' nature of the figures (both derived from the NSCH initiative). As I mentioned in my last discussion of the Kogan paper, a quote from the lead author Michael Kogan is important in the context of those parent-report 'issues' that some people seem to have: "We know that in terms of having a major condition like autism, parents are usually pretty good reporters compared to medical records." Indeed they are.

Other details to add? Well, the Xu paper also reported on "state-level prevalence of ASD in the United States." They observed variations in the reported prevalence of autism (ASD) across the different states: "The state-level prevalence varied from 1.54% (95% CI, 0.60-2.48) in Texas to 4.88% (95% CI, 2.72-7.05) in Florida." Little explanation is given about such a discrepancy in their paper and so further research is implied.

Also: "Among those who had ever been diagnosed as having ASD, 92.79% (95% CI, 90.19-95.39) reported currently having ASD." This is interesting. Allowing for the fact that the diagnosis of autism or ASD is often more of an art form than a scientific endeavour, I did wonder whether the loss of about 8% of children who were previously diagnosed with autism but did not report currently having autism might overlap with the 9% figure with regards to the term 'optimal outcome' (see here). Y'know, the ever-growing body of peer-reviewed research that seems to suggest that for some people, a diagnosis of autism is not necessarily 'lifelong' (see here) (even if 'optimal outcome' is not necessarily the best phrase to use). Again, further research is implied.

For now however, we can conclude that there is : "a relatively high prevalence of ASD among US children" mirroring that in other parts of the world (see here for example). We really need to be asking questions like 'why?' and also 'are the relevant mechanisms in place to ensure that money, resources and services are directed towards this growing population?'

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[1] Kogan MD. et al. The Prevalence of Parent-Reported Autism Spectrum Disorder Among US Children. Pediatrics. 2018 Nov 26. pii: e20174161.

[2] Xu G. et al. Prevalence and Treatment Patterns of Autism Spectrum Disorder in the United States, 2016. JAMA Pediatrics. 2018. Dec 3.

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Depressive symptoms in ADHD: "comparing child and parent reports"

I was drawn to blogging about the results published by Annie Fraser and colleagues [1] for a few reasons. Their observation that: "Young people with ADHD [attention-deficit hyperactivity disorder] are at high risk of experiencing symptoms of depression but may under‐report the severity of their symptoms" was interesting. It potentially ties into some other important observations about 'happiness' in the context of ADHD (see here) and also how there is an elevated risk of suicidality when ADHD is part of the clinical picture (see here). Similarly, it fits the narrative that various developmental and/or behavioural labels/conditions/disorders are typically never really stand-alone diagnoses...

So: "This study used a subsample of children originally recruited as part of the Cardiff University Study of ADHD Genes and Environment (SAGE)." As per the 'comparing child and parent reports' part of the Fraser paper, both parents and children completed the Mood and Feelings Questionnaire (MFQ) to measures depressive signs and symptoms in participating children/young adults ("mean age was 14.6 years (range 8–20 years)"). The MFQ "is a widely used depression screening instrument" according to the authors, and has some pretty good backing. Results from the MFQ were compared with a non-ADHD (I assume?) general population sample from a similar part of the United Kingdom (UK) and statistics were applied.

Having already alluded to the observation that depression scores on the MFQ were higher (indicative of more depressive symptoms) in the ADHD group than the population control group (N=1460), there are some further details to mention. Both parent- and child-rated MFQs showed the trend of more depressive symptoms in participants with ADHD. And when it came to clinical cut-off points for suspected depression, quite a few more of those diagnosed with ADHD reached them compared with controls (parent‐report 54.5% vs. 10.6%... child‐report 32.4% vs. 10.5%).

"Amongst the most common depression symptoms found in our ADHD sample were difficulty concentrating, restlessness and feeling grumpy with parents. These symptoms overlap with those of ADHD, so it is unsurprising that they were common in our sample." Think of those last sentences in one particular context: the rise and rise of the term 'ESSENCE' (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) and all the chatter about how behavioural symptoms across various different labels seem to 'overlap' with one and another. How also, developmental and behavioural labels rarely exist alone or in some sort of diagnostic vacuum (see here for example). And add them to another sentence from the authors: "This could suggest that depression scores in this sample are artificially elevated by symptoms which overlap with ADHD symptoms." Indeed.

"Suicidal thoughts and symptoms of psychomotor and cognitive retardation (i.e. talking more slowly than usual, moving and walking more slowly than usual, and sleeping more than usual) were the lowest scoring symptoms on both parent‐ and child‐report." Having already mentioned those quite worrying statistics on how a diagnosis of ADHD seems to elevate the risk of suicidality, this might initially seem like better news from the Fraser paper. Items such as "S/he thought about death or dying.... S/he thought his/her family would be better off without him/her... S/he thought about killing him/herself" were not, in the majority, reported on with great fervour. But one needs to be cautious. I say that because the authors also added: "symptoms of suicidality (‘I thought about killing myself’) were present in 20%–25% of the ADHD sample, according to both parent‐report and child‐report, compared to 2%–7% of the population sample." This is a more worrying way of looking at the findings.

So to conclude: depression or depressive symptoms are no stranger to ADHD, the symptoms of ADHD probably overlap with some of the symptoms of depression (at least according to the MFQ), and an enhanced risk of suicidality seems to be confirmed as and when ADHD is diagnosed. There's more than enough further investigations to be done on those topics; perhaps also drawing on a few other important observations too (see here and see here and see here).

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[1] Fraser A. et al. The presentation of depression symptoms in attention‐deficit/hyperactivity disorder: comparing child and parent reports. Child and Adolescent Mental Health. 2018;23(3):243-250.

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1 in 10 kids: the estimated prevalence of ADHD in the United States in 2016

Credit: Xu et al (2018) JAMA Network Open

"In a nationally representative population, we estimated that the prevalence of diagnosed ADHD [attention-deficit hyperactivity disorder] among US [United States] children and adolescents was 10.2% in 2016."

So said the findings published by Guifeng Xu and colleagues [1] who relied on data derived from the National Health Interview Survey (NHIS) in the United States over the course of two decades (1997-2016). As per an accompanying editorial [2] with the smart title "Paying Attention to Attention-Deficit/Hyperactivity Disorder", the Xu findings "fills an important need" insofar as their plotting a significant increase in the estimated prevalence rate of ADHD. The stats: "the estimated prevalence of ADHD significantly increased during the past 20 years—from 6.1% in 1997-1998 to 10.2% in 2015-2016." The year-on-year percentage figures considered by Xu et al showed a rise almost every year when it came to the [estimated] ADHD prevalence. Such figures are quite distinct from other (point) estimates in other parts of the world (see here).

Of course there are upsides and downsides to the authors' reliance on the NHIS dataset. So: the reliance on "parental reports about psychopathology rather than actual standardized assessments administered face-to-face with parents and/or children by trained evaluators" is one of the main limitations talked about across many different labels (see here). This has to be balanced with the large sample size included in the NHIS initiative and the "high response rate (child response rate of 85.6%-93.3%)." Personally I'm not inclined to believe that significant numbers of parents would provide 'false' answers to questions like: “Has a doctor or health professional ever told you that [the sample child] had attention-deficit/hyperactivity disorder (ADHD) or attention-deficit disorder (ADD)?” or “Does [the sample child] currently have attention-deficit/hyperactivity disorder (ADHD) or attention-deficit disorder (ADD)?” but ho-hum.

Then to the million dollar question: why has the estimated ADHD prevalence rate increased so dramatically across a relatively short period of time? Well, some well-worn explanations also seen with regards to the autism prevalence statistics (see here) have been banded around. So: "Nonetiologic factors may partly explain the apparent increase in the prevalence of diagnosed ADHD in this study" such as physician "sensitivity" to a diagnosis of ADHD, alongside the changes in ADHD diagnostic criteria already talked about in the peer-reviewed domain (see here). The issue of screening and diagnosis among non-white groups and their accessibility to said screening/diagnostic services is also discussed (something else that cropped up with the recent autism stats in mind too). And since I've just mentioned autism, it's also likely that the increasing recognition that ADHD is part of the clinical picture for quite a few on the autism spectrum (see here) probably contributes to the increase too.

But then there is the idea that the increase may also be - in part - reflective of a real increase too (see here). There are lots of possible candidates that may be contributory (see here and see here for examples) covering a multitude of genetic and non-genetic factors appearing during the nine months that makes us and beyond. As with any other developmental label and the reason(s) it comes about, there are going to be a multitude of potentially important factors to consider that may be quite individual. One thing is evident however, for whatever reason(s), the numbers are only heading in one direction...

A final question: what can be done to improve the life outcomes of those diagnosed with ADHD in ever-increasing numbers? I mention that question in the context that ADHD seems to elevate the risk of various adverse life events occurring (see here and see here and see here for examples) as well as being a potential 'driver' for other psychopathology appearing too (see here). In this context, we are already beginning to appreciate the benefits of certain types of intervention (see here) as well as the potential value of various other intervention options that are not yet considered 'mainstream' (see here and see here for examples). Further research is required to understand the societal and biological factors linked to a diagnosis of ADHD, and whether further advances in intervention and management can be made as a result, and onward lives (hopefully) enhanced...

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[1] Xu G. et al. Twenty-Year Trends in Diagnosed Attention-Deficit/Hyperactivity Disorder Among US Children and Adolescents, 1997-2016. JAMA Network Open. 2018; 1: e181471.

[2] Dickstein DP. Paying Attention to Attention-Deficit/Hyperactivity Disorder. JAMA Newtork Open. 2018; 1: e181504.

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On transparency in science: lessons from the Pandemrix vaccine and 'partial' evidence-based practice

Minus any hype or sweeping generalisation, I want to draw your attention to a feature article recently published by Peter Doshi [1] titled: "Pandemrix vaccine: why was the public not told of early warning signs?" complete with some media interest (see here).

The feature is based around the vaccines developed to counter the 2009 flu pandemic that starred the H1N1 influenza virus which was sweeping across the globe at the time. The 2009 flu pandemic was potentially serious insofar as its infection pattern and fatalities linked to infection although in reality did not turn out to be quite the 'global killer' that was prophesied. The rush to bring to market a vaccine to protect lives and counter the rise of H1N1 also brought with it controversy from several perspectives [2]; some later talking points seemingly stemming from the inclusion of a specific adjuvant - AS03 - in some vaccine preparations, and data suggestive of a possible correlation between onset of narcolepsy and use of certain flu vaccines containing the AS03 adjuvant (see here). Narcolepsy - a sleep disorder - was one potential adverse side-effect talked about, but other labels/conditions were also the source of some inquiry too (see here). On the basis of the emerging published data, court cases ensued, some of which have apparently unearthed some "internal reports" suggesting that some manufacturers "were aware of other serious adverse events logged" in relation to certain H1N1 vaccines...

The Doshi feature goes through some of these 'revelations' that did not seem to have been made public at the time. He talks about an 'undisclosed problem' whereby one vaccine in particular, Pandemrix, seemed to have a greater frequency of various adverse events reported according to those internal company reports. Most worrying are the reports of 'fatal outcome' across different vaccine preparations, particularly Pandemrix. He also writes: "And the raw numbers of adverse events were not small" highlighting how in one of the latest internal reports dated March 2010 seen by himself (or at least, the British Medical Journal) over 5000 reports of "serious adverse events for Pandemrix" had been received by the company behind the vaccine.

It's timely that the Doshi feature appears now at the time of writing this post, just days after the Peter Gøtzsche - Cochrane drama (see here) and at the same time as other relevant pieces have been published (see here and see here [3]). The similarities around questions of transparency in science (particularly industry-derived science that has a public health aspect attached to it) are very noticeable. As is also the question of 'how much detail should the public be provided with?' when it comes to science in general and then specifically, science and science communication linked to the potential cost-benefit ratio of particular medicines or medical preparations. It's interesting too that Doshi also references some past debate in Germany [4] about the 2009 flu pandemic where it was apparently reported that "the German interior ministry rejected accusations that the ministry had ordered a less risky vaccine for top officials" in light of some newspaper headlines published at the time. 'All animals are equal, but some animals are more equal than others' perhaps springs to mind...

I don't think the issue of less than full transparency in science and the question 'how much detail should the public be provided with' are going to go away any time soon. Such issues strike to the heart of the matter of how peer-reviewed published science is seemingly only one part of a much bigger picture when it comes to the search for a complete truth. One wonders for example, how many other 'internal reports' lie in [research] file cabinets around the world that could conceivably influence evidence-based decisions on the effectiveness and safety of various medicines and other interventions indicated for various conditions? Without such documents ever seeing the cold light of day, how can science ever truly be said to be complete, transparent or indeed settled?

Such a 'transparency' situation also makes initiatives like OpenTrials - calling for all research to be more 'discover-able' and 'traceable' - all the more vital and important. Issues such as the requirement for pre-registration of all studies via databases such as ClinicalTrials.gov and importantly, the timely release and publication of results (see here) are pressing features. Study pre-registration (especially prospective registration) in particular, should perhaps be pushed a lot more than it currently is, and shouldn't just be reserved for big studies of drugs and medicines either.

Science is great and is getting better all the time. But it still has lots of issues and problems to overcome. A lack of research transparency seems to be a particularly important issue that, whilst starting to receive some much required attention, will if present, always mean that evidence-based practice really should be re-branded as 'partial evidence-based practice'. And that has lots of implications...

To close, given the subject matter included in the Doshi paper, I want to end with a reminder about not making sweeping generalisations. At the same time I'd also champion the words included in another recent article by Jørgensen and colleagues [5] (yes, also including Peter Gøtzsche as an author) responding to the idea that public confidence in public health initiatives such as vaccination may be "undermined" by even having such discussions in public. To quote: "Debates over sources of evidence must take place in public, especially when public health interventions are at stake." This is again, with the idea that science needs transparency - even better in the peer-reviewed domain - and closed door discussions rarely aid such transparency.

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[1] Doshi P. Pandemrix vaccine: why was the public not told of early warning signs? BMJ 2018;362:k3948

[2] Doshi P. Influenza: marketing vaccine by marketing disease. BMJ 2013;346:f3037.

[3] Jørgensen L. et al. Challenges of independent assessment of potential harms of HPV vaccines. BMJ 2018;362:k3694

[4] Stafford N. Only 12% of Germans say they will have H1N1 vaccine after row blows up over safety of adjuvants. BMJ 2009;339:b4335.

[5] Jørgensen L. et al. Response to Cochrane editors: Jørgensen, Gøtzsche and Jefferson. BMJ EBM Spotlight. 2018. Sept 23.

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"The Importance of Adolescent Self-Report in Autism"

The findings reported by Jessica Keith and colleagues [1] provide the blogging fodder today and a rather important message about the value of self-report in the context of autism, but also with one or two caveats too.

The name of the research game was to investigate the "consistency of adolescent and parent reports of anxiety and auditory sensitivity in individuals with ASD [autism spectrum disorder]" as well as examine "their validity via comparisons with sympathetic arousal at baseline and in response to an auditory challenge." This, on the basis that anxiety is not an uncommon diagnostic bedfellow when it comes to autism (see here for example) and alongside, auditory sensitivity also having quite a long established relationship with some autism (see here).

As per the title of this post taken from the Keith paper - "The Importance of Adolescent Self-Report in Autism" - an important focus of the study was to look-see whether parental reports of anxiety and auditory sensitivity 'matched up' with self-reports from adolescents with autism themselves. Authors reported that they did to a degree, but that also self-report might also provide some greater depth: "demonstrating greater self-reported (than parent-reported) anxiety and sensory symptoms." Indeed authors concluded: "adolescents with ASD have a unique perspective on their internal experience, which can complement parent reports and provide a more comprehensive assessment of symptoms in research and clinical settings."

I don't think anyone should be too surprised that asking adolescents about their own experiences of anxiety, sensory issues or anything else is probably going to yield far more accurate results than proxy reporting or second-hand accounts alone. Indeed, in these days where more and more people diagnosed as being on the autism spectrum are offering up their own first-hand accounts of their experience of autism, this represents a good thing in terms of 'getting it right' when it comes to diagnosing and managing important and often life-affecting symptoms or clinical diagnoses such as anxiety.

Caveats? Well, yes. I'm all in favour of people self-reporting and providing valuable insight into their own experiences. What is slightly less appealing however is that such self-reporting is not a luxury shared by all on the autism spectrum. The lack of self-report coming say, from some under-represented parts of the autism spectrum (see here) can sometimes mean that 'autistic experiences' are skewed towards more 'able' (or should that be 'vocal') parts of the autism spectrum; this despite the oft-used phrase: if you've met one autistic person, you've met one person with autism (or words to that effects). A solution? How about devoting more research and clinical resources to 'enabling' those traditionally not thought to have the capacity for complicated self-report to do so? Indeed, a participatory solution would perhaps be the best step forward I think (see here).

Oh, and also bear in mind that it needn't be self-report versus parent-report when it comes to something like anxiety in the context of autism. Both viewpoints can provide something important [2] on the basis that individuals know themselves but parents also have quite a unique viewpoint of their children and their behaviour across their formative years...

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[1] Keith JM. et al. The Importance of Adolescent Self-Report in Autism Spectrum Disorder: Integration of Questionnaire and Autonomic Measures. J Abnorm Child Psychol. 2018 Aug 2.

[2] Adams D. et al. Parent descriptions of the presentation and management of anxiousness in children on the autism spectrum. Autism. 2018 Aug 16:1362361318794031.

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"Many people with autism could be homeless": conflating a diagnosis of autism with significant proxy-reported autistic traits

Here I go again. Taking issue with a media headline seemingly designed to grab attention and clicks: "Many people with autism could be homeless." And how said headline doesn't quite match up with the findings of a study upon which it is supposed to be based. It's not the first time this has happened (see here) and I very much doubt that it will be the last...

The study in question was the one published by Alasdair Churchard and colleagues [1] who attempted to fill "a gap in knowledge" concerning anecdotal evidence suggesting that "autistic people experience an elevated risk of homelessness." Researchers report results based on the "entire caseload ( N = 106) of a UK homeless outreach team" where data about autistic signs and symptoms were gathered from second-hand accounts (outreach workers). Authors reported that around 1 in 10 homeless people who underwent such proxy reporting *could* have fulfilled the diagnostic criteria for autism (one homeless person had a previously recorded diagnosis of autism apparently). Around a further 9% received a 'marginal' report insofar as autistic traits reported as being potentially present, but not necessarily to the extent of reaching clinical cut-off points. Researchers also summarised their results for the lay audience too (see here).

I'm pretty sure that you can see some of the 'incongruence' between the 'many people with autism could be homeless' headline and what the study actual did and reported on. I should also mention that although the DSM-5 was the diagnostic criteria relied on during the study, the authors highlight how this was administered via their own 'creation' - "a DSM-5 Autistic Traits in the Homeless Interview, which we call the DATHI." I don't want to poo-poo such an instrument and it's usefulness in the context of autism and homelessness, but I would like to see a lot more work on its reliability and validity in future studies before any big judgements (or even bigger headlines) are made. Even better would be talking to and directly screening homeless people for autism as a next research stage; to help for example, with important clinical decisions such as whether 'symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning' to them as per the DSM-5 guidance on receipt of an autism diagnosis. Obviously such direct questioning might not be easy. One also needs to consider whether the status of homelessness might itself contribute to such 'significant impairment in social and occupational' functioning? Also throw in the idea that autistic traits are not necessarily just indicative of autism (see here for one example) and you have a recipe for some significant misunderstanding around the risk of homelessness and a diagnosis of autism which could further stigmatise. Sweeping generalisations about autism have already done more than enough damage down the years, often built on fairly flimsy evidence.

I'm not saying that there is no possible connection between autism (or autistic traits) and the status of homelessness. On the contrary, when one looks as the some of the myriad of reasons why a person becomes homeless (see here), there's more than a pinch of overlap with issues faced by those with autism. I will particularly highlight vulnerability variables like unemployment, poverty, poor physical and mental health and a lack of social support as being some of the most obvious commonalities. There are probably others. And where autism is identified in the homeless, one would expect there to be some added incentive to ensure they are well and given the advice and help they want/need to take care of themselves. Bearing in mind that is, that we aren't really in any position to dictate anyone's living arrangements to them...

And there's one final point to consider: various studies for example, have already talked about 'homelessness and the mental health scandal' (see here) where, in some cases, 4 out of 5 homeless people have been identified as having a mental health issue. Symptoms and diagnoses such as schizophrenia/psychotic disorder, mood and anxiety disorders and intellectual disability have all been talked about in the context of homelessness [2] alongside issues like substance abuse. Some of these labels/diagnoses have even been identified as having a direct influence on rough sleeping behaviour by some people (see here). You could well say that many of those behavioural and psychiatric labels/diagnoses have also featured in autism (see here and see here and see here for examples) and that within the context of 'autism rarely appearing in a diagnostic vacuum', so autism might then show a link to homelessness. But I'd be very careful to just singling out autism in this context. Very, very, very careful indeed...

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[1] Churchard A. et al. The prevalence of autistic traits in a homeless population. Autism. 2018 Apr 1:1362361318768484.

[2] Nishio A. et al. Prevalence of Mental Illness, Cognitive Disability, and Their Overlap among the Homeless in Nagoya, Japan. PLoS One. 2015 Sep 17;10(9):e0138052.

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Shocker alert: gut problems in autism impact on sleep (again)

"Increased odds of sleep problems were most frequently associated with gastrointestinal distress (GID) and non-verbal IQ (NVIQ), followed by male sex and age."

That was one of the findings reported by Ann Johansson and colleagues [1] who set out to examine "the relationship between sleep problems and characteristics of children with ASD [autism spectrum disorder] in a large, nationwide sample." Mention of the words 'Simons Simplex Collection' in the Johansson article provides a clue as to the source population examined in this study and some of the hows-and-whys of the research. From what I also understand, this paper is part of a doctoral thesis by Johansson looking at some of the possible genetics of sleep with autism in mind (see here). Indeed, if one scrolls to page 70 of the thesis, one finds the study in question...

The Simons Simplex Collection Sleep Interview (SSCSI) was the instrument of choice for assessing sleep issues. This is a short parent-report questionnaire that includes both a composite score for total sleep issues and subscale scores for things like 'sleep duration issues'. Alongside, GID was classified "if they were reported (yes/no) to have bloating/excess gas, celiac disease, constipation, diarrhea, ulcers, gastroesophageal reflux disease, inflammatory bowel disease (Crohn’s disease, ulcerative colitis), irritable bowel syndrome, abdominal pain, unusual stools, vomiting, and/or other GID." Throw in scores on the ADOS "used to measure ASD severity" and crunch the data...

I've inserted the word 'again' into the title of this post because this is not the first time that functional gastrointestinal issues 'over-represented' in autism have been connected to sleep issues (see here). This time around, researchers mention that over 40% of their cohort (2000+ children) "were categorized as having mild or moderate/severe sleep problems" according to their SSCSI composite score. 'Difficulty falling asleep' seemed to be one of the more frequently reported issues. GID - gastrointestinal distress - was the strongest factor linked to sleep issues (odds ratio = 2.79), again based on the SSCSI composite score for sleep issues. There were other combinations of symptoms potentially linking to sleep noted by the authors but I'm minded to put them to one side for now.

Caveats? Well, one big caveat sticks out: the reliance on parent-reported responses to a questionnaire about sleep without any reference to objective measures of sleep. I've gone on and on (and on) about the use of actigraphy when it comes to sleep research relating to various diagnostic labels (see here and see here for examples) and well, keep coming to the same conclusion about a strong requirement for such objective measures on sleep-wake cycles. I appreciate that there may be some 'consumer resistance' to wearing a wristband for example, to measure activity and rest cycles (see here), but surely someone, somewhere can engineer something when kids don't want to wear such gadgets? Insofar as the classification of GID also relying on parental report, I'm a little kinder to this because the evidence is pretty good for suggesting that parents might be tuned into what is typical and what is not typical from a functional bowel habits perspective in their offspring (see here)...

No mind, the results do accord with other independent data on how gut issues present in autism can seemingly have some far-reaching effects. As to 'how', well, I would always start with the obvious explanation: pain and discomfort caused by bowel issues affecting sleep, and then work back from there. Indeed, as if I need to say it again, bowel issues (both functional and more pathological) are truly 'over-represented' when it comes to a diagnosis of autism (see here) and science and clinical practice really need to do a lot more to tackle such issues as and when they are reported/detected...

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[1] Johansson AEE. et al. Characteristics of sleep in children with autism spectrum disorders from the Simons Simplex Collection. Research in Autism Spectrum Disorders. 2018; 53: 18-30.

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Headline fail: "Autism traits could be 'edited' out genetic trial suggests"

The Telegraph June 25 2018

"Autism traits could be 'edited' out genetic trial suggests" was one of the headlines that accompanied the publication of the findings by Bumwhee Lee and colleagues [1].

The Lee article details some interesting science following the use of something called CRISPR-Cas9 gene editing (see here) or more precisely the use of a new-ish development to this technique - "CRISPR–Gold, a nonviral delivery vehicle for the CRISPR–Cas9 ribonucleoprotein." CRISPR is one of the hottest things in science at the moment, as the words 'find, cut and paste' move to a genetic level (see here) and promises so much. In the Lee study, the target was the metabotropic glutamate receptor 5 (mGluR5) gene as a move to "efficiently reduce local mGluR5 levels in the striatum."

Oh, did I also mention that this research was done using mice? Indeed, this was a study of mice engineered to display some of the molecular and behavioural characteristics of a condition called Fragile X syndrome (FXS). As such, authors reported that the use of CRISPR-Gold injections into the striatum of said FXS mice correlated with a reduction in certain behaviours such as obsessive digging and leaping into the air. The authors opine that such behaviours 'overlap' with those noted in autism (FXS has a 'connection' to autism) and voilà, a link to autism is made.

Aside from that brief overview of the findings from Lee et al just mentioned, I'm not going to go too much into the nitty-gritty of the actual results. A cobbler should stick to his last and all that, and others have done a far better job than I ever could in discussing the science (see here). I do however want to make a case that the 'autism traits could be edited out' headline represents a fail when covering the Lee findings.

I say 'headline fail' in the title of this post because well, it is. Not only does it assume that obsessive digging and sporadic leaping into the air made by mice are singularly autistic traits, it takes a few sentences before the word 'mice' is even mentioned in the coverage. I've talked before about the caution(s) needed when translating animal findings to real people (see here) and how autism in particular, seems to be a label ripe for mass sweeping generalisations from 'autistic animals' to autistic people. I'm not saying that some of the features of autism are uniquely human (see here) but rather that is it premature to even imply that the traits of autism can be 'edited out' on the basis of a single mouse or other animal genetic study.

I've already mentioned about a 'connection' between FXS and autism but it is perhaps also important to realise that there seem to be many routes that bring someone to a diagnosis of autism. FXS is one condition that manifests autistic traits but it is not the only one and certainly science does not yet know everything there is to know about the genetics of autism and FXS. And just before anyone starts talking about autism being universally 'in-born' and 'genetic' as it is [assumed] in FXS, well, the peer-reviewed research evidence might just disagree with you (see here for one example)...

Finally there's another aspect to this work that requires sensitive media handling: the ethics of 'editing out' autistic traits. I know this is a 'hot potato' area, as an increasingly vocal - certainly on social media - group of people on the autism spectrum talk about their strengths as well as their disabilities. Much of this discussion is framed around the notion that autism is not something separate from who they are but rather a fundamental part of who they are. If one takes this viewpoint, it is logical to assume that 'editing out' autistic traits might mean something rather ominous to some people...

The point I'm trying to get across is that the Lee paper is seemingly good science. It faithfully reported the results of an exciting new technology that holds promise for many different labels, conditions and diseases (see here). The issue however, is that the reporting of such research needs to be accurate and responsible. Headlines in particular, need to mention the word 'mouse' if it was a mouse study. They need to avoid sweeping generalisations that infer that digging and leaping behaviour in animals are generalisable as autistic traits (certainly the latest ICD-11 schedule says nothing about such behaviours), and they need to be sensitive to the fact that 'editing out' may very well provoke significant anxiety among some people on the autism spectrum. All for the sake of an attention-grabbing headline...

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[1] Lee B. et al. Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours. Nature Biomedical Engineering. 2018. June 25.

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Allergy and autism linked (again)

There was something rather timely about the publication of the result by Guifeng Xu and colleagues [1] observing that: "In a nationally representative sample of US children, a significant and positive association of common allergic conditions, in particular food allergy, with ASD [autism spectrum disorder] was found."

Timely, because earlier the same day I read a rather disparaging piece titled 'oversold diets' *trying* to condense down the findings reported by Gogou & Kolios [2]. This duo looked at the "current literature data about the effect of therapeutic diets on autism spectrum disorder", where certain diets are often put in place because of a perceived allergy or intolerance to certain foodstuffs and effects on behaviour and physiology. Gogou & Kolios concluded that: (a) "No serious adverse events have been reported" ('first, do no harm' and all that) and (b) the currently available peer-reviewed data on things like the use of a ketogenic diet and/or a gluten- and casein-free (GFCF) diet 'for' autism is promising but: "More research is needed to provide sounder scientific evidence." I agree that lots more resources and money need to be put into the scientific examination of such diets in the context of autism (see here and see here) including identifying potential best-responders [3]. I'd also like to see gastrointestinal (GI) issues included in the research agenda, in light of other promising peer-reviewed data too on a potential tie-up with said diets and autism (see here)...

Anyhow, back to the Xu findings, which have seemingly attracted some media attention (see here for example). The source of the data was the "National Health Interview Survey [NHIS] collected between 1997 and 2016", a US initiative designed to 'monitor the health of the United States population through the collection and analysis of data on a broad range of health topics'. Including parent or guardian responses on a questionnaire used as part of the NHIS, and specifically the questions: "during the past 12 months, has your child had (1) any kind of food or digestive allergy; (2) any kind of respiratory allergy; (3) eczema or any kind of skin allergy?", data was crunched for nearly 200,000 children.

Authors reported that as a total group (N=199,520), the weighted prevalence of food allergy being reported was about 4%. For a respiratory allergy, the prevalence came in at about 12% and 9% for a skin allergy.

Then to the autism vs. not-autism comparisons where: "A diagnosis of ASD was reported in 1868 children (weighted prevalence, 0.95%; 95% CI, 0.89%-1.01%)." Parents/guardians of those diagnosed with autism were significantly more likely to report all of those various allergies compared to the not-autism group. The figures were: food allergy (autism: 11.25% vs. not-autism: 4.25%), respiratory allergy (autism: 18.7% vs. not-autism: 12%) and skin allergy (autism: 16.8% vs. not-autism: 9.8%). Further: "After adjustment for age, sex, race/ethnicity, family highest education level, family income level, and geographical region, the OR [odds ratio] of ASD was more than doubled (OR, 2.72; 95% CI, 2.26-3.28; P < .001) among children with food allergy compared with those without food allergy." This last observation basically said that there was more chance of autism being reported among those with a food allergy than those without a food allergy.

Caveats? Well, a few to mention. First of all, you'll have noted the words 'parent or guardian responses on a questionnaire' being used, which need to be taken into consideration. No, I'm not casting any aspersions on reporting accuracy of anything like that (parents can be very sensitive to lots of things), but this was not a study of hospital records and tests or anything like that. Second is the use of the word 'allergy'. The medical definition of allergy (see here) is something like 'a biological response to a normally harmless substance'. Allergy is obviously immune-related and typically involves something called IgE (immunoglobulin E) among other things. Whilst some people might think they have an allergy to this, that or t'other, there is still some confusion about whether 'allergy' is the most suitable word in that context without for example, suitable allergy testing being undertaken. I might be being a bit pedantic, but words count...

That all being said, the Xu findings are not the first time that allergy and autism has been raised as being *associated* (see here and see here for examples). Indeed, allergic illness such as something like asthma, has quite a long association with autism (see here) and hints at a possible 'immune-related' connection to at least 'some' autism. That also one of the most common 'comorbid' conditions over-represented in relation to autism - attention-deficit hyperactivity disorder (ADHD) - seems to have an even stronger connection with allergy (see here) is also important to mention, and further strengthens some immune system involvement where there is diagnostic intersection. It also *might* have intervention implications too (see here) (with no medical advice given or intended)...

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[1] Xu G. et al. Association of Food Allergy and Other Allergic Conditions With Autism Spectrum Disorder in Children. JAMA Network Open. 2018; 1: e180279.

[2] Gogou M. & Kolios G. Are therapeutic diets an emerging additional choice in autism spectrum disorder management? World Journal of Pediatrics. 2018. May 30.

[3] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2015 Aug;74(3):202-7.

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Anxiety symptoms are frequent in relation to childhood autism

The findings reported by Lieke Wijnhoven and colleagues [1] observing that "children with ASD [autism spectrum disorder] have a high risk to have co-occurring anxiety symptoms" are not likely to win any awards in relation to novelty. Most people, I assume, with some knowledge about autism will know that anxiety seems to be a quite consistent 'partner' to the label both in children and adults, and can for some, be absolutely disabling (see here).

But that's not to say that the Wijnhoven findings aren't important; as authors describe results both giving "an overview of the prevalence of anxiety symptoms in a clinical Dutch sample of children with ASD" and also examining "age, gender, ASD subtype, and IQ as potential risk factors for anxiety" in their sample of over 170 children diagnosed with an ASD.

Using a participant group already signed up for a "randomized controlled trial (RCT) testing the effect of an anxiety intervention for children with an ASD" [2], researchers analysed their responses to the Spence Children’s Anxiety Scale for Children and Spence Children’s Anxiety Scale for Parents (translated into Dutch). They also relied on data from cognitive testing, and just for good measure, added in data on the various comorbid diagnoses held by their participant group: "attention deficit hyperactivity disorder (45.3%), (persistent) depressive disorder (7.0%), oppositional defiant disorder (3.5%), obsessive–compulsive disorder (1.7%), reactive attachment disorder (1.7%), and posttraumatic stress disorder (1.2%)." Yes, those figures do put attention-deficit hyperactivity disorder (ADHD) at being present in over 45% of participant cases (see here).

Results: "In total, 66.3% of the participating children with ASD had child-rated subclinical or clinical anxiety symptoms on the total scale and/or on at least one subscale and 81.4% of the participating children with ASD had parent-rated subclinical or clinical anxiety symptoms on the total scale and/or on at least one subscale." Yep, just as you and I suspected, anxiety symptoms whether clinical or sub-clinical, are pretty rife in relation to autism. Additionally, girls seemed to present with more anxiety symptoms than boys; particularly when it came to "separation anxiety symptoms..., social phobia symptoms..., panic disorder/agoraphobia symptoms..., and generalized anxiety symptoms."

Age was and wasn't an issue, insofar as total anxiety symptoms being more 'intensely' reported for younger children than older children but: "Age was not a significant predictor of social phobia symptoms, specific phobia symptoms, panic disorder/agoraphobia symptoms, and generalized anxiety symptoms" based on child ratings. A similar pattern was also seen for parent-reports too.

What's more to say? Well, very little really. Anxiety once again, turns up as a frequent 'comorbidity' (if I can still - Mildred Creak - call it just comorbidity) and the challenges remain as to what can be done to minimise it and its effects (see here). Here's to hoping...

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[1] Wijnhoven LAMW. et al. Prevalence and Risk Factors of Anxiety in a Clinical Dutch Sample of Children with an Autism Spectrum Disorder. Front. Psychiatry. 2018; March 2; 9: 50.

[2] Wijnhoven LAMW. et al. The effect of the video game Mindlight on anxiety symptoms in children with an Autism Spectrum Disorder. BMC Psychiatry. 2015 Jul 1;15:138.

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Regression in autism: the rule rather than the exception?

"Declining trajectories of development, consistent with a regressive onset pattern, are common in children with ASD [autism spectrum disorder] and may be more the rule than the exception."

So said the findings reported by Sally Ozonoff and colleagues [1] who reported results based on a study of developmental / behavioural regression in autism, and specifically: "how rates of regression differed by measurement method."

Regression in relation to autism is a topic I've covered a few times on this blog (see here and see here for examples). I've followed the [peer-reviewed] story from where behavioural and/or developmental regression was initially thought to be a figment of the [parental] imagination, right up to these days where regression is pretty much accepted as being part and parcel of quite a few cases of autism. The road has not been a smooth one; but the question of whether autism is universally something inborn and hereditary for everyone is slowly starting to be answered: no, it is probably not. The reason(s) for regression still remain fertile grounds for discussion / debate / argument, but there are some important clues in the science literature (see here and see here for examples) with the caveats that autism is a very heterogeneous condition and onset patterns are likely to be influenced by all-manner of different variables. Think different phenotypes in the context of autism (see here) for example; and that's outside of the label previously known as Heller's syndrome.

Anyhow, Ozonoff et al report results for infants "with (n = 147) and without a family history of ASD (n = 83)" who were "seen prospectively for up to 7 visits in the first three years of life." Various different ways and means of assessing reports of symptom onset were collected, "that systematically varied the informant (examiner vs. parent), the decision type (categorical [regression absent or present] vs. dimensional [frequency of social behaviors]), and the timing of the assessment (retrospective vs. prospective)."

Depending on who said what and how they said it, patterns of regression in skills were noted in quite a large proportion of the Ozonoff cohort. So: "A majority of the sample was classified as having a regressive onset using either examiner (88%) or parent (69%) prospective dimensional ratings." The authors suggest that their observations highlight how quite a few more resources (and cautions) need to go into looking at symptom onset patterns in relation to autism.

For quite a few people, the findings reported by Ozonoff et al are 'catch-up' rather than something novel. I can think of quite a few instances where parents / guardians have had their important observations - very important observations - described as being 'talked down' when it came to reporting a regression in previously acquired skills in the context of autism. This should no longer be the case; particularly when also set in the context of the increasing pluralisation of the label of autism (see here) and perhaps even, the changing face of autism (see here) compared with yesteryear.

Then to the next important questions: how and why? I've already alluded to a role for infection in relation to the onset of regressive autism for some, but much more data is required on the specific details and mechanisms. There is also the issue of what *might* potentially be done to minimise factors linked to regression in autism too. Minus any sweeping generalisations, I'd also direct your attention to other mentions of regressive autism in the peer-reviewed science literature [2] and where, minus any hype, there could be some important clues for some. The important point once again, is that the diagnosis of autism should be the start of further investigations, not the finishing line.

To close, don't ask me how or why but one of my brood has started watching and enjoying an old staple part of the weekend TV quiz scene in 1980s Blighty... BFH by the way, is most classically referred to as your 'bus fare home'.

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[1] Ozonoff S. et al. Onset patterns in autism: Variation across informants, methods, and timing. Autism Res. 2018 Mar 10.

[2] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.

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MoBa does... maternal pregnancy iodine intake and offspring ADHD symptoms and diagnosis

Yet another 'MoBa does...' post today, reflecting data derived from the Norwegian Mother and Child Cohort Study and the findings reported by Marianne Hope Abel and colleagues [1] (open-access available here).

Maternal pregnancy iodine intake (both calculated from food sources and also as a supplement) was the starting variable, where responses to "a food frequency questionnaire (FFQ)" provided researchers with enough data to categorise mums-to-be in terms of their iodine intake. Iodine, by the way, is something of an important nutrient from many biological reasons; not least for optimal thyroid function. During pregnancy, suitable iodine levels are also seemingly required to ensure that the developing child is able to reach their full potential (see here).. seemingly.

Alongside, researchers also looked at both children diagnosed with attention-deficit hyperactivity disorder (ADHD) and "maternal report of child ADHD symptoms at eight years of age" on the basis of other data talking about "a negative impact on child behavior problems when mothers had inadequate iodine intake from food and initiated use of supplemental iodine in the first trimester of pregnancy." Keep in mind that last part about supplemental use during early pregnancy...

So, including some 77,000 mother-child pairs where "for 27,945 there were data on maternally reported ADHD scores when the child was aged eight years", what did the researchers find?

"Iodine from food was significantly associated with maternally reported child ADHD symptoms at eight years of age... but not with risk of child ADHD diagnosis." Authors expanded on this observing that the 'inattention' side of ADHD symptoms, derived from a questionnaire covered in independent research [2], was the driving force behind the connection being made, not the hyperactivity subscale. They also noted that "maternal iodine intake of less than ~200 µg/day" seemed to be the crucial cut-off point when it came to those maternal reports of ADHD symptoms.

But... I'm sure it can't have escaped your attention that although maternal reports of offspring ADHD symptoms - indeed, inattention - *correlated* with maternal iodine intake, there was little to see when it came to "risk of specialist-diagnosed ADHD in the child." Indeed, the authors also note that they found "no evidence of any beneficial effect of supplemental iodine in pregnancy" and even that "initiating iodine supplement use within the first trimester in mothers with inadequate iodine intake from food (<EAR) was associated with both an increased risk of ADHD diagnosis and higher ADHD symptom score at eight years of age."

Science is [almost] never clear-cut in the conclusions it arrives at and the Abel results just add to that sentiment. Given that this authorship group seemingly having a considerable research interest in all-things iodine and health, I'm assuming that these latest results were quite the talking point. Certainly, just a little bit different from their other recent publication on this topic [3] that concluded: "Maternal iodine intake below the Estimated Average Requirement during pregnancy was associated with symptoms of child language delay, behavior problems, and reduced fine motor skills at 3 y of age" but perhaps not with the supplementation angle in mind: "results showed no evidence of a protective effect of iodine supplementation during pregnancy."

I don't know what and how much to make of the findings as they stand, aside from suggesting that other recent findings [4] also questioning the value of daily iodine supplementation "in mildly iodine-deficient pregnant women" perhaps add to the discussions in this area. MoBA represents a great resource in these days of population science, so one can't blame the findings on a lack of "large sample size, prospective design, extensive collection of data, and the possibility of linking the cohort to national registries." It could, therefore, well be that talk on iodine supplementation during early pregnancy perhaps needs a lot more science behind it before anyone makes any grand, sweeping claims about its usefulness...

To close, in case you're wondering about the photo included in this post, it's all part of the Public Health England 'celebrations' for 100 years of public health marketing (see here).

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[1] Abel MH. et al. Maternal Iodine Intake and Offspring Attention-Deficit/Hyperactivity Disorder: Results from a Large Prospective Cohort Study. Nutrients. 2017 Nov 13;9(11). pii: E1239.

[2] Silva RR. et al. A rating scale for disruptive behavior disorders, based on the DSM-IV item pool. Psychiatr Q. 2005 Winter;76(4):327-39.

[3] Abel MH. et al. Suboptimal Maternal Iodine Intake Is Associated with Impaired Child Neurodevelopment at 3 Years of Age in the Norwegian Mother and Child Cohort Study. J Nutr. 2017 Jul;147(7):1314-1324.

[4] Gowachirapant S. et al. Effect of iodine supplementation in pregnant women on child neurodevelopment: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017 Nov;5(11):853-863.

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Extended release melatonin for sleep issues in autism

"PedPRM was efficacious and safe for treatment of insomnia in children with ASD [autism spectrum disorder] with/without ADHD [attention-deficit hyperactivity disorder] and NGD [neurogenetic disorders]."

So said the results published by Paul Gringras and colleagues [1] (open-access) covering a topic that is bound to create some excitement/interest given that the diagnosis of autism is no stranger to the issue of sleep problems (see here). Indeed, some have talked about sleep issues/problems in the context of autism as being an important influencing variable on parental well-being too [2].

From a starting population of over 250 children diagnosed with an ASD who were reported to have sleeping issues "(minimum 3 months of impaired sleep defined as ≤6 hours of continuous sleep and/or ≥0.5-hour SL from lights-off on 3 of 5 nights based on parent reports and patient medical history)" but not necessarily a sleep disorder, some 95 children / young adults completed the randomized, double-blind, placebo-controlled element of the trial. PedPRM - Paediatric Prolonged-Release Melatonin - was the active treatment option, compared against a placebo given over 13 weeks. "The a priori primary endpoint was SND [Sleep and Nap Diary]-reported total sleep time (TST) after 13 weeks of treatment." Melatonin, by the way, is one of the treatment options of choice when it comes to sleeping issues across various different clinical scenarios.

"The study met the primary endpoint demonstrating statistically significant effects of PedPRM vs. placebo on change from baseline in mean SND-assessed TST after 13 weeks of double-blind treatment." In other words, it worked. Indeed, when researchers set a standard of 45 minutes or more extra total sleep time as an indication of clinical response to PedPRM, almost 40% of their cohort taking the drug fitted that category compared with only 16% of those taking the placebo. "The 21.5% difference in percentage between groups equals NNT [number needed to treat]=4.7 for any additional responder above placebo."

When first looking at the study design presented by Gringras et al I was about to comment on a potential weakness based on the [subjective] use of caregiver report when it came to total sleep time. I'm not saying that this may not have provided a good rough-and-ready measure of TST but rather that it cannot provide actual physiological data on something like sleep duration and 'intensity' for example. As it happens however: "Actigraphy monitors (Actiwatch) were included in the study as a secondary objective measurement tool for the primary (TST) and first secondary (SL) sleep parameters." They weren't used throughout the whole study duration and were subject to some consumer resistance - "Despite major efforts to ensure adherence, actigraphy monitoring was challenging in this population, and a majority of participants (75% in the PedPRM and 77% in the placebo group) refused to wear the device during one or both periods and/or took it off some time during the night" - but did appear to show some effect in favour of PedPRM on TST and sleep latency (the time taken to fall asleep) for those who wore them during the study period. I guess the challenge for future studies is to make research actigraphy more 'autism-friendly'...

On the important issue of side-effects, the authors also report some observations. Treatment-emergent adverse events (TEAEs) were reported in not-insignificant numbers in both active (PedPRM) and placebo groups: "TEAEs judged by the clinician as treatment-related occurred in 12 (20.0%) participants in the PedPRM and 11 (16.9%) in the placebo group (28 and 20 events respectively)." Somnolence defined as sleepiness and drowsiness was one of them(?) but on the whole, the cost-benefit balance of the intervention seemed to favour use over non-use of PedPRM. There are a few other details included in the Gringras findings but I'm satisfied that the trial showed quite a good profile for the preparation in terms of efficacy and safety. Given also that melatonin is one of the more widely used medicines when it comes to autism, such results are perhaps not unexpected.

I do think more needs to be done in this area, not least on the hows-and-whys of melatonin working on sleep and other physiological functions. Yes, I know the whole biological pathway of melatonin (I've blogged about it before) but like many other medicines, melatonin has other many effects too, not least potentially affecting something else potentially important to some autism - intestinal barrier integrity a.k.a the leaky gut (see here). I wonder therefore if, when it comes to looking at potential responders and non-responders to such melatonin use, researchers might consider measuring gut permeability and perhaps other related compounds (see here) as part of their clinical research scheduling?

And whilst talking about sleep issues in the context of autism, I'll be coming to the findings reported by Len McCue and colleagues [3] on gut and sleep issues potentially intersecting in autism quite soon...

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[1] Gringras P. et al. Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children With Autism Spectrum Disorder. Journal of the American Academy of Child & Adolescent Psychiatry. 2017. Sept 19.

[2] Bourke-Taylor H. et al. Relationships between sleep disruptions, health and care responsibilities among mothers of school-aged children with disabilities. J Paediatr Child Health. 2013 Sep;49(9):775-82.

[3] McCue LM. et al. Gastrointestinal dysfunctions as a risk factor for sleep disorders in children with idiopathic autism spectrum disorder: A retrospective cohort study. Autism. 2017 Nov;21(8):1010-1020.

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