Gluten and autism: probably not coeliac disease but...

No link between autism and coeliac (celiac) disease.

That's the very loud proclamation from quite a bit of the media talking about the study by Jonas Ludvigsson and colleagues* as per sources like this one. That being said, the idea that issues with gluten reported in cases of autism might be reflective of something separate from coeliac disease (CD) has definitely gained some traction with the publication of the Ludvigsson results.

Non coeliac gluten sensitivity celebrates? @ Wikipedia 

For those who might not know CD is an autoimmune condition which basically represents the archetypal 'gluten is the baddie' condition. I've already posted a quite detailed entry on the basics of CD, or at least what we currently think we know about CD, which can be viewed here.

That post includes some of the biochemistry involved which revolves around (a) parts of the gluten protein not being easily degraded by the various enzymes charged with this task, (b) said peptides - short chains of amino acids formed during the digestion of the gluten protein - gaining entry to a part of the gut barrier, (c) the 'super-charging' of the those gluten peptides by something called tissue transglutaminase, and finally (d) the sparks that fly as a result of a certain kind of immune system meeting these modified peptides. References for the diagnostic serological criteria for CD are also included in that post.

Back to the Ludvigsson paper. The basic premise of the study was to look at Swedish registry data from patients with various stages of small bowel pathology linked to CD based on the Marsh criteria. This included those with Marsh stage 3 illustrative of villous atrophy (n=26,995), Marsh stages 1 & 2, categorised as 'inflammation' (n=12,304) and those with Marsh stage 0 (i.e. a normal gut mucosa) (n=3,719) but still with the serological markers of CD.

These cases were then compared against a control group (n=213,208) not presenting with CD in order to calculate "estimated odds ratios (ORs) for having a prior diagnosis of an ASD" (autism spectrum disorder). As per the headlines: "A prior ASD was not associated with CD".

But... with an OR of 4.57 a prior diagnosis of ASD was associated with having the serological markers of CD without the flattened or inflamed mucosa. Ergo, not full blown CD but having the serology indicating that gluten is immunologically active and potentially exerting an effect. The authors even found that presenting with CD or inflammation of the mucosa "were both associated with moderate excess risks of later ASDs". One question in that scenario could be: was CD and/or inflammation a possible factor in the development of autism?

Most people with some interest in autism, whether professionally or personally, will have heard about the various research rumblings suggestive that adoption of a gluten (and casein) free diet might, just might, have some impact on the presentation of autism - or at least some of the comorbidity which seems to follow autism. The body of work making up this suggestion is still a little bit methodologically 'frail' (including some of my own contribution to this area**) but isn't that the same for most intervention areas when it comes to the autisms?

The explanations as to why the gluten- and casein-free (GFCF) diet might impact on the presentation of at least some autism are still a matter of some debate. Although there is probably no condition-wide link to CD as per the Ludvigsson results, that doesn't mean that CD is not associated with some individual cases of autism (see here). A diagnosis of autism is after all, seemingly protective of nothing when it comes to other comorbidity. There is also an increasing realisation that issues with gluten might not just be reflective of CD as per the rise and rise of something called non-coeliac gluten sensitivity (see here). Efforts continue to describe this spectrum of gluten-related conditions outside of just CD (see here) and it is indeed timely that part of those additional efforts have just been published*** even mentioning autism.

This year (2013) has seen some quite important papers published which imply that the immune system is probably involved in some way (see my discussions of the Lau paper) in that gluten-autism relationship. That and the distinct possibility that, horror of horrors, leaky gut (gut hyperpermeability) might also show some connection (as per the de Magistris papers). That last paper by Laura de Magistris and colleagues**** also in many ways, pre-empted some of the latest findings from Ludvigsson insofar as reporting on a pattern overlapping serological parameters with CD in their cohort of children with autism, but not necessarily demonstrating enough to warrant a formal diagnosis of CD. This on top of related work (see here).

I'm going to finish with a quote from one Alessio Fasano on the Ludvigsson results: "In the past, we have had the believers and nonbelievers when it came to the role of gluten in autism ... Hopefully this paper can clarify, once and for all, that a subset of those with autism has gluten sensitivity, a condition triggered by gluten but distinct from celiac disease."

Who am I to argue?

To close, something up-beat to finish with... I've linked to this before but how about the Housemartins and Happy Hour?

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* Ludvigsson JF. et al. A Nationwide Study of the Association Between Celiac Disease and the Risk of Autistic Spectrum Disorders. JAMA Psychiatry. 2013. Sept 25.

** Whiteley P. et al. The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Nutr Neurosci. 2010 Apr;13(2):87-100.

*** Catassi C. et al. Non-Celiac Gluten Sensitivity: The New Frontier of Gluten Related Disorders. Nutrients. 2013: 5: 3839-3853.

**** de Magistris L. et al. Antibodies against Food Antigens in Patients with Autistic Spectrum Disorders. BioMedRes Int. 2013: 729349.

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Jonas F. Ludvigsson (2013). A Nationwide Study of the Association Between Celiac Disease and the Risk of Autistic Spectrum Disorders JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2013.2048

Anxiety disorder comorbid to autism

I've said it before and I'll say it again: a diagnosis of autism (or autism spectrum disorder) is seemingly protective of nothing when it comes to other comorbidity. Indeed, with the range of comorbidity associated with autism - physical (see here) and psychiatric (see here) - in some instances, one has to wonder whether some of that comorbidity is actually more 'disabling' for a person than the autism itself. Think epilepsy for example (see here) and where that can lead...

The great orator @ Wikipedia 

As a case in point, have a look at the paper by Charlot and colleagues* and a quote from their abstract: "Anxiety disorders were reported in 62% of individuals with ASD" - referring to perhaps one of the more widely discussed comorbidities with autism in mind.

Indeed, in today's post I'm going to explore some of that collected work on anxiety and autism bearing in mind that the diagnostic label anxiety includes quite a few elements one to two of which have already been discussed on this blog (see here). I will also tip my hat to Zoe over at Food for Thought and her recent post on social and emotional development in autism (see here) which was also contributory to my undertaking this post and topic.

The National Autistic Society (NAS) here in the UK carry about as good a description as any of what anxiety is and just how much anxiety can affect the life of a person with autism (see here). Interestingly, the NAS carry a link to the 'survival guide' written by the late Marc Segar (see here) and his very insightful view of his life and the various observations he made including the ways and means he coped with his Asperger syndrome. Dare I say that there are also a few tips included for everyone there irrespective of autism or not...

More recently, the final strand of the NICE guidance for autism also carries quite a bit of discussion about anxiety and autism and in particular, the potential merits of CBT - cognitive behavioural therapy - to tackle said issue. I'm not necessarily going too far into the pros and cons of CBT for anxiety occurring alongside autism; allowing that is, for the paper by Micah Mazurek and colleagues (discussed here) and the notion that CBT is probably not going to be right for everyone.

There are several areas of interest when it comes to anxiety and autism. One of the more interesting ones for me is the issue of whether autism, or autistic traits, are somehow predisposing to anxiety (i.e. whether anxiety should perhaps be classified as a core part of autism) or whether it is something independent bearing in mind the notion of a social anxiety spectrum (see here). In attempting to answer this question I was drawn to the paper by Freeth and colleagues** who are quoted as saying that: "students with high levels of autistic traits were more likely to report increased social anxiety" in their analysis of autistic traits and social anxiety in a UK University population. Similarly, the results reported by van Steensel and colleagues*** are also potentially pertinent: "As compared to the AD [anxiety disorder] group, parents from the ASD group reported their children to have higher scores for total anxiety, social anxiety disorder, and panic disorder". One of other points this particular question leads into is whether anxiety is more or less of a feature of certain types of autism; so Asperger syndrome / high-functioning autism compared with those who are more severely affected with autism. One can see how for those who are more floridly autistic in terms of the presence of speech and communication issues and intellectual disability, it might be more difficult to diagnose anxiety. But does that necessarily mean anxiety is less of an issue in such cases? Indeed, what are the implications for screening for anxiety?

Drawing on the mention of CBT as a potential therapeutic route for anxiety in autism****, are the other suggestions reported to ameliorate the signs and symptoms. Again, the Mazurek paper***** might offer some options here if we assume that anxiety, sensory issues and gastrointestinal (GI) complaints are all inter-linked. Treat one element and you treat all? A familiar name in autism research has also been pitted against anxiety, at least occurring in cases of Fragile X syndrome: oxytocin. The trial by Hall and colleagues****** talked about ameliorating social anxiety via oxytocin administration, bearing in mind the small participant numbers included and the exclusivity of the group analysed.

Although perhaps met with a rolling of the eyes by some people, there is a growing interest in the use of animal-assisted interventions as being a potential ameliorative tool for anxiety*******. I'm taken back for example, to the 'pets win prosocial prizes' suggestion as a starting point, following on from the speculation on the amygdala. Obviously I'm not suggesting that animal-assisted intervention just targets one area of the brain (don't be absurd) or that such intervention is for everyone with autism and anxiety. Indeed, anxiety about animals may very well be a feature for some people on the spectrum as it is for quite a few people not diagnosed with autism.

Whilst it may not be a great topic of conversation, I do also wonder whether there may be some self-medicating strategies already being adopted by some people on the autism spectrum when it comes to anxiety. Without casting any aspersions or making any sweeping generalisations, I've heard accounts of alcohol use (and abuse) being used by some of those on the spectrum as a way of dampening down things like anxiety issues. Anyone who has drank a little too much knows what effect alcohol can have on various cognitive and social features. That and the quite strong association between social anxiety disorder and alcohol issues******** provides some food for thought in terms of screening for, and potentially explaining, such problem habits when they do occur.

Finally(!) I recently talked about the application of a Chan-based mind-body exercise program being experimentally tested with autism in mind (see this post). Mentioning also the concept of mindfulness and the particular interest that this technique seems to be enjoying for all manner of things (including autism), one has to wonder whether there is merit in looking at such approaches for anxiety with greater assiduity.

I can't possibly do justice to all the research that has been done on anxiety issues presenting alongside autism. What I hope you will take from this post is (a) that anxiety issues (in all their forms) can and do present alongside cases of autism; also able to be self-reported too*********, and (b) when it comes to the question of which aspects of autism (or its comorbidities) most fundamentally affect daily quality of life, anxiety must rank up near the top of the list for quite a few on the spectrum. Perhaps some factors to consider when it comes to the question of how to improve quality of life?

U2 to close, and a classic: Pride (In the Name of Love).

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* Charlot L. et al. Mood and Anxiety Symptoms in Psychiatric Inpatients with Autism Spectrum Disorder and Depression. J Ment Health Res Intellect Disabil. 2008;1(4):238-253.

** Freeth M. et al. The distribution of and relationship between autistic traits and social anxiety in a UK student population. Autism. 2013 Sep;17(5):571-81.

*** van Steensel FJ. et al. Anxiety and quality of life: clinically anxious children with and without autism spectrum disorders compared. J Clin Child Adolesc Psychol. 2012;41(6):731-8.

**** Storch EA. et al. The effect of cognitive-behavioral therapy versus treatment as usual for anxiety in children with autism spectrum disorders: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry. 2013 Feb;52(2):132-142.e2.

***** Mazurek MO. et al. Anxiety, sensory over-responsivity, and gastrointestinal problems in children with autism spectrum disorders. J Abnorm Child Psychol. 2013 Jan;41(1):165-76.

****** Hall SS. et al. Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome. Psychoneuroendocrinology. 2012 Apr;37(4):509-18.

******* Muñoz Lasa S. et al. Animal-assisted interventions in internal and rehabilitation medicine: a review of the recent literature. Panminerva Med. 2011 Jun;53(2):129-36.

******** Buckner JD. et al. Implications of comorbid alcohol dependence among individuals with social anxiety disorder. Depress Anxiety. 2008;25(12):1028-37.

********* Ozsivadjin A. et al. Brief Report: The Use of Self-Report Measures in Young People with Autism Spectrum Disorder to Access Symptoms of Anxiety, Depression and Negative Thoughts. J Autism Dev Disord. September 2013.

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Charlot L, Deutsch CK, Albert A, Hunt A, Connor DF, & McIlvane WJ Jr (2008). Mood and Anxiety Symptoms in Psychiatric Inpatients with Autism Spectrum Disorder and Depression. Journal of mental health research in intellectual disabilities, 1 (4), 238-253 PMID: 24009649

Ear, ear and hyperactivity

The BBC headline - Inner ear disorders 'linked to hyperactivity' - caught my eye recently. Detailing a fascinating piece of research by Michelle Antoine and colleagues* published in the journal Science the suggestion is that issues with the inner ear that affect hearing and balance might also show some relationship with hyperactivity and in mice at least, might be amendable to treatment.

van Gogh @ Wikipedia  

Before going on, I'd like to point out that Science (the publishing journal) has produced some pretty interesting papers at a similar time to the publication of the Antoine research. I'm talking specifically about the gut bacteria from obese discordant twins producing obese mice research (see here) which discusses the 'transmissibility of obesity' among other things (see here for my previous blogging interest in this area of research). There was also that letter on MAR autism which I've covered recently....

Back to the ears - and no, not whale ears either. Apparently this is not the first time that the presence of inner ear disorders have been linked to behavioural issues as per the description from other media on this research (see here). The long-and short of the paper was the study of mice who were bred to carry a mutation in the Slc12a2 gene (see here for more information about the gene) involved with the transportation and reabsorption of sodium and chloride ions. Said mice with genetic mutation in the inner ear were observed to show "increased locomotor activity".

It was then a case of finding out why this genetic glitch produced such effects which eventually led to a part of the brain dealing with motor output: the striatum and the over-production of two proteins (pERK and pCREB) linked to the control of some important neurotransmitters: glutamate and dopamine (and GABA). Confirmation of these proteins as being involved also led to speculation that something could be done about the behaviours noted in their mouse model as per the use of a pERK inhibitor: SL327 wherein "Hyperactivity was remedied by local administration of the pERK inhibitor SL327".

I'll reiterate that as with many experimental studies these days involving knocking out genes and looking at the effects of genetic mutations, this was a study of mice and so one needs to be cautious about making too many sweeping generalisations to humans and the particular complexities that we have. I note that at least one quite prominent ADHD researcher (whose work has appeared previously on this blog) has cautioned against assuming that all ADHD is just a one gene disorder, much in the same light that autism is seemingly getting past that research hurdle too (see here).

A little light background reading on the Slc12a2 gene reveals some other interesting factoids. Schizophrenia for example, has more than one mention when it comes to looking at the expression of the gene; mainly tied back to that GABA link (see the paper by Hyde and colleagues** for example). Panichareon and colleagues*** (open-access) also detailed some potential connection between gene polymorphisms as being associated with cases of schizophrenia.

Taking into account one of the synonyms for the gene - NKCC1 - I note some mention of the drug bumetanide (see this previous post) as being involved (see here****) which 'potentially' suggests some cross-over into cases of autism too. That and the fact that hyperactivity as part of the diagnosis of ADHD may be part of the ESSENCE of at least some autism, although I hasten to add that the Antoine work did not explicitly mention autism. Ears and hearing, have been talked about previously on this blog with autism in mind though (see here and here).

I suppose the thing that really fascinates me about this work is the link between physical presentation and behavioural presentation not necessarily just exclusive to the brain in terms of origin. To me at least, it's of a similar ilk to other research; for example the observation that lower airway abnormalities might be linked with autism (see here) which still requires some follow-up. A real mind-body or body-mind connection you might say?

Some music. How about The Pixies and Here Comes Your Man.

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* Antoine MW. et al. A Causative Link Between Inner Ear Defects and Long-Term Striatal Dysfunction. Science. 2013; 341: 1120-1123.

** Hyde TM. et al. Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia. J Neurosci. 2011 Jul 27;31(30):11088-95.

*** Panichareon B. et al. Association of CTXN3-SLC12A2 polymorphisms and schizophrenia in a Thai population. Behav Brain Funct. 2012; 8: 27.

**** Lemonnier E. & Ben-Ari Y. The diuretic bumetanide decreases autistic behaviour in five infants treated during 3 months with no side effects. Acta Paediatr. 2010 Dec;99(12):1885-8.

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Antoine MW, Hübner CA, Arezzo JC, & Hébert JM (2013). A causative link between inner ear defects and long-term striatal dysfunction. Science (New York, N.Y.), 341 (6150), 1120-3 PMID: 24009395

Autism and the GFCF diet: ScanBrit episode 2

"These preliminary observations on potential best responder characteristics to a gluten- and casein-free diet for children with autism require independent replication".

That sentence, taken from a recent (pre-print) publication I was very peripherally involved in writing, is probably the most important thing to take from the paper by Lennart Pedersen and colleagues* and certainly is a message that I would be very keen to promote.

Skandinavism @ Wikipedia 

ScanBrit, was/is a meeting of minds between the group I work with and other research groups based in Denmark and Norway, who wanted to experimentally examine the question of whether a diet devoid of foods containing gluten and casein might be able to impact on the presentation of autism in children.

Combined with a small but growing bank of research, the net outcome was that science should perhaps be looking at a possible dietary effect at least in relation to some cases of autism. One of the main issues being that the evidence base (including our own results**) was still limited in terms of the methodological quality of the investigations*** being undertaken (see here for a review). Oh and mechanism-wise, (i.e. how and why did diet 'work'?) we are still feeling around the edges, despite a few avenues of potential further inquiry (see here and here) including revisiting some older ideas.

In the most recent paper, (we) the ScanBrit collaboration were looking to further analyse the wealth of data which was generated over the course of the 2 years of experimental study and in particular, try and ascertain whether there were certain characteristics which might be markers for dietary response or not. As any person following the GFCF diet or their parents know, this is not an easy diet to follow and might, under certain circumstances, place a person at risk of nutritional deficiencies (see here) and/or other more socially-mediated issues (see here). Identifying markers of who might be a responder or non-responder would therefore save quite a lot of time, effort and expense.

Interestingly, as I've indicated in a previous post, some of the most significant and consistent behavioural changes which were noted in our original trial as correlating with the installation of a gluten- and casein-free (GFCF) diet were actually outside of the core symptoms of autism; instead potentially reflecting changes to attention and hyperactivity, more traditionally linked to the symptoms of attention-deficit (hyperactivity) disorder (ADHD). In other words, the effect of a GFCF diet might be more peripheral than anything else in cases of autism, in terms of targeting issues associated with ADHD which might also be present alongside the core autism symptoms (see my ESSENCE post and the very interesting paper by Sprenger and colleagues****).

Chronological age was identified as potentially being a factor influencing response to the GFCF diet, and in particular, those children aged between 7 and 9 years old as being potential best responders. I have to say that I am still mystified by this finding. Traditionally, I'd always assumed that there was a 'younger, the better' sentiment when applied to the possible effectiveness of dietary intervention on cases of autism, as per the rising tide of literature on other early interventions. Outside of the relatively small participant numbers we included for study, this could mean that there is some tie-in with the ADHD symptoms which seem to be targeted, bearing in mind my relative inexperience when talking about the manifestation of ADHD throughout childhood. In light of the recent case study from Dr Martha Herbert on a GFCF diet morphing into a ketogenic diet (see here), I do wonder if there might be other comorbidities also being affected which might also have some tie-in too. Who knows.

Again, without making too much of this variable at the current time, there was also a possibility for some involvement of one of the urinary compounds***** we focused on in the original ScanBrit trial as potentially being involved in response. I know biomarkers and autism is still a very complicated subject (see here) bearing in mind the heterogeneity of presentation and the potential influence of all that heightened risk of comorbidity. That all being said, trans-indolylacryloylglycine (IAG) whilst not being a biomarker for autism****** continues to garner interest with its possible connection to gastrointestinal (GI) comorbidity*******. More investigation needed here methinks.

I don't think we have made any startling discoveries with the publication of this paper. We were limited to the variables that we examined over the course of the study and so were unable to talk about whether other, more diet-relevant factors such as coeliac disease (CD) or related pathology - non-coeliac gluten sensitivity for example - might also be involved in response to diet. This was a major shortcoming of our original paper I'll freely admit.

That we found that inattention and hyperactivity might be key factors in dietary response however, is to my mind, potentially very important. That targeting such behavioural issues might also have a knock-on effect to more core autism presentation (as per our ADOS results on communication) is also an area requiring further investigation and perhaps reflects how autism (or should that be the autisms) is so very much more than just the formal clinical descriptions we give it. RDoC anyone?

Blogging about ones own peer-reviewed research is something that I've always been a little bit hesitant about doing. Aside from the possible charge of self-publicity and the natural tendency to think that yours is obviously an important paper (who wouldn't think that about their own work?), one might argue that important features such as the objectivity required for good science blogging, might to some degree be compromised. Sort of like marking your own homework as per one of my colleagues oft-cited phrases. I very much hope that I've not over-stepped the mark on good science blogging in this post on Lennart's paper. Indeed I'll end by reiterating part of the opening sentence to this post on the requirement for independent replication before anyone gets too excited about these results, as indeed the dietary research base as it presently stands is in need of more inquiry********.

And since we're on the topic of diet and autism, would that be one hump or two*********?

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* Pedersen L. et al. Data mining the ScanBrit study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders: behavioural and psychometric measures of dietary response. Nutr Neurosci. 2013 (pre-print)

** Whiteley P. et al. The ScanBrit randomised, controlled, single-blind study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders. Nutr Neurosci. 2010 Apr;13(2):87-100.

*** Millward C. et al. Gluten- and casein-free diets for autistic spectrum disorder. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD003498.

**** Sprenger L. et al. Impact of ADHD symptoms on autism spectrum disorder symptom severity. Res Dev Disabil. 2013 Aug 21;34(10):3545-3552.

***** Anderson RJ. et al. Identification of indolyl-3-acryloylglycine in the urine of people with autism. J Pharm Pharmacol. 2002 Feb;54(2):295-8.

****** Wright B. et al. Is the presence of urinary indolyl-3-acryloylglycine associated with autism spectrum disorder? Dev Med Child Neurol. 2005 Mar;47(3):190-2.

******* Wang L. et al. Is urinary indolyl-3-acryloylglycine a biomarker for autism with gastrointestinal symptoms? Biomarkers. 2009 Dec;14(8):596-603.

******** Winburn E. et al. Parents' and Child Health Professionals' Attitudes Towards Dietary Interventions for Children with Autism Spectrum Disorders. J Autism Dev Disord. 2013 Sep 1.

********* Al-Ayadhi LY. & Elyass Elamin N. Camel Milk as a Potential Therapy as an Antioxidant in Autism Spectrum Disorder (ASD). Evidence-Based Complementary and Alternative Medicine, 2013, Article ID 602834, 8 pages, 2013. doi:10.1155/2013/602834

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Lennart Pedersen, Sarah Parlar, Kajsa Kvist, Paul Whiteley, & Paul Shattock (2013). Data mining the ScanBrit study of a gluten- and casein-free dietary intervention for children with autism spectrum disorders: Behavioural and psychometric measures of dietary response Nutritional Neuroscience

Pregnancy antiepileptic use and offspring autistic traits

I'm a little bit slow in arriving at the paper by Gyri Veiby and colleagues* reporting a connection between maternal antiepileptic use and issues with offspring development (see here also for some news content). It's not that I don't find this particular topic to be absolutely fascinating - I most certainly do - but rather that other commitments, deadlines and interests keep getting in the way. Don't you sometimes wish you could be Multiple Man?

My first photo... @ Wikipedia 

Anyhow, for those of you who that haven't read my previous discussions on the growing body of research suggesting that we should perhaps be particularly mindful about the use of certain antiepileptic medicines during pregnancy (see here and here), the crux of the 'association' being made is that there may be some elevated risk of offspring autism under certain circumstances.

An automatic response to hearing about this possible link (aside from asserting that 'correlation does not equal causation') might be to say something along the lines of 'ban them' during pregnancy, as per another medicine (see here) with a very unfortunate history. But here's the thing: anti-epileptics aren't just some routine medicine used as pain relief or to help with other grumbling health-related issues that can be readily substituted. They can be, and often are, lifesavers: be in no doubt that untreated epilepsy can kill. And whilst it sounds easy to say that we should be prohibiting their use during pregnancy, the question then arises about what alternative you might suggest to control maternal epilepsy? Even though I'm enthused about things like ketogenic diets (see here) for example, and their growing use in treating some types of epilepsy, such measures are not always a good alternative to medication nor potentially great news for the developing child either (see here**). So we have a quandary.

Going back to the Veiby paper, it followed a slightly different vein to the previous work which looked at 'diagnosed' childhood outcomes such as autism following maternal use of anti-epileptics. Instead inquiring about specific facets of behaviour and development of offspring at 18 months and 36 months of age based on maternal report.

Using data derived from the Norwegian Mother and Child Cohort Study (MoBa) which covered a considerable sized cohort of pregnant women (more details are reported in this paper by Per Magnus and colleagues*** open-access), several thousand children were followed and included for the current study. MoBa, by the way, was also the source of data for one of the big folic acid studies with autism in mind (see here) and other interesting work (see here).

Anyhow, based on the analysis of records, some 333 children were reported to be exposed to antiepileptics in-utero as a result of maternal epilepsy. These children, when compared with non-exposed children, showed an increased frequency of issues with things like motor skills at 18 months alongside greater scores based on maternal reports of autistic-like behaviours.

At 36 months of age, these issues were still present in the exposed group. The frequency percentages for autistic traits in exposed and non-exposed children at the two time points were interesting (3.5% vs. 0.9% at 18 months, and 6% vs. 1.5% at 36 months). Just in case you're thinking that there might have been an effect from mum's epilepsy on child development and not the medication, the authors also reported no similar increased risk of developmental issues in those children born to mothers with epilepsy but who were unmedicated during pregnancy. Likewise when dads were diagnosed with epilepsy.

It's hard not to say that the evidence is stacking up for some effect of such medication when it comes to autism as a diagnosis and as a collection of symptoms/traits bearing in mind that risk is risk not fact. The announcement that the US FDA has now issued a warning about using the antiepileptics in question during pregnancy (which includes valproate) for treating things like migraine is testament to how seriously this issues is being taken. For many people, this is probably going to be worrying news.

With my cold, objective science hat on I'd also reiterate the suggestions from my previous posts on this topic that we have an interesting model developing potentially illustrative of how autism, at least some autism, might come about. Yes, autism research already uses a valproate mouse model of autism (see here for example) illustrative of the potential teratogenicity of the drug. But further than that are the reports that valproate for example, might have some interesting epigenetic effects on the genome, as per it being "a powerful HDAC inhibitor"*** (HDAC = histone deacetylases); indeed what effects it might have on certain comorbidity too****. One has to wonder whether this might have some effect also.

To close, I will reiterate the sentiments of this blog about not providing medical or clinical advice. Anyone requiring further information about this association, is directed to their supervising medical practitioner for further advice. Don't mess with epilepsy.

Something musical to close.... The Smiths and Sheila Take A Bow and the news that Morrissey has pulled his autobiography (which I assume would have been quite an interesting read).

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* Veiby G. et al. Exposure to antiepileptic drugs in utero and child development—A prospective population-based study. Epilepsia. 2013. doi: 10.1111/epi.12226

** Sussman D. et al. Effects of a ketogenic diet during pregnancy on embryonic growth in the mouse. BMC Pregnancy and Childbirth 2013, 13:109 doi:10.1186/1471-2393-13-109.

*** Haberland M. et al. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet. 2009 January; 10(1): 32–42.

**** Turgeon N. et al. HDAC1 and HDAC2 Restrain the Intestinal Inflammatory Response by Regulating Intestinal Epithelial Cell Differentiation. PLoS ONE. 2013. 8(9): e73785. doi:10.1371/journal.pone.0073785

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Veiby G, Daltveit AK, Schjølberg S, Stoltenberg C, Oyen AS, Vollset SE, Engelsen BA, & Gilhus NE (2013). Exposure to antiepileptic drugs in utero and child development: A prospective population-based study. Epilepsia, 54 (8), 1462-72 PMID: 23865818

MAR autism: a storm brewing?

It looks like a storm is brewing.

I refer to the commentary by Emily Underwood* titled: Alarm over autism test. The centre of the argument is the commercialisation of all that work coming out of the MIND Institute looking at maternal antibody reactivity to specific fetal brain proteins being fairly exclusively reported in mothers of children with an autism spectrum disorder (ASD). I've talked about this work a few times on this blog (see here and here); the important post seems to be the one on MAR autism (that's maternal autoantibody related autism to you and me) as per the papers by Melissa Bauman and colleagues** (open-access) and Dan Braunschweig and colleagues*** (open-access).

The regular readers of this blog might have seen a quite recent post extending the whole maternal immune activation link to autism (and other conditions). I don't think anyone can argue with the fact that this is a very, very interesting line of inquiry for at least some autism (or should that be some of the autisms?). Indeed, it's timely that another paper comes out with this field of study in mind: Rossi and colleagues****.

I'm not going to dwell too much on the Rossi findings aside from highlighting (a) they pretty much got the same results as previously reported but this time based on a cohort based in the Basque Country (yep, the same place that hosted IMFAR this year (2013), and (b) to quote: "plasma reactivity to fetal brain a combination of proteins at 37 and 73 kDa or 39 and 73 kDa was found exclusively in mothers of children with ASD". That and mention of one Joaquin Fuentes as part of the authorship group who I fondly remember as being the 'fingers of fire' as per his guitar skills at a conference in Ireland I attended many moons ago.

I'm not going to be drawn to deeply into the arguments about any 'alarm' over the proposed translation of the maternal autoantibody findings. I get the impression that for some, quite a bit of the 'alarm' is mention of the immune system being related to a behavioural condition like [some of] the autisms (who'd have thunk it...). I would however perhaps replace alarm with 'caution' in how this issue develops and the ethical questions that it raises as per pregnancy screening and previous examples of this line of investigation (see here). Indeed, in place of screening, the associated question is whether this line of work might have more therapeutic implications for at least some on the autism spectrum?

Update: 16-09-13. A full-text PDF of the original paper is available here.

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* Underwood E. Alarm Over Autism Test. Science. 2013; 341: 1164-1167.

** Bauman MD. et al. Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Transl Psychiatry. 2013 Jul 9;3:e278. doi: 10.1038/tp.2013.47.

*** Braunschweig D. et al. Autism-specific maternal autoantibodies recognize critical proteins in developing brain. Transl Psychiatry. 2013 Jul 9;3:e277. doi: 10.1038/tp.2013.50.

**** Rossi CC. et al. Brief Report: Antibodies Reacting to Brain Tissue in Basque Spanish Children with Autism Spectrum Disorder and Their Mothers. J Autism Dev Disord. 2013 Sep 11.

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Rossi CC, Fuentes J, Van de Water J, & Amaral DG (2013). Brief Report: Antibodies Reacting to Brain Tissue in Basque Spanish Children with Autism Spectrum Disorder and Their Mothers. Journal of autism and developmental disorders PMID: 24022729

Signs of autism in eating disorders?

To mention 'food and autism' in the same sentence can conjure up images of quite a few associations made in the peer-reviewed research literature over the years. You have for example, the growing body of work talking about how certain dietary interventions might be useful for some people on the autism spectrum (see here) and all the accompanying science on potentially why which seems to follow (see here).

Your differential analyser or mine? @ Wikipedia 

In another vein, issues with food and feeding behaviours, present in quite a few cases of autism, represent a far more practical issue to contend with; something which I've talked about before on this blog (see here).

Outside of the various sensitivities to things like taste, texture and smell which can affect a person's relationship with food (see here for a great overview* with autism in mind), questions are being asked about whether there may be more pathological issues to contend with as a result (see here**). I refer readers to the question asked by Prof. Gillberg 30 years ago on whether autism and familial anorexia might be linked (see here).

With this in mind, and slightly reversing the nature of any relationship, I want to discuss the paper by Baron-Cohen and colleagues*** (open-access) which suggested that females diagnosed with anorexia nervosa (AN) might being more likely to present with a cognitive style reminiscent of that seen in autism. Quite a nice overview of the study and its findings can be found here and due credit should be given to the article by Clare Allely which recently appeared in The Psychologist.

In essence (no, not that ESSENCE) we are talking about a group of adolescent females diagnosed with AN (n=66) compared with a control group of similarly aged young women without AN (n=1609). Based on the previous work looking at empathising and systemising (see here) styles in autism, participants completed questionnaires (EQ --- SQ-R --- AQ) to report on these attributes.

The results: "As predicted, the patients with anorexia has a higher AQ and SQ". In other words, the distribution of AN cases scoring higher on the AQ (see here for some more chatter about this instrument) was greater than that seen in the non-AN controls (see Figure 1 of the paper here). Ergo, more autistic traits in the AN group as per earlier research****. That also the AN group seemed to be better systemisers was another finding.

Whilst I have had my doubts about some of the earlier manifestations of the whole empathising-systemising theory (think the sweeping generalisations of Theory of Mind and autism) I have to say I am really interested in these recent results. I note also that another review study looking at the presence of autism in eating disorder populations***** likewise suggests that this might be a relationship which requires much further investigation.

If I had to throw a few spanners into the works outside of the study limitations already talked about by the authors, it would have to be that we should be cautious of making too many over-generalisations from this work. The recent 'mixed' findings by Courty and colleagues****** need to be considered. Although I am not an expert on eating disorders, it's still possible that we might also consider some shared comorbidity outside of autism as potentially accounting for some of the results at least in a sub-group. So for example, are features such as anxiety or obsessionality potential links between AN and the autism spectrum disorders particularly when talking about being better systemisers? The paper by Morsanyi and colleagues******* might be relevant here: [the systemising quotient] "was correlated with statistics-related attitudes, self-efficacy, and anxiety". I tip my hat also to the findings reported by Coombs and colleagues********. I'd also like to see more data on whether the described relationship between eating disorders and autistic traits holds for other kinds of eating disorders such as bulimia too?

Without also wishing to cause any offence, I do wonder about these results potentially being extended following in the tracks of the Gillberg letter. Take for example the paper by Grove and colleagues********* who talked about the empathising-systemising results being extended to other family members where autism is present. Does this therefore imply that we should be thinking about eating disorders potentially being more prevalent in other family members where autism is present? Indeed should we consider the possibility that the presence of a maternal (or paternal) eating disorder could be [another] subsequent risk factor for offspring autism?

To close, an Elvis track for you... His Latest Flame. I'd also like to mark the passing of David Barker (see here for his obituary) and his insightful contribution to science discussed in an earlier post (see here) which in an odd sort of way might also be relevant to today's discussions.

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* Cermak SA. et al. Food selectivity and sensory sensitivity in children with autism spectrum disorders. J Am Diet Assoc. 2010 February; 110(2): 238–246.

** Råstam M. et al. Eating Problems and Overlap with ADHD and Autism Spectrum Disorders in a Nationwide Twin Study of 9- and 12-Year-Old Children. Scientific World Journal. 2013; 2013: 315429.

*** Baron-Cohen S. et al. Do girls with anorexia nervosa have elevated autistic traits? Mol Autism. 2013; 4: 24.

**** Hambrook D. et al. Empathy, systemizing, and autistic traits in anorexia nervosa: a pilot study. Br J Clin Psychol. 2008 Sep;47(Pt 3):335-9. doi: 10.1348/014466507X272475.

***** Huke V. et al. Autism spectrum disorders in eating disorder populations: a systematic review. Eur Eat Disord Rev. 2013 Sep;21(5):345-51.

****** Courty A. et al. Levels of autistic traits in anorexia nervosa: a comparative psychometric study. BMC Psychiatry. 2013 Sep 10;13(1):222.

******* Morsanyi K. et al. Are systemizing and autistic traits related to talent and interest in mathematics and engineering? Testing some of the central claims of the empathizing-systemizing theory. Br J Psychol. 2012 Nov;103(4):472-96.

******** Coombs E. et al. An investigation into the relationship between eating disorder psychopathology and autistic symptomatology in a non-clinical sample. Br J Clin Psychol. 2011 Sep;50(3):326-38.

********* Grove R. et al. Empathizing, systemizing, and autistic traits: latent structure in individuals with autism, their parents, and general population controls. J Abnorm Psychol. 2013 May;122(2):600-9.

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Baron-Cohen S, Jaffa T, Davies S, Auyeung B, Allison C, & Wheelwright S (2013). Do girls with anorexia nervosa have elevated autistic traits? Molecular autism, 4 (1) PMID: 23915495

Maternal immune activation and monkeys continued

I sure do hope that all those fictional stories of apes turning the tables on humans don't ever come true. Indeed should you ever hear a Charlton Heston-esque character uttering 'You cut up his brain, you bloody baboon!' you might want to look to those in the field of monkey research as being the first ones with their brains on the chopping block in a sort of tit-for-tat style.

I jest of course. But the theme of monkey research runs strong in today's post as I introduce the paper by Melissa Bauman and colleagues* adding yet further evidence to the possible connection between maternal immune activation (let's call it MIA for short) and offspring behavioural development and characteristics.

For those with a close eye on autism and schizophrenia research, you'll probably already have heard of the work of Paul Patterson and colleagues (see here) and that coming out of the MIND Institute (see here) on how mothers' immune function during pregnancy might influence the risk of offspring presenting with said conditions. Indeed, with no clinical advice given or intended, the extended work looking into things like the use of suramin (see here) on offspring of mouse models with MIA in mind is also worthy of attention (note: the stress is on mouse models not human models).

For those who follow this blog, you might remember that I've already talked about some of the other work of Melissa Bauman and colleagues and the concept of maternal autoantibody-related autism (MAR). The emphasis there was on how monkeys have been introduced into MIA research and so perhaps relieving the burden on our poor Murine friends. If you happen to be a rat however, be warned... it looks like autism research is moving its eye of Sauron on to you.

The latest paper from Bauman (which also included Paul Patterson on the authorship list) differed from their MIA paper** insofar as instead of transplanting purified IgG brain reactive antibodies derived from mums of children diagnosed with an autism spectrum disorder (ASD) into monkeys, they used an artificial 'viral mimic'*** to stimulate the maternal immune system. The mimic was administered to pregnant monkeys either early or late gestation and compared with a non-mimic control group of rhesus monkeys.

As per the previous study, offspring behaviour was analysed over a 2-year period and some notable differences were reported: "MIA yields offspring with abnormal repetitive behaviors, communication, and social interactions". Readers might see a few similarities between the areas reported and the main topic of this blogsite.

This is interesting data of that there is no doubt. Allowing for the relatively small groups of animals included for study (13 experimental animals and 11 controls) and the important fact that monkeys are monkeys and not human beings with all their complexities, one might be inclined to think that MIA is certainly a field making advances.

With my own research hat on, bearing in mind MIA is most definitely not my field of expertise, I do wonder whether we might be hearing more from this group on something reported (but still awaiting peer review publication) by Prof. Patterson not so long ago: leaky gut being present in the offspring of MIA mother mice (see here). Ah yes, leaky gut (gut hyperpermeability if you will). The same leaky gut in cases of autism which has very recently been confirmed by the research tour-de-force that is Laura de Magistris and colleagues (see here). I'd be really quite interested to see if they looked at gut permeability in those MIA offspring monkeys too....

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* Bauman MD. et al. Activation of the Maternal Immune System During Pregnancy Alters Behavioral Development of Rhesus Monkey Offspring. Biol Psychiatry. 2013 Sep 4. pii: S0006-3223(13)00673-2. doi: 10.1016/j.biopsych.2013.06.025.

** Bauman MD. et al. Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Transl Psychiatry. 2013 Jul 9;3:e278. doi: 10.1038/tp.2013.47.

*** Caskey M. et al. Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans. J Exp Med. 2011 Nov 21;208(12):2357-66. doi: 10.1084/jem.20111171.

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Bauman MD, Iosif AM, Smith SE, Bregere C, Amaral DG, & Patterson PH (2013). Activation of the Maternal Immune System During Pregnancy Alters Behavioral Development of Rhesus Monkey Offspring. Biological psychiatry PMID: 24011823

Measuring autism: ATEC rising?

Throughout many of my posts talking about autism research and in particular, the plethora of research suggesting that product A or diet B or drug C might impact on presentation, one important issue has surfaced again and again: how do we measure autism, or more specifically, how do we measure change in the presentation of autism?

Measuring up? @ Wikipedia  

A couple of years back (yes, it's been that long!) I posted about assessing change in autism. With what I thought was a great David Bowie link - ch-ch-changes - I talked about how autism research really needed to get its act together when it came to devising a comprehensive and open-access tool which could be universally adopted to assess interventions.

Importantly too, a tool to assess across different interventions to pick out (a) likely important interventions, (b) start to work on those all-important responders and non-responders groupings which one would expect from a heterogeneous condition(s) like the autisms and (c) provide a picture of how autism ages and the ebbs and flows of symptoms as a result of factors like maturation or even comorbidity.

It is with all this in mind that I'm posting about the study by Geier and colleagues* (open-access) who suggested that the parent-report measure, the Autism Treatment Evaluation Checklist (ATEC) might show more than a modicum of overlap with a more professionally administered schedule, the Childhood Autism Rating Scale (CARS).

The ATEC is a bit of rising star in the autism research assessment world in recent years. In my previous changes post, I referenced the very respectable paper by Magiati and colleagues** (see the authorship list) and their conclusion: "This study provides some preliminary evidence of the ATEC's potential value for monitoring progress of children with ASD over time". That is, bearing in mind the quite small participant group (N=22). Subsequently, the ATEC also seems to have made it across another language too***.

The ATEC has the advantage of being parent-administered and freely available without training. I appreciate that when one looks at the types of study which have used the ATEC to date, one might get the sense that the type of research is not exactly 'mainstream' when it comes to it's use (see here), but please dear readers, refrain from making any snap judgements about the potential of the instrument on that basis.

The Geier paper is open-access and actually pretty easy-going to read. The main findings:

• There was a significant correlation between total scores on the ATEC and CARS. That finding was based on CARS being administered first by one of the authors "formally trained in the administration of the CARS" and then "the participant's parent completed at ATEC form". In-between the professional and parents were not privy to the "scores generated from their respective completed tests".
• Specific domains of the two instruments also seemed to correlate well, particularly when it came to the sensory/cognitive awareness domain.
• The addition of items related to health/physical behaviour as part of the ATEC was an added bonus bearing in mind how much attention is starting to turn towards some of these comorbidities in relation to autism (see here).

Again, the Geier study was relatively small in terms of participant numbers (N=56) and as the authors pointed out, this was a snapshot study looking at comparing the instruments at one single time point rather than using different times. I'm also minded to bring into the conversation the paper by Ben-Sasson and colleagues**** at this point, and their suggestion that mums and dads don't always say the same things when it comes to the reporting of the presentation of autism. A variable which perhaps needs more investigation with regards to any parent-report measure methinks.

Still, I'm not going to take anything away from the recent results and the 'not bad' report for ATEC. Indeed, in these times of austerity and dwindling resources, combined with the increasingly important point that parents are the experts on their own children (see here and here), the addition of ATEC as a free and relatively resource-friendly instrument must be seen as a bonus to any future study.

Even I'm thinking very seriously about adding it to the list in my future work...

To close, Pavement and the ever-so mellow Shady Lane.

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* Geier DA. et al. A Comparison of the Autism Treatment Evaluation Checklist (ATEC) and the Childhood Autism Rating Scale (CARS) for the Quantitative Evaluation of Autism. J Ment Health Res Intellect Disabil. 2013 Oct;6(4):255-267.

** Magiati I. et al. Is the Autism Treatment Evaluation Checklist a useful tool for monitoring progress in children with autism spectrum disorders? J Intellect Disabil Res. 2011 Mar;55(3):302-12.

*** Memari AH. et al. Cross-cultural adaptation, reliability, and validity of the autism treatment evaluation checklist in Persian. Iran J Pediatr. 2013 Jun;23(3):269-75.

**** Ben-Sasson A. et al. Cross-parent reliability in rating ASD markers in infants. Dev Neurorehabil. 2013 Aug 7. [Epub ahead of print]

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Geier DA, Kern JK, & Geier MR (2013). A Comparison of the Autism Treatment Evaluation Checklist (ATEC) and the Childhood Autism Rating Scale (CARS) for the Quantitative Evaluation of Autism. Journal of mental health research in intellectual disabilities, 6 (4), 255-267 PMID: 23914277

Antibiotic exposure and coeliac disease

I know that sometimes I sound a little bit ungrateful on this blog when it comes to important scientific advances and what they have done for modern day humans. Take for example antibiotics (antimicrobials if you wish) and how they have revolutionised medicine over the past few generations. Without them, even relatively minor infections and injuries which are nowadays routinely treated with antibiotics could prove as fatal as they were in the centuries before their discovery. Antibiotics have saved countless lives.

Dinner is served... @ Wikipedia  

But, as with many medical advances, success can also have its down-side too; as we are all now warned about the growing tide of antibiotic resistance and how this threatens our new-found reliance on these almost 'miraculous' pharmaceutical products.

The realisation also that antibiotic use and their subsequent effects might also impact on important environments such as the delicate balance of micro-organisms which call us home in our deepest, darkest recesses is also growing in importance as per some very recent research (see here) on the potential hows and whys. Upsetting the balance of the various bacteria which reside in our gut (dysbiosis) following antibiotic use has been a topic appearing more than once on this blog in relation to conditions like autism (see here) and the inflammatory bowel diseases (IBDs) (see here). Indeed it is with such a relationship in mind with regards to another bowel related condition, coeliac (celiac) disease (CD), that this entry focuses on the paper by Karl Mårild and colleagues* (open-access).

The Mårild paper is free for all to read and so no need for me to go to deeply into the paper. Suffice to say that based on an analysis of some quite large numbers of people diagnosed with CD or small intestinal inflammation or CD serology defined as "a positive IgA or IgG AGA (antigliadin), EMA (endomysial), or TTG (tissue transglutaminase) test less than 180 days before or no later than 30 days after a normal biopsy (and with no prior or subsequent biopsy showing villous atrophy or inflammation)", there was an association found with prescription patterns for antibiotics in Sweden. Inevitably the discussion leads on to how antibiotics alter the gut microbiota and potentially too the risk of developing CD although the door is left open for a purely epiphenomenal explanation.

A quick trawl through PubMed reveals that this research group have some history looking at various factors potentially 'associated' with the onset of coeliac disease. A six-fold increased risk of CD in cases of Down syndrome (see here), elective c-sections potentially being linked (I've talked about this one before) but not so for serious psychological stress (see here) have all been mentioned. Certainly with that elective c-section link there is some possible connection to the recent work as per the function of the bacteria that vaginal birth puts baby into contact as it traverses the birth canal before hitting the bright lights of the real world complete with bacterial passengers.

I know some people are probably furrowing their brow at the moment whilst uttering the words 'correlation is not causation' as a result of the implication that antibiotic use (or over-use) might impact on the gut microbiome and onwards impact on risk of conditions like coeliac disease or IBDs. I'll reiterate again that a purely epiphenomenal explanation has not been ruled out by the authors or me.

That being said, knowing that our gut bacteria might be doing so much more than just aiding food digestion and other related tasks, research in pursuit of any connection with conditions like CD should continue. If only to offer potentially something more than just a lifelong gluten-free diet as a management option (see here** with the caveat that no medical advice is given or intended) or indeed to further all that non-CD gluten sensitivity chatter (see here).

Who knows it might even provide some further evidence for the routine use of probiotics following completion of an antibiotic course?

So then, "shooting at the walls of heartbreak"? Any warriors out there?

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* Mårild K. et al. Antibiotic exposure and the development of coeliac disease: a nationwide case--control study. BMC Gastroenterology 2013, 13:109 doi:10.1186/1471-230X-13-109

** Smecuol E. et al. Exploratory, randomized, double-blind, placebo-controlled study on the effects of Bifidobacterium infantis natren life start strain super strain in active celiac disease. J Clin Gastroenterol. 2013 Feb;47(2):139-47. doi: 10.1097/MCG.0b013e31827759ac.

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Karl Mårild (2013). Antibiotic exposure and the development of coeliac disease: a nationwide case--control study BMC Gastroenterology DOI: 10.1186/1471-230X-13-109