Gender, autoimmunity and autism

With all the challenges facing autism research in terms of the heterogeneity of the condition, the increased likelihood of certain comorbidity and the lack of objective markers (despite some good efforts), a touch of blue-sky thinking is often required. So for example, appreciating that there may be subgroups of people diagnosed with an autism spectrum condition who present with common issues as per the up-coming area of endophenotypes or looking at possible commonalities outside of the immediate parameters of the condition for potential clues about the condition, bearing in mind the correlation-is-not-causation motif.

With such sentiments in mind I'd like to talk about some speculative but interesting thoughts from this paper by Kevin Becker* on the male gender bias in autism and pediatric autoimmunity. I have had some contact with Dr Becker about this and his other papers** and he is interested to see what opinions there are about some of the ideas he is expounding. Viewers, after reading this, please do opine.

Before progressing through the paper, Dr Becker has quite a publication record in autism and other areas as evidenced by papers such as this one on autism, asthma, immunity and the hygiene hypothesis (full-text) and this one on autism, asthma and paracetamol (acetaminophen) use (full-text), both of which approach areas near to my research heart. This paper (full-text) on the tight junction protein, claudin 7 also caught my eye in view of my interest in the extra-intestinal effects of gut permeability (see here) as did this paper (full-text) on that most lovable tryptophan hydroxylase. Do I even need to mention reference to the science of epigenetics (full-text) or are you getting bored of that already?

Enough of the appreciation society comments and onwards to the current paper:

• As per previous mentions, the often quite startling gender differences skewed towards males is one of the more defining characteristic of autism spectrum conditions (not including Rett syndrome). One could therefore suggest that this sex ratio difference might be a good place to start in research terms for quite a few people on the autism spectrum.
• Autoimmunity has also had more than a passing interest in relation to some cases of autism (remember this post) and in particular the coincidence of various autoimmune conditions in cases of autism - and their families - such as diabetes (type 1) for example. 
• Becker hypothesises on some connection between the male bias in both presentation of autism and pediatric autoimmune conditions and the possibility of some shared aetiological features. His evidence is multi-fold but includes: (a) autoimmune conditions normally come in packs as per the suggestion on the recent psoriasis post remembering the possibility of a relationship between autoimmunity and autism, (b) you may well be saying to yourself that autoimmune conditions in general tend to favour females rather than males so how could there be a connection? Well you'd be half right because adult presentation is often more frequent in females. The same however does not necessarily apply to pediatric presentation where roles seem to be reversed and males are perhaps the more fragile gender. Becker presents quite a bit of data to support a variable male skewing of rates of some autoimmune conditions in pediatric cohorts, (c) hormones inevitably get a mention and the testosterone-autism link including the recent RORA findings, (d) remembering the chromosomal makeup of males compared to females, the X chromosome also comes into view and various research on how issues with the X chromosome might similarly impact on both autism and various autoimmune conditions.

There are some interesting ideas in the paper which make a lot of sense. The focus on hormonal issues during pregnancy affecting subsequent offspring function is a trendy area for autism research at the moment and follows quite a few other papers in looking at this sensitive period such as the vits & SNPs research publication.

Having said that the suggestions are still speculative and perhaps require further study in a real-world setting. So, things like comparisons between male and female children both with and without autism (and/or learning disability, speech & language disorder, even the BAP) in terms of autoimmune comorbidity, more detailed inspection of some of the underlying genetic findings overlapping between the two sets of conditions importantly controlling for other comorbidities as well, and perhaps even introducing a little more epigenetics into proceedings bearing in mind that your genes might not necessarily be your destiny. Going back to the whole endophenotypes thing, I also wonder about the involvement of things like the MET gene work and any differences in early presentation (i.e. regression) as potentially important factors. Noting also that as per the example of the autoimmune condition, coeliac (celiac) disease, genetic predisposition also often requires an environmental counterpart for the disease to become fully evident. Dr Becker's paper on SES, autoimmune disease and autism** kinda hints at something similar with some discussion on the hygiene hypothesis and how we might actually need that environmental exposure in some cases.

While writing this post, I was taken back to another researcher with an interest in the genetics of the immune system with autism in mind, the late Reed Warren, and his papers going back 20+ years now on things like the C4B null allele and various studies on other immune-related functions in autism. I'd like to think that we have come some way in the intervening period in terms of technology, methods and realisation at just how complicated our genes and immune system are both with autism and the more general population in mind.

Granted we aren't really any nearer to identifying the underlying issues as to why autism presents and sometimes presents alongside autoimmune conditions, but I suppose at least it is now generally recognised that autism can present alongside issues with immune function and those issues might, just might, be one key to knowing a little more about some of the aetiology and nature of autism.

* Becker KG. Male gender bias in autism and pediatric autoimmunity. Autism Research. March 2012.
DOI: 10.1002/aur.1227

** Becker KG. Autism, autoimmune disease and socioeconomic status. Autism - Open Access. March 2012.
DOI: 10.4172/2165-7890.1000104

Six developmental trajectories, autism and bloomers

"If you've met one person with autism, you've met one person with autism" is how the saying goes. Heterogeneity is a keyword accompanying most descriptions of autism spectrum conditions; that and the fact that comorbidity is a mighty complex thing when it comes to presentation and interaction with core autism features.

Enter then a study by Christine Fountain and colleagues* (full-text) and the suggestion that from diagnosis in early infancy to aged 14 years old, children with autism spectrum conditions are likely to fall into one of six developmental trajectories related to their symptom presentation and progression. Perhaps even more surprising is the suggestion that within one of these trajectory groups, about 10% of children experience "rapid gains", blooming and outgrowing their severe disabilities by adolescence according to some of the media reports. Interesting isn't it?

The paper is open-access but here is a short summary of the findings:

• Group based trajectory modelling was carried out based on the core triad of symptoms for 6975 children with autism identified through the California Department of Developmental Services (DDS) records.
• Core symptoms of autism were assessed based on a Client Development Evaluation Report (CDER) which whilst not diagnostic for autism, has items covering the domains of communication, social interaction and repetitive behaviours. Several CDERs for each participant provided a longitudinal measure of how symptoms developed over time.
• Six groups were modelled from the cumulative data and grouped high to low based on functioning within the triad of domains.
• The results: based on the CDER scores for the communication domain, all groups showed an improvement in communicative function at 14 years compared with 2-3 year old baseline scores. Where you started in terms of 'functioning' seemed to determine where you ended up: more able children finished with better scores at study end. This was true aside from one group, termed 'bloomers', who showed some quite astonishing improvements in communicative function crossing over other group profiles and peaking at the time puberty would be expected before plateauing slightly. Same scenario for the social area trajectory. Group scores for repetitive behaviours were less uniform, with several groups actually showing a greater frequency of such behaviours over time and maturation as per other studies (here and here).
• There was some noticeable heterogeneity between participants and groups and intellectual / learning disability also seemed to play a hand in outcome.
• What were the characteristics of 'bloomers'? Well, generally-speaking, aside from presenting with quite severe problems in communicative and social areas at an early age, they were more likely not to have intellectual disability comorbid and perhaps have mothers who were white and quite well-educated. I'm not totally impressed by these last socio-economic factors and their involvement, but can perhaps see why they might be included in the analysis.

As the authors note, this study is a bit of a first in that it collected lots of consistently-derived data over quite a long period of time charting childhood for quite a lot of children diagnosed with autism. Following on from another quite recent paper asking about whether it is possible to grow out of autism, the answer from this study is that at least for a proportion of children who start with quite severe autism, the prospects for improvement are potentially really quite good over the period of childhood. Puberty however seems to offer its own little challenges as many parents of children with autism can testify.

There are however a few gaps not covered in this latest paper. So for example, how many children used some kind of intervention, be it educational, behavioural or biomedical and what effect this might have had on core symptom presentation; whether other important comorbidity such as epilepsy or seizure-type disorders had any bearing on symptom progression; and more practically whether behavioural scores relating to the triad of autism symptoms reflected real-world progression in terms of educational attainment and use or loss of the diagnostic label of autism.

I have to say that I am really interested in this paper. Interested because of the close developmental trajectory across both language and social domains noted in this paper as conceivably offering support for the proposed dyadisation (is that a real word?) of the diagnosis of autism. But mainly interested in the 'bloomer' category of children across the different domains.

All participants were diagnosed with autism, but I wonder about this bloomer group and whether their 'autism' was somehow different in terms of something mimicking a more classical presentation of the condition. Without trying to sound too contentious, the first thing that passed my mind was infection as being potentially related. Encephalitis, meningitis and other related conditions affecting children early and leading to the kind of symptoms noted in the current paper. As time goes on, the infection passes, the brain taps into its fantastic plasticity properties and hey presto, symptoms start to abate - at least to some degree.

Post-encephalitis cases of autism have been reported down the years (here and here) and whilst correlation does not imply causation, autism cases overlapping with the seasonality of viral meningitis have also been recorded. Of course there are lots and lots of other potential infections which could also show some involvement as per the suggestion 40 years ago now linking autism and rubella. I made a suggestion a post back about looking at T.gondii antibodies in relation to autism given the quite startling links being made with other conditions. Who's to say that they might also show some involvement? (Dare I even mention PANDAS or is it called PANS now?)

Those that read this blog will know that I am a fan of looking at endophenotypes in relation to autism and other conditions. The way I see it is that the categories reported in this study are ripe for this 'phenotype' kind of approach and in particular a detailed inspection of those bloomers in relation to the immune system, mitochondrial function, overlapping autoimmune conditions, even bowel symptoms, alongside lots and lots of other parameters just to see if there are any potentially important differences.

I don't want to lose sight of the 'individuality' that accompanies autism and its presentation despite the evidence presented by Fountain and colleagues. The move however to recognising that a group of children on the autism spectrum may possess a slightly different developmental trajectory to others is something that really should start to make people sit up and ask 'who' and 'why'?

* Fountain C. et al. Six developmental trajectories characterize children with autism. Pediatrics. April 2012.
DOI: 10.1542/peds.2011-1601

Gastrointestinal inflammation and immune activation in schizophrenia

Monday 2nd April 2012. It is World Autism Awareness Day today and, in light of the 1 in 88 figure recently published by the CDC, perhaps more poignant than ever. Today's post is not specifically autism research orientated but might provide an idea or two for any budding autism researcher out there.

Every now and again a paper comes along which seems to fill in a gap in the research literature. I'm not saying that said paper is anything definitive, as if such a thing exists in science, and in particular science about behaviour and psychology. But rather another piece of the puzzle seems to fit into a spare slot.

The paper in question on this occasion is this one by Emily Severance and colleagues* reporting on the presence of gastrointestinal inflammation and associated immune activation linked to cases of schizophrenia. I'm not the first to blog about this paper as viewers will see from the excellent shakedown from Dr Deans [see here]. Regular readers of this blog will probably understand why I had also to post about this paper with keywords like gastrointestinal (GI), inflammation, immune system and schizophrenia; all of which have littered various posts on a possible gut-brain connection. I should perhaps point out that as is usually the case, Dr Severance has 'some research form' in this area as per papers like this one and this one. I probably don't even need to mention the quite widely known papers of some of the other authors with particular focus on Faith Dickerson and Robert Yolken.

Where to start with this research. Well, I very recently talked about schizophrenia and some indication of overlap with cases on the autism spectrum. Schizophrenia has also figured in this post on comorbidity with coeliac (celiac) disease and the potential for a gluten-free diet to solve more than just underlying gastrointestinal pathology à la the work of the late Curt Dohan. The appearance of our parasitic friend, Toxoplasma gondii might also be of some relevance to this recent piece of research although more peripherally than anything else.

Details of the current paper are shown below with apologies that I can't link to the full-text of the article as things stand so you'll have to take my word for it:

• Similar to some research undertaken in autism, the starting point for this paper is that there is some evidence of 'issues' with the gastrointestinal barrier in some cases of schizophrenia - the so-called leaky gut. The source of this permeability has not been definitively uncovered yet, but the speculation is that gastrointestinal inflammation as per what is observed in inflammatory bowel conditions such as Crohn's disease, might be a candidate. Sounds familiar doesn't it?
• This study examined a marker of intestinal inflammation in the measurement of anti-Saccharomyces cerevisiae IgG antibodies (ASCA) more traditionally used as part of the diagnostic work-up for diagnosing Crohn's disease. I should note that Saccharomyces cerevisiae is not to be confused with a relation Saccharomyces boulardii covered in an earlier post. Alongside, various measures of exposure to food antigens and infectious agents in serum and plasma were also examined based on IgG antibodies in various patient groups at different stages of their condition. My recent post on the finding of Sutterella species in some cases of autism provides some logic for looking at IgG antibodies as a sort of peripheral indicator of GI contents meeting the immune system where it really shouldn't meet.
• Two geographically separate participant groups were included for study: cohort 1 based in Baltimore, USA and cohort 2 based in Cologne, Germany. Within these two cohorts, cohort 1 groups were split into non-recent onset schizophrenia (SZ) (n=193), recent onset schizophrenia (ROSZ) (n=67) and controls (CO) (n=207); cohort 2 were split into first episode schizophrenia medicated (n=63) and first episode schizophrenia unmedicated (n=40). Mean ages across the cohorts and groups ranged from 22 years - 42 years with a real mix of genders and ethnic groups.
• The findings: levels of ASCAs from the Baltimore cohort were significantly higher in both SZ and ROSZ groups compared with controls (p<0.004 and p<0.00001). Levels of ASCAs also significantly correlated with anti-casein and anti-gluten IgG antibodies in the SZ group and anti-gluten IgG antibodies with the ROSZ group. No significant correlation was found for the food antibodies and ASCAs in the non-psychiatric control group.
• Looking at any effect from pharmacotherapuetic treatment, attention turned to cohort 2 based in Germany. Levels of ASCAs were significantly higher in unmedicated participants than medicated participants (taking anti-psychotics) and males seemed to be a key factor in this relationship. Indeed the unmedicated group also showed the only significant correlation with both IgG anti-casein and anti-gluten antibodies driven this time by females.
• IgG antibodies to that most cunning of protozoan, T.gondii, suggested some possible connection with anti-casein antibodies in the ROSZ group with a particularly male slant (males in this group also showing some connection between T.gondii antibodies and anti-gluten antibodies with a slight typo in the paper when it came to the R-squared value).

So, one marker of intestinal inflammation was elevated (on the whole) in participants with schizophrenia compared with controls and depending on whether you had recent onset or not, and whether you were under medication or not, seemed to determine your antibody response to foods containing gluten and casein as a marker of permeability and its effects.

If I were to be at all critical of this work, I could have done with seeing a few more direct measures of things like inflammation such as levels of C-reactive protein and perhaps a more direct measure of gut permeability would not have gone amiss. I'm not going to get too heavy into things like measuring those tight junction proteins and the type of permeability present but it would have been great to see more detail.

There are lots of 'possibilities' arising from these findings.  For some reasons I am taken back to a post last year on a the study by Col. David Niebuhr and colleagues regarding the presence of casein antibodies as potentially being predictive of future symptom onset of schizophrenia. I know that the two sets of results are not wholly compatible but it does make me wonder about whether the ASCA test might have similarly been predictive.

The differences between medicated and unmedicated participants in terms of ASCAs also ask an important question on whether anti-psychotics might have more than just an anti-psychotic mode of action in terms of pharmacology. The answer, with quite high probability, is yes as per studies like this one and this one. Notice the focus on an anti-inflammatory effect.

The late Curt Dohan (and indeed Dr Dohan Jr. continuing the family research tradition) would perhaps be casting a smile at reading this text based on his ideas stretching back 40 years now about a possible connection between food - gluten and casein containing foods - and schizophrenia, at least some cases of schizophrenia. I have to wonder how these results might possibly tie into similar observations seen comorbid to some cases of autism and whether applying the tests and methods used in the current study to autism, anti-Saccharomyces cerevisiae IgG antibodies, anti-casein and anti-gluten IgG (and T.gondii IgG antibodies) might also be a study worth doing.

To finish, the JCB song.

* Severance EG. et al. Gastrointestinal inflammation and associated immune activation in schizophrenia. Schizophrenia Research. March 2012.
DOI: 10.1016/j.schres.2012.02.025

CDC and the autism numbers game

Static @ Paul Whiteley

The waiting is over. The speculating is done. They're here...

Three years after the last update in 2009*, the US Centers for Disease Control and Prevention (CDC) have revealed their latest estimate for US childhood autism prevalence.

The 2009 estimate, based on surveillance in 2006, suggested that 1 in 110 US children (roughly equating to 1%) aged 8 years old - so born in 1998 - has an autism spectrum disorder. The caveat to that data was that the estimates fluctuated to some degree across the 11 States included in the analysis ranging from 12.1 per 1000 in the States of Arizona and Missouri to 4.2 per 1000 in the sunshine State of Florida. The overall figures nevertheless represented a 57% increase in the numbers of diagnosed cases compared with data from 2002** which previously estimated a rate of about 1 in 150 US children.

The paper trail of recent autism prevalence studies by the CDC using the same DSM-IV - DSM-IV TR criteria makes for some nice standardised methods for screening and case ascertainment which are not to be sniffed at.

So what is the latest estimate?

1 in 88.
[Update: the full report can be found here***]


Childhood autism in the United States has officially broken through the 1% prevalence threshold.

Are these latest figures a great surprise? Probably not to anyone who has followed the numbers over the years. Some people will remember the South Korea (SK) study from last year (2011) which suggested that 1 in 38 children (2.64% cumulative) may present with an autism spectrum condition. The data from Utah, USA, however, and their suggestion of 1 in 77 children with autism, seemed not to have received the same level of media interest despite being closer to the recent CDC mark. Utah also having the benefit of a good history on estimating autism prevalence down the years.

So, where next?

Based on the new estimate, I assume a familiar story will be put out to account for the change (better awareness, diagnostic substitution, more willingness to diagnose, widening of diagnostic criteria, etc) which whilst perfectly acceptable explanations still might not provide the full picture; not at least according to the Nature article from last year (2011). I have to say that I am always struck by how sure some people are that they know what is driving the increase in cases of autism as per one of the commentators on this recent newspaper article on autism going up here in the UK.

Autism on the rise as a consequence of better awareness? Well we do have World Autism Awareness Day on April 2nd and every year it seems to get bigger and bigger in terms of events and participation. Personally I'd like to think that the over the years of the DSM-IV and ICD-10, most professionals, whether teachers, health visitors, psychologists / psychiatrists, SALTs, know what to look for when it comes to autism in the early years. I think also that we should perhaps not underestimate parents and their observations in the early days of autism manifesting itself as important to this process. I could perhaps argue therefore that the awareness issue is probably to some extent covered in terms of the expertise and the various screening programmes in operation around the globe for autism. I'm not saying that awareness might not be contributory to the increasing prevalence but find it very difficult to say this is the sole 'cause' of the increase.

Diagnostic substitution? Widening of the criteria? Again, possible reasons, although probably more important reasons about 10-15 years ago following the replacement of DSM-III for example. Nowadays I'm not as sure that they still carry the same sort of weight.

So what are we left with? I've talked quite a bit on this blog about the rise and rise of epigenetics with autism in mind; that is genes and environment interacting together. Environment covers a lot of ground and I don't really want to start speculating on what facets of environment may or may not be linked. I do however think that we need to start shifting research attention away from the purely 'autism is genetic' model which has persisted for quite a few years. Autism may well have genetic underpinnings, which variably act on different people to different extents, but I don't seriously think that anyone would entertain all autism as being solely genetic. Indeed, epigenetics is beginning to turn quite a few areas on their research head and, in coming years, I am sure we will hear much more about it.

One final point to make: if the changes being suggested to DSM-5 (and I assume ICD-11 for that matter) for autism are actually implemented, we could be looking at a totally new way of coding for autism in subsequent CDC and other reports which will break those years of standardised measure based on DSM-IV. Will these changes affect the numbers of cases, and if so, in what direction? Mmm, a tough one.

* Prevalence of autism spectrum disorders - Autism and Developmental Disabilities Monitoring Network, United States, 2006. Autism and Developmental Disabilities Monitoring Network
MMWR Surveill Summ. 2009; 58: 1-20.

** Prevalence of autism spectrum disorders - Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2002. Autism and Developmental Disabilities Monitoring Network
MMWR Surveill Summ. 2009; 58: 1-20.

*** Prevalence of autism spectrum disorders - Autism and Developmental Disabilities Monitoring Network, 14 sites, United States 2008. Autism and Developmental Disabilities Monitoring Network
MMWR Surveill Summ. 2012; 61: 1-19

Labels and lumping: is autism common in schizophrenia?

As a species, we love our labels. I'm not talking about your fashion labels or anything like that but rather our love of compartmentalising things; to divide them up into groups or categories, put them in a box and with the giant social marker pen of the time give them a descriptor.

Labels have had an absolutely vital relationship to autism and how it has been viewed down the years. Indeed the proposed changes to the way DSM labels autism (DSM-5) have been fodder for discussion after discussion in many an online and print forum. I might just throw this paper by McPartland and colleagues* into the mix given the column inches that some of the authorship team have created with certain soundbites.

It is with labels in mind that I would like to discuss this paper** by Unenge Hallerbäck and colleagues who asked: is autism spectrum disorder common in schizophrenia? Before going to work on the paper and its very interesting and possibly contentious findings, I did find the thesis of Dr Unenge Hallerbäck online (see here) which, if you have the time, is certainly worth a read.

A summary of the research:

• The aim of the study was to look at the rates of autism spectrum conditions in a cohort of people diagnosed with schizophrenia and whether the presence of autism is more or less common in any sub-type of schizophrenia and vice-versa. I suppose to be accurate I should be using the term schizophrenia spectrum disorder (SSD) as per the realisation that health is not necessarily all about absolutes but rather degrees and spectrums.
• A participant group of 46 young adults with a diagnosed SSD were included in the study. Their initial diagnosis was evaluated using the SCID. The parents of 32 participants agreed to complete the DISCO-11, a semi-structured interview covering a 'spectrum' of clinical domains with autism as a focus. Participants also completed the Autism Quotient (AQ) for a more personal view.
• The results: most participants' diagnoses (and their variants) were corroborated by the SCID. Of the 32 parental reports via the DISCO-11, 41% of these participants had "an algorithm diagnosis of ASD". With specific regards to the confirmed diagnosis via the SCID and where parental data was available (n=23), 52% fulfilled the DISCO-11 diagnosis of ASD. Indeed the authors note that within the SCID diagnosis of paranoid schizophrenia, 60% of participants had an algorithm diagnosis of ASD too. Based on the Gillberg criteria for Asperger syndrome, five participants (all male) from the participant group could be diagnosed with Asperger syndrome (AS).

Agreeing with the authors, over 40% of their participants with schizophrenia also presenting with symptoms concordant to a diagnosis of autism spectrum disorder, is quite a high prevalence. Obviously the numbers of participants for whom complete data was available were relatively low. That combined with the use of retrospective interview introducing confounders like recall bias, means some caution needs to be applied to the current findings.

The first thought passing through my mind is the exclusionary criteria normally applied to the great label-givers like DSM-IV when it comes to autism and AS; as in, if schizophrenia is present, don't bother trying to diagnose an autism spectrum condition unless something like AS was clearly apparent before the onset of schizophrenia symptoms. Both Fitzgerald and Corvin*** (full-text) and Dr Tom Berney**** (full-text) provide quite good overviews of how this rule might apply in clinical practice alongside some of the potential pitfalls of mistaking AS for say, psychosis.

My second thought is not so much a scientific analysis but rather some cultural questions: how would people feel about autism being quite intricately linked to schizophrenia and vice-versa? Are we indeed seeing the diagnostic merry-go-round potentially reverting back to the 'olden days' and autism as childhood schizophrenia and beyond? What would happen to the rates of autism if the exclusionary clause on schizophrenia were no longer present in diagnostic manuals? I pass no opinion by the way, but will refer you to this paper by King and Lord***** as a possible clue to the future direction of the great psychiatric labeling machine.

As much as the current paper is interesting it is not the first time in recent research history that autism and schizophrenia have been 'overlapped' particularly as maturation kicks in and children progress through infancy into adolescence and adulthood and their behavioural presentation changes. Indeed outside of diagnosis, there is quite a bit of evidence to suggest that the overlap extends well beyond just diagnostic circles into areas such as genes and biochemistry. Do I even mention one of my real areas of interest on gluten- and casein-free dietary intervention for autism sprouting from the earlier work of the late Curt Dohan in schizophrenia?

We have to be careful when looking at any similarities and differences between labels like autism and schizophrenia. I've pretty much exhausted the times that I've said that autism is not seemingly protective of any other condition, which should surely also include schizophrenia with the current diagnostic caveats taken into consideration. If there is a positive side to any attempt to 'lump' the two conditions into some kind of 'spectrum' it would probably be the wealth of research undertaken on both conditions and how each could potentially inform the other. Staying out of the pharmacotherapy side of things (e.g. neuroleptic use), I'm thinking about the five serum (and one urinary) biomarkers study published not so long ago on schizophrenia and whether the diagnostic (and pathological) implications of that work might further inform at least some cases of autism?

To finish, Led Zeppelin ("who were they Daddy?") and a question: how long has it been since you've rock n' roll-ed? If the answer is too long, then clear a space and let Jimmy and the boys help with that 3 minute workout.

* McPartland JC. et al. Sensitivity and Specificity of Proposed DSM-5 Diagnostic Criteria for Autism Spectrum Disorder. Journal of the American Academy of Child & Adolescent Psychiatry. March 2012.
DOI: 10.1016/j.jaac.2012.01.007

** Unenge Hallerbäck M. et al. Is autism spectrum disorder common in schizophrenia? Psychiatry Research. March 2012

*** Fitzgerald M. & Corvin A. Diagnosis and differential diagnosis of Asperger syndrome. Advances in Psychiatric Treatment. 2001; 7: 310-318
DOI: 10.1192/apt.7.4.310

**** Berney T. Asperger syndrome from childhood into adulthood. Advances in Psychiatric Treatment. 2004; 10: 341-351
DOI: 10.1192/apt.10.5.341

***** King BH. & Lord C. Is schizophrenia on the autism spectrum? Brain Research. 2011; 1380: 34-41

Allergy-related autism, communication and NAET

For quite a while now I have been catching the odd mention of something called NAET with regards to lots of different conditions. NAET stands for the Nambudripad Allergy Elimination Technique coincidentally named after its discoverer Dr Devi S. Nambudripad.

Looking more closely at the description of NAET, my brow becomes slightly furrowed as words like 'selective energy balancing' are used to describe part of a process to desensitise a person from their allergies. I don't want to seem unfair or exclusionary to such concepts, and please no hate comments from any NAET supporters, but in my ignorance I do find it slightly difficult to picture such energy and how or what relationship it might have to the body. Certainly it is not something that my doctor ever shared with me about my childhood cat allergy and I would have probably had a hard time bringing it into any consultation with them. Having said that I can't [normally] see magnetism or gravity either but don't give them such a hard time; assuming that is, that they don't start to claim to affect things like allergy or autism without the appropriate research evidence as back up.

I would therefore not normally be paying too much attention to NAET. When however the results of a randomised-controlled trial are published, I tend to become a little more attentive. So it is that thanks to Research Autism, I stumbled upon this paper by Teitelbaum and colleagues* (full-text) looking at the use of NAET with a group of children with autism. The study was also registered with the NIH ClinicalTrials.gov site (here) although no raw results have been posted following the last review in June 2008.

So what did this paper say?

• Sixty children with a diagnosis of autism and a history 'suggestive' of food sensitivity (bowel, skin and/or other issues) were randomly allocated to a treatment (n=30) or control group (n=30). The randomisation method was an interesting one in that a 5-year old child picked names on papers from a bowl. What a great introduction to the scientific method for him!
• Treatment consisted of acupressure along the spine, hands and feet while the participant was holding particular allergens followed by something called neuromuscular sensitivity testing (NST), a procedure described as being similar to muscle response testing to assess effectiveness of treatment. Fifty allergens were treated consisting of 100 treatment occasions (twice a week); the study ran for a year. Controls received no NAET treatment during that time.
• Parents or primary caregivers completed the ATEC and a couple of other measures grading outcome.
• Results: 23 children in the NAET treatment group were described as improving to such an extent that "..they were able to function in regular school classes instead of special education classes". By contrast, none of the control group improved or "..were able to function in regular school classes". 
• There were also statistically significant group improvements on all of the subscales of the ATEC and total score when comparing treatment vs. control groups. The results also include a case study of a young boy with autism who was reported to improve considerably during the study period.

At first glance and without knowing what NAET was, I think most people would be impressed with these results. Twenty-three out of 30 participants using NAET went from an SEN to mainstream classes because of their improvement and none from the control group. Indeed this should really be 23 out of 26 children bearing in mind the participants who dropped out of the treatment group and I assume a protocol not including intention-to-treat. All of the ATEC subscales showed significant group improvements for the treatment group compared to controls and as far as I can see, no significant adverse effects were reported. Not bad at all.

But here's the thing. If I were to compare these [preliminary] results with any other intervention experimentally looked at for autism, these findings would probably indicate that NAET ranks up near the top of the table of autism interventions even if only for those allergy-related cases. My question therefore is why has this paper not created more excitement and a thirst for more research in this area?

The answer lies perhaps with a few 'issues' with this study and techniques described. As per the authors' comments, applied kinesiology is rather on the periphery when it comes to modern medicine and indeed its failings when appropriately tested. My attention is immediately drawn to a recent study by O'Reilly and colleagues** examining the professional view of alternative medicine with autism in mind which highlights some of the main issues. I would imagine that applied kinesiology is probably not central to the traditional medical model. That and the continuing attention raised with other complementary techniques such as the recent Singh/British Chiropractic Association saga and an even more recent post detailing a checklist for intervention therapies. At this point I might add that I offer no opinion on whether things like applied kinesiology work or not; merely that its principles and rather subjective methods have not (yet) produced unequivocal data on reliability or response.

One could also highlight that some of the methodology of this study as being a potential source of bias. So, for example, this was not a double-blind study and as far as I can see no placebo condition was applied. The question of how this type of method could be double-blinded and placebo-controlled is the counter argument which would require some sideways thinking in any future study design. As for the placebo effect, one should never underestimate how powerful an action this can exert on a person when specific elements are in place e.g. administered by a doctor in a white coat with lots of encouragement about positive effects, bearing in mind also who was rating participants on outcome.

I am also interested in the medical treatment as usual instructions provided to parents of participants in both groups. "In both groups, parents were instructed to continue any medical treatments the child was receiving prior to enrolment in the study". Unfortunately I can't see anywhere in the article information about what these treatments were, how they changed over the experimental period and importantly, whether any other interventions were introduced during the long study duration. Is it indeed likely that 30 children with autism would not adjust/undertake educational, behavioural or other intervention for a whole year?

I don't want to be overly critical or anything about this paper just because it details techniques which I don't understand or don't fit with the current way of thinking. Indeed the dietary trial I was involved with has similar methodological failings in terms of lacking double-blindedness and final analysis based on a per protocol decision. Having said that there is a difference between changing a persons diet and asking them to hold a carrot or a jar containing a carrot or other carrot essence whilst someone manipulates their back (as per the story of the discovery of NAET).

I know quite a few people would probably like to draw a line under this study and put it down to a fluke finding with methodological issues. Personally, if there is any possibility that NAET, for whatever reason including a placebo effect, might be able to clinically impact so positively on a persons functioning and quality of life as to move them from SEN to mainstream school, I would like to see a more methodologically-sound, independent study undertaken on it. Bearing in mind also the potential power of touch and massage as per this previous post, it is not beyond the realms of possibility that independent of the allergy-perspective, there may not have been some effect from the acupressure side of things, which itself needs a little bit more investigation particularly from a safety perspective.

To finish a treat for my oldest offspring with a catchy tune from recent Brit winners One Direction (God, did I actually link to this ..?)

* Teitelbaum J. et al. Improving communication skills in children with allergy-related autism using Nambudripad's Allergy Elimination Techniques: a pilot study. Integrative Medicine. 2011:10; 36-43

** O'Reilly M. et al. Complementary or controversial care? The opinions of professionals on complementary and alternative interventions for Autistic Spectrum Disorder. Clinical Child Psychology & Psychiatry. February 2012.