Friday, 23 June 2017

How helpful is a 'geek index'?

A quote to begin: "male offspring of older fathers had higher ‘geek index’ scores, a composite measure of high IQ, strong focus on the subject of interest and social aloofness."

So said the findings published by Magdelena Janecka and colleagues [1] (open-access) who set out to determine whether "having an older father is associated with certain beneficial traits" in offspring. Their use of the term 'geek index' (GI) was derived from a "composite measure of non-verbal intelligence, restrictive interests and reduced need to fit in with the peer group" based on data derived from the TEDS (Twin Early Development Study) initiative (something that has cropped up before on this blog). As one might imagine, use of the term 'geek index' in a science article was always likely to make some media headlines (see here for example).

In terms of study design and numbers, this was a biggie with study participants in the thousands. The geek index was derived from scores "of (i) non-verbal intelligence, (ii) restrictive and repetitive behaviours (RRBs) and (iii) social aloofness." Further: "Scores on the Raven’s Standard Progressive Matrices test were used to obtain (i). Childhood Autism Spectrum Test (CAST) scores were used to obtain both (ii) and (iii)." Various statistical 'transformations' were conducted on said scores to give that geek index sum and, not forgetting the parental age bit, paternal age was also thrown into the statistical mix.

As per the opening sentence, those children born to older fathers (but not older mothers) seemed to more frequently present with a higher geek index. This association persisted after controlling for various potentially confounding variables: "maternal age, sex, zygosity and SES [socio-economic status]." Researchers further observed that: "GI was positively linked with future academic attainment—including the key predictors of future SES—suggesting a phenotypic advantage in the offspring of older fathers."

These are interesting results and notwithstanding some study limitations i.e. "It was not possible to determine whether the advantageous effects of GI extend beyond secondary education, and correlate with future SES" require further independent investigation. Offspring being born to older fathers has generally been associated with various less-than-positive outcomes so this article kinda paints a more positive picture for children and families. Indeed, one of the commentators talking about these findings suggests that "perhaps we are destined for future society of geniuses that are going to help us solve all the world's problems." One would hope so.

As per the title of this post, I would however question how useful/helpful the term 'geek index' is when it comes to outcomes and implications. Yes, I know there is such a thing as 'geek chic' these days, but let's not forget that the word 'geek' has it's primary origins as a term of ridicule in many languages. To quote one definition: "the word typically connotes an expert or enthusiast or a person obsessed with a hobby or intellectual pursuit, with a general pejorative meaning of a "peculiar person, especially one who is perceived to be overly intellectual, unfashionable, or socially awkward."" I'm not so sure that every child (youngster or teenager) would be particularly happy to be labelled as scoring high on a geek index. Surely something a little more scientific could replace such a term?

Going also back to those study caveats provided by the authors, I might also raise the idea that just because someone shows an intellectual advantage when it comes to something like STEM (science, technology, engineering and mathematics) subjects does not necessarily mean that their future is going to be a rosy one in terms of employment, income or other markers of SES. “If you look at who does well in life right now, it’s geeks” is one of the quotes attributed to the first author of the paper; and with it as massive a sweeping generalisation as you will ever see.

If we for example, assume that strengths in STEM might be over-represented when it comes to the autism spectrum (see here) we should be seeing lots and lots of people either diagnosed with autism or possessing significant autistic traits thriving in such roles and in life in general. The reality however is that skills pertinent to STEM often do not appear in a vacuum (see here) as I would put forward the suggestion that future research might also consider the possibility of a relationship between the geek index (or other term) and the presentation of something like anxiety or depression and how that might also impact on later adult outcomes for example. The additional idea that social aloofness also makes up part of the geek index is something else that needs quite a lot more work on as part of any 'advantage' arguments being put forward...

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[1] Janecka M. et al. Advantageous developmental outcomes of advancing paternal age. Translational Psychiatry. 2017. 7; e1156.

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Thursday, 22 June 2017

Autism, learning disability and diagnostic substitution

The findings reported by Cynthia Nevison and Mark Blaxhill [1] represent the source blogging material today. Their quite detailed analysis of individual state data based on the "United States Individuals with Disabilities Education Act" (IDEA) is front and centre and what it might mean for the argument that the quite phenomenal rise in diagnoses of autism or autism spectrum disorder (ASD) is due wholly or in part, to a switch from the diagnosis of intellectual (learning) disability to autism.

Based on examining IDEA data for each of the 50 states of the United States covering various years, various years of birth and various ages, authors concluded that sweeping generalisations about widespread diagnostic switching/substitution were not necessarily borne out in such State level data analysis. They did find that: "Nationwide ID [intellectual disability] prevalence declined steeply over the last two decades, but the decline was driven mainly by ~15 states accounting for only one-fourth of the U.S. school population." Further, when assigning specific statistical conditions to states based on things like the decrease in ID being comparable to the increase in autism diagnoses or the increase in autism diagnoses being substantially greater than the decrease in ID diagnoses, authors reported a complex picture generally pertinent to the idea that "ID prevalence stayed relatively constant while ASD prevalence rose sharply."

This is not the first time that some of these authors have used IDEA data to put forward a view that the increase in cases of autism is real and not just an artifact of changing diagnostic criteria for example (see here). Indeed, both authors have an interest in this area [2] and dedicated some peer-reviewed science time to it. Personally, I find this kind of detailed scrutiny to be refreshing in these days of sweeping generalisations and soundbites about many facets of autism. Indeed, as time goes on and the numbers of those being diagnosed with autism creep ever higher worldwide (see here), older arguments about diagnostic substitution have seemingly become less and less convincing. No, diagnosticians weren't that bad at diagnosing autism X number of years ago...

Having said that, I do still think there is a place for diagnostic substitution when it comes to explaining *some* of the increase in cases being diagnosed. Data such as that from King & Bearman [3] estimating that about a quarter of the increase in cases of autism in places such as California might be due to diagnostic switching from ID cannot simply be forgotten or brushed under the scientific carpet. I should also mention that autism can very well exist in the presence of ID too (see here); even more so in specific populations (see here).

I know that old battle lines about a real vs. artificial increase in cases of autism still persist in many circles and I understand some of the reasons why each side believe what they believe. What is however not in dispute, is the fact that there are quite massive numbers of people (children and adults) being diagnosed as on the autism spectrum year-on-year worldwide (with additional many unable to access timely and appropriate diagnostic services) and resources aplenty are required to identify their specific needs and provide accordingly. No easy task in these continuing days of austerity, cuts and the like...

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[1] Nevison CD. & Blaxill M. Diagnostic Substitution for Intellectual Disability: A Flawed Explanation for the Rise in Autism. J Autism Dev Disord. 2017 Jun 6.

[2] Blaxill MF. What's going on? The question of time trends in autism. Public Health Rep. 2004 Nov-Dec;119(6):536-51.

[3] King M. & Bearman P. Diagnostic change and the increased prevalence of autism. Int J Epidemiol. 2009 Oct;38(5):1224-34.

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Wednesday, 21 June 2017

Schizophrenia and CRP meta-analysed again

"Our study provides evidence that higher CRP [C-reactive protein] levels are associated with increased risk of SZ [schizophrenia], especially for young adult patients less than 30 years."

So said the results of the 'updated' meta-analysis by Zhichao Wang and colleagues [1] (open-access available here) surveying the peer-reviewed literature on this topic "from inception to November 1, 2016." The 'updated' bit to their discussion refers to the fact that this is not the first time that CRP - a molecule associated with inflammation or inflammatory processes - and schizophrenia have received the meta-analysis treatment (see here for example).

So, "18 studies representing 1963 patients with SZ and 3683 non-SZ controls" were identified and as per the opening sentence to this post, "blood CRP levels were moderately increased in people with SZ... irrespective of study region, sample size of included studies, patient mean age, age of SZ onset and patient body mass index."

The authors do mention the idea that elevated levels of CRP in cases of schizophrenia fits in with the idea that immune function might be doing so much more than just fighting off infection and the like (see here). Indeed, they talk about: "The rationale that plasma CRP levels were increased significantly in studies with participants’age less than 30 years probably lies in that in the early stages of SZ, a particularly large number of inflammatory substances will be secreted, such as blood CRP and interleukin-10, which are very likely to be related to the development of SZ" with the requirement for further investigations. They also talk about how "high peripheral levels of CRP could increase the permeability of the blood–brain barrier through the adjustment of the function of tight junctions, which contributed to the increase in some pro-inflammatory cytokines, such as CRP to enter the central nervous system." This is an idea that has found favour in other quarters too [2].

Armed with such data, one might envisage that further studies on the possibility of controlling CRP and other related compounds (see here) *could* represent one route to eventually treating at least some types of schizophrenia...

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[1] Wang Z. et al. Association between C-reactive protein and risk of schizophrenia: An updated meta-analysis. Oncotarget. 2017 May 18.

[2] Najjar S. et al. Neurovascular Unit Dysfunction and Blood-Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence. Front Psychiatry. 2017 May 23;8:83.

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Tuesday, 20 June 2017

Oral vitamin D and the inflammatory effects of sunburn

In something of a departure from the typical content of this blog, I want to briefly introduce the paper by Jeffrey Scott and colleagues [1] and specifically the findings that: "Compared to placebo, participants receiving vitamin D3 (200,000 IU) demonstrated reduced expression of pro-inflammatory mediators TNF-α... and iNOS... in skin biopsy specimens 48 hours after experimental sunburn."

Based on a small number of participants who either received a high dose of vitamin D - "vitamin D3 (cholecalciferol)" - or a placebo one hour after experimental sunburn, authors describe how there seemed to be some merit in supplementing with vitamin D (oral dosage form) to help mitigate some of the more damaging, inflammatory effects of sunburn based on their observations. They further noted: "increased skin expression of the anti-inflammatory mediator arginase-1, and a sustained reduction in skin redness, correlating with significant expression of genes related to skin barrier repair" in their supplemented group.

It is perhaps timely that this research is discussed today given the current heatwave that has settled over most of Blighty. If like me, you are sometimes prone to the odd bout of sunburn (8 hours at Flamingo Land has quite a lot to answer for!) such findings could eventually prove to be quite useful. Obviously there is the strong advice not to get sunburn in the first place but added to the various creams and lotions to soothe the skin after sunburn, the possibility that vitamin D supplementation might also come in handy is worthwhile experimentally investigating further. The fact that vitamin D is produced in the skin (albeit in a quite complicated series of biological processes) suggests that Mother Nature knew what she was doing when it came to skin exposure to (excess) sunlight.

On one last point - that related to "the immunotherapeutic properties of vitamin D" - I'd also like to think that other areas of science and medicine could benefit from further research in this area. I've discussed research before on this blog talking about how vitamin D supplementation might be important to certain labels under certain conditions with an immune system/inflammatory component attached to them (see here). Assuming that what goes on in the skin under inflammatory conditions following sunburn is not necessarily a hundred million miles away from what happens to other parts of the body under similar inflammatory conditions, there is perhaps quite a bit we can learn from the sunshine vitamin/hormone and it's multi-faceted effects...

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[1] Scott JF. et al. Oral vitamin D rapidly attenuates inflammation from sunburn: an interventional study. J Invest Dermatol. 2017 May 30. pii: S0022-202X(17)31558-0.

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Monday, 19 June 2017

The ADOS-2, autism and "complex psychiatric conditions"

The findings reported by Brenna Maddox and colleagues [1] caught my eye recently and the specific finding that: "The ADOS-2 accurately identified all adults with ASD [autism spectrum disorder]; however, it also had a high rate of false positives among adults with psychosis."

ADOS-2 as in the Autism Diagnostic Observation Schedule mark 2, represents one of the premier gold-standard observational instruments for the assessment of autism or ASD. I've talked about ADOS quite a bit on this blog including the various efforts to further 'reduce down' this schedule and it's counterpart, the Autism Diagnostic Interview (ADI) to speed up the diagnostic/assessment process for example (see here).

Drawing on data derived from "adults in community mental health centers (n = 75)" where ADOS-2 was delivered, researchers observed something of a recurrent theme in screening/assessment circles in that the instruments used to look for autistic traits might not necessarily just be picking up exclusively autistic traits (see here for another example). That and/or the idea that the presentation of autistic traits might not be just confined to autism; important in these days of realisation that autism rarely exists in some sort of diagnostic vacuum (see here).

There is an interesting note added to the Maddox paper insofar as their findings serving "as a reminder that social communication difficulties measured by the ADOS-2 are not specific to ASD, particularly in clinically complex settings." This is not necessarily a new finding [2] but does further stress the 'interconnections' between autism and other labels/diagnoses (see here) as once again, the important observations made by people such as Mildred Creak and colleagues [3] are forgotten/brushed under the carpet at our peril.

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[1] Maddox BB. et al. The Accuracy of the ADOS-2 in Identifying Autism among Adults with Complex Psychiatric Conditions. J Autism Dev Disorder. 2017. June 6.

[2] Morrison KE. et al. Distinct profiles of social skill in adults with autism spectrum disorder and schizophrenia. Autism Res. 2017 May;10(5):878-887.

[3] Evans B. How autism became autism: The radical transformation of a central concept of child development in Britain. History of the human sciences. 2013;26(3):3-31.

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Saturday, 17 June 2017

Vitamin D deficiency is rife in an in-patient psychiatric unit for young people

"Adolescents within tier 4 adolescent mental health services may be at higher risk of vitamin D deficiency and so assessment of vitamin D levels should be considered as part of a standard physical health review for this group of young people."

So said the results reported by Neil Stewart & Simon Lewis [1] (open-access) who surveyed blood test results of patients admitted to a tier 4 psychiatric unit for vitamin D levels. Such a study was conducted on the basis that "it is plausible that vitamin D and/or vitamin D deficiency have a role in the pathogenesis of mental illness." Yes, indeed I might agree (see here and see here for examples).

Authors identified some 27 individuals who were tested for vitamin D deficiency between 2012 and 2014 from a population of 56. Over 80% (22/27) had vitamin D levels falling into the deficient or severely deficient range, and none of them had vitamin D levels reaching the bottom end of the typical range (75–250 nmol/L). A few other points are worthwhile noting: "In individuals from BME [black and minority ethnic] groups, who were potentially at higher risk of vitamin D deficiency due to increased skin pigmentation, 52.9% (9/17) were tested for vitamin D levels and 100% were deficient or severely deficient."

I was rather happy to see that authors have very much stuck to their findings minus too much speculation about their meaning. They, for example, suggest that all patients entering their particular service should "be considered at high risk of vitamin D deficiency" for whatever reason(s). They emphasise that vitamin D testing should be part and parcel of the routine physical examination normally provided to patients. They even talk about correcting any deficiency/insufficiency whilst monitoring vitamin D levels for any adverse effects or toxicity. In short, treat the physical health of their patients/service users despite the focus of their service being psychiatric. Lessons I'm sure that could be applied to many different labels/diagnoses with a behavioural or psychiatric element to them.

Going back to the idea that vitamin D deficiency might play a role in various conditions/states outside of those linked to bone health, the authors add to other voices suggesting that more investigation is needed to confirm/refute links between vitamin D status and behavioural or psychiatric issues. They note: "If an association between depression and vitamin D deficiency were to be confirmed through future study, vitamin D supplementation could potentially be a cost-effective treatment adjunct with minimal adverse effects." Again, I can't argue with the logic.

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[1] Stewart NF. & Lewis SN. Vitamin D deficiency in adolescents in a tier 4 psychiatric unit. BJPsych Bull. 2017 Jun;41(3):133-136.

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Friday, 16 June 2017

Food neophobia and autistic traits (or at least AQ defined autistic traits)

I was rather interested in the findings reported by Lorenzo Stafford and colleagues [1] suggesting "a positive association between food neophobia and the magnitude of autistic traits." Food neophobia is a fear of eating new or unfamiliar foods, and is something that most parents will have encountered at some point in their child/children's lives. With autism in mind, this type of issue is seemingly not uncommon in amongst various other food-related symptoms that can also be present.

Looking at the "broader aspects of autistic traits" and specifically whether a non-autistic (not diagnosed with autism) population showed any connection between their scores on the Autism Spectrum Quotient (AQ) and their scores on the Food Neophobia Scale (FNS), authors set about their study. They also examined whether olfactory sensitivity - "an olfactory threshold test for a food related odour" - might also show an effect in any relationship.

As per the opening paragraph to this entry, authors reported something of a relationship between AQ scores and FNS scores. Importantly, olfactory sensitivity did not seem to link in with AQ scores, suggesting that the link with food neophobia was not necessarily because of enhanced food odour perception for example. At least in this cohort.

This is potentially important work. Bearing in mind the quite small participant group (N=50), the reliance on "student participants" (not always the most representative of groups) as a non-clinical group and the assumption that AQ is actually measuring just the traits of autism (see here), the findings carry some interest. If there is indeed a connection between autistic traits and food neophobia, one could quite sensibly ask whether intervention(s) to ameliorate or reduce certain autistic traits might have some important knock-on effects for aspects of problematic food-related behaviours in relation to autism. Y'know, similar to the idea offered by other independent studies suggesting for example, that anxiety in the context of autism might be influenced by core traits (such as RRBs [restricted and repetitive behaviours]) and the implications thereof. Further investigations are implied.

And for those who might not fully understand just what food-related issues can mean in the context of autism...

Music to close: Harder, Better, Faster, Stronger.

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[1] Stafford KD. et al. Autistic traits associated with food neophobia but not olfactory sensitivity. Appetite. 2017. June 3.

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Thursday, 15 June 2017

On baby teeth, metals and autism

So: "using novel biomarkers of early life exposure, we observed differences in uptake of multiple toxic and essential elements over the second and third trimesters and early postnatal periods in MZ [monozygoticand DZ [dizygotic] twins discordant for ASD [autism spectrum disorder]."

That was the conclusion reached in the paper by Manish Arora and colleagues [1] (open-access). Using baby teeth as a sort of 'biologic hard drive' according to the accompanying press release (see here), researchers observed some interesting differences across twin groups with or without a diagnosis of ASD according to various pre- and post-natal periods. In particular they noted that: "In ASD cases, higher lead levels were observed over the prenatal period and first 5 months postnatally" and: "Zinc levels were lower in cases during the third trimester."

This paper has already received quite a lot of media attention (see here for example). Thankfully, many of the media outlets have focused on some of the quite important details when it comes to the study; namely that the total number of participants was quite small overall, despite being drawn from a larger research initiative: the Roots of Autism and ADHD Twin Study in Sweden (RATSS).

I am however very interested in both the methods employed during the Arora study and the results obtained. Baby teeth as a focus of autism research? I've speculated on that before (see here). The use of "Laser ablation-inductively coupled plasma mass spectrometry" is also rather good to see; being a method of choice for the determination of metals in various samples (ICP mass spectrometry) coupled to the use of laser ablation to free up the dentine surface of baby teeth for said analysis.

The results talking about levels of lead (Pb) and zinc (Zn) are also not entirely novel in relation to the autism spectrum. On this blog I've talked before about other, independent research observing a possible relationship between lead exposure and autistic traits (see here) on the basis that lead is a known neurotoxin and seemingly serves no physiological function in the body. Zinc, typically reductions in zinc levels, are also not entirely unknown to the autism spectrum either (see here); where zinc is required for quite a few important biological reactions/processes [2].

What's missing from the Arora study? Well, without trying to 'rock the boat' or anything, the focus on lead, zinc and manganese is a little limited given that other types of metals have also been discussed in the context of autism (see here). Yes, I know to mention mercury in the same sentence as autism is high on the 'hot potato' scale but peer-reviewed science is peer-reviewed science (see here). I might also have liked to see how tooth levels of those metals also correlated with blood levels of metals in the context that exposure might not be the only issue when talking about atypical metal levels and autism (see here).

Still, this is a good initial effort and should hopefully pave the way for further investigations into how metal exposure and/or inadequacies can very much impact on behaviour and development.

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[1] Arora M. et al. Fetal and postnatal metal dysregulation in autism. Nat Commun. 2017 Jun 1;8:15493.

[2] Frassinetti S. et al. The role of zinc in life: a review. J Environ Pathol Toxicol Oncol. 2006;25(3):597-610.

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ResearchBlogging.org Arora M, Reichenberg A, Willfors C, Austin C, Gennings C, Berggren S, Lichtenstein P, Anckarsäter H, Tammimies K, & Bölte S (2017). Fetal and postnatal metal dysregulation in autism. Nature communications, 8 PMID: 28569757

Wednesday, 14 June 2017

Autism and phenylketonuria: a double syndrome

I want to briefly talk about the letter to the editor from Esra Demirci [1] (open-access) today and a continuation of some rather important research/clinical chatter about the inborn error of metabolism called phenylketonuria (PKU) intersecting with cases of autism (see here).

The author describes a case report of a child who was diagnosed with an autism spectrum disorder (ASD) "after performing a clinical assessment that included the Autism Behavior Checklist (ABC) and Childhood Autism Rating Scale (CARS)" and then subsequently diagnosed with PKU following some important metabolic investigations. They also highlight how instigation of a low phenylalanine diet - the treatment of choice for PKU - seemed to impact on the presentation of autism: "Eight months after the phenylalanine intake diet was initiated, he began to make eye contact, look when his name was said, and form two word sentences. His ABC scores fell from 57 to 46, and his CARS scores fell from 48 to 42."

The 'double syndrome' mentioned in the title of this post refers to the idea that there may be those on the autism spectrum who also have "an already described medical condition" and findings of autism and PKU comorbid fall into that category. I have to say that I'm a fan of this kind of thinking given the range of particularly metabolic conditions that do see to have 'an autistic element' to them (see here for another example). Screening is yet again implied (bearing in mind that PKU is already fairly routinely examined in all newborns in many countries). The idea, also yet again, that use of a low phenylalanine diet might also affect some of the signs and symptoms of autism in such cases remains a point for further investigation into hows and whys...

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[1] Demirci E. Autism Spectrum Disorder and Phenylketonuria: Dyzygotic Twins with Double Syndrome. Noro Psikiyatr Ars. 2017 Mar;54(1):92-93.

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ResearchBlogging.org Demirci E (2017). Autism Spectrum Disorder and Phenylketonuria: Dyzygotic Twins with Double Syndrome. Noro psikiyatri arsivi, 54 (1), 92-93 PMID: 28566968

Tuesday, 13 June 2017

ADHD and risk of injuries meta-analysed

I have already covered the growing peer-reviewed research base looking at the diagnosis of attention-deficit hyperactivity disorder (ADHD) and risk of injuries on this blog before (twice in fact, see here and see here).

The results of the systematic review and meta-analysis by Shahrokh Amiri and colleagues [1] (open-access hopefully available here) therefore come as little surprise: "Those with ADHD are nearly two times more likely to be injured" and necessitates only a brief blogging entry today.

Based on cumulative results - "35 studies were selected for quantitative analysis" - drawn from the peer-reviewed science literature between 2000 and 2014, something of a 'strong' association was determined between ADHD and risk of injuries.

The authors talk about how facets of ADHD might more readily predispose someone to a greater risk of injury as things like risk-taking behaviour(s) "a well-known predictor in road traffic injuries" provide an important connection, also complemented by other behaviours typically associated with ADHD. All-in-all the Amiri results again suggest that yet again, much more clinical inspection is required to (a) inform those diagnosed with ADHD about their enhanced risk, and (b) perhaps reduce the signs/symptoms and/or effects of ADHD so to modify any excess injury risk. Common sense it seems.

To close, Adam West sings...

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[1] Amiri S. et al. Attention deficit/hyperactivity disorder and risk of injuries: a systematic review and meta-analysis. J Inj Violence Res. 2017 Jun 1;9(2).

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ResearchBlogging.org Amiri S, Sadeghi-Bazargani H, Nazari S, Ranjbar F, & Abdi S (2017). Attention deficit/hyperactivity disorder and risk of injuries: a systematic review and meta-analysis. Journal of injury & violence research, 9 (2) PMID: 28554188

Monday, 12 June 2017

Cannabidiol for drug-resistant seizures in Dravet syndrome

"Cannabis drug cuts seizures in children with severe epilepsy in trial" went one of the headlines referencing the results published by Orrin Devinsky and colleagues [1]. Accompanied by an editorial talking about 'real data, at last' [2] on how a chemical component of cannabis - cannabidiol - might be rather useful for some forms of drug-resistant seizures in Dravet syndrome, there is quite a bit of enthusiasm about these latest findings added to other results from this authorship group (see here). The trial details for their latest results can also be found on the ClinicalTrials.gov website (see here).

Dravet syndrome is something that I had previously heard of in light of some connections being made with the presentation of autism or autistic features [3]. Indeed, in these days of the plural autisms (see here) and adherence to the old 'we don't know what causes autism' mantra (see here), there is still quite a bit more investigation needed on autism appearing alongside known genetic or metabolic conditions and what this might mean for prevalence estimates of autism for example.

Dravet syndrome (DS) - also called severe myoclonic epilepsy in infancy (SMEI) - is primarily characterised by a severe type of epilepsy present in early infancy that continues accompanied by a progressive decline of other developmental functions. Such a regression accompanying seizures has attracted some autism researchers' attention (see here) in view of the clinical profile of DS not being a million miles away from that seen in other instances of autistic regression (see here). This also bearing in mind that autism and epilepsy are also not unstrange bedfellows (see here).

In the latest study Devinsky et al set about testing the possible effectiveness of cannabidiol in cases of DS under the gold-standard - double-blind, placebo-controlled - conditions. Some 120 children and young adults diagnosed with DS were randomly allocated to receive "either cannabidiol oral solution [GWP42003-P] at a dose of 20 mg per kilogram of body weight per day or placebo" over a 14 week period. I should also mention that this was pharmaceutical grade cannabidiol. Researchers primarily focused on seizure frequency between the two groups but did also look at important issues such as the instances and types of adverse events (AEs).

As per the headlines, the results suggested that cannabidiol did seem to be quite effective at reducing the frequency of seizures in the treated group compared to controls. Over 40% of those in receipt of the active medication showed at least a 50% decrease in seizure frequency over the course of study. Perhaps a little worrying were the observations that around a quarter of those in receipt of the placebo also showed a similar pattern of reduction (and why this finding just escaped statistical significance for the group taking the active medicine). Results also showed a pattern of possible 'super-responders' to cannabidiol intervention: "The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo."

But then there were the AEs also identified. So: "Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group." This also is a bit of worry, particularly if cannabidiol is something that needs to be constantly taken to maintain any seizure-reducing effects.

On the whole these are interesting findings in need of greater research scrutiny. I will reiterate that this was a controlled study using pharmaceutical grade cannabidiol, so one has to be careful not to assume that either the findings or the intervention will be successful or available to the general population. This is a particularly important point in these days of talk about medicinal cannabis use and condition such as epilepsy (see here) for example.

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[1] Devinsky O. et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017 May 25;376(21):2011-2020.

[2] Berkovic SF. annabinoids for Epilepsy - Real Data, at Last. N Engl J Med. 2017 May 25;376(21):2075-2076.

[3] Li BM. et al. Autism in Dravet syndrome: prevalence, features, and relationship to the clinical characteristics of epilepsy and mental retardation. Epilepsy Behav. 2011 Jul;21(3):291-5.

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ResearchBlogging.org Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S, & Cannabidiol in Dravet Syndrome Study Group. (2017). Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. The New England journal of medicine, 376 (21), 2011-2020 PMID: 28538134

Saturday, 10 June 2017

The inflammatory effects of unemployment?

"Our study demonstrates that systemic inflammation is associated with an important but little-studied aspect of the social environment, as it is elevated in unemployed compared to employed survey participants."

So said the results of the meta-analysis produced by Amanda Hughes and colleagues [1] (open-access) including data from "12 national studies, incorporating data collected between 1998 and 2012 from all countries in Great Britain" looking at two markers of systemtic inflammation: C-reactive protein (CRP) and fibrinogen. The numbers of participants available for study complete with biological data were "30,037 for CRP analyses and 28,661 for fibrinogen analyses" aged between 22-64 years old.

Alongside the biological information on CRP and/or fibrinogen, researchers also importantly analysed for employment status including "unemployment as commonly understood – the state of being in the labour force and available for work, but currently without it" as distinct from "non-employment categories such as retirement, homemaking or sickness/disability." Data from various other potentially confounding variables were also collected and included in the statistic mix including: age, gender, "socioeconomic position", tobacco smoking status and body mass index (BMI).

Bearing in mind the correlative nature of this research, various potentially important results emerged, not least that "markers of systemic inflammation were elevated for unemployed compared to employed participants." Authors undertook 'robustness checks' to see whether the various potentially confounding variables might have exerted a significant effect on their results and concluded that: "Associations were robust to adjustment for age, gender, education, long term illness, smoking classified using both heaviness and duration, adiposity specified using three BMI-based measures, and mental health, indicating these factors did not explain differences."

What does this research mean then? Well, based on the idea that something like elevations in CRP might be a risk factor for cardiovascular mortality in the general population [2] authors suggest that unemployment might be of 'clinical significance' when it comes to adverse health conditions associated with such an employment status.

There are a few other key points to emerge from the Hughes findings, not least that they may have turned up evidence for "a stronger inflammation-unemployment association in higher-unemployment areas." Their data for example, suggested that unemployment rates were lower in England than in Wales or Scotland over the study period, and that this may have been reflected in their combined data analysis. Different age groups also seemed to show some differences as per the observation that "associations were stronger in the 45–54 group than for younger participants or those approaching retirement."

Stressing again the correlational nature of this meta-analysis, these are potentially informative results. They suggest that, for whatever reasons, the state of being unemployed may not just have social and psychological effects on a person (and their families) but also a somatic element too. I assume one further stage of any research in this area would be to see whether a switch from unemployment to employment has any effects on those inflammatory measures and what element of employment might produce any reductions [3]. Another area of interest might be to see whether factors such as socio-economic status (SES) might also be an important correlate to inflammatory measures [4]. Alongside implications for the general population, I might also advance the idea that where specific groups are 'under-employed', similar inflammatory effects and onward elevated risks for various inflammatory-derived conditions could be something in need of investigation and intervention.

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[1] Hughes A. et al. Unemployment and inflammatory markers in England, Wales and Scotland, 1998–2012: Meta-analysis of results from 12 studies. Brain, Behavior, and Immunity. 2017. March 30.

[2] Li Y. et al. Hs-CRP and all-cause, cardiovascular, and cancer mortality risk: A meta-analysis. Atherosclerosis. 2017 Apr;259:75-82.

[3] Kim S. & Ferraro KF. Do productive activities reduce inflammation in later life? Multiple roles, frequency of activities, and C-reactive protein. Gerontologist. 2014 Oct;54(5):830-9.

[4] Liu RS. et al. Socioeconomic status in childhood and C reactive protein in adulthood: a systematic review and meta-analysis. J Epidemiol Community Health. 2017. 10 May.

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ResearchBlogging.org Hughes A, Kumari M, McMunn A, & Bartley M (2017). Unemployment and inflammatory markers in England, Wales and Scotland, 1998-2012: Meta-analysis of results from 12 studies. Brain, behavior, and immunity PMID: 28365380

Friday, 9 June 2017

Reducing depression scores (in IBS) using a probiotic?

"Probiotics can reduce symptoms of irritable bowel syndrome (IBS), but little is known about their effects on psychiatric comorbidities."

OK, go on...

"In a placebo-controlled trial, we found that the probiotic BL [Bifidobacterium longum NCC3001] reduces depression but not anxiety scores and increases quality of life in patients with IBS."

So said the findings reported by Maria Ines Pinto-Sanchez and colleagues [1] extending their research interest in all-things 'anxiety and depression related to functional bowel issues' (see here). Just in case you were wondering whether probiotics might be an effective intervention for at least some cases of IBS, yes, there is some meta-analysed evidence of positive effects (see here) albeit with more work to do.

This time around the name of the research game was to see whether various psychological issues that can very much accompany cases of IBS (see here) might also be affected by administration of a particular probiotic under gold-standard - "double-blind, placebo-controlled" - experimental conditions. Based on data from "44 adults with IBS and diarrhea or a mixed-stool pattern (based on Rome III criteria) and mild to moderate anxiety and/or depression (based on the Hospital Anxiety and Depression scale)" researchers followed participants taking either BL or a placebo capsule for 6 weeks. Alongside looking at bowel and behavioural signs and symptoms, they also collected blood and urine specimens and assessed using functional magnetic resonance imaging (fMRI).

As per the sentences above, use of the probiotic seemed to have some effect on scores of depression in the supplemented group when compared to the placebo-receiving participants. Indeed: "At week 6, 14/22 patients in the BL group had reduction in depression scores of 2 points or more on the Hospital Anxiety and Depression scale, vs 7/22 patients in the placebo group." Such an effect also seemed to carry forward when it came to another important measure: quality of life.

The authors also talk about seeing some changes on the imaging side of their study alongside: "reduced urine levels of methylamines and aromatic amino acids metabolites" in the probiotic supplemented group. All-in-all there was quite a bit to see from this study; certainly enough to provoke further investigations.

Of course, one needs to be a little careful based on the idea that not all probiotics are the same and further questioning is required on the specific mode of action. But, given the pretty good safety profile of various probiotics alongside an increasing volume of peer-reviewed research suggesting positive effects for some using such preparations when it comes to things like [some kinds of] depression (see here), I'm minded to suggest that the future is looking pretty bright when it comes to the use of probiotics for various conditions/labels/states...

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[1] Pinto-Sanchez MI. et al. Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: a Pilot Study in Patients With Irritable Bowel Syndrome. Gastroenterology. 2017 May 5. pii: S0016-5085(17)35557-9.

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ResearchBlogging.org Pinto-Sanchez MI, Hall GB, Ghajar K, Nardelli A, Bolino C, Lau JT, Martin FP, Cominetti O, Welsh C, Rieder A, Traynor J, Gregory C, De Palma G, Pigrau M, Ford AC, Macri J, Berner B, Bergonzelli G, Surette MG, Collins SM, Moayyedi P, & Bercik P (2017). Probiotic Bifidobacterium longum NCC3001 Reduces Depression Scores and Alters Brain Activity: a Pilot Study in Patients With Irritable Bowel Syndrome. Gastroenterology PMID: 28483500

Thursday, 8 June 2017

The PANDAS hypothesis is supported

PANDAS - pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection - is, as the name suggests, a condition / group of conditions? characterised by bacterial infection, or response to bacteria infection, leading to behavioural / psychiatric presentation(s).

Although fairly widely accepted (at least in the United States) there are some that still question this diagnosis and the idea that infection or response to infection can affect functioning in many more ways than just the somatic. There are, I might add, other examples of this in the clinical literature (see here).

The paper by Sonja Orlovska and colleagues [1] should put a few minds at rest with their 'large-scale' findings that "individuals with a streptococcal throat infection had elevated risks of mental disorders, particularly OCD [obsessive compulsive disorder] and tic disorders"; both key facets of a diagnosis of PANDAS. The additional finding that "nonstreptococcal throat infection was also associated with increased risks, although less than streptococcal infections for OCD and any mental disorder" adds something further to this area.

So, examining one of those oh-so important Scandinavian population registries - this time in Denmark - individuals with "registration of a streptococcal test" were followed up for "a diagnosis of any mental disorder, OCD, or tic disorders." The numbers of participants eventually included were in the hundreds of thousands (+600K) about half of whom at evidence of at least one positive strep test. The authors found that: "Individuals with a positive streptococcal test result had an increased risk of any mental disorder..., particularly of OCD... and tic disorders..., compared with individuals without a streptococcal test."

These are important results. Reiterating the title of this post, the concept of PANDAS is supported by the Orlovska findings. Noting the name Michael Benros on the authorship group of this current paper - someone who has previously explored the possibility that immune function/dysfunction can impact on psychiatry - I daresay that the previous ideas on how infection can affect cognitive abilities for example, (see here) are further extended by this work. Not least that possible identification of bacterial infections as one *cause* of issues such as OCD or tics gets a boost; as does the idea that treating said infections might lead to some rather interesting outcomes. There could also be tie-ups with specific diagnostic labels too (see here)...

To close, there is an election here in Blighty today, so here is party political broadcast for the largest party in the country: The ‘Can’t Be Arsed’ Party. Please exercise your democratic right.

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[1] Orlovska S. et al. Association of Streptococcal Throat Infection With Mental Disorders. JAMA Psychiatry. 2017. May 24.

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ResearchBlogging.org Orlovska, S., Vestergaard, C., Bech, B., Nordentoft, M., Vestergaard, M., & Benros, M. (2017). Association of Streptococcal Throat Infection With Mental Disorders JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2017.0995

Wednesday, 7 June 2017

The strengthening relationship between eating disorders and ADHD

The results from Loretta Sala and colleagues [1] confirms a recent trend in research circles observing a potentially important relationship between various types of eating disorder and the presence of traits/behaviours consistent with a diagnosis of attention-deficit hyperactivity disorder (ADHD).

It's something that has been covered on this blog previously (see here) and represents an extension to the idea that the presentation of autistic traits might not be the only relevant comorbidity when it comes to eating disorders (ED) (see here).

Sala et al report results based on a sample of some 70 female inpatients "all with longstanding histories of eating disorder (ED)." Various scales and instruments were used to assess both ED and ADHD traits/symptoms including the "presence of a diagnosis of ADHD." Accepting the rather nebulous term ED, participants were divided up into specific groups based on the type of eating disorder present: anorexia nervosa restricting type (AN-R), anorexia nervosa binge-eating/purging type (AN-BP) and bulimia nervosa (BN).

Results suggested that ADHD comorbidity is not necessarily an uncommon feature among quite a few cases of ED: "13 patients reported comorbidity with ADHD; three in the AN-R subtype, nine in the AN-BP and one in the BN." Findings also suggested that further research efforts might need to be directed into how ADHD traits/symptoms correlates with other features in cases of ED; specifically in relation to scores on the EAT-40 and the presence of anxiety as measured by the Hamilton scales for Anxiety (HAM-A).

It can only be a good thing that science and clinical practice is beginning to understand that various behavioural/psychiatric labels are rarely observed in isolation to other comorbidity. Not only does this offer potential new avenues for screening/prevention/treatment (see here for one example) but could also provide some much-needed clues as to why conditions such as ED might come about and indeed, who might be particularly at risk for such conditions.

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[1] Sala L. et al. Attention-deficit/hyperactivity disorder symptoms and psychological comorbidity in eating disorder patients. Eat Weight Disord. 2017 May 22.

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ResearchBlogging.org Sala L, Martinotti G, Carenti ML, Romo L, Oumaya M, Pham-Scottez A, Rouillon F, Gorwood P, & Janiri L (2017). Attention-deficit/hyperactivity disorder symptoms and psychological comorbidity in eating disorder patients. Eating and weight disorders : EWD PMID: 28534123

Tuesday, 6 June 2017

Probiotics degrading gluten peptides - part 3

So: "14 bacterial strains belonging to 32 species were isolated; 85 strains were able to grow in a medium containing gluten as the sole nitrogen source, 31 strains showed extracellular proteolytic activity against gluten protein and 27 strains showed peptidolytic activity towards the 33 mer peptide, an immunogenic peptide for celiac disease patients."

Those findings came from the paper published by Alexandra Herrán and colleagues [1] continuing a research theme discussed on this blog on how some of the trillions of bacteria that inhabit the human body - specifically the gastrointestinal (GI) tract - may possess some important gluten degrading properties (see here and see here).

With the requirement for further research, authors talk about how individuals might have their "own population of gluten-hydrolyzing bacteria" and how further knowledge in this area "could help to improve the quality of life of celiac disease patients" (where celiac or coeliac disease is the archetypal autoimmune condition triggered by the ingestion of dietary gluten and is managed by use of a gluten-free diet).

This area of work continues to fascinate me. It suggests for example, that the research chatter about the gut microbiome - factors affecting the gut microbiome - being linked to risk of coeliac disease might eventually turn out to be pretty important. Not least that a dysbiotic gut microbiome in relation to coeliac disease (see here) may affect some of those important gluten degrading bacterial species in particular. This might have repercussions for lots of areas; not least the prescription of antibiotics (see here) that can, for example, affect the quite delicate gut microbiome on quite a grand scale.

Such research also potentially extends to the idea that, outside of diagnosed coeliac disease, there may be a whole spectrum of gluten-related ills under the banner of non-coeliac gluten/wheat sensitivity (see here). If - and it is only an 'if' at this point - various gut bacterial species have special abilities when it comes to dining on something like dietary gluten, such effects are likely to extend to a whole range of people/labels not just core coeliac disease where gluten is implicated.

Does this  research also suggests that probiotic supplementation might be indicated for some types of non-coeliac gluten/wheat sensitivity too...?

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[1] Herrán AR. et al. Gluten-degrading bacteria are present in the human small intestine of healthy volunteers and celiac patients. Res Microbiol. 2017 May 16. pii: S0923-2508(17)30092-X.

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ResearchBlogging.orgHerrán AR, Pérez-Andrés J, Caminero A, Nistal E, Vivas S, Ruiz de Morales JM, & Casqueiro J (2017). Gluten-degrading bacteria are present in the human small intestine of healthy volunteers and celiac patients. Research in microbiology PMID: 28526528

Monday, 5 June 2017

Cerebral palsy and autism continued

"Our findings support the need for a multidisciplinary approach to management of children with CP [cerebral palsy] to adequately identify and address all facets of presentation, including ASD [autism spectrum disorder]."

So said the results of the study published by Malika Delobel-Ayoub and colleagues [1] who looked at the "prevalence of co-occurring autism spectrum disorders (ASDs) among children with cerebral palsy (CP)" among other things. Continuing a research theme (see here), researchers reported that around 9% of their 1200+ cohort of children diagnosed with CP had an "associated diagnosis of ASD". Said participant data coming from various European registries including one here in the bracing North-East of England.

What's more to say other than yet again, preferential screening for autism might be indicated? One might also advance the idea that clues about the origins of at least some autism may be forthcoming when the label is comorbid to CP. The particular finding that 'co-occurring epilepsy' might be something important for example, is as good a research starting point as any given what other independent datasets have similarly observed [2] combined with the ever-growing [bidirectional] links being discussed between epilepsy and autism / autistic traits (see here).

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[1] Delobel-Ayoub M. et al. Prevalence and characteristics of autism spectrum disorders in children with cerebral palsy. Dev Med Child Neurol. 2017 Apr 25.

[2] Christensen D. et al. Prevalence of cerebral palsy, co-occurring autism spectrum disorders, and motor functioning - Autism and Developmental Disabilities Monitoring Network, USA, 2008. Dev Med Child Neurol. 2014 Jan;56(1):59-65.

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ResearchBlogging.org Delobel-Ayoub M, Klapouszczak D, van Bakel MME, Horridge K, Sigurdardottir S, Himmelmann K, & Arnaud C (2017). Prevalence and characteristics of autism spectrum disorders in children with cerebral palsy. Developmental medicine and child neurology PMID: 28439889

Saturday, 3 June 2017

Adenotonsillectomy for obstructive sleep apnea and autistic behaviours?

Adenotonsillectomy refers to the surgical removal of the tonsils and adenoids and is typically indicated for a variety of reasons, not least in cases of obstructive sleep apnoea (OSA) (where breathing is interrupted during sleep). It's not an unfamiliar operation and is generally categorised as low-risk surgery. The positive outcomes following surgery have been described as 'dramatic' both in clinical terms and also related to quality of life [1].

A recent study published by Emi Murata and colleagues [2] (open-access available here) adds a further dimension to the use of adenotonsillectomy (AT) for obstructive sleep apnoea specifically with the autism spectrum in mind. They concluded that: "Behavioral problems were significantly improved following AT in ASD [autism spectrum disorder] children with OSA."

First off, I'll direct you to a previous post that I wrote about sleep apnoea and autism (see here) based on the findings reported by Hirata and colleagues [3]. They concluded that within their research cohort: "sleep problems, especially obstructive sleep apnea, are more common in ASD preschoolers than in community preschoolers." Then there are the study results by Malow and colleagues [4] who detailed a case report of treating sleep apnoea in a child with autism via use of AT. Bearing in mind this was an N=1, they observed that treatment coincided with "improvements in sleep, social communication, attention, repetitive behaviors, and hypersensitivity" based on use of the ADOS among other measures.

Set within this context, the Murata paper detailed the results of a study including some 54 children diagnosed with ASD. Their aims were two-fold: "to determine whether AT for the treatment of OSA improves the behavior of Japanese children with ASD using the Child Behavior Checklist (CBCL)" and "to identify characteristics for behavioral improvement following the treatment of OSA in these children with ASD." Thirty of the study participants were diagnosed with OSA and all underwent surgery for AT. I must also stress that said surgery was a clinical decision: "Because hypertrophy of the adenoids and/or palatine tonsils was observed." The rest of the cohort served as a control group used "to establish whether observed changes in CBCL scores were due to the natural course or a result of the experimental intervention."

The results are pretty interesting: "After AT, T-scores of the CBCL scales were significantly improved in the OSA group, but no change was observed in the control." This was based on before and after inspection at 0 months (before surgery) and 6 months after surgery. The sorts of things seemingly improved in the AT group were aspects of behaviour and functioning linked to being withdrawn, social problems. attention issues and aggressive behaviour. Authors noted that: "The domain of “thought problems” showed the largest decrease... in the OSA group."

When it came to the 'characteristics for behavioural improvement' side of their study, authors noted that: "the improved group show[ed] significantly higher scores on the CBCL at pre-AT than the unchanged/deteriorated group in ASD children with OSA after OSA treatment". This implies that baseline presentation might be important when it comes to behavioural outcomes following the use of AT and also that not every child with ASD and sleep apnoea undergoing AT will show the same pattern of behavioural changes.

I find these results to be fascinating. Not least because they offer a roadmap for (a) screening for sleep apnoea in cases of autism and (b) details of how a treatment for one cause of sleep apnoea in such cases might have effects well beyond just related to breathing patterns. Then also, there is the question of why such surgery might impact on presented behaviour? I'm afraid I don't know enough about such issues to offer any definitive explanations. I might refer you back to some other discussions on this blog about middle ear infections and autism (see here) in the context of ear, nose and throat being linked on several levels but further investigations are very much required on the biological parameters potentially important to findings such as those described by Murata et al. That being said [5] there may already be some clues in the peer-reviewed science literature...

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[1] Mitchell RB. Adenotonsillectomy for obstructive sleep apnea in children: outcome evaluated by pre- and postoperative polysomnography. Laryngoscope. 2007 Oct;117(10):1844-54.

[2] Murata E. et al. Evaluation of behavioral change after adenotonsillectomy for obstructive sleep apnea in children with autism spectrum disorder. Res Dev Disabil. 2017 May 14;65:127-139.

[3] Hirata I. et al. Sleep problems are more frequent and associated with problematic behaviors in preschoolers with autism spectrum disorder. Research in Developmental Disabilities. 2016; 49-50: 86-99.

[4] Malow BA. et al. Impact of treating sleep apnea in a child with autism spectrum disorder. Pediatr Neurol. 2006 Apr;34(4):325-8.

[5] Mitchell RB. & Kelly J. Behavioral changes in children with mild sleep-disordered breathing or obstructive sleep apnea after adenotonsillectomy. Laryngoscope. 2007 Sep;117(9):1685-8.

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ResearchBlogging.org Murata E, Mohri I, Kato-Nishimura K, Iimura J, Ogawa M, Tachibana M, Ohno Y, & Taniike M (2017). Evaluation of behavioral change after adenotonsillectomy for obstructive sleep apnea in children with autism spectrum disorder. Research in developmental disabilities, 65, 127-139 PMID: 28514706