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.

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[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.

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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

Stability and trajectories in childhood autism

A quote to begin this post taken from the paper by Patricia Towle and colleagues*: "approximately 20% no longer had ASD diagnoses". The background to this observation was a study utilising a "chart abstraction protocol" to examine the longitudinal presentation of autism and in particular, "establishing a rate of diagnostic stability for school-aged children diagnosed with ASD early".

Keep calm and... @ Wikipedia

Stability, and in particular, the diagnostic stability of autism, is fast becoming an interest of mine. I've talked about it a few times with reference to the continued rush to diagnose autism earlier and earlier (see here) and that rather interesting body of work which suggests that in amongst the various trajectories of autism, one of them might include an "optimal outcome" group of children who move out of the diagnostic boundaries that are autism.

Some details. The Towle paper looked at 80 children who were identified with an autism spectrum disorder (ASD) early; as in before the age of 3 years (16-36 months; Time 1). Parents of some of the children provided various details about their child at a follow-up period (7-16 years; Time 2) in order to ascertain where they were at school age including determining diagnosis. As you've probably realised, determining diagnosis involved a review of the various data available to authors and not a formal face-to-face assessment.

Their results from the various data sources analysed suggested a few things. As per the beginning quote, about 20% of the children went "off the spectrum". That being said the authors also report that "important learning challenges" remained for this group which ties in quite nicely with my recent review of optimal outcome (see here). Off the spectrum did not also imply free of the need for classroom support. Towle and colleagues also reported some interesting trends across their various groupings outside of just those related to the "No ASD/LD" category. That for example, attentional issues were pretty widespread across their cohort with a diagnosis of ASD (whether moderate/severe or mild) is informative. Again without boasting, I have talked about the link between autism and conditions like ADHD, and in particular the question of whether managing attentional issues might have some knock-on effects to the presentation of core behaviours. There are quite a few other important factoids to take from the Towle paper but not for today and not for this post.

Whilst however I'm on the topic of trajectories, I wonder if it might also be worthwhile introducing the paper by Venker and colleagues** and their analysis of trajectories of autism severity based in part on calibrated severity scores derived from the Autism Diagnostic Observation Schedule (ADOS). The long-and-short of it was that based on a group of children diagnosed with an ASD, severity trajectories, four of them, were plotted derived from annual follow-ups using ADOS and other measures. Those trajectories were: persistent high, persistent moderate, worsening and improving.

Venker et al found that 80% of their participant group fell into the persistent high and persistent moderate groupings meaning that for the majority of children, there was "little change in overall severity level during early development". That being said, 14% of their sample were placed in the 'improving' grouping and 6% in the 'worsening' grouping hinting at a more fluidic profile for some children on the autism spectrum.

So, there you have it. Two very different ways of looking at autism: chart abstraction vs. annual formal assessment demonstrating both diversity in developmental trajectories in autism and also at least some degree of instability in terms of presented symptoms for some. Whilst the Venker paper has the upper hand in terms of the use of a formal, objective assessments, it's actually the Towle paper which perhaps gives a bigger picture of autism in terms of their focus on other comorbidity and how it may very much complete the clinical picture of autism. Comorbidity might actually turn out to be pretty important for autism as I've hinted about in other posts.

Oh, and I'll be talking about the Deborah Anderson paper*** fairly soon too so stayed tuned.

To close, the picture included with this post, of the 'Keep calm and carry on' ilk also ties into a recent feature I read about the Minnesota experiment during WW2. If you're really interested, I was also brought to quite an interesting paper on the topic (see here, open-access) (with thanks to Mary Mangan & Jeremy Yoder on G+ for the link).

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* Towle PO. et al. School-Aged Functioning of Children Diagnosed with Autism Spectrum Disorder Before Age Three: Parent-Reported Diagnostic, Adaptive, Medication, and School Placement Outcomes. J Autism Dev Disord. 2013 Dec 18.

** Venker CE. et al. Trajectories of Autism Severity in Early Childhood. J Autism Dev Disord. 2013 Aug 2.

*** Anderson D. et al. Predicting young adult outcome among more and less cognitively able individuals with autism spectrum disorders. J Child Psychol Psychiatry. 2013 Dec 9. doi: 10.1111/jcpp.12178.

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Towle PO, Vacanti-Shova K, Shah S, & Higgins-D'alessandro A (2013). School-Aged Functioning of Children Diagnosed with Autism Spectrum Disorder Before Age Three: Parent-Reported Diagnostic, Adaptive, Medication, and School Placement Outcomes. Journal of autism and developmental disorders PMID: 24346492



Venker CE, Ray-Subramanian CE, Bolt DM, & Weismer SE (2013). Trajectories of Autism Severity in Early Childhood. Journal of autism and developmental disorders PMID: 23907710

Bacterial infections and behaviour

I'm more than a little interested in bacteria on this blog. Indeed, quite a lot of chatter here has been dedicated to the various bacteria residing in our deepest, darkest recesses specifically with conditions like autism in mind. I'm also pretty interested in how other bacteria might also have the potential to do so much more than just affect a physical response. Take the issue of PANDAS (or PANS) as one example or even the notion of psychological development being linked to bacteria (in mice at least). Indeed, this piece in the New Scientist was a particularly interesting read for me (although I prefer the term psychobacteriomics...).

Garden of Earthly Delights @ Wikipedia 

Today's post deals with a triad of papers which are united in their suggestion that infection caused by bacteria may indeed have some important repercussions for conditions such as autism, schizophrenia and psychotic illness. So without further ado...

First we have the paper by Ousseny Zerbo and colleagues* who reported that although no overall "association between diagnoses of any maternal infection during pregnancy and ASD [autism spectrum disorder] was observed" in their cohort, women diagnosed with a bacterial infection during a hospital admission were "at increased risk of delivering a child with ASD". You can read more details about this study in the accompanying press release (see here) or media (see here). I should point out that this authorship group have some research form in the area of infection and autism as per my 'you give me fever' post.

Then we have the paper by Nielsen and colleagues** who, based on quite a large study group, reported that "individuals who have had a hospital contact with infection are more likely to develop schizophrenia". Further that: " Bacterial infection was the type of infection that was associated with the highest risk of schizophrenia (RR = 1.63; 95% CI: 1.47-1.82)".

Finally, the paper by Blomström and colleagues*** completes the triad and their suggestion of "a small but statistically significant association between hospital admissions for infections, in general, throughout childhood (0-13 years) and a later diagnosis of nonaffective psychosis" which "seemed to be driven by bacterial infection".

As you might already have noticed these are studies of association and correlation and so can't necessarily show causality (i.e. that bacterial infection caused autism or schizophrenia or psychotic illness). Indeed, given the complexity and heterogeneity present in these conditions, including quite a lot of chatter about spectrums, it would be foolhardy to pin it down to just one factor as being causative. I should also point out that the relative risk of bacterial infection being linked to autism, schizophrenia or psychosis were also quite low in these studies despite the connections being made.

That being said, the suggestion of a link between behaviour and a history of direct or indirect contact with bacterial pathogens is not something new. I've gone on (and on) about the concept of maternal immune activation and autism for example (see here and here) and the interesting data being generated in this area of investigation culminating with things like MAR autism and the recent leaky mice guts study. That alongside the fact that use of LPS (lipopolysaccharides) is a tool of choice when it comes to modelling bacterial infection on mouse models of autism or schizophrenia (see here). When it comes to specific agents harbouring bacteria, that's also been the topic of some discussion too (see here).

There is more to do in this area in terms of issues like tracking down exactly what types of bacteria might show more involvement in any relationship and the mechanism of effect (Inflammation? A link to those jumping genes?). Indeed, whether certain types of bacterial infection might be more commonly associated with parts of the autism or schizophrenia spectrums as per what we found on two occasions (here**** and here*****) when it came to the parent-reported frequency of impetigo in some cases on the autism spectrum. Just one example of where research might start looking.

Likewise, questions remain about the early treatment of bacterial infections and whether these might modify the risk of future development of the conditions being associated by these studies. Bear in mind however, that the use of antimicrobials (antibiotics) as the treatment of choice have also received some research attention both positive and not-so-positive (see here and here) when it comes to autism and schizophrenia.

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* Zerbo O. et al. Maternal Infection During Pregnancy and Autism Spectrum Disorders. J Autism Dev Disord. 2013 Dec 24.

** Nielsen PR. et al. Hospital Contacts With Infection and Risk of Schizophrenia: A Population-Based Cohort Study With Linkage of Danish National Registers. Schizophr Bull. 2013 Dec 30.

*** Blomström A. et al. Hospital Admission With Infection During Childhood and Risk for Psychotic Illness--A Population-based Cohort Study. Schizophr Bull. 2013 Dec 23.

**** Whiteley P. Developmental, behavioural and somatic factors in pervasive developmental disorders: preliminary analysis. Child Care Health Dev. 2004 Jan;30(1):5-11.

***** Whiteley P. et al. Trends in Developmental, Behavioral and Somatic Factors by Diagnostic Sub-group in Pervasive Developmental Disorders: A Follow-up Analysis. Autism Insights 2009:1 3-17

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Zerbo O, Qian Y, Yoshida C, Grether JK, Van de Water J, & Croen LA (2013). Maternal Infection During Pregnancy and Autism Spectrum Disorders. Journal of autism and developmental disorders PMID: 24366406

The potential impact of DSM-V on autism numbers

I don't really want to get too bogged down with the various discussions which have passed to-and-fro when it came to the expected impact of the introduction of DSM-V on autism prevalence estimates. I couldn't however let the publication of the paper by Matthew Maenner and colleagues* pass by without making some comment on it (or at least directing readers the various comments being made about it: see here and see here).

To summarise the new study: retrospectively apply the new DSM-V criteria for receiving a diagnosis of autism (sorry, autism spectrum disorder) to data pertaining to a cohort of children previously diagnosed with DSM-IV autism and see how much overlap there is. I think back to similar study when it came to comparing even earlier versions of DSM on autism prevalence estimates (see here) and the interesting effects that seemed to have.

The good news from the Maenner study: 81% of those DSM-IV classified as having autism were also DSM-V classified as having autism. Interestingly, also that those with comorbid intellectual disability or with a history of developmental regression were slightly more likely to meet the DSM-V criteria for autism. The not-so-good news: er, what happens to those children who didn't quite reach the DSM-V diagnostic thresholds..? Social communication disorder (SCD)? Well, we don't know yet because SCD wasn't looked at in the current study, and as far as I can ascertain, SCD is still wanting in terms of research into the diagnosis and indeed, outcomes. Just as an aside, I wonder if it might however also cover some of those unusual ICD codes relevant to autism?

Of course, as the various media on this paper point out, this was a study based on case notes or rather "clinician review of coded behaviors documented in children’s medical and educational evaluations" so one has to be a little bit cautious of making too many judgements. According to the Autism Speaks website there is further work coming to publication soon looking at more "in-person diagnostic evaluations" across both DSM-IV and DSM-V (see here). Perhaps some more concrete answers might emerge from that data; hopefully slightly more optimistic than the results from Wilson and colleagues**.

I'm gonna finish with a link to an interesting blog post by Allen Frances, who was previously Chair of the DSM-IV taskforce, titled: "Will the DSM-5 Reduce Rates of Autism?". According to the Maenner results, Dr Frances is correct in his assertion "Yes, by a lot" (or at least by about 20%). The arguments will no doubt rumble on about DSM-V (and don't even mention RDoC).

Update: 27 January 2014. And then came the paper by Kim and colleagues*** and some chatter about their findings. It seems that the SCD diagnostic coding would serve as a catch-all after all, for most of those not fulfilling the DSM-V criteria for ASD. All well and good I suppose but the questions about SCD remain in terms of what a diagnosis will actually mean for access to services and required provisions.

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* Maenner MJ. et al. Potential Impact of DSM-5 Criteria on Autism Spectrum Disorder Prevalence Estimates. JAMA Psychiatry. January 22, 2014. doi:10.1001/jamapsychiatry.2013.3893

** Wilson CE. et al. Comparison of ICD-10R, DSM-IV-TR and DSM-5 in an adult autism spectrum disorder diagnostic clinic. J Autism Dev Disord. 2013 Nov;43(11):2515-25.

*** Kim YS. et al. A Comparison of DSM-IV PDD and DSM-5 ASD Prevalence in an Epidemiologic Sample. Journal of the American Academy of Child & Adolescent Psychiatry. 2014. 23 Jan.

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Matthew J. Maenner, Catherine E. Rice, Carrie L. Arneson, Christopher Cunniff, Laura A. Schieve, Laura A. Carpenter, Kim Van Naarden Braun, Russell S. Kirby, Amanda V. Bakian, & Maureen S. Durkin (2014). Potential Impact of DSM-5 Criteria on Autism Spectrum Disorder Prevalence Estimates JAMA Psychiatry : 10.1001/jamapsychiatry.2013.3893

NICE Quality Standard on Autism published

A very short post to bring to your attention the publication of the Quality Standard on Autism (see here) from NICE (the National Institute for Health and Care Excellence) here in the UK. The press release accompanying publication can be viewed here.

NICE represents the UK (well, most of the UK) attempt at promoting the current and the best in evidence-based medicine when it comes to all manner of health related conditions. Previously they produced initial guidance on 3 strands with autism in mind: (i) pathways to diagnosis for children and young people (see here), (ii) recognition, referral and management for adults on the autism spectrum (see here) and (iii) the management of autism in children and young people (see here). The Quality Standard aims to bring these strands together into a coherent policy also overlapping with the provisions of the landmark Autism Act.

From one point of view, it is indeed a really proud moment that the UK has put pen to paper and published these collected documents. The themes of coordinated services, ensuring appropriate training and competency when it comes to knowledge about autism and including parents and carers in the various decisions made for and on behalf of people with autism are valuable ones. That being said, in this climate of austerity, where cuts are impacting on both finances and services across the board (see here for example) one has to wonder whether these documents will truly positively change the lives of people with autism. Only time will tell...

The gut and 22q11.2 deletion syndrome

A rather peculiar thing seems to be happening in autism research. For years, to make mention that at least some cases of autism might also show involvement of the gastrointestinal (GI) tract would in some quarters, automatically invoke eye-rolling, furrowed brows and in some cases, sanctions. Then, slowly but surely, research started to accumulate suggesting that yes, in at least some cases of autism, GI issues - whether functional or more pathological - do seem to be present and in some cases, over-represented.

Genes not jeans @ Wikipedia 

Last year (2013), details started to emerge about the form those GI issues might take, as per papers like the one from Ludvigsson and colleagues* on the possibility of a non-coeliac gluten sensitivity - type condition potentially being related. Then came the mouse models of autism suggestive of intestinal involvement; first in the maternal immune activated (MIA) model (see here) and then in the valproate model (see here and more recently here**). Talking about GI issues and autism became, well, not so taboo.

Today's post adds to the interest with the findings from Giardino and colleagues*** suggesting involvement of the GI tract in cases of 22q11.2 deletion syndrome, using words like "abnormal intestinal permeability" and "high prevalence of AGA [anti-gliadin] IgA and IgG positivity".

From the beginning: 22q11.2 deletion syndrome or Del22 as Giardino et al call it, is a genetic condition occurring when a small piece of genetic material is deleted from chromosome 22. The q11.2 bit refers to an area on the chromosome, thought to contain about 30 genes, which is affected. Name- and presentation-wise, Del22 is varied and includes both physiological and behavioural pathology (see here with thanks to Robert for the link). The precise nature of any concurrent psychopathology however is still a source of investigation.

Insofar as the autism connection, well autism or the presentation of autistic symptoms, certainly does seem to be a feature of some cases of Del22 as per the paper by Vorstman and colleagues**** for example. The research chatter a few months back about children being misdiagnosed with autism when in fact they presented with Del22 supports this strong link between the two conditions*****.

In their paper, Giardino and colleagues asked some further questions about whether there may be some GI involvement in cases of Del22 based on a suite of different variables: "Plasma levels of hemoglobin, iron, ferritin, albumin, total protein, calcium, phosphorus, transaminase levels, antigliadin (AGA) IgA and IgG, and antitissue transglutaminase (anti-TGase) titers were measured". They found that within their small participant group (N=26) "GI involvement was identified in the 58% of patients" comprising things like abdominal pain and constipation. Further when it came to the presentation of coeliac (celiac) disease, or at least some of the outwards signs and symptoms linked to coeliac disease, the talk was about quite a few of the participants presenting with things like short stature and/or failure to thrive. Oh and "Celiac disease (CD) was suspected in three patients, and in one of them confirmed by histology".

Then comes those words again: "an abnormal intestinal permeability" (yes, leaky gut) alongside the presence of those anti-gliadin antibodies. In short, there appears to be something going on with regards to the gut in quite a proportion of cases of Del22. Commonalities with other research are present particularly implicating an immune response to certain foods.

Now, far be it from to jump to too many conclusions, but it strikes me that we seem to have a pattern emerging in quite a few conditions with an autism link. I assume most people have heard about the gut-brain axis (see here) and how brain and 'second brain' seem to show quite an important connection in at least some presentations of autism. The potential importance of detecting both autism or autistic traits in cases of Del22 alongside other GI related comorbidity in that research has a sort of 'heads-up' in terms of where one might start looking if we're to assume that said GI comorbidity might have a genetic element to it. By saying that, I don't want to imply that all GI comorbidity in relation to autism is purely a result of genetic issues, despite evidence for example from the very important de Magistris paper****** on possible hereditary issues in relation to gut hyperpermeability. But still looking at what might be 'deleted' in cases of Del22 is an obvious starting point.

Assuming that the Giardino findings are replicated, the obvious question is how deep the rabbit hole really goes? Are there other conditions defined by the presence of known genetic findings which present as autism or autistic traits which might also be ripe for inquiry into the presence of GI findings? How about the discovery of that BCKDK phenotype for example, supposedly "treatable" by the branched-chain amino acids? Questions, questions, questions.

Some music to close. How about Björk Guðmundsdóttir and Venus as a Boy?

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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 Nov;70(11):1224-30.

** Kim JW. et al. Gastrointestinal tract abnormalities induced by prenatal valproic Acid exposure in rat offspring. Toxicol Res. 2013 Sep;29(3):173-9.

*** Giardino G. et al. Gastrointestinal involvement in patients affected with 22q11.2 deletion syndrome. Scand J Gastroenterol. 2013 Dec 18.

**** Vorstman JA. et al. The 22q11.2 deletion in children: high rate of autistic disorders and early onset of psychotic symptoms. J Am Acad Child Adolesc Psychiatry. 2006 Sep;45(9):1104-13.

***** Angkustsiri K. et al. Social Impairments in Chromosome 22q11.2 Deletion Syndrome (22q11.2DS): Autism Spectrum Disorder or a Different Endophenotype? J Autism Dev Disord. 2013 Sep 18.

****** de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24.

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Giardino G, Cirillo E, Maio F, Gallo V, Esposito T, Naddei R, Grasso F, & Pignata C (2013). Gastrointestinal involvement in patients affected with 22q11.2 deletion syndrome. Scandinavian journal of gastroenterology PMID: 24344832

Complementary and Alternative Medicine (CAM) use and autism

I want to talk today about the paper by Roger Akins and colleagues [1] and their finding that: "Use of CAM [Complementary and Alternative Medicine] is common in families of young children with neurodevelopmental disorders". I know that this topic has a tendency to furrow brows and roll eyes in some quarters, particularly when written or spoken alongside the word 'autism', so I'm treading carefully with this quite long post. I will also make reference to my oft-cited caveat: no medical or clinical advice is given or intended on this blog.

elixir vitae @ Chemical Heritage Foundation

CAM - not to be mistaken for CAMHS - covers an awful lot of ground when it comes to the range of 'treatment' options available; as the NHS Choices website puts it "treatments that fall outside of mainstream healthcare". Under the CAM umbrella you have a range of procedures and interventions which cover everything from nutrition to mind-body interventions and seemingly everything in between. Views on CAM - the various ideas behind it and it's perceived effectiveness in general - tend to be split as a function of lots of different variables.

I found quite a good overview looking at the main reasons why people tend to use CAM from a cancer care perspective (see here) which I assume can be similarly applied to CAM use for other conditions or ailments too. Specifically with autism in mind, I dare say that the issues of 'feeling more in control' and 'natural and healing therapies' (bearing in mind the continued mis-representation of the word 'chemical') would probably rank high on the list of why CAM enjoys a following. Indeed, other autism research seems to back up some of these assertions [2].

I've been aware of CAM with autism in mind pretty much from the beginning of my research career, and this is certainly not the first time that it's been talked about in the peer-reviewed domain [3] (open-access) with some pretty good reviews of what CAM covers autism-wise [4] (open-access). The fact that I embarked on a research life examining the potential effectiveness of a gluten- and casein-free (GFCF) diet as an intervention for some of the signs and symptoms associated with autism (and possibly some of it's various comorbidities) might even put me in the CAM researcher box. If the truth be known however, I've never been particularly happy with giving the GFCF diet a place under the CAM umbrella, simply because more and more we are seeing peer-reviewed evidence emerging suggestive that food does seem to be implicated in some cases of autism (remembering the 'not quite coeliac disease paper' for example) and, in a similar vein to the condition called PKU, how food may for some people, have effects that go well beyond just a nutritional perspective. Just sayin'.

Anyhow, the Akins paper, which has received quite a bit of media attention (see here and see here and see here), looked at data derived from the CHARGE initiative (beincharge!) which on this occasion asked parents of young children with autism (n=453) or developmental delay (DD) (n=125) what kinds of interventions or therapies had been used to try and affect the presentation of autism, both conventional and falling under the CAM label. They reported that roughly a third of children in both their autism and DD groups were or had used intervention(s) described as CAM.

Some of the most popular interventions reported were those related to nutrition; be that the use of vitamin and mineral supplements or the implementation of a GFCF diet (or combinations thereof). Indeed to quote from one of the media sources on this paper: "Nearly 7 percent of children with autism were on the gluten-free/casein-free diet, particularly children with frequent gastrointestinal problems". Interestingly these interventions alongside the use of things like probiotics were generally considered 'safe' by researchers. Several other interventions were also reported including vitamin B12 injections and the use of chelating agents which have also been talked about on this blog (see here and see here).

One of the first things to pass through my mind upon reading the Akins paper was the parent survey results from the Autism Research Institute (ARI) which asked parents 'what worked for their child with autism' (see here). I know, I know, the ARI document is not peer-reviewed science and subject to all manner of biases including that of potentially bringing out more positive than negative responses for specific interventions, but that was where the Akins paper led me and indeed, how the CAM use results seem to map on to the ARI results.

I personally think autism research can learn a few lessons from the Akins paper from several different perspectives. So:

• When setting the research agenda for autism in terms of where money and resources might be needed, further examination of the safety and efficacy of some of the interventions reported as being used might be a wise move [5]. As I've talked about before on this blog, there is some preliminary evidence that for example, dietary intervention (see here) or the use of vitamin and mineral supplements (see here) might be helpful for some people on the autism spectrum (or for some of the autisms if you prefer), but more study [methodologically stronger and replicative] is required. And some investigators have been trying to get funding for such research [6] for quite a while now...

• Going back to that suggestion that CAM might reflect more 'natural' therapies, I know there is some continued chatter about where CAM fits into the evidence-based medicine (EBM) model which we subscribe to these days. I don't want to get into the quagmire of EBM vs. the power of personal experience, but rather that further study is also required into the possible interactions that such CAM therapies may have with more conventional medicine. Quite a while back I talked about the interaction between fish oil supplements and chemotherapeutics (that is medication used in the treatment of cancer). What this and other studies point out is that your vitamin or nutritional supplement might be currently classified as a food supplement but that does not mean it can't have often quite potent biological effects. And certainly with the medicines cabinet seemingly being used for quite a few people on the autism spectrum (see here), there is scope for lots of potential interactions.

• It was interesting to read that Akins and colleagues examined various correlates which potentially might explain CAM use as opposed to non-CAM use. So, they report that "Families who used >20 [greater than] hours per week of conventional services were more likely to use CAM" which could indicate an issue of either degree of parent involvement or severity of autistic symptoms [7] in the decision to use CAM or not. Interesting too was the focus on "immunization status" as a variable examined with CAM use or non-use in mind and their finding that "Underimmunized children were marginally more likely to use CAM but not more likely to have received potentially unsafe or disproven CAM". I probably don't need to point this out, but this perhaps again might be further evidence for that 'natural vs. synthetic or man-made' issue potentially at the core of CAM use. It also illustrates one possibility why CAM use in autism still resides on the edge of mainstream autism research insofar as the generalised association often [incorrectly] made between certain types of CAM and the issue of vaccination (or rather 'anti-vaccination') [8]. I'm not saying that there isn't alignment between some purveyors of CAM and specific views on issues like vaccination [9], merely that not everyone holds those views and this should not be a barrier to further research on CAM. A little bit like what happens when talking about certain gastrointestinal (GI) issues in relation to autism and the way that conversation sometimes goes....

• The relationship between parents of children with autism and their healthcare providers is also touched upon in the Akins paper and how: "Further research should address how health care providers can support families in making decisions about CAM use". Huang and colleagues [10] recorded a potentially important point when it came to CAM use and autism in their study when indicating: "In children with ASD (the diagnostic group with the highest use of and satisfaction with CAM), physician's perceived knowledge of CAM was lower (14% versus 38%; p<0.05), as was perceptions of the physician's interest in learning more (p<0.05)." It is of course slightly unreasonable to expect every physician to know everything there is to know about CAM, particularly when applied to a condition as complex as autism. But given the age of the Internet and Dr. Google where all kinds of information is available to all, there is perhaps an even greater need for physicians to inform themselves about the ins-and-outs of such interventions and strategies and be able to advise accordingly based on the available evidence. Indeed, some physicians seem to be doing just that [11].

The Akins paper is certainly an interesting one in terms of highlighting how frequent CAM use is when it comes to autism. More than that though, it opens up a variety of discussion points [12] on the medical model, use of EBM, the patient-physician relationship and some of the complexities and politics of autism. That being said, we shouldn't lose sight of the fact that there are probably lots of reasons why parents of children with autism use or don't use CAM; probably in all cases, such decisions arrived at as a consequence of many very individual factors.

What the Akins paper did not address however was the important issue of how effective CAM use was and just as important, how ineffective CAM use was and for whom. This I assume being the next step in the research agenda...?

To close, readers in the UK will probably have heard about the death of Roger Lloyd Pack a.k.a Trigger from Only Fools and Horses. So, here's a theme tune which should bring back a memory of two... Dave.

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[1] Akins RO. et al. Utilization Patterns of Conventional and Complementary/Alternative Treatments in Children with Autism Spectrum Disorders and Developmental Disabilities in a Population-Based Study. J Dev Behav Ped. 2014; 35: 1-10.

[2] Hanson E. et al. Use of complementary and alternative medicine among children diagnosed with autism spectrum disorder. J Autism Dev Disord. 2007 Apr;37(4):628-36.

[3] Levy SE. & Hyman SL. Complementary and Alternative Medicine Treatments for Children with Autism Spectrum Disorders. Child Adolesc Psychiatr Clin N Am. 2008 October; 17(4): 803–ix.

[4] Lofthouse N. et al. A Review of Complementary and Alternative Treatments for Autism Spectrum Disorders. Autism Res Treatment. 2012; 870391.

[5] Anagnostou E. & Hansen R. Medical treatment overview: traditional and novel psycho-pharmacological and complementary and alternative medications. Curr Opin Pediatr. 2011 Dec;23(6):621-7.

[6] 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.

[7] Perrin JM. et al. Complementary and alternative medicine use in a large pediatric autism sample. Pediatrics. 2012 Nov;130 Suppl 2:S77-82.

[8] Gupta VB. Communicating with parents of children with autism about vaccines and complementary and alternative approaches. J Dev Behav Pediatr. 2010 May;31(4):343-5.

[9] Ernst E. Rise in popularity of complementary and alternative medicine: reasons and consequences for vaccination. Vaccine. 2001 Oct 15;20 Suppl 1:S90-3

[10] Huang A. et al. Parental perspectives on use, benefits, and physician knowledge of complementary and alternative medicine in children with autistic disorder and attention-deficit/hyperactivity disorder. J Altern Complement Med. 2013 Sep;19(9):746-50.

[11] Golnik AE. & Ireland M. Complementary alternative medicine for children with autism: a physician survey. J Autism Dev Disord. 2009 Jul;39(7):996-1005.

[12] Committee on Children with Disabilities. American Academy of Pediatrics: Counseling families who choose complementary and alternative medicine for their child with chronic illness or disability. Committee on Children With Disabilities. Pediatrics. 2001 Mar;107(3):598-601.

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Akins, Roger S., Krakowiak, Paula, Angkustsiri, Kathleen, Hertz-Picciotto, Irva, & Hansen, Robin L. (2014). Utilization Patterns of Conventional and Complementary/Alternative Treatments in Children with Autism Spectrum Disorders and Developmental Disabilities in a Population-Based Study Journal of Developmental & Behavioral Pediatrics : http://journals.lww.com/jrnldbp/Abstract/2014/01000/Utilization_Patterns_of_Conventional_and.1.aspx

Gastrointestinal inflammation and immune activation in bipolar disorder

I want to take you back to a post I published back in April 2012 (see here) on some very interesting work coming out of the Stanley Division of Developmental Neurovirology at Johns Hopkins by Dr Emily Severance.

The Railway (Manet) @ Wikipedia 

It was concerned with the discovery that in cases of schizophrenia, measurement of anti-Saccharomyces cerevisiae antibodies (ASCA) revealed possible (probable?) signs of intestinal inflammation at greater levels than controls*.

Alongside, depending on whether onset of symptoms was recent or not and whether specific pharmacotherapy was in place or not, some interesting effects were noted in relation to mounting an immune response to foods specifically containing gluten and/or casein.

I don't mind telling you that I found these results to be absolutely fascinating; in a similar vein to some of the other work by Dr Severance and her collaborators (which includes some pretty high profile research names). As perhaps you'd imagine, I was therefore more than intrigued to read of similar findings published by Dr Severance and colleagues** this time in relation to bipolar disorder which used to be called manic depression.

The research story is quite a similar one to that noted with schizophrenia in mind: look at levels of ASCA - more typically used to differentiate between specific inflammatory bowel diseases - in quite a large group of participants, this time diagnosed with bipolar disorder (with or without recent onset of psychosis), as well as antibody responses to various other food and viral or parasitic agents. And yes, under parasite I do mean 'the gondii' and everything that has been suggested to go along with that.

The results: "Elevated ASCA conferred a 3.5–4.4-fold increased odds ratio of disease association". In other words, one marker of intestinal inflammation may very well be associated with bipolar disorder. That and: "ASCA correlated with food antibodies in both bipolar disorder groups".

I have to say that I'm not overly surprised by that last quote correlating (yes, correlating) food antibodies against gluten and/or casein with intestinal inflammation. That is, if one simplistically assumes that an inflamed gut barrier is probably going to be more porous (leaky...) than a typical non-inflammed barrier (see here***). So y'know... leaky gut, gut contents meeting immune system and antibodies being formed and that needn't just apply to antibodies to the remnants of our diet either (see here).

As for the other results reported in the Severance paper such as elevations in ASCA antibodies also being correlated with "measles and T. gondii immunoglobulin G (IgG) in the recent onset psychosis bipolar disorder group", autism research history tells me it's probably not a good idea to go too far down that path. So I won't; aside that is, from pointing out some related research from the likes of Neibuhr - that's Col. Neibuhr - and colleagues**** who talked about "antibody levels to several combinations of agents, to include casein, measles, CMV, T. gondii and vaccinia, was predictive of an 18-34% increase in the risk of developing schizophrenia".

So then, some cases of schizophrenia and now some cases of bipolar disorder seem to share some non-brain related pathology with a specific focus on inflammation*****, and particularly inflammation of that important barrier in our deepest, darkest recesses. Alongside the suggestion of similar 'issues' potentially being present in cases of autism, quite a collection of conditions are being flagged up with that gut-brain axis in mind. It brings to mind all that common ground talk when it comes to overlapping genes in various 'psychiatric' related conditions (see here) and whether from a gut physiology point of view, this might be a new element to add to the RDoC? I'm just speculatin' of course...

Issues with gut inflammation also raises some potentially important questions about what might happen when inflammatory bowel or barrier issues are treated for example, or indeed when foods potentially linked to that antibody response are removed from the diet (bearing in mind, no medical or clinical advice is given).

And then there are those trillions of bacterial passengers we all carry to consider and any potential effect from them too...

Music then to finish. How about something a little bit tranquil today... Clair de Lune by Debussy, or as being the uncultured man that I am, 'that classical music piece from Ocean's 11'. Toodle pip.

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* Severance EG. et al. Gastrointestinal inflammation and associated immune activation in schizophrenia. Schizophr Res. 2012 Jun;138(1):48-53.

** Severance EG. et al. Seroreactive marker for inflammatory bowel disease and associations with antibodies to dietary proteins in bipolar disorder. Bipolar Disord. 2013 Dec 6. doi: 10.1111/bdi.12159.

*** Hietbrink F. et al. Systemic inflammation increases intestinal permeability during experimental human endotoxemia. Shock. 2009 Oct;32(4):374-8.

**** Li Y. et al. Association between antibodies to multiple infectious and food antigens and new onset schizophrenia among US military personnel. Schizophr Res. 2013 Dec;151(1-3):36-42.

***** Berk M. et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013 Sep 12;11:200.

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Severance EG, Gressitt KL, Yang S, Stallings CR, Origoni AE, Vaughan C, Khushalani S, Alaedini A, Dickerson FB, & Yolken RH (2013). Seroreactive marker for inflammatory bowel disease and associations with antibodies to dietary proteins in bipolar disorder. Bipolar disorders PMID: 24313887

Atopic disease and adolescent psychotic experiences

I was intrigued to read the paper by Khandaker and colleagues [1] (open-access here) reporting results based on a longitudinal study that suggested: "Childhood atopic disorders increase the risk of psychotic experiences in adolescence".

Bish, bash, Bosch @ Wikipedia 

I've talked about the issue of atopic disease and it's potential overlap with something like neurodevelopment before on this blog (see here) based on the possibility of a neuro-immune interaction (i.e. that our immune system might be involved in many more processes than just fighting infection as per the microglia work) as suggested by Meldrum and colleagues [2]. The recent paper from Chang and colleagues [3] reporting a possible connection between allergic disease and behavioural issues in preschoolers adds to that debate. I very much consider the Khandaker findings to be of a similar ilk in terms of potential mechanisms of effect (accepting though that correlation does not necessarily mean causation).

In brief, Khandaker et al followed several thousand children over the course of their trial (data from the ALSPAC cohort which has just received some good news), detailing the presence of atopic diseases such as asthma and eczema of participants at age 10 and any subsequent psychotic experiences at age 13. Various markers linked to inflammation (C-reactive protein and IL-6) were also assessed at age 9. It was then a case of comparing those with atopic disease, whether present singularly or combinatorially, with those without atopic disease on whether the risk of a psychotic episode (PE) was more or less likely. And it was more likely in the atopic group; although strangely enough those markers of inflammatory processes did not seem to "mediate association between atopy and PEs" bearing in mind that inflammatory markers were not seemingly assessed at the time of the PE.

As per the authors findings, I'm not yet able to provide a specific hypothesis to explain the Khandaker findings. I do hark back to my previous chatter about the 'skin-brain axis' for example (see here) as potentially being important although not specifically related to the psychosis findings. The accompanying literature on psychocutaneous disorders [4] "conditions that are characterized by psychiatric and skin manifestations" may very well be something of a research focus to account for at least the proposed eczema - PE link.

With regards to asthma, well there is the suggestion from Moreno and colleagues [5] that asthma was one of a number of conditions "more frequent in individuals with psychotic symptoms but no psychosis diagnosis" but again, comparatively little to suggest a mechanism of connection outside of individual case reports on steroid medication for example (used for some cases of asthma) being linked to the presence of psychotic episodes [6]. I could be really speculative and talk about physiological mechanisms other than atopy potentially linked to such somatic and psychiatric symptoms such as that encompassed by the body of work looking at dietary elements [7] (and this paper by Faith Dickerson and colleagues [8]) but don't want to get ahead of myself given the lack of testing for such parameters in the Khandaker paper.

What however we can take from the Khandaker results is that a possible connection between somatic and psychiatric symptoms should remain an important area of research particularly with regards to shared genetics, epigenetics or biological markers. Perhaps also that more emphasis should be placed on screening for psychotic episodes and related conditions in cases where atopy is present. The tantalising question of whether treating somatic symptoms might have a potential knock-on effect on psychiatric symptoms or vice-versa also remains, as for example, per the recent update on the use of anti-inflammatory agents for schizophrenia by Sommer and colleagues [9]. There doesn't at the moment appear to be an awful lot of research on the potential usefulness of antihistamines (H1-receptor antagonists) commonly used to treat allergic disorders, in cases of psychosis or conditions manifesting psychosis. When however it comes to H2-receptor antagonists and accepting that these medicines are not generally viewed as antihistamines, I am drawn to the chatter about famotidine and schizophrenia [10] for example, something which I think was also mentioned with regards to autism at one point [11] and seemingly never heard of again. So, with no medical advice given or intended, there's still quite a bit more research to do in this area.

To close, having watched the recent BBC4 documentary about The Doors and really appreciating the musical talent they were, a classic: Riders on the Storm... sit back and enjoy.

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[1] Khandaker GM. et al. A population-based study of atopic disorders and inflammatory markers in childhood before psychotic experiences in adolescence. Schizophr Res. 2013 Nov 21. pii: S0920-9964(13)00520-3. doi: 10.1016/j.schres.2013.09.021.

[2] Meldrum SJ. et al. Allergic disease in the first year of life is associated with differences in subsequent neurodevelopment and behaviour. Early Hum Dev. 2012 Jul;88(7):567-73. doi: 10.1016/j.earlhumdev.2011.12.032.

[3] Chang HY. et al. Allergic diseases in preschoolers are associated with psychological and behavioural problems. Allergy Asthma Immunol Res. 2013 Sep;5(5):315-21.

[4] Al Hawsawi K. & Pope E. Pediatric psychocutaneous disorders: a review of primary psychiatric disorders with dermatologic manifestations. Am J Clin Dermatol. 2011 Aug 1;12(4):247-57.

[5] Moreno C. et al. Psychotic symptoms are associated with physical health problems independently of a mental disorder diagnosis: results from the WHO World Health Survey. World Psychiatry. 2013 Oct;12(3):251-7.

[6] Lee KM. et al. Steroid-induced acute psychosis in a child with asthma: report of one case. Acta Paediatr Taiwan. 2001 May-Jun;42(3):169-71.

[7] Karlsson H. et al. Maternal antibodies to dietary antigens and risk for nonaffective psychosis in offspring. Am J Psychiatry. 2012 Jun;169(6):625-32.

[8] Dickerson F. et al. Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia. Biol Psychiatry. 2010 Jul 1;68(1):100-4.

[9] Sommer IE. et al. Efficacy of Anti-inflammatory Agents to Improve Symptoms in Patients With Schizophrenia: An Update. Schizophr Bull 2014; 40: 181-191.

[10] Martinez MC. Famotidine in the management of schizophrenia. Ann Pharmacother. 1999 Jun;33(6):742-7.

[11] Linday LA. et al. Famotidine treatment of children with autistic spectrum disorders: pilot research using single subject research design. J Neural Transm. 2001;108(5):593-611.

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Khandaker GM, Zammit S, Lewis G, & Jones PB (2013). A population-based study of atopic disorders and inflammatory markers in childhood before psychotic experiences in adolescence. Schizophrenia research PMID: 24268471

The gut microbiome and autism... so far

A micropost if you will, to provide readers with a link to the paper by Xinyi Cao and colleagues* (open-access) reviewing where autism research is up to when it comes to those trillions of beasties - the various gut bacteria - which call our deepest, darkest recesses home.

Regular readers probably already know about my borderline obsession with the gastrointestinal tract (gut) and its inner workings when it comes to at least some cases of the autisms and how the gut microbiome represents a potentially valuable new research frontier for lots of different states and conditions.

The paper by Cao et al lists just about everything, research-wise, related to the analysis of gut bacteria pertinent to autism up to October 2013, with all the big players so far included - from Williams (see here) to Wang (see here) and lots in-between. The final conclusions are a familiar one: more research needed and a requirement to ensure that "confounding variables" are controlled for as best they can be. Of course, as is common in research, one might argue that the Cao paper is already out of date given for example, the replication of that Sutterella finding by Wang and colleagues (see here). And slightly outside of studies of looking at gut bacteria in real people, there is the emerging evidence from mouse models too (see here) which sparked talk about probiotics and the feasibility of trying to alter gut bacterial arrangements**. I'm not yet entirely convinced about this probiotic method in the longer-term but alongside other suggestions (see here) will be keeping my research eyes open for any trial results.

A final quote to leave you with: "There does, however, appear to be a ‘signal’ suggesting significant differences in the GI microbiome between ASD [autism spectrum disorder] children and children without ASD, so there would be value in continuing this line of research". I can't argue with that.

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* Cao X. et al. Characteristics of the gastrointestinal microbiome in children with autism spectrum disorder: a systematic review. Shanghai Archives of Psychiatry. 2013; 25: 342-353.

** Critchfield JW. et al. The potential role of probiotics in the management of childhood autism spectrum disorders. Gastroenterol Res Pract. 2011;2011:161358.

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Xinyi CAO, Ping LIN, Ping JIANG, & Chunbo LI (2013). Characteristics of the gastrointestinal microbiome in children with autism spectrum disorder: a systematic review Shanghai Archives of Psychiatry Other: http://www.saponline.org/upload/2013/1231/342.pdf