"greater autism severity predicted greater pain response"

Among the many pressing topics that require [significant] research funds and attention when it comes to autism, I can think of only a few (one actually) that top the observation that pain *might* be something particularly important when it comes to autism (see here). It is with this in mind that I briefly bring the findings reported by Domingo Garcia-Villamisar and colleagues [1] to the blogging table, and their conclusion that: "greater autism severity predicted greater pain response" that "was partially mediated by anxiety and depression."

Authors describe how they 'observed' over 40 adults diagnosed with autism and "intellectual delay" whilst they were undergoing either vaccination or dental cleaning. We are told that "their pain behaviours [were] coded and measures of autism symptom severity, anxiety, depression and obsessivity taken." When the data was gathered and analysed, authors observed that *association* between the intensity/severity of autistic signs and symptoms and the expression of pain. They concluded also that: "Mood must therefore be considered in future research on pain in ASD [autism spectrum disorder] as well as clinical pain management."

Accepting that 'pain coding' is something that requires a little more research, particularly in the context of autism, I'm willing to accept the authors' findings as a road-map to further investigations in this area. Given that conditions/states/symptoms like depression and anxiety are no strangers to autism (see here) it's perhaps implied that they may have quite a large bearing on pain expression in the context of autism.

And if something like anxiety and depression might be 'mediators' of the pain response, shouldn't we doing everything we can to alleviate such issues in the context of autism? Even if that means targeting core symptoms (see here and see here)?

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[1] Garcia-Villamisar D. et al. Internalizing Symptoms Mediate the Relation Between Acute Pain and Autism in Adults. J Autism Dev Disord. 2018 Sep 27.

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Is 'escape' the most common function of challenging behaviours in autism?

'Challenging behaviour', 'disruptive behaviour' and 'behavioural crises' are terms that have been used to describe a range of behaviours "that are not culturally or socially acceptable, put the physical safety of the individual and/or others in jeopardy, affect learning, and/or limit access to community setting" in the context of autism and beyond.

A recent paper published by Esther Hong and colleagues [1] continued the research interest in this area (see here and see here) specifically focusing on gaining "perspective on what are the most commonly treated topographies of challenging behaviors" and "to identify the most commonly reported functions of those challenging behaviors." I'm assuming use of the word 'topography' in this context means 'profile' in terms of what types of challenging behaviours were noted.

Relying on behavioural data from over 3200 people diagnosed with an autism spectrum disorder (ASD) who were "receiving a minimum of 20 h of ABA [applied behavior analysis] treatment per month", researchers examined data on a range of behaviours falling into the category of 'challenging'. These included: "(a) aggression, (b) disruption, (c) elopement, (d) inappropriate sexual behavior, (e) lying, (f) noncompliance, (g) obsessive behaviors, (h) pica, (i) self-injurious behavior, (j) stealing, (k) stereotypy, (l) tantrums, and (m) teasing/bullying." Accepting that ABA in the context of autism is not everyone's cup of tea (despite some important data emerging [2]), one of the 'benefits' to this study at least, was that behaviour was recorded in some detail as a function of the implementation of ABA using something called The Skills™ database. This also allowed researchers to examine the potential 'function' of such behaviours too: "Skills™ also contains a field denoting the function of the behavior as identified by the supervising behavior analyst at the time of observation. Functions are classified as “attention,” “automatic,” “escape,” or “tangible.”."

Results: "The most commonly treated challenging behaviors were stereotypy, noncompliance, aggression, tantrums, SIB, elopement, disruption, and obsessive behaviors, respectively." Although 'stereotypy' ('the persistent repetition of an act) was the most frequently observed 'challenging behaviour', I'd personally be a little reluctant to put it into this category. I say this because there have been some reports suggesting that such a behaviour serves an important purpose in terms of being calming and aiding coping in certain situations for certain people. The majority of those challenging behaviours were coded most frequently in terms of 'escape' when it came to perceived function by the therapists who were doing the coding. Interestingly, and going back to my point about stereotypy, this behaviour was most frequently coded as 'automatic' alongside another behaviour that probably shouldn't be seen as a challenging behaviour: obsessive behaviours. Automatic, I assume, means just that: involuntary and well, automatic.

Alongside such information, authors also detail some nice Venn diagrams to illustrate how various categories of behaviours (and their specific manifestations) might meet and *correlate* based on their acquired data. Certainly, in the context of aggression and self-injurious behaviour (another important topic), there are some potentially important details to discern.

Although ABA still remains a point of contention among some, in the context of the Hong report, I can see how the quite detailed data collection on behaviour that it accrues holds some important information in the presence of some often, quite distressing behaviours. I'm happy to think that 'escape' could be a quite common function of various challenging behaviour(s), and moves to making 'some controlled escape' from particular situations might perhaps be useful to reduce the presence of such challenging behaviours. I know others will talk about 'demand avoidance' as being important too, but I'm cautious that this might not be an effective strategy in the longer term in helping people to build up 'resilience' to certain situations and environments.

But... I also think that 'escape' is not the whole story when it comes to challenging behaviours. I do still think that issues such as 'frustration' for example, can play a role. Also moving away from a purely 'behavioural' point of view, there is other evidence pointing to biology and physiology as being potentially involved in the presence of certain challenging behaviours. Fatigue? Yep, that's been mentioned (see here). Communication? Yep, that too (see here); particularly when verbal communication might be limited. And I'm also minded to mention that challenging behaviours can also be associated with things like the expression of pain (see here) that probably ties into the communication issue(s) too. In short, it's going to be complicated [3].

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[1] Hong E. et al. Topography and Function of Challenging Behaviors in Individuals with Autism Spectrum Disorder. Advances in Neurodevelopmental Disorders. 2018; 2: 206-215.

[2] Makrygianni MK. et al. The effectiveness of applied behavior analytic interventions for children with Autism Spectrum Disorder: A meta-analytic study. Research in Autism Spectrum Disorders. 2018; 51: 18-31.

[3] Rattaz C. et al. Challenging behaviours at early adulthood in autism spectrum disorders: topography, risk factors and evolution. J Intellect Disabil Res. 2018 May 24.

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Challenging behaviour and autism: how do parents manage it?

I'm not going to dwell too much on the findings reported by Elizabeth O’Nions and colleagues [1] discussing some of the ways-and-means used "to manage problem behaviour" in the context of autism, but I did want to bring it to your attention.

It's an important summary because (a) it highlights how a diagnosis of autism or autism spectrum disorder (ASD) does seem to increase the risk of various 'challenging behaviours' appearing above and beyond what would typically be expected (see here), (b) it illustrates how said behaviours have an important impact both on the person themselves and significant others around them (see here), and (c) it details 'what might help' in terms of parents or significant others managing such behaviour(s) as well as providing a road map for further study and potentially, further guidance.

The O'Nions paper is open-access so you can read for yourself what the findings were. The main points as I saw them were:

• Challenging behaviours covers a lot of ground.
• Said behaviours can and do affect quality of life for all concerned.
• Various strategies are employed by parents to cope with such behaviours including "accommodating the child... modifying the environment... providing structure, routine and occupation... managing non-compliance with everyday tasks and activities... [and] managing distress."
• Strategies for 'dealing' with such behaviour(s) often take into account their effects not only on the person/child concerned but also the family unit.

What's missing from this review? Well, accepting that the focus was "to identify how parents and caregivers spontaneously manage problem behaviour in ASD" I found the O'Nions paper to be rather light on anything not related to behaviour and/or psychology. Take for example, the growing realisation that challenging behaviour(s) seem to show some connection to sleep patterns in the context of autism [2] and what that could mean for intervention(s) to manage sleep issues for example (see here). Similarly, the idea that challenging behaviours can, on some occasions, seem to be linked to the experience of pain (see here) and/or fatigue (see here) is perhaps something else important to reiterate, as part of a suite of potential factors to consider (see here). I might also add that a certain type of pain/discomfort (e.g. gastrointestinal) together with sleep issues in the context of autism have been a source of some joint inquiry (see here). There is also a case for further research looking at targeted pharmacotherapy in the context of some challenging behaviours too (see here) with appropriate concerns and caveats noted.

There is another aspect raised by the O'Nions review that also needs to be mentioned: "This analysis shows that many of the strategies used by parents of children with ASD are specifically targeted to manage particular vulnerabilities (e.g., sensory sensitivities, rigidity, insistence on sameness), or accomplish particular behavioural goals, and may be relatively unique to this population." I stress of course, the idea that the core features of autism / ASD seem to be 'targets' of intervention in this area illustrating the link between core behaviours and challenging behaviours. Although I've made quite a big thing on this blog about how 'comorbidity' appearing alongside autism is probably not just comorbidity (see here), I'm taking a slightly opposite view on this occasion, and suggesting that one also needs to be mindful that issues such as anxiety and depression may very well exert an effect on the presentation of challenging behaviour(s) and perhaps need to be looked at separately?

And whilst we're on the topic of challenging behaviours in the context of autism, the review of social outcomes for a sample of adults with autism published by Megan Farley and colleagues [3] provides some further interesting discussions on this topic. Specifically that: "most participants were only aggressive in response to frustrating situations or when experiencing problems with medical conditions." There's [seemingly] always a reason...

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[1] O'Nions E. et al. How do Parents Manage Irritability, Challenging Behaviour, Non-Compliance and Anxiety in Children with Autism Spectrum Disorders? A Meta-Synthesis. J Autism Dev Disord. 2017. Dec 8.

[2] Cohen S. et al. Sleep patterns predictive of daytime challenging behavior in individuals with low-functioning autism. Autism Res. 2017 Dec 1.

[3] Farley M. et al. Mid-life social outcomes for a population-based sample of adults with ASD. Autism Res. 2017 Dec 20.

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MoBa does... prenatal exposure to acetaminophen and offspring ADHD risk

MoBa mentioned in the title of this post refers to the Norwegian Mother and Child Cohort Study, an initiative that has figured quite a few times on this blog (see here and see here and see here for examples).

This time around [1] scientific attention turned to a question of growing research importance: does acetaminophen - paracetamol to us here in Blighty - use during pregnancy affect the risk of offspring being diagnosed with attention-deficit hyperactivity disorder (ADHD)? The data thus far on the issue of this pain-relieving, antipyretic medicine and offspring health has been discussion-provoking to say the least (see here and see here)...

The findings reported by Eivind Ystrøm and colleagues [1] are based on observations for over 100,000 offspring "including 2246 with ADHD." Both "maternal use of acetaminophen during pregnancy and... paternal use before pregnancy" were included in the statistical mix designed to estimate "hazard ratios (HRs) for an ADHD diagnosis."

The results were not exactly unexpected given what has gone on before in this area of investigation. Acetaminophen use was pretty widespread across all pregnancies; approximately 50% of mums had used it at some point. Short-term use during pregnancy - less than 8 days - actually correlated with a decreased risk of offspring ADHD according to the Ystrøm findings. More chronic use of the medicine however - "more than 29 days of maternal acetaminophen use" - showed an opposite relationship, yielding something like a 200% increase in offspring ADHD "even after adjusting for indications of use, familial risk of ADHD, and other potential confounders."

Alongside the suggestion that short-term paracetamol use was associated with a decreased risk for offspring ADHD was another 'make you think' finding: "Paternal and maternal use of acetaminophen were similarly associated with ADHD." Here, a father's use of paracetamol a month or so before conception seemed also to affect the risk for offspring ADHD too. In some media interest on this paper, the authors speculate "that "it could be that fathers who use a lot of acetaminophen have a higher genetic risk for ADHD" or that long-term use of the medicine might lead to changes in sperm." I might add that given the focus on paracetamol as a pain-relieving medicine, the topic of pain and ADHD is already something present in the peer-reviewed science domain (see here). Further research is called for in an accompanying editorial on the Ystrøm paper by Mark Wolraich [2] noting the benefits of using 'big data' from initiatives such as MoBA.

Accepting that the Ystrøm results suggest correlation and not necessarily causation, not everyone has been overwhelmed by the findings. I note in that lay media piece about the research, a few critical voices have suggested that "children diagnosed with ADHD by codes in their medical records" is no substitute for the real 'diagnostic' thing. Personally, I don't see this argument as being particularly valid as anyone that reads anything about MoBA would probably realise. Scandinavian countries and their population databases have some of the best collected and kept databases in the world in terms of reliability and applicability of population health data and statistics. A quick check on PubMed regarding the amount of peer-reviewed data that has been generated from MoBA for example, illustrates that point well.

Perhaps a more pertinent issue is the question of whether longer-term use of paracetamol during pregnancy could denote a more serious underlying maternal illness/injury which might have a more powerful effect on the risk of offspring ADHD than medicine use itself. This is a similar sort of argument to that put forward in relation to pregnancy antidepressant use and various offspring outcomes detailed in the research literature (see here) and similarly, is not something that can be answered by study designs such as those used by Ystrøm.

But then other the questions arise: 'Is paracetamol use during pregnancy safe?' 'How much is safe?' and 'What are the alternatives?' At this point I'm going to stand back and say little more given my blogging caveats of no medical and/or clinical advice given or intended. I will refer you to some current opinion on this topic provided in the peer-reviewed domain [3] alongside suggesting that more large and smaller-scale investigations are required, including that on 'adjacent' diagnoses in relation to pregnancy paracetamol use too (see here)...

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[1] Ystrøm et al. Prenatal Exposure to Acetaminophen and Risk of ADHD. Pediatrics. 2017. Oct 30.

[2] Wolraich ML. An Association Between Prenatal Acetaminophen Use and ADHD: The Benefits of Large Data Sets. Pediatrics. 2017. Oct 30.

[3] Andrade C. et al. Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring. J Clin Psychiatry. 2016 Mar;77(3):e312-4.

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ADHD (symptoms) and pain

If a primary goal of medicine is to relieve pain and suffering then the paper by Andrew Stickley and colleagues [1] might provide an important insight into how medicine might be missing some important groups when it comes to the experience of pain "assessed by the degree to which it interfered with work activity in the previous month."

Drawing on data from the English 2007 Adult Psychiatric Morbidity Survey (APMS) (a resource that has cropped up on this blog before), authors set about examining "the association between ADHD [attention-deficit hyperactivity disorder] symptoms and pain in the general adult population" to ascertain any connection or not. Bearing in mind a 'screener' was employed when it came to ADHD symptoms (and the problems that other screeners have had when it comes to APMS (see here)) authors concluded that even after adjustment for "comorbid common mental disorders" those adults presenting with self-reported ADHD symptoms had "higher odds for experiencing pain."

This is of course not the first time that pain has been suggested to be more frequent where ADHD symptoms or even ADHD is concerned. Fuller-Thomson and colleagues [2] reported that women diagnosed with ADHD were quite a bit more likely to report 'chronic pain' than not-ADHD controls alongside a spectrum of other adversities and issues. Even children / young adults with 'attention problems' have been reported to show a higher frequency of "chronic multisite pain" [3] thus potentially extending the relationship further through the age-groups.

So what could be the reason(s) behind such an association? Well, outside of the large body of peer-reviewed evidence suggesting that the risk of injury is enhanced in relation to ADHD (see here) and what influence this might have, other work is potentially revealing. So, traumatic dental injuries and ADHD [4], the persistence of headaches and ADHD [5], the list goes on with regards to potential factors that could influence the presentation of pain. I might also draw your attention to the idea that the perception of pain may be 'altered' [6] when it comes to ADHD or the presentation of ADHD symptoms as demonstrated under experimental conditions. Indeed, this side of things might have some rather important implications for autism too (see here) given the 'over-representation' of ADHD in autism (see here). The idea also that use of something like methylphenidate, traditionally indicated for ADHD, might affect pain responses in ADHD is also worthy of greater research consideration [7].

Finally, I'm also minded to suggest that rather than 'blaming it all on ADHD' pain accompanying ADHD or ADHD symptoms could also be due to other coexisting conditions. It's not for example, completely unknown for ADHD to coexist alongside conditions such as fibromyalgia for example [8] bearing in mind that fibromyalgia has a very definite connection to pain. I'm also wondering whether the quite strong link between ADHD and something like asthma (see here), might also be an additional source of pain either directly or indirectly too?

The bottom line: yet another case of screening for / asking about other things when a psychiatric / behavioural diagnosis is given and treating / managing accordingly. Screen don't assume.

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[1] Stickley A. et al. ADHD symptoms and pain among adults in England. Psychiatry Res. 2016 Oct 3;246:326-331.

[2] Fuller-Thomson E. et al. Attention-deficit/hyperactivity disorder casts a long shadow: findings from a population-based study of adult women with self-reported ADHD. Child Care Health Dev. 2016 Jul 20.

[3] Skrove M. et al. Chronic multisite pain in adolescent girls and boys with emotional and behavioral problems: the Young-HUNT study. Eur Child Adolesc Psychiatry. 2015 May;24(5):503-15.

[4] Sabuncuoglu O. & Irmak MY. The ADHD modeL for traumatic dental injuries: A critical review and update of the last 10 years. Dent Traumatol. 2016 Oct 17.

[5] Parisi P. et al. Headache and attention deficit and hyperactivity disorder in children: common condition with complex relation and disabling consequences. Epilepsy Behav. 2014 Mar;32:72-5.

[6] Treister R. et al. Alterations in pain response are partially reversed by methylphenidate (Ritalin) in adults with attention deficit hyperactivity disorder (ADHD). Pain Pract. 2015 Jan;15(1):4-11.

[7] Wolff N. et al. Reduced pain perception in children and adolescents with ADHD is normalized by methylphenidate. Child Adolesc Psychiatry Ment Health. 2016 Jul 22;10:24.

[8] Derksen MT. et al. High frequency of adult attention deficit hyperactivity disorder among fibromyalgia patients in the Netherlands: should a systematic collaboration between rheumatologists and psychiatrists be sought? Clin Exp Rheumatol. 2015 Jan-Feb;33(1 Suppl 88):S141.

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Stickley A, Koyanagi A, Takahashi H, & Kamio Y (2016). ADHD symptoms and pain among adults in England. Psychiatry research, 246, 326-331 PMID: 27750114

Paracetamol for fever 'associated' with autism?

"In this study, we again show that acetaminophen use is associated with ASD [autism spectrum disorder]."

That was one of the results reported by Stephen Schultz & Georgianna Gould [1] (open-access available here) as part of their survey of the US "National Database for Autism Research (NDAR) of the National Institute of Mental Health (NIMH)" looking at "whether ASD is associated with acetaminophen use." Acetaminophen by the way, is another name for paracetamol, the over-the-counter pain relief medication that is going through some turbulent times at the moment (see here for example).

Shultz & Gould - one of whom has some research form in this area [2] - eventually relied on information for 118 children diagnosed with an ASD and 79 'non-ASD' children with an average age of about 11 years old. The sorts of data they looked at surrounded the parental choice of medication to treat fevers (I think) including whether paracetamol, ibuprofen or aspirin were used. I have to say that the authors could have made the methodology behind their analysis a little bit clearer in terms of how the questions were posed and to whom rather than just referring to another study with regards to participant selection for example. I had to go fishing for various details which is guaranteed to furrow my brow...

Results: well, I'm slightly puzzled it has to be said. When it came to questions about paracetamol use (I use the term paracetamol 'cos that's what us Limeys are used to) between the ASD and non-ASD groups I didn't see too much difference overall. Take for example the questions about 'only using paracetamol' for fever or 'first choice' use for fever. The percentage figures for the ASD and non-ASD group were 15% and 12% respectively for 'only use this' and 35% and 46% respectively for 'first choice'. Given the participant numbers, I'm not sure that these stats are so wildly different. Yes, I appreciate that when it came to the question about 'rarely or never using' paracetamol to treat fever, 17% of those with ASD reported positive to this question compared with only 3% of controls, but does this really tell us much about very different patterns of paracetamol use?

Further, the authors report results based on "age-adjusted models for levels of fever medication use". They observe that using "acetaminophen as a first choice was 83% less likely in children with ASD... while use of acetaminophen if other medication doesn’t bring down fever was 82% less likely in children with ASD." They interpret this to mean that compared with their previous results [2] findings were reversed in that "older children with ASD compared to control children were significantly less likely to use acetaminophen for fever; whereas, in our 2008 study, younger children with ASD compared to control children were significantly more likely to use acetaminophen at 12-18 months of age and after the MMR vaccination." The mention of immunisation in that last sentence was based on their 2008 paper suggesting that "acetaminophen use after measles-mumps-rubella vaccination was associated with autistic disorder" but I have to say that I'm left a little wanting in terms of these recent findings by Shultz & Gould.

I do think there is a 'where next?' discussion to be had when it comes to the idea that paracetamol use might be linked to 'some' autism. Given the growing research interest in paracetamol use and a 'hyperactive phenotype' of autism (see here), this stalwart of pain relief is deserving of much further inspection in relation to autism. Shultz & Gould do offer one possible research direction based on some speculation about the how the endocannabinoid system might fit into this (something mentioned by other authors too). I am interested in the hypothetical situation they conclude their paper with implicating the endocannabinoid system and how paracetamol might affect 'endocannabinoid tone' but to what extent is perhaps another question.

Just before I finish on this topic I'm minded to bring to your attention another detail from the Shultz / Gould paper with regards to the sentence: "children with ASD vs. non-ASD children are significantly more likely to show an increase in sociability when they have a fever." I've always thought the observations on behaviour and fever when it comes to [some] autism to be quite important (see here). Speculation that "this increase [in sociability] is due to anandamide activation of the endocannabinoid system in ASD children" is also ripe for further scientific investigation...

It's been a while but here is some music to close: Mrs Robinson.

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[1] Schultz ST. & Gould GG. Acetaminophen Use for Fever in Children Associated with Autism Spectrum Disorder. Autism Open Access. 2016 Apr;6(2). pii: 170.

[2] Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

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Schultz ST, & Gould GG (2016). Acetaminophen Use for Fever in Children Associated with Autism Spectrum Disorder. Autism-open access, 6 (2) PMID: 27695658

Neonatal pain 'causing' autism? I'm not so sure...

I wasn't actually going to talk about the paper by Jin Hwan Lee and colleagues [1] on this blog and the suggestion that: "severe inflammatory pain in neonates and persistent inflammatory reactions may predispose premature infants to development delays and psychiatric disorders including ASD [autism spectrum disorder]." I changed my mind however when a piece appeared on-line titled: 'New Autism Dispute: Is Circumcision a Factor?' with mention of 'ritual circumcision and autism' being made based on some research a while back (see here) and a possible "pain-autism connection" being introduced.

From the outset I'll admit that I'm pretty unconvinced about sweeping notions that 'pain' in early infancy can later manifest as a complicated condition like autism. My viewpoint is based on the idea that (a) pain (different types of pain) is a fairly regular passenger for nearly all of us over our lifetime and (b) unfortunately, whilst some young infants do experience significant pain during their earliest days, not all go on to develop autism or other behavioural labels as a result of their pain. I'm not saying that pain can't have longer term effects when severe enough, just that plausible evidence of a link specifically with autism is currently quite sparse.

Bearing in mind my view, the Lee paper describes how rats were the participants in question when it came to their study on whether "repeated inflammatory pain experienced by preterm/premature babies could lead to acute and delayed brain damage that might be associated with social and behavioral abnormalities at the juvenile age." Aside from utilising an animal model, you'll note there is mention of the word 'inflammatory' in their hypothesis, which already implies that pain is not the only variable under investigation. I'll come back to this shortly.

Said rat pups whose age modelled the "brain developmental stage to human preterm infants" were rather unpleasantly given an injection of formalin (a fairly standard method of stimulating inflammatory pain) or saline and various measures including behavioural and physiological were assessed. Unfortunately, those physiological measures involved the rat brain so animals were eventually sacrificed.

Results: well, there were quite a few of them. Perhaps unsurprisingly, formalin treated rats "travelled less distance and showed a lower velocity than control rats" as a consequence of receiving their injection in their hindpaw. Behaviourally, the formalin treated group were also subsequently described as showing "more time engaging in repetitive behaviors such as self-grooming, repetitive jumping, and spontaneous muscle twitching" and "showed sleeping disorder, exhibited as marked increases in bouts of awake and sleep activities." Increases in various cytokines - chemical messengers of the immune system - were noted in treated rats: "increased levels of inflammatory cytokines, TNF-α, and IL-1β in the blood as well as in the brain, and increased microglia in the brain." The authors also noted "significant cell death" in parts of the brain in those treated rats. Interestingly however: "an anti-inflammation treatment using indomethacin (10 mg/kg, i.p.) at the time of formalin injections suppressed inflammatory responses and neuronal cell death." Finally: "the inflammatory pain led to long-term regulation of ASD [autism spectrum disorder]-associated genes NRXN1, FMR1, and oxytocin/oxytocin receptor in the brain."

Going back to point made a few paragraphs back about the concept of 'inflammation' or inflammatory processes/responses potentially being more important than 'pain' in these results, you can perhaps see what I was trying to get at. Indeed, in their discussion the authors note: "inflammation and pain are distinct insults although may sometimes reciprocal. The pathogenic effects of pain and inflammation may play distinctive roles in ASD, while this is unclear based on available data." Certainly, there is a growing recognition that inflammation/inflammatory processes do seem to show an important relationship to at least some autism (see here and see here for example) although there are some details that still need to be investigated. As part of a wider scheme of research implicating immune-related processes (see here) I'm tempted to err on the side of inflammatory issues being more pertinent to the Lee and other results over and above any 'memory of pain' having a large effect. I say all that accepting that rats are rats not people and that there is still a degree of not knowing...

In terms of the coverage of the paper by Frisch & Simonsen [2] talking about ritual circumcision potentially being associated with an increased risk for autism and 'a pain-autism connection', I'm gonna again link you back to what I said the last time I covered this work (see here). Namely, that studies of association where only a few variables are analysed together should always be treated with caution; also bearing in mind some important details were missing from their analysis on that occasion: "Unfortunately, we had no data available on analgesics or possible local anaesthetics used during ritual circumcisions in our cohort" so other potentially relevant hypotheses could still exert an effect [3].

Pain can very much be a feature of autism (see here) but on the question of pain 'causing' or leading to autism, I'm yet to be convinced with the currently available evidence...

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[1] Lee J-H. et al. Neonatal inflammatory pain and systemic inflammatory responses as possible environmental factors in the development of autism spectrum disorder of juvenile rats. Journal of Neuroinflammation. 2016; 13: 109.

[2] Frisch M. & Simonsen J. Ritual circumcision and risk of autism spectrum disorder in 0- to 9-year-old boys: national cohort study in Denmark. JRSM. 2015. 8 January.

[3] DiMaggio C. et al. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg. 2011 Nov;113(5):1143-51.

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Lee JH, Espinera AR, Chen D, Choi KE, Caslin AY, Won S, Pecoraro V, Xu GY, Wei L, & Yu SP (2016). Neonatal inflammatory pain and systemic inflammatory responses as possible environmental factors in the development of autism spectrum disorder of juvenile rats. Journal of neuroinflammation, 13 (1) PMID: 27184741

Autism and the [different] expression of pain

Two papers provide some brief discussion today. The first by Janice Goldschmidt [1] titled: 'What Happened to Paul? Manifestation of Abnormal Pain Response for Individuals With Autism Spectrum Disorder' provides an account of a young man with autism who during a "pilot nutrition intervention designed to teach cooking skills to young adults with autism spectrum disorder (ASD)" fell quite seriously. We are told that: "After his accident, which resulted in broken and dislocated bones in his ankle, his demeanor was dramatically altered, program gains were lost, and staff noted the appearance of many new challenging behaviors."

The second paper by Andrea Courtemanche and colleagues [2] continues a theme looking to "measure expressions of pain among young children being evaluated for autism and other neurodevelopmental disabilities." Authors concluded that their results among other things "support that individuals with self-injury may have enhanced expressions of pain."

The commonality in these papers, aside from looking at pain, is the idea that autism might 'lead' to a "blunted pain response" is not necessarily one that fits uniformly across the autism spectrum. To quote: "The consequence is not a reduction in pain sensation, but a different expression of pain, determined by that individual's particular communicative, cognitive, or physiological challenges." Of course science already knows much of what is being said here as I've covered topics such as the fact that yes, people on the autism spectrum do get headaches (see here) and how pain may be quite a significant predictor of things like sleeping problems in relation to autism (see here). I might add that some of the source of that pain could also be linked to some of the over-represented comorbidity that can/does follow a diagnosis of autism (see here) (and hence should be perfectly treatable).

The discussions about self-injury being potentially linked to the expression of pain also ties into related topics covered on this blog insofar as such 'challenging behaviours' normally having some reasoning behind them (see here). Self-injurious behaviour (SIB) can often be a harrowing thing to see (no parent or sibling wants to see a loved one hurting themselves) but with the right investigative approach can sometimes provide important information about a person and their wants and wishes (see here). I don't say that to somehow encourage SIB nor to lessen the impact that biology can have on its expression; merely that some other person perspective-taking should accompany analysis of any behaviours that challenge as and when they present (before reaching for the anti-challenging behaviour meds) as well as making moves towards breaking down things like communication barriers (see here) that potentially contribute to such behavioural manifestations.

Pain is very much part of the human experience. Whilst efforts should indeed continue to ensure that everyone lives a life as pain-free as possible, the importance of short-term pain or rather the importance of short-term pain expression should not be under-estimated. Likewise, sweeping generalisations about altered pain sensitivity applying across the autism spectrum need not necessarily apply. I'm also happy to report that pain is a topic being discussed at IMFAR today...

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[1] Goldschmidt J. What Happened to Paul? Manifestation of Abnormal Pain Response for Individuals With Autism Spectrum Disorder. Qual Health Res. 2016 Apr 26. pii: 1049732316644415.

[2] Courtemanche AB. et al. The Relationship Between Pain, Self-Injury, and Other Problem Behaviors in Young Children With Autism and Other Developmental Disabilities. Am J Intellect Dev Disabil. 2016 May;121(3):194-203.

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Goldschmidt J (2016). What Happened to Paul? Manifestation of Abnormal Pain Response for Individuals With Autism Spectrum Disorder. Qualitative health research PMID: 27117957




Courtemanche AB, Black WR, & Reese RM (2016). The Relationship Between Pain, Self-Injury, and Other Problem Behaviors in Young Children With Autism and Other Developmental Disabilities. American journal on intellectual and developmental disabilities, 121 (3), 194-203 PMID: 27119211

Gender differences in chronic fatigue syndrome

The title of this post matches the title of the paper published by Monica Faro and colleagues [1] (open-access here) and some potentially important data on "whether there are gender-related differences in CFS [Chronic Fatigue Syndrome], and to define a clinical phenotype in men."

Starting with the idea that the prevalence of CFS - a generic term covering a spectrum of conditions characterised by severe and debilitating fatigue among several other things - may have a gender skew towards females over males [2], Faro and colleagues set about looking at whether the presentation of CFS might also differ between males and females. I should perhaps back-up a little and highlight how the sex differences in CFS frequency might be somewhat clouded by the fact that quite a few diagnostic criteria systems are currently around for CFS (also called myalgic encephalomyelitis, ME) and that under-diagnosis of men cannot yet be discounted as contributing to any gender differences. Think autism and the perceived gender skew there as an example of potential under-diagnosis in action with another label in mind.

Based on the analysis of over 1300 patients formally diagnosed with CFS (using the Fukuda 1994 definition), 119 (9%) of the cohort were described as male. Following the administration of a clinical interview "conducted by 2 specialized internists in the diagnosis of the disease" among other things, researchers reported a few interesting details. First, men in general seemed to be diagnosed slightly earlier than women. It wasn't a stark difference measured in decades for example, but a difference of on average, 4-5 years. Further: "Widespread pain, muscle spasms, dizziness, sexual dysfunction, Raynaud's phenomenon, morning stiffness, migratory arthralgias, drug and metals allergy, and facial oedema were less frequent in men." Fibromyalgia as "defined by the criteria of the ACR" was also reported to be less frequent in men than women (29% vs 58% respectively). Also of interest was the suggestion that: "The most common triggering factor was an infection" where men were more likely than women to relate their symptoms to such a factor.

These are interesting findings that add an extra dimension to discussions about CFS with a view to a possible role for gender differences. Obviously one has to be a little guarded about making too many sweeping generalisations that for example, CFS is a 'different condition' for men and women because we don't really have a great deal of evidence to back up such a claim. Insofar as the possibility that men are diagnosed earlier than women, this could point to a number of things. Either this is reflective of an earlier onset of the illness in men or that women find it more difficult to get diagnosed with CFS. I'd be interested to see how this variable pans out as and when more research in this area is forthcoming.

Music: The Calling - Wherever You Will Go.

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[1] Faro M. et al. Gender differences in chronic fatigue syndrome. Reumatol Clin. 2015 Jul 16. pii: S1699-258X(15)00081-9.

[2] Líndal E. et al. The prevalence of chronic fatigue syndrome in Iceland - a national comparison by gender drawing on four different criteria. Nord J Psychiatry. 2002;56(4):273-7.

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Faro M, Sàez-Francás N, Castro-Marrero J, Aliste L, Fernández de Sevilla T, & Alegre J (2015). Gender differences in chronic fatigue syndrome. Reumatologia clinica PMID: 26190206

Objective measures of sleep in autism meta-analysed

"Children with ASD [autism spectrum disorder] have small but measurable objective differences in their sleep parameters that are consistent with subjective reporting."

That was the main conclusion reached in the meta-analysis from Marilisa Elrod and Bradley Hood [1] who looked at the collected peer-reviewed data "that used objective measures such as actigraphy or polysomnography (PSG) to describe the sleep parameters of TST [total sleep time], SL [sleep latency], and SE [sleep efficiency] in children with ASD compared with children with TD [typical development]."

Just in case you didn't want to click on the links to some of those explanations, actigraphy is all about measuring movements and so useful in analysing the 'rest/activity' cycle; PSG is a slightly move comprehensive way of measuring various biophysical parameters during sleep; sleep latency is basically the amount of time it takes for a person to fall asleep, and sleep efficiency refers to how much sleep a person gets from time of lying down to getting up from bed (usually expressed as a percentage).

Ten studies met the authors' inclusion criteria covering nearly 350 children diagnosed with an ASD and 221 asymptomatic controls. Researchers reported that children with autism spent on average half an hour less per day TST (total sleep time) and took about 10 minutes longer to fall asleep than controls. Sleep efficiency was also marginally reduced for the autism group. As one might have expected, there was some "notable heterogeneity" across the various study results. That and the fact that comorbidity (if I can still call it that) such as intellectual (learning) disability also seemed to play some hand in the results obtained: "those with ASD and intellectual disability (ID) had a significant decrease in TST as compared with TD peers."

There are a few points to make about this research. First is the continuing idea that 'subjective reporting' when it comes to autism is actually not a bad indicator of what might be going on or have been going on. We've seen evidence of this quite a few times now in the peer-reviewed literature: maternal recall vs. medical records (see here), the reported presence of gastrointestinal (GI) symptoms (see here), first concerns about autism (see here) and now possibly with sleep in mind. Obviously this doesn't mean that every single person questioned about a topic area of autism is going to be providing an authoritative history allowing research to 'do away' with more objective measures. But it does mean that parent or caregiver report might be a very good place to start.

Next, allowing for the text "small but measurable", Elrod & Hood further add to the quite voluminous literature indicating that sleep issues can be a real point of contention for quite a few people on the autism spectrum. I've talked about sleep a few times on this blog (see here and see here) including the idea that melatonin might be a medication of consideration for some [2]. More recently I've also discussed the idea that other factors might play some role in sleep issues in cases of autism as per some research on pain predicting sleeping problems (see here) and/or behavioural sleep intervention being indicated (see here) (particularly when certain comorbidity might be present). Whatever the reasons/intervention suggested, sleep or rather a lack of sleep (quality sleep), is probably not a great thing for anyone.

And with that, some music and a song about a sidewinder sleeping...

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[1] Elrod MG. & Hood BS. Sleep Differences Among Children With Autism Spectrum Disorders and Typically Developing Peers: A Meta-Analysis. J Dev Behav Pediatr. 2015 Feb 18.

[2] Rossignol DA. & Frye RE. Melatonin in autism spectrum disorders. Curr Clin Pharmacol. 2014;9(4):326-34.

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Elrod, M., & Hood, B. (2015). Sleep Differences Among Children With Autism Spectrum Disorders and Typically Developing Peers Journal of Developmental & Behavioral Pediatrics DOI: 10.1097/DBP.0000000000000140

More evidence for non-coeliac gluten sensitivity?

"In a cross-over trial of subjects with suspected NCGS [non-coeliac gluten sensitivity], the severity of overall symptoms increased significantly during 1 week of intake of small amounts of gluten, compared with placebo."

That was the conclusion reached in the study by Antonio Di Sabatino and colleagues [1] who applied the gold standard research methodology - "a randomized, double-blind, placebo-controlled, cross-over trial" - to studying the effects of small amounts of gluten on those "who believe ingestion of gluten-containing food to be the cause of their intestinal and extra-intestinal symptoms" despite being free of the autoimmune condition coeliac (celiac) disease or wheat allergy. Further information about this research can be seen on the trial registration page.

Various symptoms were reported to be increased following gluten ingestion (4.375 g/day gluten) over and above placebo (rice starch) including abdominal bloating/pain. Extra-intestinal symptoms - that is symptoms that are not necessarily centred on the gastrointestinal (GI) tract - also seemed to increase during the active supplementation of gluten including: "foggy mind.., depression..., and aphthous stomatitis [mouth ulcers]". Depression potentially being linked to gluten consumption is something that has appeared [in quite preliminary form] before in the peer-reviewed research literature and this blog (see here). 'Foggy mind' is not a very technical term but again has been mentioned in other research papers talking about the use of a gluten-free diet and cognitive performance in cases of coeliac disease (CD) (see here).

I was rather interested in these results given that NCGS has been to topic of quite a bit of material on this blog (see here for example) and the idea of something of a spectrum of gluten-related issues being present outside of those classical examples of coeliac disease and wheat allergy (see here). In recent times, attention has shifted away from gluten (or wheat) as being the potential culprit in such cases as per the rise and rise of FODMAP sensitivity as another potential explanator based on research such as that from Jessica Biesiekierski and colleagues [2]. I've watched this area closely and often thought that there may be room for both FODMAP sensitivity and NCGS being present in different people or even the same person. It appears from the results of the controlled trial from Di Sabatino et al, this might not be too far off the mark. Other research might also agree with such sentiments [3].

Then to the questions: (a) what is the potential mechanism/s of effect? and (b) are we moving closer to identifying those who might fall into that NCGS category and so benefit from a gluten-free diet or even beyond [4]? Well, unfortunately I can't definitively answer either of those questions at the moment, but can perhaps offer a few areas where further investigations might be indicated.

I was privileged to review the paper by Catassi and colleagues [5] (open-access) which provides quite a nice overview of NCGS and some directions where science is heading. One of the papers cited in that overview was that from Anna Sapone and colleagues [6] and their 2012 consensus paper on "new nomenclature and classification" when it came to gluten sensitivity (see here). I'm not altogether sure how well their 'proposed algorithm' has done in clinical practice but it strikes me that it's a good start when ruling out CD and wheat allergy. I might also add that there may be quite a bit more to see when it comes to looking at serology vs. histopathology at differentiating CD from NCGS [7] as per what has been talked about with [some] autism in mind (see here) and [some] cases of schizophrenia too (see here). Transglutaminase is also something in need of a lot more study with autism in mind (see here) by the way.

The other area that I think would be rather interesting to look at is gut barrier function. Again, wearing my autism research hat, I'm pretty impressed with what has been reported in the peer-reviewed literature when it comes to 'leaky gut' and some autism (see here). Although by no means a universal aspect to autism (see here) it does happen, and more generally is in the research ascendancy (see here) for quite a few reasons. Allied to the the idea that (General) zonulin might be something related (see here) I'm also wondering whether it might be a good idea to look at this parameter comparing CD, wheat allergy and NCGS? I'm not expecting too much based on the work by Hollon and colleagues [8] on intestinal permeability and gluten for example, but you never know.

And then there is the review from Molina-Infante and colleagues [9] to bring to your attention...

Music then. Hey Joe by Jimi et al.

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[1] Di Sabatino A. et al. Small Amounts of Gluten in Subjects with Suspected Nonceliac Gluten Sensitivity: a Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. Clin Gastroenterol Hepatol. 2015 Feb 19. pii: S1542-3565(15)00153-6.

[2] Biesiekierski JR. et al. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology. 2013 Aug;145(2):320-8.e1-3.

[3] Carroccio A. et al. Non-Celiac Wheat Sensitivity Diagnosed by Double-Blind Placebo-Controlled Challenge: Exploring a New Clinical Entity. Am J Gastroenterol 2012; 107:1898–1906.

[4] Makharia GK. Current and emerging therapy for celiac disease. Front Med (Lausanne). 2014 Mar 24;1:6.

[5] Catassi C. et al. Non-Celiac Gluten sensitivity: the new frontier of gluten related disorders. Nutrients. 2013 Sep 26;5(10):3839-53.

[6] Sapone A. et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012 Feb 7;10:13.

[7] Brottveit M. et al. Mucosal Cytokine Response After Short-Term Gluten Challenge in Celiac Disease and Non-Celiac Gluten Sensitivity. Am J Gastroenterol 2013; 108:842–850.

[8] Hollon J. et al. Effect of Gliadin on Permeability of Intestinal Biopsy Explants from Celiac Disease Patients and Patients with Non-Celiac Gluten Sensitivity. Nutrients. 2015; 7: 1565-1576.

[9] Molina-Infante J. et al. Systematic review: noncoeliac gluten sensitivity. Alimentary Pharmacology & Therapeutics. 2015. March 6.

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Di Sabatino A, Volta U, Salvatore C, Biancheri P, Caio G, De Giorgio R, Di Stefano M, & Corazza GR (2015). Small Amounts of Gluten in Subjects with Suspected Nonceliac Gluten Sensitivity: a Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association PMID: 25701700

What factors are linked to behavioural crises in autism?

The question posed in the title of this post was asked and [partly] answered by the paper by Vincent Guinchat and colleagues [1] based on the analysis of 58 adolescents diagnosed with an autism spectrum disorder (ASD) and "hospitalized for severe challenging behaviors." Challenging behaviours, by the way, refers to a whole spectrum of presentations which doesn't just include aggressive or violent behaviours (see here). Indeed, I recently talked about irritability and autism (see here), which might also fall into this category under certain circumstances.

Guinchat and colleagues "aimed to assess risk factors associated with very acute behavioral crises in adolescents with ASD" by way of collecting various data on participants (both retrospectively and prospectively) including the severity of their presentation, the presence of "comorbid organic conditions" and assessing "predictors of Global Assessment Functioning Scale (GAFS) score and duration of hospitalization at discharge."

Results: well, an inpatient stay did seem to have a positive effect on participants as per the findings that: "During the inpatient stay... patients doubled on average their GAFS scores." A higher score translates as better outcome. Comorbid psychiatric conditions, known and unknown, was the most frequently cited reason for behavioural crises, with depressive episode and schizophrenia representing the known conditions cited most. Organic causes, including epilepsy and "painful medical conditions" followed in frequency, with environmental causes "including lack of treatment... and adjustment disorder" bringing up the rear. The authors also suggest that the severity of autism presentation (I draw back from using the idea of 'functioning') had a negative effect on GAFS scores at discharge. This point may also tie into some recent findings reported by Rattaz and colleagues [2] where symptom severity of autism might be a risk factor for the presence of self-injurious behaviours.

The authors conclude: "Challenging behaviors among adolescents with ASD may stem from diverse risk factors, including environmental problems, comorbid acute psychiatric conditions, or somatic illness such as epilepsy or acute pain. The management of these behavioral challenges requires a unified, multidisciplinary approach."

I know that some people might look at this data, shrug and say 'what did you expect', but I'm not one of them. Challenging behaviours can occur in relation to autism for all-manner of reasons but as per other discussions on this topic, one should never assume that challenging behaviours are just 'part and parcel' of a diagnosis of autism. They aren't, even if some of the signs and symptoms of autism may make a person more likely to present with such issues at certain times (including puberty).

I've talked before about some of the circumstances around challenging behaviours and autism as per the idea that pain and discomfort for example, might sometimes facilitate the presence of such issues (see here) particularly in the absence of functional language use. Indeed, a lack of communicative abilities (or rather suitable ways or avenues to communicate) can be a real obstacle to health equality more generally when it comes to autism (see here). Epilepsy or seizure-type disorders have also figured on the autism landscape (see here) and potentially contribute as an important factor when it comes to challenging behaviours for some [3]. Ideas on the possibility of overlap between autism and conditions like certain types of depression and/or schizophrenia are gaining traction in recent times (see here and see here respectively) and again, suggest that 'diagnostic vigilance' are the keywords (see here).

To close: Take on Me by Harry Hill (and others)?

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[1] Guinchat V. et al. Acute behavioral crises in psychiatric inpatients with autism spectrum disorder (ASD): Recognition of concomitant medical or non-ASD psychiatric conditions predicts enhanced improvement. Research in Developmental Disabilities. 2015; 38: 242-255.

[2] Rattaz C. et al. Symptom severity as a risk factor for self-injurious behaviours in adolescents with autism spectrum disorders. J Intellect Disabil Res. 2015 Jan 12.

[3] Ito M. et al. Subacute postictal aggression in patients with epilepsy. Epilepsy Behav. 2007 Jun;10(4):611-4.

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Guinchat V, Cravero C, Diaz L, Périsse D, Xavier J, Amiet C, Gourfinkel-An I, Bodeau N, Wachtel L, Cohen D, & Consoli A (2015). Acute behavioral crises in psychiatric inpatients with autism spectrum disorder (ASD): Recognition of concomitant medical or non-ASD psychiatric conditions predicts enhanced improvement. Research in developmental disabilities, 38C, 242-255 PMID: 25575287

Ritual circumcision and risk of autism

A quote to begin: "We confirmed our hypothesis that boys who undergo ritual circumcision may run a greater risk of developing ASD [autism spectrum disorder]."

"Objetos dispersos" de Xulio Formoso 2008

That was the rather surprising finding reported by Morten Frisch & Jacob Simonsen [1] (open-access) following their register-based cohort study based in Denmark. Some of the media following this paper can be seen here.

I'll be honest with you and say that my brow furrowed somewhat upon first reading about this paper. Of all the correlations associated with 'risk of autism' this has to be one of the more unusual (aside that is from meat consumption perhaps). That brow furrowing however softened as I read the study and realised that (a) the source data for the 'correlation' relied on one of those ever-so interesting Scandinavian population databases that have suggested quite a few important factors might be linked to autism (see here and see here), and (b) the authors make mention of the accumulating data looking at certain types of pain relief - yes, you paracetamol - as potentially being something requiring further investigation with regards to autism and other neurodevelopmental risks (see here).

Anyhow, the Frisch/Simonsen paper is open-access but as always, a few pointers...

• The rationale for the study seems to stem from "recent animal findings linking a single painful injury to lifelong deficits in stress response" and data from the paper by Bauer & Kriebel [2] (open-access) suggesting "that with each 10% increase in a population’s neonatal circumcision rate, the estimated prevalence of ASD increased significantly by 2.01 per 1000 boys."
• Based on a cohort of over 340,000 boys born and 'tagged' in the Danish healthcare system between 1994 and 2003, the authors located just over 5000 boys "diagnosed with ASD before their 10th birthday". Ritual circumcision - that is circumcision with a specific religious significance - is coded in Denmark, whether carried out in a state hospital or at a private clinic (subsidised by the state healthcare system). Sources of those codings were tracked. Out of a total of 3347 circumcisions (in the entire cohort) the authors found 57 boys with ASD included in that category. 
• Results: after various statistical procedures and correction for confounding variables including cultural background and birth and perinatal characteristics, the authors concluded: "Ritual circumcision among Danish boys is linked to an overall 46–62% increase in ASD risk in the first 10 years of life". Further: "More strikingly, risk was 80–83% increased in the first 0–4 years of life, an increase that was restricted to infantile autism." At the same time, there was no significant link between circumcision and "risk of hyperkinetic disorder" nor risk of asthma.
• The authors offer some 'significant' discussion about the limitations of their findings including the possibility that circumcision rates were under-estimated: "Muslim authorities in Denmark explained to the National Board of Health that Muslim circumcisions are often made by private practitioners in their clinics or in the boys’ homes." They also go on quite a bit in the paper and in the media reports on the paper about how the early life pain/stress of circumcision somehow might translate into an increased risk for autism. I'd tend to agree however with an external commentator talking about the study who said: "I have some issues with the premise in that their speculations regarding early pain as a cause of autism are, to say the least, highly speculative."

These are interesting findings albeit observational. Correlation is not the same as causation is also a term which should be reiterated when it comes to such data but there are some potentially important gems of information included in the Frisch/Bauer study. Capitalising on the idea that modern circumcision (the practice itself being around for quite a while) normally involves the use of pain relief following surgical anaesthetic, I want to emphasise something the authors said about this: "Unfortunately, we had no data available on analgesics or possible local anaesthetics used during ritual circumcisions in our cohort, so we were unable to address the paracetamol hypothesis directly."

I'm not necessarily saying that there is a connection between anaesthetics and autism, even though other data has hinted that there may be more to see [3]. On the strength of that study by DiMaggio and colleagues for example, and their suggestion of an increasing risk of "developmental or behavioral disorders" it would be interesting to see how many more times anaesthesia was used in the circumcised autism group vs. other groupings and whether 'the dose [really does] make(s) the poison'.

I've already mentioned pain relief as being something already on the autism/neurodevelopmental research radar insofar as the growing interest into how something like prenatal paracetamol (acetaminophen) exposure might 'correlate' with various offspring outcomes. Although stepping onto even more contentious autism research ground, the idea that post-vaccination paracetamol use is potentially linked to cases of autism [4] offers something of a template for further study in this area.

I'm a little unsure how to end this post bearing in mind my blogging caveats about not giving anything that looks, sounds or smells like medical or clinical advice. I appreciate that this study might not be particularly well received by religious groups who undertake ritual circumcision, or to others, might just seem like a bit of daft 'correlation is not causation' autism research. I'd however be minded to suggest that there could be more research to see and do in this area when brows are a little less furrowed...

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[1] Frisch M. & Simonsen J. Ritual circumcision and risk of autism spectrum disorder in 0- to 9-year-old boys: national cohort study in Denmark. JRSM. 2015. 8 January.

[2] Bauer AZ. & Kriebel D. Prenatal and perinatal analgesic exposure and autism: an ecological link. Environ Health. 2013 May 9;12:41.

[3] DiMaggio C. et al. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg. 2011 Nov;113(5):1143-51.

[4] Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

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Frisch, M., & Simonsen, J. (2015). Ritual circumcision and risk of autism spectrum disorder in 0- to 9-year-old boys: national cohort study in Denmark Journal of the Royal Society of Medicine DOI: 10.1177/0141076814565942