Bone health and autism continued

It's been a while since I last wrote about the topic of bone health and autism (see here). On that particular occasion, it was the work by Ann Neumeyer and colleagues [1] that provided the blogging fodder and the observation that: "BMD [bone mineral density] is lower in peripubertal boys with ASD [autism spectrum disorder]." BMD is important because of a possible association between lower BMD and risk of fracture or indeed, something more pathological.

Today I continue with this topic as per further work from Neumeyer and colleagues [2] looking to "examine macro- and micronutrient intakes and self-reported physical activity in boys with ASD compared to TDC [typically developing controls] and the relationship of these variables with BMD."

Based on data from nearly 50 boys aged 8-17 years of age (25 diagnosed with ASD and 24 not-autism controls), researchers once again relied on the technique known as dual-energy x-ray absorptiometry (DXA) for the measurement of bone mineral density. Various measures were taken from various parts of the body -"whole body less head, hip, and spine." Alongside, food diaries provided a rough-and-ready measure of food intake, self-reported physical activity (that's self-reported) did what it said on the tin, and fasting levels of 25(OH) vitamin D and calcium were garnered. I'll come back to some of the pros-and-cons of some of these measures shortly.

Results: consistent with the peer-reviewed data that has come before, BMD z scores at the lumbar spine, femoral neck, total hip, and whole body less head were lower in those with autism compared with control participants. A BMD z score by the way, is basically a comparison of BMD with that of standardised data (i.e. an average person of the same sex and age). Added to such results, authors also observed that less calorie intake was present in the ASD group (again compared with controls) and a "lower proportion of ASD participants were categorized as "very physically active" (27% vs 79%; P<0.001)." Interestingly however: "Body mass index and serum vitamin D and calcium levels were similar."

I was rather intrigued by the Neumeyer results. Not least that vitamin D and calcium levels were 'similar' in the autism and control groups. As I've discussed before on this blog, there have been calls for preferential screening for these biological parameters as and when an autism diagnosis is received (see here) in light of other findings (see here). The Neumeyer observations perhaps reflect a wider need for such screening.

The use of self-report as a measure for physical activity, whilst useful, is slightly outdated in these times of actigraphy. Wearable technology to measure activity and rest cycles is cheap and abundant these days and, as I've mentioned on other occasions, really should be the research industry standard. I'm not saying people might not be accurate in reporting their short-term physical activity but...

I do think there are some additional 'where next?' things to consider when it comes to future work looking at BMD and autism. Noting for example, that both dietary and malabsorptive issues seem to be able to influence BMD [3] there are additional parameters to be looked at. Given previous peer-reviewed reports on lactose issues being present in relation to autism (see here), this could feature in future work. Although still possessing the ability to furrow brows in certain quarters, the observation of issues with intestinal permeability ('leaky gut') in relation to some autism (see here) also could be an additional parameter to examine. I daresay also that some initial chatter about a compound called zonulin potentially serving as a 'biomarker of impaired gut barrier function' in relation to some autism (see here) might also be revealing. And then there is the important issue of epilepsy / seizure disorder often being comorbid with autism (see here), and how certain [important] intervention measures for said issues might affect parameters such as vitamin D (see here) and what that might mean for long-term bone health...

----------

[1] Neumeyer AM. et al. Bone density in peripubertal boys with autism spectrum disorders. J Autism Dev Disord. 2013 Jul;43(7):1623-9.

[2] Neumeyer AM. et al. Nutrition and Bone Density in Boys with Autism Spectrum Disorder. J Acad Nutr Diet. 2018 Feb 3. pii: S2212-2672(17)31749-5.

[3] Di Stefano M. et al. Lactose malabsorption and intolerance and peak bone mass. Gastroenterology. 2002 Jun;122(7):1793-9.

----------

No unique patterns of gut issues in autism? Headline fail...

"This study supports the observation that children with autism who have symptoms of gastrointestinal disorders have objective findings similar to children without autism. Neither non-invasive testing nor endoscopic findings identify gastrointestinal pathology specific to autism, but may be of benefit in identifying children with autism who have atypical symptoms."

So concluded Rafail Kushak and colleagues [1] (them of "Lactase deficiency not associated with intestinal inflammation or injury is common in autistic children and may contribute to abdominal discomfort, pain and observed aberrant behavior" [2]) who undertook some important work around the topic of gastrointestinal (GI) issues being over-represented in cases of autism (see here). Some media on their recent findings can be read here (see here).

Looking at the results of 61 children diagnosed with autism and presenting with GI issues and data from 50 non-autistic individuals also being assessed for GI problems, researchers examined whether there were any differences between the groups on a range of measures including disaccharidase activity, intestinal inflammation and gut permeability (the so-called 'leaky gut'). They reported finding some discrepancies between the groups - including "mild levels of mucosal inflammation on intestinal biopsy" for some of those with autism -  but nothing that seemed to point to a 'GI fingerprint' specifically relevant to just autism. They concluded that where GI issues appear alongside autism, the same level of assessment and care should be afforded as it is when GI issues are present outside of autism. Tim Buie, one of the study authors, had said as much quite a few years back.

I would draw attention to a few important points included in the Kushak study. First, are the participant groups. This was a study comparing children with and without autism who were both under investigation following the presentation of GI issues. They were not comparing children with autism with GI issues with non-autistic children without gut issues. I say this just in case anyone assumes that the findings point to no significant gut issues being identified in those with autism. That is absolutely not the case. Headlines might need some adjustment.

Second, the results reported are to some degree at odds with other findings published by independent groups - specifically those reported by Stephen Walker and colleagues [3] (see here for my take). Although perhaps not exactly overlapping in terms of methods and outcomes, Walker et al concluded that their data was evidence that "ASDGI children have a gastrointestinal mucosal molecular profile that overlaps significantly with known inflammatory bowel disease (IBD), yet has distinctive features that further supports the presence of an ASD-associated IBD variant, or, alternatively, a prodromal phase of typical inflammatory bowel disease." I might add that at the time of writing this post and despite the Walker findings being published some 3 years ago, no-one has taken up the research gauntlet to try and replicate/challenge the Walker publication. That IBD might be over-represented when a diagnosis of autism is received is also an important point to make (see here).

Finally, mention of the words "leaky gut" in the Kushak report are a continued welcome sign. That measurement via "rhamnose/lactulose test and measured by HPLC-MS" did not appear to differentiate kids with autism with GI issues vs, kids without autism with GI issues is an important addition to the debate in this area. I know discussions of intestinal permeability with autism in mind can furrow brows in certain quarters but there is a growing recognition that (a) this is a real phenomenon (see here) and (b) for at least some people on the autism spectrum, gut permeability issues are present (see here). That gut permeability issues might be a 'later life event' when detected in 'some' autism (see here) is also worth re-iterating as is the idea that 'treating' gut permeability might be something that many people are already doing without even knowing it (see here).

Now, about that study on the use of dietary intervention for children with autism WITH bowel issues...

----------

[1] Kushak RI. et al. Evaluation of Intestinal Function in Children with Autism and Gastrointestinal Symptoms. J Pediatr Gastroenterol Nutr. 2016 Feb 20.

[2] Kushak RI. et al. Intestinal disaccharidase activity in patients with autism: effect of age, gender, and intestinal inflammation. Autism. 2011 May;15(3):285-94.

[3] Walker S. et al. Identification of unique gene expression profile in children with regressive autism spectrum disorder (ASD) and ileocolitis. PLoS ONE. 2013; 8: e58058.

----------

Kushak RI, Buie TM, Murray KF, Newburg DS, Chen C, Nestoridi E, & Winter HS (2016). Evaluation of Intestinal Function in Children with Autism and Gastrointestinal Symptoms. Journal of pediatric gastroenterology and nutrition PMID: 26913756

Camel milk and autism: two humps or three?

In a previous post with the cringe-worthy title: 'Camel milk for autism: one hump or two?' (you can see why I could never be a comedian) I talked about some rather intriguing research [1] asking whether, under double-blind, placebo-controlled conditions, camel milk could affect various clinical measures of severity when it comes to the label of autism, some autism. The answer was very possibly, yes; with the strong requirement for quite a bit more follow-up research in this area.

Lo and behold, yet more data has emerged from the research pen of one Laila Al-Ayadhi and colleagues [2] (open-access available here) on the topic of camel milk and autism and specifically the idea that: "camel milk could be [a] very promising therapeutic intervention in ASD [autism spectrum disorder]." Again, under double-blind, placebo-controlled conditions, Al-Ayadhi et al describe how 2 weeks of camel milk (raw or boiled) seemed to show some 'significant differences' on schedules such as the CARS (Childhood Autism Rating Scale), SRS (Social Responsiveness Scale) and the ATEC (Autism Treatment Evaluation Checklist). The placebo (cow milk) group by contrast, didn't show anything at all in terms of significant changes between baseline and post-intervention testing occasions.  The ATEC in particular, is something I'm quite keen to see more autism investigations using (see here).

I have some time for Dr/Prof. Al-Ayadhi and colleagues given some previous musings on their wide and varied research with autism in mind (see here). This recent work continues one of their important themes based on the idea that not all mammalian milk forms are alike (see here) and hence, following a tradition potentially implicating milk and dairy products in some autism (see here), a switch to other varieties of milk outside of those normally populating our diet might be beneficial for at least some. Other more 'N=1' reports [3] have offered similar discussions on this topic.

As per my previous musings on this topic, I can't readily offer a substantial and/or universal reason for what it is about camel milk that may be important to some people on the autism spectrum. Lactose content, milk protein structure or nutritional content are perhaps some of the most pertinent variables to consider given that all have some research 'history' when it comes to at least some autism (see here for some discussion on the seemingly forgotten work by Tim Buie et al on lactose issues and autism for example). In other peer-reviewed publications, Dr/Prof. Al-Ayadhi has talked about the antioxidant properties of camel milk as being key [4]. I'm hoping that in future times I might be able to discuss further this area of investigation as and when some research ideas in my own day job reach fruition.

And just in case you think I'm advocating camel milk for all autism, no I'm not. As we've seen from other research outside of autism recently, personalised nutrition is the way forward [5] not sweeping generalisations...

Music to close and a song that's growing on me (I think I need some earworm therapy).
----------

[1] Al-Ayadhi LY. et al. Behavioral Benefits of Camel Milk in Subjects with Autism Spectrum Disorder. J Coll Physicians Surg Pak. 2015 Nov;25(11):819-823.

[2] Bashir S. & Al-Ayadhi LY. Effect of camel milk on thymus and activation-regulated chemokine in autistic children: double-blind study. Pediatr Res. 2014 Apr;75(4):559-63.

[3] Adams CM. Patient report: autism spectrum disorder treated with camel milk. Glob Adv Health Med. 2013 Nov;2(6):78-80.

[4] Al-Ayadhi LY. & Elamin NE. Camel Milk as a Potential Therapy as an Antioxidant in Autism Spectrum Disorder (ASD). Evid Based Complement Alternat Med. 2013;2013:602834.

[5] Zeevi D. et al. Personalized Nutrition by Prediction of Glycemic Responses. Cell. 2015 Nov 19;163(5):1079-1094.

----------

Al-Ayadhi LY, Halepoto DM, Al-Dress AM, Mitwali Y, & Zainah R (2015). Behavioral Benefits of Camel Milk in Subjects with Autism Spectrum Disorder. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP, 25 (11), 819-823 PMID: 26577969

Breast milk protects against GI symptoms in high risk autism?

Happy house @ Paul Whiteley

"Late weaning and EBM [exclusive breast milk] were associated with protection against GI [gastrointestinal] symptoms in High-risk infants."

That was one of the conclusions presented in the paper by Alexander Penn and colleagues [1] who asked some pretty important questions when it comes to the increasingly strong relationship between bowel issues and autism spectrum disorder (ASD) (see here).

"Using questionnaires, diet history and gastrointestinal problems were tracked prospectively and retrospectively in 57 High-risk infants, and for comparison, in 114 Low-risk infants (infants from families without ASD history)." The main aims of this study were to examine whether those at an enhanced risk for autism by virtue of having a sibling already diagnosed were at any greater risk of presenting with functional bowel symptoms, and whether such bowel issues were "associated with diet and age at weaning from breast milk."

Early weaning - the introduction of solid foods to an infant - seemed to be more frequently present in high-risk infants with bowel issues as did "a no breast milk (NBM) diet" compared with an exclusive breast milk diet. This was particularly true for the bowel symptom constipation and especially for those who were weaned earlier than 6 months of age.

The authors suggest that their data indicate that weaning and breast milk diet practices might have some bearing for the presentation of bowel symptoms in those at high-risk for autism. Further: "The greater prevalence of GI symptoms in High-risk infants suggests that GI dysfunction during early infant development may be a part of the ASD endophenotype." That all sounds rather important.

I'm drawing back from making too many sweeping statements about this research bearing in mind the participant number, the use of the term 'high-risk' and elements of the questionnaire design of the study. There is quite a bit more research required in this area.

That all being said, I do think there are more than a few future studies that might come from such findings. So, thinking back to the paper by Afzal and colleagues [2] and the idea that "consumption of milk to be the strongest predictor of constipation" among their cohort diagnosed with autism, is the suggestion that more attention might be needed for specific elements of the diet such as cows milk. Added to the findings from Kushak and colleagues [3] (see here for a past post on this work) regarding lactose intolerance as being pretty rife in their cohort with autism (importantly, "not identified by clinical history"), and clues start to emerge alongside possible alternative strategies (see here and see here)...

Music: Stevie Wonder - Superstition.

----------

[1] Penn AH. et al. Breast Milk Protects Against Gastrointestinal Symptoms in Infants at High Risk for Autism During Early Development. J Pediatr Gastroenterol Nutr. 2015 Jul 29.

[2] Afzal N. et al. Constipation with acquired megarectum in children with autism. Pediatrics. 2003 Oct;112(4):939-42.

[3] Kushak RI. et al. Intestinal disaccharidase activity in patients with autism: effect of age, gender, and intestinal inflammation. Autism. 2011 May;15(3):285-94.

----------

Penn AH, Carver LJ, Herbert CA, Lai TS, McIntire MJ, Howard JT, Taylor SF, Schmid-Schönbein GW, & Dobkins KR (2015). Breast Milk Protects Against Gastrointestinal Symptoms in Infants at High Risk for Autism During Early Development. Journal of pediatric gastroenterology and nutrition PMID: 26230900

Milk has gotta lotta bottle?

"High milk intake was associated with higher mortality in one cohort of women and in another cohort of men, and with higher fracture incidence in women". Those were some of the conclusions reached in the study by Karl Michaëlsson and colleagues [1] (open-access) looking at milk consumption and "mortality and fractures in women and men". The BBC among other media have covered the study (see here).

Take me out tonight

Based on quite a large participant group (two actually) who completed a food frequency questionnaire among other things, researchers followed over 100,000 people some 10-20 years later to ascertain details on "fracture events" and mortality. For a smaller subgroup, they also reported on: "the urine oxidative stress marker 8-iso-PGF2α, a dominant F2-isoprostane and an ideal standard biomarker of oxidative stress in vivo" on the basis of analysing any connection between: "D-galactose in milk with theoretical influences on processes such as oxidative stress and inflammation". Oh, and a familiar cytokine also gets a mention: interleukin-6.

Authors, with caveats, reported something of a possible connection between milk intake and outcomes: "a dose dependent higher rate of both mortality and fracture in women and a higher rate of mortality in men with milk intake, a pattern not discerned with other dairy products" and "positive associations between milk intake and concentrations of markers for oxidative stress and inflammation". IL-6 levels were also correlated with milk intake (although surprisingly little is made of this association in my opinion bearing in mind some of the other literature in this area [2]). For quite a thorough review of the study and findings, I will refer you to the NHS Choices take on it (see here).

Milk has been something of some interest to this blog down the year based on my preoccupation with diet and [some] autism [3] (see here and see here for examples) and further a possible relationship with other behaviourally-defined conditions (see here). I have tried not to come down too heavy on the white stuff (see here) given that it's not all doom and gloom when it comes to the benefits of milk for quite a few people albeit with the sunshine vitamin/hormone also needing to be considered. As an aside, the recent coverage of the the Caerphilly Cohort Study and their 'roadmap to healthy ageing' (see here) previously also talked about milk products and "a markedly reduced prevalence of the metabolic syndrome" [4], so one has to be slightly cautious about demonising milk generally.

The Michaëlsson results however cannot be readily ignored given the impressive participant size and prospective design of study used. The fact that authors reported findings pertinent to milk consumption but that "intake of fermented milk products such as yogurt and soured milk and cheese were associated with lower rates of fracture and mortality" is also potentially important. I could start going on about how processing might affect lactose / galactose content in some cheeses [5] and yoghurts [6] but this is perhaps fodder for another day. Likewise the findings reported by Ji and colleagues [7] suggesting "people with lactose intolerance, characterised by low consumption of milk and other dairy products, had decreased risks of lung, breast, and ovarian cancers" might also be relevant. I note also that chatter about casein (the protein in milk) content as a function of researchers findings are largely absent from the discussions but are perhaps also potentially relevant in light of the whole A1-A2 milk issue rising in prominence these days (also including mention of oxidative stress too).

Music to close: Lorde - Yellow Flicker Beat.

----------

[1] Michaëlsson K. et al. Milk intake and risk of mortality and fractures in women and men: cohort studies. BMJ. 2014; 349.

[2] Labonté MÈ. et al. Dairy Product Consumption Has No Impact on Biomarkers of Inflammation among Men and Women with Low-Grade Systemic Inflammation. J Nutr. 2014 Nov;144(11):1760-7.

[3] Whiteley P. Nutritional management of (some) autism: a case for gluten- and casein-free diets? Proc Nutr Soc. 2014 Oct 14:1-6.

[4] Elwood PC. et al. Milk and dairy consumption, diabetes and the metabolic syndrome: the Caerphilly prospective study. J Epidemiol Community Health. Aug 2007; 61(8): 695–698.

[5] Portnoi PA. & MacDonald A. Determination of the lactose and galactose content of cheese for use in the galactosaemia diet. J Hum Nutr Diet. 2009 Oct;22(5):400-8.

[6] Alm L. Effect of fermentation on lactose, glucose, and galactose content in milk and suitability of fermented milk products for lactose intolerant individuals. J Dairy Sci. 1982 Mar;65(3):346-52.

[7] Ji J. et al. Lactose intolerance and risk of lung, breast and ovarian cancers: aetiological clues from a population-based study in Sweden. Br J Cancer. 2014. October 14.

----------

Michaelsson, K., Wolk, A., Langenskiold, S., Basu, S., Warensjo Lemming, E., Melhus, H., & Byberg, L. (2014). Milk intake and risk of mortality and fractures in women and men: cohort studies BMJ, 349 (oct27 1) DOI: 10.1136/bmj.g6015

Soy infant formula and seizures in autism

Spring @ Wikipedia 

'Association' is a word I'm sure many people with a connection to autism will have heard a lot about. Y'know gene X or compound Y is the plat du jour when it comes to autism aetiology; more often than not carrying the caveat 'requires further investigation'. As to whether such investigations are ever truly carried out would perhaps be an interesting piece of research on autism research.

Today I'm talking about another association, another variable to throw into the statistical risk mix derived from the paper by Cara Westmark [1] (open-access here) suggesting that where seizures or epilepsy present alongside (or as part of) autism, there may be a curious correlation to be had with the use of soy infant formula.

I'll readily admit that when first reading the title to this study I was more than a little reluctant to blog about it. I can't really explain why - whether it was yet another study of 'association' or something about what appears to be quite a well-used feeding strategy for infants where traditional methods are not indicated - there wasn't the initial appetite to talk about it. Following some light reading around the topic and what looks to be some quite strongly held views on the use of infant soy formula (see this BBC report) including mention of a possible relationship with ADHD (see here) I eventually decided that this might be something to cover. The press release covering the study also helped (see here and see here) in making my decision.

A few details:

• The hypothesis: "the use of soy-based infant formulas could be contributing to seizure incidence in autism and other neurodevelopmental disorders" came about apparently on the basis of some earlier work by the authors [2] (open-access here) which suggested that a component of soy-feed (daidzein) given to rats might have the ability to induce seizures after a few days consumption. More discussion about this earlier trial can be found here.
• So, based on an analysis of data derived from the Simons Foundation Autism Research Initiative (SFARI), Westmark and colleagues looked at the occurrence of seizures and if available, the types of seizures reported, alongside the frequency of soy infant formula use, using sex as a differentiating variable in cases of autism.
• Results: "There was a 2.6-fold higher rate of febrile seizures in the soy-fed cohort (4.2% seizures with soy and 1.6% seizures without soy)". That being said, the results only passed significance for females who were fed soy formula; males were more likely to present with seizures after soy feeding "but [results] were not statistically significant".
• Also: "A comorbid diagnosis of autism and epilepsy was more prevalent in males fed soy-based formula (odds ratio = 2.4, 95% confidence interval 1.1–5.2; P = 0.02) than females (odds ratio = 1.4, 95% confidence interval 0.056–14; P = 0.8)". This does sound a little counter-intuitive given what the last sentence said about febrile seizures and gender but I would draw your attention to the use of the diagnostic term 'epilepsy' as opposed to 'febrile seizure'.

I'm pretty sure that you can see from the collected data included in this paper there are some potentially interesting details which require further analysis. I'm for example interested in seeing more about the proposed mechanism to account for the correlation reported between soy formula use and an elevated frequency of seizures/epilepsy in relation to autism. The authors suggest "the effects of an underlying genetic mutation that lowers seizure threshold may be exacerbated, for example, by dietary exposure to high concentrations of phytoestrogens". Yes, possibly; although with various other autism-related research areas in mind, I'd be interested to see whether there may other effects from for example, the gut microbiota [3] and how they might also play their part.

Perhaps another question would be whether the underlying reason why soy infant formula was used in the first place might also have played some role in the results. The authors do approach this topic as per the sentences: "A possible criticism is that subjects, who were fed soy-based infant formula because they were allergic to cow's milk, had allergies that made them vulnerable to illnesses associated with fever-induced convulsions. Though the retrospective nature of the data does not allow us to make definitive conclusions regarding this point, we found that 2.7% of females and 1.7% of males in the study population reported allergies, but no subjects reported both allergies and febrile seizures suggesting that this criticism may not be valid". I'd perhaps chime in here and suggest that 'allergy' might be a bit of a red herring here as per the research looking at something like lactose intolerance in relation to autism (see here) and the still quite speculative role of milk peptides (see here). There is also the potential issue of something like those folate receptor autoantibodies to consider (see here) which also seem to be affected by old fashioned milk although I am speculating here. There is the odd study (case report) talking about something like lactose intolerance and epilepsy for example [4] but still a lot more scope for further investigation in this area.

As per my introduction to this post on the role of 'association' when it comes to autism research, one always needs to be a little careful when interpreting such data and drawing too many conclusions. I'm not saying that seizures or epilepsy in autism may not be linked to something like early infant feeding choice, but with the same logic, I'd be hard pressed to say there is conclusive evidence of any association yet. And remember, the plural condition of autisms are a very complicated set of conditions indeed.

Finally, quite by coincidence, just yesterday I received an email invite to submit to a Frontiers journal topic headed by Dr Westmark on a favourite topic of mine (diet and the brain) which reminded me of an equally interesting research area on the use of ketogenic diets with autism and epilepsy in mind... more food for thought? (without any medical or clinical advice given or intended)

Music to close. Bowie and Jagger and a great video with some contrasting dancing styles. Condolences also to Sir Mick and the family of L'Wren Scott.

-----------

[1] Westmark CJ. Soy infant formula and seizures in children with autism: a retrospective study. PLoS One. 2014 Mar 12;9(3):e80488.

[2] Westmark CJ. et al. Soy-based diet exacerbates seizures in mouse models of neurological disease. J Alzheimers Dis. 2013;33(3):797-805.

[3] Atkinson C. et al. Gut bacterial metabolism of the soy isoflavone daidzein: exploring the relevance to human health. Exp Biol Med (Maywood). 2005 Mar;230(3):155-70.

[4] Yaman H. et al. Epileptic seizures associated with lactose intolerance in a child: A causal relationship? J Pediatr Neurology. 2012; 10: 151-154.

-----------

Westmark CJ (2014). Soy infant formula and seizures in children with autism: a retrospective study. PloS one, 9 (3) PMID: 24622158

Pain predicting sleep problems in autism

Not so long ago I talked about the paper from Smith and colleagues [1] on autism and obstacles to medical [comorbidity] diagnosis and treatment (see here). Aside from the need for professionals to overcome the issue of "a lack of expressive speech" as an impediment to undertaking a thorough medical work-up when presented with a person with autism, an important theme of that paper was the requirement to see beyond autism as being the 'reason' for every single behaviour or issue that affects a person. It's not.

Indeed, the paper by Megan Tudor and colleagues [2] which makes up the material for today's post, adds to that message with their report on pain as being a predictor of sleep problems for some children/young adults with autism. Once again, my thanks go to Natasa for providing the full-text version of the paper for my blogging consumption (yum!).

The long-and-short of the Tudor paper was as follows:

• Take two issues which have cropped up in the autism research literature more than once - sleeping issues and pain - and aim to examine "pain-related behaviors as a predictor of sleep problems in youth with parent-reported ASD using standardized parent-report measurement of both variables".
• Mothers of a sample of 62 children/young adults drawn from a larger study [3] [note to authors, your date is wrong for this reference] were questioned using several measures including the NCCPC-R (see here) and the CSHQ [4] (open-access) looking at pain and sleep respectively. I should also note that questionnaires were completed on-line and participants received a financial incentive to complete [a large chunk of] questionnaires.
• Results: parent-reported participant pain levels according to NCCPC-R scores "was high compared to normative information for this measure". Sleep issues were similarly elevated in the sample, particularly parasomnias. The discussion notes that pain scores were gathered across a slightly different timespan to the normative data (1 week retrospective report for the study vs. 2-hour observation period for the normative data) so one perhaps need to be a little cautious about this.
• Some regression analysis for scores on the two instruments revealed some potentially important results. So higher pain scores "predicted higher scores on CSHQ Total Sleep Disturbance" although with an R-squared value of 0.22 this is not necessarily a straight-forward connection. 
• Specific sleep problems including sleep duration, parasomnias and sleep-disorder breathing were also reported as being accompanied by a previous weeks pain-related behaviours and may well have had some very individual behaviours linked to them e.g. "problems with sleep duration were predicted by social communication of pain, such as comfort-seeking and being difficult to pacify" and "Parasomnias were predicted by facial communication of pain, such as grimacing or brow furrowing".
• The authors conclude that whilst there is more to do in this area of investigation (including the important use of control groups) their results should serve as a marker for healthcare professionals when dealing with children with autism who also present with sleeping issues. To quote: "how pain and sleep problems relate to one another and may affect children's daytime functioning...". This may have some far-reaching effects in terms of how sleep issues are traditionally managed when it comes to autism and other developmental disorders.

Going back to the my starting paragraph about autism not being to blame for every single behavioural manifestation noted among cases, I can't help but ask the question: why were parent-reported indicators of pain-related behaviours seemingly elevated in this sample? As far as I know - and I am just an outsider looking in - autism is not necessarily defined as a painful condition. Indeed, even the authors point to the possibility of a "high threshold for pain" [5] described in the DSM-IV TR diagnostic schedule for autism. Certainly if it was shown that autism 'is a painful condition', it would perhaps change some of the dialogue noted in Dr Insel's Four Kingdoms of Autism.

I do have a few theories about this notion of pain and autism however so bear with me. Tudor and colleagues allude to one of them insofar as discussions about "ongoing mild digestive discomfort" and "severe inflammatory bowel disease" with both issues having cropped up before on this blog previously. Thinking back to the paper by Kushak and colleagues [6] discussed in this post on lactase enzymes and autism, there is the suggestion that lactose intolerance (related to the sugar found in milk and dairy produce) "may contribute to abdominal discomfort, pain and observed aberrant behavior". With autism and inflammatory bowel disease in mind, the Walker paper [7] published a while back (discussed in this post) springs to mind.

Of course, I don't claim that every expression of pain noted in autism is necessarily one of being related to gastrointestinal (GI) function or dysfunction but one could certainly look to rule these issues out if one were being assiduous. As per some other potentially important issues, I might also refer you to a post I wrote a while back on self-injurious behaviour (see here) and other areas that one might look at when it comes to pain being potentially present in cases of autism.

The final angle that is perhaps worthy of exploration has already been touched upon in the additional reference by Allely [5] (see here again) in relation to how one of the core aspects of autism might itself have the ability to induce pain: sensory sensitivity. I say core aspect but am referring to the recent inclusion of sensory issues into DSM-V noting that not everywhere in the world has made the shift over the DSM-5. So, things like over sensitivity to sound for example, I assume may register on someone's behaviour and manner, just as issues with the visual modality might also have the ability to induce something like pain (see here). Indeed, migraine might be something else to look at with pain and autism in mind [8] and not just with the head in mind either [9]. As per previous statements, it all depends on how far one is willing to look into the issue of pain and the potential reasons for its presence...

----------

[1] Smith MD. et al. Autism and Obstacles to Medical Diagnosis and Treatment. Focus Autism Other Dev Disabl 2012; 27: 189-195.

[2] Tudor ME. et al. Pain as a predictor of sleep problems in youth with autism spectrum disorders. Autism. 2014 Feb 4. [Epub ahead of print]

[3] Walsh CE. et al. Predictors of parent stress in a sample of children with ASD: Pain, problem behavior, and parental coping. Res Autism Spec Disorder. 2013; 7: 256-264.

[4] Owens JA. et al. The Children's Sleep Habits Questionnaire (CSHQ): psychometric properties of a survey instrument for school-aged children. Sleep. 2000 Dec 15;23(8):1043-51.

[5] Allely CS. Pain Sensitivity and Observer Perception of Pain in Individuals with Autistic Spectrum Disorder. ScientificWorldJournal. 2013; 2013: 916178.

[6] Kushak RI. et al. Intestinal disaccharidase activity in patients with autism: effect of age, gender, and intestinal inflammation. Autism. 2011 May;15(3):285-94.

[7] Walker S. et al. Identification of unique gene expression profile in children with regressive autism spectrum disorder (ASD) and ileocolitis. PLoS ONE. 2013; 8: e58058.

[8] Fors S. & Fors MF. Is autism linked to migraine aura? Epidemiology. 2013 May;24(3):472-3.

[9] Casanova MF. The minicolumnopathy of autism: A link between migraine and gastrointestinal symptoms. Med Hypotheses. 2008;70(1):73-80.

----------

Tudor ME, Walsh CE, Mulder EC, & Lerner MD (2014). Pain as a predictor of sleep problems in youth with autism spectrum disorders. Autism : the international journal of research and practice PMID: 24497628

Camel milk for autism: one hump or two?

I am so sorry dear readers for the dreadful pun used in the title of this post. It comes from years of reading books about 'knock-knock' jokes and the ever versatile 'the boy stood on the burning deck' ditties. More so in recent times with the advent of one of my brood starting to use the old 'Dr Who' version of the knock-knock joke. Having said all that I'm sure some people might think I am joking when it comes to talking about camel milk as a potential intervention for autism (some autism).

Send in the camel corp @ Wikipedia 

But I assure you readers that I am quite serious...

The primary fodder for this post comes in the shape of the trial results reported by Bashir and Al-Ayadhi [1] and their assertion that "camel milk administered for 2 weeks significantly improved clinical measurements of autism severity". The results are based on a small sample of children diagnosed with an autism spectrum condition and who were randomly assigned to one of three conditions: (a) boiled camel milk (CM), (b) raw camel milk and (c) normal cows milk (acting as a placebo). Alongside plotting responses to group assignment based on the CARS, the authors also reported on serum levels of Thymus and Activation-Regulated Chemokine (TARC) otherwise known as CCL17.

The results: well bearing in mind this was a small study looking at intervention over the course of only 2 weeks "significant improvements were observed in CARS score (p=0.04) in raw CM group only". That and levels of TARC also being reported to have dropped significantly in both the CM groups but not the placebo group.

I would echo the sentiments of the authors in their desire to see further more methodologically strong trials on whether CM might indeed have some potentially important effects for at least some people on the autism spectrum. One might argue that use of cows milk as a placebo may be problematic or indeed that the study may have benefited from a milk exclusion or non-mammalian milk source group as part of the trial. But it didn't.

This is also not the first time that the words 'camel milk and autism' have appeared together in a research sense as per the study by Al-Ayadhi & Elamin [2] (open-access here) looking at what happened to antioxidant biomarkers as a function of adopting camel milk including that very important compound, glutathione (see here). That and some research write-up of a case study of camel milk use in one child with autism [3] (open-access here). Don't underestimate the value of the N=1 when it comes to autism... 'if you've met one person with autism' and all that.

As for the hows and whys of camel milk potentially affecting the presentation of autism, well, outside of the possible immunological effects as per other research from some of the same authors [4] I'm inclined to suggest a few areas which might be important:

• Lactose, the sugar in milk, has previously appeared on the autism research radar as per the Kushak findings a few years back (see here). Although I'm no expert on the chemical composition of camel milk, there is some evidence to suggest that some of those with a lactose intolerance might be able to better 'tolerate' camel milk [5]. One might envisage similar things where lactose intolerance / lactase deficiency is present in cases of autism too.
• Milk protein structure is another area of possible inquiry. Harking back to some elements of the opioid-excess hypothesis of autism [6] the suggestion is that not all milk protein derived from various mammals is the same. Indeed, even within the same species, milk protein composition might not necessarily be the same [7]. So, would the subtle changes in milk protein (and subsequent peptide formation) be different in camel milk vs. cows milk?
• Interestingly, camel milk is nutritionally different from other forms of milk [8]. When we're talking about higher levels of things like iron or zinc being present in comparison to more typical bovine milk samples, there's always the possibility that this might also have an effect. Having said that iron and calcium for example, aren't necessarily good bed-fellows...
• The very interesting paper by Yang and colleagues [9] describing the proteomic analysis of various types of milk, placed camel milk in its very own category when it came to the expression of proteins distinct from every other animal milk investigated (cow, goat, buffalo, yak). I might be making mountains out of molehills here but this could be potentially important. I could spend all night listing the correlations being made from GABA to phospholipids. Take yer pick... Oh, and on the topic of GABA, I'll also direct you some other recent preliminary research from some of the authors of the camel milk trial (see here).

Science is science, and whether or not you believe that camel milk or any other alternative to regular cow milk might be able to exert an effect on at least some cases of autism, this is nevertheless a potentially interesting area of autism research. Complimentary perhaps to some of the other dietary intervention research that has been done (see here) but with the added bonus that, if found to be effective in larger scientific trials, exclusion of milk may not be as daunting a prospect as it is currently for many people with autism.

So the question remains, one hump or two?

And since we're on the topic of camels and the very soft connection with Egypt, I leave you with a song about walking [like an .....] by the Bangles.

----------

[1] Bashir S. & Al-Ayadhi L. Effect of camel milk on Thymus and Activation-Regulated Chemokine (TARC) in autistic children: double blind study. Pediatr Res. 2013 Dec 27. doi: 10.1038/pr.2013.248.

[2] Al-Ayadhi LY & Elamin NE. Camel Milk as a Potential Therapy as an Antioxidant in Autism Spectrum Disorder (ASD). Evid Based Complement Alternat Med. 2013;2013:602834.

[3] Adams CM. Patient report: autism spectrum disorder treated with camel milk. Glob Adv Health Med. 2013 Nov;2(6):78-80.

[4] Al-Ayadhi LY. & Mostafa GA. Elevated serum levels of macrophage-derived chemokine and thymus and activation-regulated chemokine in autistic children. J Neuroinflammation. 2013; 10: 72.

[5] Cardoso RR. et al. Consumption of camel's milk by patients intolerant to lactose. A preliminary study. Rev Alerg Mex. 2010 Jan-Feb;57(1):26-32.

[6] Shattock P. & Whiteley P. Biochemical aspects in autism spectrum disorders: updating the opioid-excess theory and presenting new opportunities for biomedical intervention. Expert Opin Ther Targets. 2002 Apr;6(2):175-83.

[7] Kamiński S. et al. Polymorphism of bovine beta-casein and its potential effect on human health. J Appl Genet. 2007;48(3):189-98.

[8] Sawaya WN. et al. Chemical Composition and Nutritional Quality of Camel Milk. J Food Sci. 1984; 49: 744-747.

[9] Yang Y. et al. Proteomic Analysis of Cow, Yak, Buffalo, Goat and Camel Milk Whey Proteins: Quantitative Differential Expression Patterns. J Proteome Res. 2013 Mar 25.

-----------

Bashir S, & Al-Ayadhi L (2013). Effect of camel milk on Thymus and Activation-Regulated Chemokine (TARC) in autistic children: double blind study. Pediatric research PMID: 24375082

Functional GI issues and autism: not just an accumulation of case reports?

I've taken my time in posting this entry specifically dedicated to the paper by Virginia Chaidez and colleagues* which "puts to rest the idea that gastrointestinal problems among children with autism spectrum disorder are just an accumulation of case reports" according to one of the paper authors (see here). It's not that I don't see these findings to be absolutely fascinating, but rather that I wanted the research dust to settle a little before I added my [inflation adjusted] 10 pence worth of commentary.

Connecting the dots? @ Wikipedia  

Whilst receiving some media exposure at the time of publication, the Chaidez paper was slightly over-shadowed by another potentially interesting autism development published at a similar time by Warren and Klin (briefly discussed in a previous post) looking at eye gaze in young infants.

I suppose it's to be expected that chatter about [potential] novel early markers for autism will garner more headlines that the mundane task of scientific replication. Indeed, replication is once again the name of the game when it comes to the Chaidez paper, building on quite a bit of previous research suggesting that functional gastrointestinal (GI) issues can and do appear alongside quite a few cases of autism.

The details of the Chaidez paper are pretty straight-forward insofar as asking parents of children involved in the CHARGE study (beincharge!) to report on their children's behaviour and bowel activity via a couple of questionnaires (the Aberrant Behavior Checklist and the CHARGE Gastrointestinal History Questionnaire (GIH)). According to the study press release, the CHARGE GIH questionnaire "measures such disorders as abdominal pain, diarrhea, constipation and difficulty swallowing" but as yet I've not been able to find out too much about it's content validity and reliability within the peer-reviewed domain. Since I've mentioned CHARGE, I'll also draw your attention to some interesting research on air pollution and autism which I'll be posting about fairly soon.

Anyhow, based on responses from just shy of 1000 participants spread across categories of autism spectrum disorder (ASD) diagnosed, developmental delay (DD) diagnosed and typically-developing (TD), the results corroborate quite a lot of previous research undertaken in this area: "Compared to TD children, those with ASD [aOR 7.92 (4.89-12.85)] and DD [aOR 4.55 (2.51-8.24)] were more likely to have at least one frequent GI symptom". Functional bowel issues do seem to be more commonly reported in cases of ASD (and DD) compared with asymptomatic controls. A shocker, I know. Oh and just in case I have to say it again, parental reports of offspring GI complaints in relation to autism are actually quite sensitive as per the findings by Gorrindo and colleagues**.

There are some other very interesting details also discussed in the Chaidez paper and commentary which are worthy of comment. A long quote for you: "The researchers said that the study suggests that a chronic GI symptom, which can cause pain, discomfort and anxiety, could contribute to increased irritability and social withdrawal, particularly in children with deficits in social and communication skills. For children with autism, hyperactivity and repetitive behaviors may represent coping mechanisms for physical discomfort".

It's not rocket science to understand that having a functional bowel issue, or perhaps even something more pathological, which may impinge on a persons quality of life and may even cause some significant amount of physical and psychological distress, is probably going to [variably] show on a person's day-to-day behaviour. I think back to the paper by Kushak and colleagues*** (which was discussed in this post) on lactose intolerance in cases of autism and their quote: "Lactase deficiency not associated with intestinal inflammation or injury is common in autistic children and may contribute to abdominal discomfort, pain and observed aberrant behavior". I've used food as the example to highlight this issue but am not as yet, making any connection with those issues identified by Chaidez et al. Indeed, in a similar vein, I'm also brought back to the findings of Micah Mazurek and colleagues which talked about gut issues being potentially linked to anxiety and sensory issues in relation to autism as further evidence for that gut-brain or rather gut-behaviour relationship. The important mention that autism is rarely, in ESSENCE, a stand-alone condition is also worthwhile reiterating here.

You can probably tell that I'm pretty much sold on the idea that digestive issues can and do appear with greater frequency alongside cases of autism. This finding now being replicated quite a few times in the peer-reviewed arena and across different geographical boundaries. I hold off from saying this is a universal issue across all autism because the data don't point to that, and universals tend to be few and far between when it comes to the autisms. Perhaps GI issues form a part of one or more particular 'types' of autism?

As per yet another quote about the Chaidez paper: "The researchers did not address the reasons why the children with autism and developmental delay experienced more GI difficulties in this study. They noted that their findings suggest that the subject warrants additional inquiry". To me this then represents the important next step in this area of investigation. We know for example, that children with autism are more likely to experience problem issues in relation to food and feeding habits (see here and here). Research is also starting to appreciate that physical activity levels are also an important area of further investigation in relation to autism (see here) which might also impact on such GI issues.

After that it starts to get a little bit more 'interesting'. Are such issues a manifestation of problems with specific food groups? Gluten, casein or something more general like carbohydrates and their metabolism (see here)? Are there other factors which might be implicated in the presentation of such GI issues, bearing in mind this could be genetic factors and possibly even more environmentally-based factors? With all the quite detailed information available to the various research groups about cohorts such as those involved in CHARGE, the possible answers are already locked in the available data.

Without giving any medical or clinical advice, if readers need any further information about this topic, you are directed to your healthcare provider and the various evidence-based guidance on the subject**** (open-access). The commentary from Dr Tim Buie on the Chaidez study also contains some nuggets of information which readers might find useful (see here). And if readers are so inclined, another big name in GI issues and autism - Prof. Simon Murch - is talking at the NAS 2014 Professional Conference here in the UK (see here). One to see I'd say.

----------

* Chaidez V. et al. Gastrointestinal Problems in Children with Autism, Developmental Delays or Typical Development. J Autism Dev Disord. 2013 Nov 6. [Epub ahead of print]

** Gorrindo P. et al. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012 Apr;5(2):101-8.

*** Kushak RI. et al. Intestinal disaccharidase activity in patients with autism: effect of age, gender, and intestinal inflammation. Autism. 2011 May;15(3):285-94.

**** Buie T. et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics. 2010 Jan;125 Suppl 1:S1-18.

----------

Chaidez V, Hansen RL, & Hertz-Picciotto I (2013). Gastrointestinal Problems in Children with Autism, Developmental Delays or Typical Development. Journal of autism and developmental disorders PMID: 24193577

Fructose and lactose intolerance are common and frequently overlap in FGID

The title of this post is a quote taken from the paper by Clive Wilder-Smith and colleagues* (open-access) who reported that issues with the metabolism of the short chain carbohydrates (sugars) fructose found in fruits and lactose found in milk and dairy products may very well be common in functional gastrointestinal disorder (FGID).

Soup again! @ Wikipedia 

I was interested in this paper on two levels.

First is a passing interest in all things FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) and some potential relationship to cases of FGIDs specifically with irritable bowel syndrome (IBS) in mind**. Indeed, I've passed mention about this on a previous post on a sister blog (see here).

Second is, as those who read this blog regularly (thank you!) might know, my interest in all things comorbidity with the autisms in mind. Specifically that growing body of evidence (peer-reviewed of course) suggesting that gastrointestinal (GI) issues might be present in a fair few cases of autism (see here). That and the links suggested between such GI issues and reports of various dietary links (see here).

Certainly on that last point, I'm entertaining the possibility that where clinician-defined FGID (constipation, diarrhoea, even IBS) is found in cases of autism  one might be so inclined to enquire whether there may be issues with fructose and lactose also comorbid.

Just in case you're thinking that I'm getting a little ahead of myself with such speculation, I should point out that: (a) autism is seemingly protective of nothing when it comes to comorbidity and (b) certainly on the issue of lactose, and in particular lactose intolerance, there is more than one study suggesting issues to be present in cases (see here) and perhaps even issues more generally with carbohydrate metabolism as per the 'game-changer' work of Brent Williams and colleagues (see here) and subsequent others (see here). At the very least there is a study there waiting to happen. Fructose by the way, has also been mentioned with autism in mind albeit rather speculatively (see here).

Just before I go there were a few other pertinent points to take from the Wilder-Smith study. "Dietary modification based on fructose and lactose intolerance testing was clearly beneficial". In other words, when it came to the presentation of FGIDs, for those who were shown to be "sugar" intolerant, there was quite a bit of relief reported. Interesting too that the authors talk about an "elevated prevalence of non-GI functional syndromes" to accompany FGID - with fatigue being the most commonly reported in their cohort. One could interpret this in several ways including taking some inspiration from the name of the author's research group  - the Brain-Gut Research Group - and perhaps even some overlap into other conditions too (see here).

I could also go on about gut bacteria and gut hyperpermeability also mentioned in the paper, but to save me getting too obsessed with these areas, I'll stop right there apart from reiterating that no medical or clinical advice was offered or intended in this blog post.

Music to close: I've linked to this record before but it is a classic so worth again a link... Buddy Holly by Weezer (including The Fonz dancing - what a mover!).

----------

* Wilder-Smith CH. et al. Fructose and lactose intolerance and malabsorption testing: the relationship with symptoms in functional gastrointestinal disorders. Aliment Pharmacol Ther. 2013 Jun;37(11):1074-83. doi: 10.1111/apt.12306.

** Shepherd SJ. et al. Short-Chain Carbohydrates and Functional Gastrointestinal Disorders. Am J Gastroenterology. 2013; 108: 707-717.

----------

Wilder-Smith CH, Materna A, Wermelinger C, & Schuler J (2013). Fructose and lactose intolerance and malabsorption testing: the relationship with symptoms in functional gastrointestinal disorders. Alimentary pharmacology & therapeutics, 37 (11), 1074-83 PMID: 23574302

Gastrointestinal comorbidity for World Autism Awareness Day

Today (Tuesday 2 April 2013) is World Autism Awareness Day (WAAD).

I don't exactly know how one is supposed to communicate this message ('Happy world autism awareness day' just doesn't roll off the tongue). So I guess all I will say is to reiterate the subtext of this blog on what the spectrum - the very wide spectrum - means: "To some it means a need for life-long support. To others it is part of the varied tapestry of humanity. To all it means a need to foster a welcoming society with appropriate support and opportunities."

Onwards. Having discussed the latest paper from Drs Stephen Walker and Arthur Krigsman on bowel pathology in cases of autism potentially denoting a distinct condition from other inflammatory bowel diseases and stumbling upon the paper by Peeters and colleagues* on functional defecation disorder and autistic traits, I thought it appropriate to pop into the DeLorean and revisit a paper which never really received the recognition it deserved.

The subject matter for today is the paper by Karoly Horvath and colleagues** published in 1999 as we begin another trip down the autism research memory lane, same as I did when covering the the Mary Goodwin paper from 1971 on the gut-brain axis and autism (see here) and the John Money autism and autoimmunity paper also from 1971 (see here).

Hadrian's Wall @ Wikipedia  

Remember my name
The name Karoly Horvath will probably be familiar to quite a few people who've been on the autism research scene for a while. Another of Dr Horvath's papers*** created a bit of stir a while back based on some very preliminary findings on the use of the digestive hormone, secretin for cases of autism.

Following some initial reports of "transient, marginally significant improvements in autistic behaviors" in some cases as per studies like the one from Coniglio and colleagues****, a whole slew of subsequent trials have painted a rather less positive picture on the use of secretin for autism as per the review by Krishnaswami and colleagues***** (open-access) which quite emphatically stated that "secretin as a treatment approach for ASDs warrants no further study".

I'm not one to normally challenge paper conclusions - particularly systematic reviews - but will perhaps contrast that quote with the closing remarks made by the Cochrane Library review of Williams and colleagues******. They left the secretin research door slightly ajar for those who were potentially able to  identify "important subgroups of children with ASD who could benefit from secretin because of a proven link between the action of secretin and the known cause of their ASD, or the type of problems they are experiencing". I'm a great believer in subgroups when it comes to autism, or rather the autisms, and how a diagnosis of autism is seemingly protective of nothing when it comes to other conditions/states, so you can perhaps assume which quote was my preference.

Factoids
Anyhow, back to the Horvath 1999 paper. A few interesting factoids from their report:

• Thirty-six children all diagnosed with an autism spectrum disorder (ASD), mean age 5.7 years, formed the participant group. Children were all referred to the gastroenterology (GI) clinic where the authors worked following the presence of various GI symptoms ranging from abdominal pain to chronic diarrhoea and various other presentations.
• As well as quite a bit of review of participants' medical history, various clinical investigations were undertaken which included a "full upper gastrointestinal workup", analysis of digestive enzyme function in the small intestine and some histological examination.
• Results: quite a few important findings. Reflux esophagitis was present in nearly 70% of participants (25/36). Chronic inflammation of the gastric mucosa was determined in 15 children. Reduced disaccharidase activity was present in approximately 60% of children, and in particular low lactase levels. Following administration of secretin, participants with autism and diarrhoea comorbid showed signs of increased pancreatico-biliary fluid output potentially indicative of "upregulation of the secretin receptors" itself potentially related to "either a defect in secretin production or a problem of release from the intestinal S cells".
• "There was no evidence of either fungal or bacterial overgrowth in the duodenum" was another finding.

I know there is a lot to take in from those results so I'm going to try and put them into some kind of perspective with some of the other related literature in the peer-reviewed domain.

Lactose intolerance
I'll start with the disaccharidase activity side of things. The Horvath results were in some respects ahead of their time with their findings in this area. I've talked previously about the Rafail Kushak paper and their findings of the frequency "of lactase deficiency was 58% in autistic children ≤ 5 years old and 65% in older patients". Notice the similarity in the percentages between Horvath and Kushak. Indeed, this whole area of carbohydrate malabsorption present in cases of autism was very nicely continued by the Brent Williams paper looking at enzyme activity and autism. I know a few people have talked about how some of these findings might overlap with for example, the various reports on the use and effectiveness of a gluten- and casein-free (cereal grains and mammalian dairy free) diet in some cases of autism. Certainly, I wouldn't rule out a possible overlap to account for any results.

Reflux and GERD
Gastroesophageal reflux and reflux esophagitis - states pertaining to inflammation of the esophagus - were also commonly reported in the participant group and indeed also correlated with various behavioural manifestations noted in some cases (nighttime wakening, signs of irritability, abdominal discomfort) which are "typically reported by non-autistic children with esophagitis". A little reading around this topic suggests that many cases of such esophagitis are tied into things like GERD - gastroesophageal reflux disease - which is basically about stomach acid rising up instead of staying where it should be and causing damage. That being said, other explanations have also surfaced to potentially account for the damage done during GERD (see the paper by Souza and colleagues*******) highlighting a possible role for cytokines in this process. I'm also conscious of the findings of eosinophilic esophagitis being reported in individual cases of autism (see here). In terms of management options and without heading down any medical advice giving path, I was very interested to see a body of work appearing supporting the use of baclofen for cases of GERD********, a derivative of which - arbaclofen - has recently been touted as a potential intervention option for cases of autism. One has to wonder whether kum-ba-arbaclofen might be doing so much more than just affecting GABA receptors?

I'm going to stop there with the Horvath paper and its quite important observations. Once again it is a good example of how, just because we see a rising tide of new findings on autism or any other condition or state, we shouldn't neglect the older literature (published pre-social media) and the valuable insights that it has provided. Indeed, I am going to champion the paper by Horvath et al as an important one; particularly when it came to the assessment of carbohydrate digestive enzyme activity because it was truly ahead of its time and very possibly something that you might hear more about in the coming years of autism research.

Importantly for WAAD, the Horvath paper is a stark reminder that awareness of the autism spectrum should extend beyond just the triad (very soon to be dyad) of core symptoms and into the range of often very pronounced comorbidities which can also exist and affect quality of life. And just in case you need a more recent example of this, have a look at this paper from Francisca van Steensel and colleagues********* (open-access) and their findings on the over 50% rate of psychiatric comorbidity reported in their pediatric cohort. Their focus on 'anxiety disorders' does not need any more chatter from me.

To close, something musically, a little more contemporary. Bruno Mars and Locked Out Of Heaven.

----------

* Peeters B. et al. Autism spectrum disorders in children with functional defecation disorders. J Pediatr. March 2013.

** Horvath K. et al. Gastrointestinal abnormalities in children with autistic disorder. J Pediatr. 1999; 135: 559-563.

*** Horvath K. et al. Improved social and language skills after secretin administration in patients with autistic spectrum disorders. J Assoc Acad Minor Phys. 1998; 9: 9-15.

**** Coniglio SJ. et al. A randomized, double-blind, placebo-controlled trial of single-dose intravenous secretin as treatment for children with autism. J Pediatr. 2001; 138: 649-655.

***** Krishnaswami S. et al. A systematic review of secretin for children with autism spectrum disorders. Pediatrics. 2011; 127: e1322–e1325.

****** Williams K. et al. Intravenous secretin for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2012; 4: CD003495.

******* Souza RF. et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology. 2009; 137: 1776-1784.

******** Cossentino MJ. et al. Randomised clinical trial: the effect of baclofen in patients with gastro-oesophageal reflux - a randomised prospective study. Aliment Pharmacol Ther. March 2012.

********* van Steensel FJA. et al. Psychiatric comorbidity in children with autism spectrum disorders: a comparison with children with ADHD. J Child Fam Stud. 2013; 22: 368–376.

----------

Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, & Tildon JT (1999). Gastrointestinal abnormalities in children with autistic disorder. The Journal of pediatrics, 135 (5), 559-63 PMID: 10547242