Autism: a spectrum, dimensions or clusters? How about a multi-dimensional cluster of spectrums?

A write-up (see here) of the paper by Hyunsik Kim and colleagues [1] was the initial impetus for formulating this blog post, but it quickly escalated into something a little larger when the findings from Frank Duffy & Heidelise Als [2] also popped up.

The question at hand: how should one conceptualise autism? Is it truly a spectrum as per the Lorna Wing proposition, or is it something a trifle more complicated? As per the title of this post, should we perhaps be thinking about autism as some sort of "multi-dimensional cluster of spectrums?" I'll come back to that idea shortly.

Well, it's not for me to make definitive conclusions on this blog. Science rarely, if at all, provides an absolute 'truth' but rather the probability that something is approaching truth. Such a notion goes double when you consider the singular label of autism and the huge heterogeneity that it encompasses. There are no easy answers and probably little or no truths.

Starting with the Kim paper (including some notable names such as the surname 'Gadow') and the name of the research game was modelling, modelling in a computational sense. So: "The sample comprised 3,825 youth, who were consecutive referrals to a university developmental disabilities or child psychiatric outpatient clinic." The CASI-4R - formulated by Prof. Gadow - was the schedule administered, which includes "an ASD [autism spectrum disorder] symptom rating scale" among other things. Some nifty statistics were applied to the data and the initial findings were 'tested' on a further group of over 2500 children.

Results: "Based on comparison of 44 different models, results indicated that the ASD symptom phenotype is best conceptualized as multi-dimensional versus a categorical or categorical-dimensional hybrid construct." And the dimensions mentioned in that 'multi-dimensional' statement? Well, lucky for us they were something familiar: "social interaction, communication, and repetitive behaving."

Then to the Duffy/Als paper (again, these authors are no stranger to autism research) and a similar starting point: "The authors postulate that the broad definition of an omnibus 'spectrum disorder' may inhibit delineation of meaningful clinical correlations." Indeed, very familiar (see here). The conclusion: "evidence that an objectively defined, EEG [electroencephalogram] based brain measure may be helpful in illuminating the autism spectrum versus subgroups (clusters) question." The tool used by Duffy/Als in their study was something called NbClust "specifically designed to provide an objective means, i.e. independent of investigator choice, to identify the ‘optimal’ cluster number within a population." Said tool was applied to EEG data derived from 400 participants diagnosed with an ASD. Statistics and more statistics applied to the data revealed that: "430 subjects diagnosed as being on the autism “spectrum” and represented by 40 EEG coherence factors..., fell into two distinct clusters." These autism spectrum clusters differed from each other and importantly, from "554 subject neuro-typical control group subjects, not involved in the clustering process." Interesting results but an unfortunate use of the term 'neurotypical' (see here). Duffy & Als conclude that their data support a view whereby "autism disorder should not be seen as a continuous spectrum." So Kim & Duffy/Als arrive at similar conclusions: a singular 'spectrum' idea of autism is probably not the best way of conceptualising the essence of the label.

I would perhaps add in a little more evidence for the idea that 'multi-dimensional clusters of spectrums' is a potentially better fit. I used the words 'spectrums' (plural) because there is a growing body of evidence to support the idea of more than one 'type' of autism. I say that from the perspective of evidence for autism being 'acquired' under several different circumstances (e.g. accompanying inborn errors of metabolism, linked to exposure to certain infections or diseases, etc). There's also evidence that clinical profiles under the umbrella term autism are not uniform (e.g. regressive autism, the so-called 'optimal outcomers', differing developmental trajectories, etc). And when one looks at something like the success (or not) of intervention, it's plain to see that there is no universally shared genetics and/or biology of autism in the singular either (see here and see here for examples). Add in the idea that autism rarely appears in a diagnostic vacuum (see here) and that said comorbidity might 'cluster' in some subgroups of autism (see here), and I hope you can see why 'plural' might be a good addition to any attempt to re-conceptualise autism: spectrum, dimension, tapestry, cluster or however you think it should be defined...

Oh, and since we're on the topic of trying to conceptualise autism, a new book out recently has been reviewed in Nature (see here). It talks about how "conclusive findings about sex-linked brain differences have failed to materialize" which is particularly apt in relation to previous talk about 'extreme male brains' as a way of conceptualising [some] autism (see here). One quote I particularly liked from the review is this one: "The brain is no more gendered than the liver or kidneys or heart."

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[1] Kim H. et al. Quantifying the Optimal Structure of the Autism Phenotype: A Comprehensive Comparison of Dimensional, Categorical, and Hybrid Models. J Am Acad Child Adolesc Psychiatry. 2018 Oct 29. pii: S0890-8567(18)31894-X.

[2] Duffy FH. & Als H. Autism, spectrum or clusters? An EEG coherence study. BMC Neurol. 2019 Feb 14;19(1):27.

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Colliding spectrums again: autism and schizophrenia meta-analysed (again)

"The systematic review and meta-analysis showed a significant association between schizophrenia and ASD [autism spectrum disorder]."

That was the conclusion made by Zhen Zheng and colleagues [1] following their trawl through the peer-reviewed science literature with a view to examining "the association between schizophrenia and ASD."

This is not the first time that Zheng et al have featured in the autism meta-analysis arena (see here and see here and see here) so one could perhaps see them as seasoned professionals when it comes to this type of science. It's also not the first time that the relationship between autism and schizophrenia has been subjected to such analyses either (see here) continuing quite a long relationship between the labels and/or spectrums [2] (see here also).

So: "The meta-analysis of the prevalence of schizophrenia in individuals with ASD encompassed 1,950,113 participants and 14,945 individuals with ASD." From such numbers/data, authors were quite confidently able to determine that schizophrenia was more frequent in cases of autism than in control participants. Indeed, this was described as a 'robust' finding and the magnitude of the risk was not to be sniffed at: "odds ratio = 3.55, 95% confidence interval: 2.08-6.05, P < .001."

In relation to the "prevalence of ASD in individuals with schizophrenia", the authors relied on a smaller number of participants but concluded that: "The prevalence of ASD in individuals with schizophrenia ranged from 3.4 to 52%." Ergo, schizophrenia occurring alongside autism and autism occurring alongside schizophrenia both show over-representation.

As I mentioned on a previous blogging occasion when these labels were discussed in an overlapping sense, there are many implications from such findings. There are implications related to the preferential screening for schizophrenia and/or autism (also including other related issues too) when one or other label is diagnosed and for timely and appropriate intervention for such issues when detected (see here). There are implications for the idea that, biologically-speaking, there may be some shared mechanisms at work covering both (heterogeneous) labels (see here and see here for examples). There are also implications in relation to the social impact of such an association; bearing in mind the often very negative image portrayed of schizophrenia in certain quarters of the media and the rise and rise of 'autistic identity' in other circles. There is lots to think about.

And finally and quite timely, the paper from Giacomo Deste and colleagues [3] talking about the PANSS Autism Severity Score (PAUSS) as a "simple, fast and reliable tool for the identification of autistic features in adult patients with schizophrenia" looks rather interesting...

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[1] Zheng Z. et al. Association Between Schizophrenia and Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. Autism Res. 2018 Oct 3.

[2] Evans B. How autism became autism: The radical transformation of a central concept of child development in Britain. History of the human sciences. 2013;26(3):3-31.

[3] Deste G. et al. Looking through autistic features in schizophrenia using the PANSS autism severity score (PAUSS). Psychiatry Research. 2018. Oct 29.

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Colliding spectrums: autism and schizophrenia (meta-analysed)

Consider this post talking about the findings reported by Jorge Lugo Marín and colleagues [1] an extension of previous chatter on this blog about the possibility of overlapping spectrums when it comes to autism and schizophrenia (see here).

I appreciate that there is some 'history' when it comes to moves to separate autism and schizophrenia [2] but the evidence being produced more recently perhaps questions whether the historical 'eagerness' to compartmentalise the labels as separate and independent was more of a socio-political thing over and above a true reflection of the state of any relationship (see here and see here for examples). Indeed, when [peer-reviewed] science for example, starts talking about a possible 'subtype of autism linked to psychosis' (see here) you know that the connections are perhaps not to be under-estimated...

Lugo Marín et al report results following a meta-analysis of the relevant peer-reviewed science done on this topic. Ten papers fulfilled their inclusion criteria. They report that: "The pooled prevalence of SSD [schizophrenia spectrum disorder] in the total ASD [autism spectrum disorder] sample was close to 6%, pointing to a high co-occurrence of the two conditions." Further, that more research is required about the specific hows-and-whys of SSD or symptoms of SSD appearing alongside [some] autism (and vice-versa) and onward, the possibility of preferential screening and intervention.

I've thought about the relationship between autism and schizophrenia quite a bit over the years. Not only because in my own area of research interest - gluten- and casein-free diets and autism - there is history linking autism and schizophrenia (see here) but also because the relationship down the years seemingly plays into the stigmatisation of a label i.e. move autism 'away' from schizophrenia because of the perceived 'dangerousness' connotations attached to schizophrenia for example (see here for a more recent example of this in action [3]). On that point, the evidence is getting clearer that whilst the diagnosis of schizophrenia (plus other factors) is by no means preventative of 'dangerous' acts being committed, people diagnosed with the condition are seemingly far more likely to be victims of something like crime than perpetrators (see here). Sounds familiar doesn't it?

Then also there is the 'identity' perspective to consider when talking about autism and schizophrenia in the same breath. Schizophrenia is considered to be a mental health issue; autism by contrast is primarily viewed as a developmental condition, which, although increasing the risk of developing a mental health issue (see here for example), is not itself described as such per se. I say this acknowledging that support for schizophrenia as being a 'neurodevelopmental disorder' is also growing [4] as words like 'prodrome' become more frequently discussed. Also important in this context, are the possible effects of certain comorbidity being 'over-represented' in cases of autism potentially also impacting on the subsequent risk of a diagnosis of schizophrenia (see here).

Keeping the theme of 'identity' going when discussing autism and schizophrenia, there is another angle to consider in terms of 'ownership' of the labels and perceptions around such a concept. I speak of the movement towards use of terms like 'autistic person' over 'person with autism' preferentially considered by some (see here) and how such a move is seemingly at odds with identity in terms of schizophrenia. The term 'schizophrenic' is considered unsuitable in this day and age (see here - "A person is not the sum total of the symptoms") alongside other 'label-first' terms such as 'manic depressive' and 'psychotic' for example. You can perhaps see how labelling someone as 'autistic' whilst at the same time labelling them has 'having schizophrenia' under circumstances where the two spectrums collide, presents a quandary when it comes to language and identity and perhaps serves to reiterate the gulf between the labels/conditions in terms of perceived stigma for example.

What we can say on the back of the Lugo Marín findings is that, in these days of ESSENCE (see here) and RDoC (see here) the possible reunification of the autism and schizophrenia spectrums in specific cases, should not be seen as something detrimental to either label and could provide some important insights into the genetic and biological nature of both spectrums (see here). I have my views about where the two spectrums might meet on a biological level [5] but no doubt there will be lots of other intersections too. Indeed, once again harking back to the [sadly forgotten] writings of Mildred Creak and colleagues and their "9 key features of ‘schizophrenic syndrome in childhood’", their description is uncannily pertinent to large parts of the autism spectrum when taking into account inclusion of diagnostic items such as "abnormal perceptual experience", "distortion in motility patterns" and "acute, excessive and seemingly illogical anxiety" and the often pronounced effects that such symptoms can have on quality of life.



To close, a picture relevant to today...

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[1] Lugo Marín J. et al. Prevalence of Schizophrenia Spectrum Disorders in Average-IQ Adults with Autism Spectrum Disorders: A Meta-analysis. J Autism Dev Disord. 2017 Oct 4.

[2] Evans B. How autism became autism: The radical transformation of a central concept of child development in Britain. Hist Human Sci. 2013 Jul;26(3):3-31.

[3] Sasson NJ. & Morrison KE. First impressions of adults with autism improve with diagnostic disclosure and increased autism knowledge of peers. Autism. 2017 Oct 1:1362361317729526.

[4] Owen MJ. et al. Neurodevelopmental hypothesis of schizophrenia. The British Journal of Psychiatry. 2011;198(3):173-175.

[5] Prata J. et al. Bridging Autism Spectrum Disorders and Schizophrenia through inflammation and biomarkers - pre-clinical and clinical investigations. J Neuroinflammation. 2017 Sep 4;14(1):179.

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A subtype of autism linked to psychosis?

"Our data show there may be a specific subtype of ASD [autism spectrum disorder] linked to comorbid psychosis. The results support findings that psychosis in people with ASD is often atypical, particularly regarding affective disturbance."

So said the findings reported by Felicity Larson and colleagues [1] (open-access available here) who bring an important topic into view that has recently been raised in the media too (see here). I appreciate that to talk about yet more comorbidity potentially following an autism diagnosis is not exactly great news. If however, one accepts that various comorbid conditions can actually be pretty disabling for many on the autism spectrum, identifying, screening and managing/treating said comorbidity then actually becomes pretty important.

Researchers set about looking to "describe autistic and psychotic phenomenology in a group of individuals with comorbid ASD and psychosis (ASD–P) and compare this group with populations affected by either, alone." Their group comprised of adults aged 16 and over diagnosed with an ASD and comorbid psychosis (N=116). This was an opportunistic cohort insofar as being recruited between January 2010 and June 2013. Eligibility was determined by a formal diagnosis of autism at referral and meeting "criteria on the Autism Diagnostic Observation Schedule (ADOS)... at the time of involvement in the study, or... meet criteria on the Autism Diagnostic Interview-Revised (ADI-R)... for a lifetime diagnosis." Psychotic illness determination was a 2-stage affair. First, inclusion was based on "a prior clinical diagnosis of psychotic illness or gave an account of an episode that was clearly psychotic" followed by evidence of psychotic symptoms being elicited using one or more questionnaires onward to the presentation of 'research-significant psychosis'.

Results: "What is clear from this research is that individuals who experience concurrent ASD and psychotic illness exist and are treated in mental health services." I don't think there is anything too earth-shattering about that statement but it does need to be said in the context of the label of autism rarely/not existing in some sort of diagnostic vacuum (see here). Next: "Mental health services in the UK are yet to be fully equipped to support people with both psychotic illness and ASD." Again, nothing new; following a trend of resources not being available or 'ready' to accommodate people on the autism spectrum and the health inequalities that inevitably follow. Insofar as the idea that psychosis presentation may at times be 'atypical' when it comes to autism, this also follows an important trend noted in other comorbidity research (e.g. when it comes to bipolar disorder for example).

The other data presented by Larson and colleagues on the profile of autistic symptoms potentially being slightly different when compared to a 'control group' of those diagnosed with autism but without evidence of psychosis - "the ASD–no psychosis (ASD–NP) group" (n=69) - is interesting but requires quite a bit more follow-up work. I might at this point drop in the paper by the wonderfully named Robustelli and colleagues [2] talking about how "youth at high-risk of developing psychosis have fewer and poorer quality social relationships" as being potentially relevant and indeed, how social functioning can be affected long-term when it comes to psychosis. Further investigation is also required around the observation that: "Individuals with ASD–P had lower rates of schizophrenia and higher rates of psychosis-NOS" in light of other work talking about spectrums (autism and schizophrenia) colliding (see here). Although not part of this study, the name of one co-author on this paper being linked to the Autism-Spectrum Quotient (AQ) is also potentially relevant, given other work asking whether the AQ might actually be picking up signs and symptoms of something like schizophrenia too (see here).

There is also the question of possible overlapping mechanisms potentially at work when it comes to autism and psychosis. In light of recent chatter about an immune system 'feature' to some psychosis (see here) and the myriad of immune related findings linked to autism, I'd suggest that this could be one area for further research inspection. The idea also that vitamin D for example, shows some relationship to some autism (see here for example) is another area for joint investigation given some chatter about levels of the sunshine vitamin/hormone and cases of psychosis [3]. There will no doubt, be other areas of overlap potentially pertinent too...

There is quite a bit more to do in this increasingly important area of research.

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[1] Larson FV. et al. Psychosis in autism: comparison of the features of both conditions in a dually affected cohort. Br J Psychiatry. 2016 Dec 15. pii: bjp.bp.116.187682.

[2] Robustelli BL. et al. Social relationships in young adults at ultra high risk for psychosis. Psychiatry Res. 2016 Dec 7;247:345-351.

[3] Suetani S. et al. Prevalence and correlates of suboptimal vitamin D status in people living with psychotic disorders: Data from the Australian Survey of High Impact Psychosis. Australian & New Zealand Journal of Psychiatry. 2016. Dec 21.

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Larson, F., Wagner, A., Jones, P., Tantam, D., Lai, M., Baron-Cohen, S., & Holland, A. (2016). Psychosis in autism: comparison of the features of both conditions in a dually affected cohort The British Journal of Psychiatry DOI: 10.1192/bjp.bp.116.187682

The bipolar - schizoaffective - schizophrenia spectrum?

"This pattern of results is consistent with the conceptualisation of a spectrum of disorders, ranging from BDP [bipolar disorder] at one end, to SAD [schizoaffective disorder] in the middle, and SCZ [schizophrenia] at the other end." So concluded the paper by Serafino Mancuso and colleagues [1] examining clinical data derived from the Australian Survey of High Impact Psychosis (SHIP).

The thing about perfection is that it's unknowable.

I'm not going to dwell too long on this paper aside from suggesting that such results add to a growing trend in psychiatry asking whether our current compartmentalising way of diagnosing mental health issues is actually fit for purpose à la RDoC (Research Domain Criteria). A few weeks back Virginia Hughes talked about 'Category Fail' based to a large extent on the paper by London [2] who suggested that: "The use of autism as a diagnostic category guiding translational research is fraught with so many problems that the validity of research conclusions is suspect." Sentiments which have been rumbling on for quite a few years now.

The Mancuso results are complemented by quite a few other findings suggestive of fuzzy boundaries when it comes to giving psychiatric labels and their associated qualities. Plucking randomly from the peer-reviewed literature, the paper from Silver & Bilker [3] for example, talking about people with schizophrenia showing "impairments in [the] recognition of identity and emotional facial clues" as part of social cognition carries hints of what has been described in cases of autism for example. The findings reported by Langdon and colleagues [4] talking about a specific Theory of Mind (ToM) impairment in their cohort with early psychosis provides further evidence for the non-exclusivity of this concept when similarly talked about with autism in mind (see here). I might add that I'm not a great fan of the link between ToM and autism anyway.

Of course, one might also see the concept of a spectrum of psychiatric conditions to be itself rather too simplified when it comes to describing and categorising behaviours and actions. The growing pluralisation of autism - 'the autisms' - and schizophrenia - 'the schizophrenias' - perhaps implies that 'tapestry' might be a better way to define presented symptoms, bearing in mind the potential number of permutations of displayed symptoms and underlying genetic/biological issues that may be evident. It might also cover the evidence talking about overlapping spectrums also.

It's all getting rather complicated...

Music: Chase & Status - Lost & Not Found.

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[1] Mancuso SG. et al. A comparison of schizophrenia, schizoaffective disorder, and bipolar disorder: Results from the Second Australian national psychosis survey. J Affect Disord. 2014 Sep 30;172C:30-37.

[2] London EB. Categorical diagnosis: a fatal flaw for autism research? Trends Neurosci. 2014 Nov 14;37(12):683-686.

[3] Silver H. & Bilker WB. Social cognition in schizophrenia and healthy aging: Differences and similarities. Schizophr Res. 2014 Nov 15;160(1-3):157-162.

[4] Langdon R. et al. Theory of mind and neurocognition in early psychosis: a quasi-experimental study. BMC Psychiatry 2014, 14:316

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Mancuso SG, Morgan VA, Mitchell PB, Berk M, Young A, & Castle DJ (2014). A comparison of schizophrenia, schizoaffective disorder, and bipolar disorder: Results from the Second Australian national psychosis survey. Journal of affective disorders, 172C, 30-37 PMID: 25451392

Diagnosing autism late: after psychosis

The case report from Marly Simoncini and colleagues [1] (open-access) is the topic of today's post. Describing the case of Mr. A, a young man who attempted suicide during a psychotic episode, the paper tracks the developmental history and diagnostic evaluation of this person culminating in a diagnosis of autism spectrum disorder (ASD) "that had been completely overlooked".

The best thing we can do is go on with our daily routine

The paper is open-access and I would encourage readers to take some time to look through the narrative. Not only are some of the more commonly cited features of autism in childhood described in the paper as per his toy preferences and his wish to "play alone for hours with a few toys" but also other potentially important points: "He continued with selecting his food (white and squared foods only) and drinking milk only from his infant feeding bottle, until he was an adolescent". The outcome of various psychometric assessments specific to autism are also discussed, including his scores on the ADOS and ADI (see here) eventually placing him on the autism spectrum.

The important story of how this case report illustrates how much further we need to go in terms of awareness of autism across the lifespan is also complemented by the discussions on how the autism spectrum seems (in some cases) to merge with other spectrums. The authors note: "signs and symptoms of both a psychotic disorder and an ASD might run isolated or in clusters during the entire lifespan, often not reaching the threshold for a categorical diagnosis until adulthood". I might add that the 'autism overlooked' part of this study is probably not something common to modern-day autism (see here).

Treading quite carefully, I have, on a few occasions on this blog, talked about how there may overlapping presentation of autism and psychosis in some cases (see here and more recently here). Indeed not so long ago, I read a very personal account of a mother caring for a child on the autism spectrum and her experiences of a meltdown: "... apparently it used to be called ‘childhood schizophrenia’ and as I watched Ethan totally lost to me at that moment, in what looked like a possessed fit, I could see how it could have been labelled as schizophrenia". I should point out that schizophrenia is not the same as a 'possessed fit' (see here) but can, and does, present as a range of psychological symptoms as part of the psychosis spectrum (see here).

Of course, one should not forget that a diagnosis of autism is seemingly protective of nothing in terms of other somatic or psychiatric conditions to be present. It might also be nothing more than coincidence that autism and psychosis ran parallel in the case of Mr. A. That being said and on the back of other texts such as the go-to paper by Tom Berney [2], I do wonder if greater thought needs to be put into looking at autism across the lifespan. How, in amongst the sometimes fluidic changes in presentation according to factors such as maturation [3], further screening for issues such as psychosis should be more regularly implemented in order to mitigate any negative effects they may have both for the person concerned and their loved ones?

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[1] Simoncini M. et al. Lifetime Autism Spectrum Features in a Patient with a Psychotic Mixed Episode Who Attempted Suicide. Case Reports in Psychiatry. 2014: 459524.

[2] Berney TP. Asperger syndrome from childhood into adulthood. Adv Psychiatr Treat. 2004; 10: 341-351.

[3] Helles A. et al. Asperger syndrome in males over two decades: stability and predictors of diagnosis. Journal of Child Psychology and Psychiatry. 2014. 3 October.

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Simoncini, M., Miniati, M., Vanelli, F., Callari, A., Vannucchi, G., Mauri, M., & Dell’Osso, L. (2014). Lifetime Autism Spectrum Features in a Patient with a Psychotic Mixed Episode Who Attempted Suicide Case Reports in Psychiatry, 2014, 1-4 DOI: 10.1155/2014/459524

Schizophrenia after child and adolescent psychiatric disorders

More of a 'bring to your attention' post today, as I bring to your attention(!) the paper by Cecilie Frejstrup Maibing and colleagues [1] who concluded: "The risk of being diagnosed with schizophrenia spectrum disorders [SSD] after a child and adolescent psychiatric disorder was significantly increased particularly in the short term but also in the long-term period".

"I coulda been a contender"

The findings were based on an analysis of one of those very informative Scandinavian registries - based in Denmark - which initially identified over 25,000 people born between 1990-2000 diagnosed "with child and adolescent psychiatric disorders". Some 1200 of these people were subsequently diagnosed with schizophrenia spectrum disorders leading to the various conclusions and statistics being produced including: "The risk of schizophrenia spectrum disorders was highly elevated, particularly within the first year after onset of the child and adolescent psychiatric disorder, and remained significantly elevated >5 years with an incidence rate ratio of 4.93". Further: "among persons diagnosed with a child and adolescent psychiatric disorder between the ages 0-13 years and 14-17 years, 1.68% and 8.74 %, respectively, will be diagnosed with a schizophrenia spectrum disorder <8 years after onset of the child and adolescent psychiatric disorder".

With my autism research blogging hat on, and without hopefully making too many sweeping generalisations, I found the Maibing research to be rather interesting. I've previously talked about spectrums colliding on this blog (see here) with specific reference to the work of Kenneth Gadow [2] for example, on "an interrelation between ASD [autism spectrum disorder] and SSD symptoms". That and a post on 'labels and lumping' (see here) affirms that there may indeed be common ground between some of the spectrums, which I might add, are probably plural spectrums [3] (see my take here). As per other research on the possibility of Asperger syndrome in first-episode psychosis (see here), diagnostic vigilance seems to be a key point to take from the Maibing work, and that appears to extend well beyond just what happens after a diagnosis of autism is received...

So, Golden Touch by Razorlight.

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[1] Maibing CF. et al. Risk of Schizophrenia Increases After All Child and Adolescent Psychiatric Disorders: A Nationwide Study. Schizophr Bull. 2014 Sep 5. pii: sbu119.

[2] Gadow KD. Schizophrenia spectrum and attention-deficit/hyperactivity disorder symptoms in autism spectrum disorder and controls. J Am Acad Child Adolesc Psychiatry. 2012 Oct;51(10):1076-84.

[3] Arnedo J. et al. Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies. Am J Psychiatry. 2014. September 15.

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Maibing CF, Pedersen CB, Benros ME, Mortensen PB, Dalsgaard S, & Nordentoft M (2014). Risk of Schizophrenia Increases After All Child and Adolescent Psychiatric Disorders: A Nationwide Study. Schizophrenia bulletin PMID: 25193974

The ESSENCE of autism comorbidity?

Like Charlie Bucket looking through the sweet shop window at the delicious chocolates produced by the workforce of a certain Mr Willy Wonka (the candyman no less), I am always quite interested in the goings-on at the IMFAR autism research conference.

  The candyman can... @ Wikipedia  

This year (2013) proved to be a bit of a vintage, as once again the great and the good presented their Wonka bars of autism research; thus hinting at the direction of future autism research and what you can expect to read on this blog in the coming months. Oh, and something about poodles(?) (thanks Carol).

I've been hearing quite a bit of chatter about the keynote speech given by Prof. Christopher Gillberg which seemed to quite strongly hint that the autism research community should be paying rather more attention to the add-ons which seem to accompany a diagnosis of autism, rather than seeing autism as just existing stand-alone in a diagnostic vacuum.

Far be it from me to say 'I told you so', but comorbidity and overlap, and the often far-reaching effects on quality of life of certain comorbidity, has been a theme running through many posts on this blog and not just the more behaviourally-defined type of comorbidity. So for example the question of 'significantly over-represented' and all that autism's' chatter (note the plural) immediately come to mind. Indeed I don't actually believe that many people in the know would view the autisms as just being the total sum of the triad (very soon to be dyad). Or would they?

Mention of the word ESSENCE - Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations* - has apparently been made in Prof. Gillberg's address denoting "the reality of children (and their parents) presenting in clinical settings with impairing child symptoms before age 3 (-5) years in the fields of (a) general development, (b) communication and language, (c) social inter-relatedness, (d) motor coordination, (e) attention, (f) activity, (g) behaviour, (h) mood, and/or (i) sleep". Before proceeding, I would perhaps suggest that Gillberg seems to have some interest in the use of acronyms in autism research and beyond as per the example of DAMP and MBD**.

Anyhow, a quick scan of the peer-reviewed research literature does indeed see a small but growing body of work discussing ESSENCE and its use in autism research circles. I note for example this paper by Prof. Brian Neville*** who highlights an essential part of the use of ESSENCE: that the presentation of behaviour in infants and young children is often complex, and the "problems are their multiplicity". Common sense perhaps?

Perhaps one of the best (so far) papers discussing the concept of ESSENCE in a real-world clinical setting is this one from Lotta Höglund Carlsson and colleagues**** (open-access) (which includes Gillberg as part of the authorship team). The paper is free for all to read so no great dissection required from me. That being said, I would highlight the fact that based on examination of just over 100 children diagnosed with an autism spectrum disorder (ASD), "a mean of 3.2 coexisting disorders or problems" were reported, including a third of children presenting with "severe hyperactivity/ADHD".

I was particularly interested in this autism-ADHD link given some other recent research on the overlap*****. That and the fact that additional reports have indicated even higher levels of overlap between autism and ADHD (see this post) calls into question whether the two labels may intersect even more than we perhaps have appreciated.

One of the potential implications of the co-occurrence of autism and ADHD is with regards to intervention and therapeutic options. Without trying to hijack the association with my dietary mumbo-jumbo, I would draw your attention to a previous post I published a while back on food and ADHD and some potential lesson for autism (see here). The suggestion there - and it was only a suggestion - was that some of the observations made when looking at the impact of a dietary intervention for autism actually working on some of the symptoms associated with ADHD might imply that targeting such comorbidity might eventually impact on more core autism presentation. A shocker I know that children being described as less impulsive and attending better might actually have better outcome.

I'm finishing shortly but before I do, I want to draw your attention to another ESSENCE mention in the paper by Stephanie Plenty and colleagues****** (open-access) who looked at the retrospective application of the concept in cases of adult ASD and ADHD. They similarly reported: "Although differences were observed between ADHD and ASD patients in the core diagnostic areas, these syndromes also shared a number of childhood difficulties".

The wave of research and opinion which is seemingly directing everyone to this idea that autism is not a stand-alone label is growing. Add into the mix the recent announcement that even before the introduction of DSM-V the NIMH prefer an even broader view of behaviour and psychiatry (RDoC) ('reorienting' apparently) and that autism-ADHD-[insert other] spectrum is starting to feel more and more like a giant tapestry.

To close, for the second time in this post I'm going to direct you to the genius of Sammy Davis Jnr - the Candyman can y'know.

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* Gillberg C. The ESSENCE in child psychiatry: Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations. Res Dev Disabil. 2010; 31: 1543-1551.

** Gillberg C. Deficits in attention, motor control, and perception: a brief review. Arch Dis Child 2003; 88: 904-910.

*** Neville B. Role of ESSENCE for preschool children with neurodevelopmental disorders. Brain Dev. 2013; 35: 128-132.

**** Höglund Carlsson L. et al. Coexisting disorders and problems in preschool children with autism spectrum disorders. Scientific World Journal. 2013: 213979.

***** Cooper M. et al. Autistic traits in children with ADHD index clinical and cognitive problems. Eur Child Adolesc Psychiatry. April 2013.

****** Plenty S. et al. Applying an ESSENCE Framework to Understanding Adult Autism Spectrum Disorder and ADHD: Retrospective Parent Reports of Childhood Problems. Scientific World Journal. 2013: 469594.

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Höglund Carlsson, L., Norrelgen, F., Kjellmer, L., Westerlund, J., Gillberg, C., & Fernell, E. (2013). Coexisting Disorders and Problems in Preschool Children with Autism Spectrum Disorders The Scientific World Journal, 2013, 1-6 DOI: 10.1155/2013/213979

Autism, the autisms or "developmental brain dysfunction"?

"If you've met one person with autism, you've met one person with autism" so the oft-cited phrase goes.

The implication is that whilst unified under the label of presenting with the triad/dyad characteristics of an autism spectrum condition, the heterogeneity present across the spectrum coupled with other comorbidity, allied to factors such as genes, personality, temperament, maturation, environment et al, mean that everyone is different and importantly everyone is dynamic.

Umbrella under an umbrella? @ Wikipedia  

Another term used by some people (including researchers) is that of 'neurotypical'  to somehow denote not-autism. For me however, that's always been a little too simplistic. It implied (a) that there is a definite line between autism and not-autism which kinda over-simplifies things including the broader autism phenotype (BAP), and (b) that there is such as thing as 'neurotypical' and indeed is counter to the phrase: 'if you've met one person, you've met one person' which should surely be as pertinent to not-autism as it is to autism; if you get me?

These concepts are relevant as today I'm talking about two papers: a paper by Whitehouse & Stanley* (open-access) questioning whether autism is one condition or multiple conditions, and a paper by Moreno-De-Luca and colleagues** which implies that we should even be doing away with behaviourally-defined labels such as autism and schizophrenia in favour of an altogether broader definition of 'developmental brain dysfunction' or DBD.

Regular readers might recognise the name Andrew Whitehouse as being one and the same researcher who has talked about various autism-related results from the Raine study (see here and here and here). His latest opinion piece builds on the fact that despite the 70 year anniversary since the first description of autism was published by Kanner (with appropriate consideration for Hans Asperger too), alongside huge amounts of time, money and research efforts, we are really still only scratching the research surface of the condition(s) known as autism. Certainly science hasn't yet come up with many defining 'universal' reasons to account for the appearance of the the clustering of symptoms and as for intervention options, well take a look at the recent draft guidance from NICE to see what I mean. One of the main stumbling blocks he and his colleague opine on is the "phenotypic variability" and how moves should be made towards defining smaller subgroups on the autism spectrum. In effect talking about the autisms over autism as per another very interesting paper by Poot*** (open-access).

To many people this is not new news. That the search for an 'autism gene' or 'autism genetic mutation' (sorry about the cold science term) or indeed 'autism environmental variable' has so far been underwhelming in terms of results coupled to the cost/benefit ratio of such research for example, is testament to the variability present in both autism and not-autism. This demonstrates also how complex a continuum the autism spectrum is. Indeed how complex a thing the human spectrum is****.

Likewise when it comes to intervention, I've talked before on this blog about how we should perhaps be re-assessing the way we look at proposed interventions and in particular focusing on subgroup responses rather than some almighty universal spectrum response to denote intervention success of not. Without equating autism with cancer or vice-versa, the recent opinion paper by Stewart & Kurzrock***** (open-access) might inform this methodological discussion somewhat further.

Whitehouse and Stanley also talk about the lessons learned from cerebral palsy (CP) and how where once CP was thought of as "a unitary disorder", the more contemporary view is somewhat more "umbrella" like. I've covered CP on this blog before so won't say much more about that; I think many people might agree that autism is similarly an umbrella term; even more so when the DSM-V comes into force in literally weeks time (Monday 20th May 2013 apparently).

The Moreno-De-Luca paper goes one stage further. As per the paper and some associated media attention (see here) the suggestion is that not only is there the autisms, but that because of the various overlapping genetic features between the autisms and conditions such as schizophrenia (the schizophrenias), we should be looking at using an even more over-arching concept to group these collected diagnoses together: developmental brain dysfunction (DBD). A sort of umbrella for the umbrella if you like. It's not a new suggestion by the way****** (open-access).

I can imagine that your view of autism - be that a personal perspective of autism, a parental perspective or just an observer looking in - is probably going to influence how you receive this suggestion to some degree. For a researcher looking at the possibility of shared genetics or even epigenetics between conditions which might overlap, there is some sense in looking at the bigger picture. My recent post on common ground (see here) based on the 'five psychiatric disorders linked' paper******* kinda reiterates this position alongside other papers including this one from Caamaño and colleagues******** on subclinical comorbid psychopathology. That and the fact that there might be some convergence when it comes to the autism and schizophrenia spectrums for example (see here) also makes a case. The authors sum it up well: "genes don't respect our diagnostic classification boundaries, but that really isn't surprising given the overlapping symptoms and frequent co-existence of neurodevelopmental disorders".

Other perspectives - and I am only speculating on such viewpoints - might not necessarily share the same sentiments. Aside from leaving out any important relationship that genes might have with little things like the environment, as in maternal immune activation during pregnancy, or all those correlations with other facets of modern living (see here and here), the implication of 'brain dysfunction' takes us back to the whole neurotypical 'us and them' scenario and the questions: what exactly is 'normal' brain function? and what factors can and do affect it? I might add that I can also see how some people might not necessarily be taken with the concept of autism being akin to 'brain dysfunction' in the same way that lumping autism and schizophrenia together might have other, more societal connotations.

I'm going to stop there with this post, save any charges of over-analysing the papers and potential implications. Accepting that a diagnosis is currently the best way for people to [theoretically] receive the help and support they may need, I'm not sure we are in a position to re-write the diagnostic manuals just yet with autism and schizophrenia in mind. That umbrella-ing (is that a word?) autism with other conditions might also impact on the autism awareness message that we've all just had with World Autism Awareness Day is another consideration to bear in mind.

That being said, I do think we have already started to see hints of this brave new world of links and threads coming together. The DSM-V diagnosis of autism seems to be quite explicitly spectral and whilst not yet knowing the consequences of removing diagnoses such as Asperger syndrome and how that Social Communication Disorder category will work, the idea behind the change is sub-type removal similar to that envisaged for schizophrenia (see here and here). I'm not altogether sure but I am also wondering how and whether there will be any exclusion criteria on for example a dual diagnosis of autism and schizophrenia in the new guidance and what effect this might have? We wait and see.

"OK stop already". And I will.

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* Whitehouse AJO. & Stanley FJ. Is autism one or multiple disorders? Med J Aust 2013; 198: 302-303.

** Moreno-De-Luca A. et al. Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence. The Lancet Neurology. 2013; 12: 406-414.

*** Poot M. Towards identification of individual etiologies by resolving genomic and biological conundrums in patients with autism spectrum disorders. Molecular Syndromology. February 2013.

**** Mitchell KJ. What is complex about complex disorders? Genome Biology. 2012; 13: 237.

***** Stewart DJ. & Kurzrock R. Fool's gold, lost treasures, and the randomized clinical trial. BMC Cancer 2013; 13: 193.

****** Hrdlicka M. & Dudova I. Controversies in autism: is a broader model of social disorders needed? Child & Adolescent Psychiatry and Mental Health 2013; 7: 9.

******* Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis The Lancet. February 2013.

******** Caamaño M. et al. Psychopathology in children and adolescents with ASD without mental retardation. JADD March 2013.

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Whitehouse AJ, & Stanley FJ (2013). Is autism one or multiple disorders? The Medical journal of Australia, 198 (6), 302-3 PMID: 23545020

Moreno-De-Luca A, Myers SM, Challman TD, Moreno-De-Luca D, Evans DW, & Ledbetter DH (2013). Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence. Lancet neurology, 12 (4), 406-14 PMID: 23518333

Autism and ID: Born again?

The recent papers published by Amanda Langridge and colleagues* (open-access) and Venla Lehti and colleagues** set some cogs running in my grey/pink matter recently with their research focus on our very earliest days and what (if any) risk for the autism spectrum disorders (ASDs) there may be when things don't go as smoothly as expected during that magical nine months and just before/after.

A new child is Björn @ Wikipedia  

I've previously talked about factors during pregnancy and parturition (child birth) in relation to autism as per posts like this one from quite a while back and all that newer stuff from initiatives like CHARGE. Combined with investigations examining everything from season of birth to birth weight to birth order, there is quite a bit of peer-reviewed literature on this area with autism in mind.

Having said all that, I don't want to give any false impression that there are any hard and fast rules about in-utero or birth factors being linked to autism, because there aren't. Indeed, it's all even further complicated by lots of other conditions potentially being linked also to pregnancy and birth and a flurry of speculation.

Nevertheless, there are some interesting points raised by each of the articles presented today which are worthy of discussion. So in turn:

The Langridge paper:

• Open-access so please do have a look at it for yourself. A huge data mining study examining the "total population data sets of children diagnosed with ID and ASD in Western Australia (WA)" between 1984 and 1999 (included among N=383,153) to see if there were any links between "maternal conditions and perinatal factors for all WA children subsequently diagnosed with ASD, with or without ID, and children with varying severity of ID, and compare findings to the rest of the birth cohort of unaffected children". Lots of description of the population and how autism and intellectual disability (ID) were ascertained. Also how this huge dataset were analysed.
• Results: yes, quite a few depending on how the data were modelled and what background characteristics were controlled for. Notably suggesting that those diagnosed with an ID were more likely to have experienced some episode or event in their earliest days when compared with those diagnosed with an ASD. I'll leave you to pick out the associations but there were some interesting findings related to gestational diabetes, threatened abortion before 20 weeks and pregnancy hypertension.
• Soundbite: "small head circumference was associated with reduced risk of ASD" bearing in mind head size and autism is a complicated area.
• Another soundbite: "These findings support the concept that ID and ASD may lie on a continuum, as opposed to being different clinical entities, and may explain why there are various ID subtypes of ASD (i.e. ASD with and without ID)". I can't fault their logic. Perhaps another addition to the spectral model of behaviour and psychiatry since that is the direction things seem to be heading these days.

The Lehti paper examined IVF (In vitro fertilisation) and...

• A very organised paper which bluntly asked: "Does IVF increase the risk of autism spectrum disorders (ASDs)?"
• Another very big participant group (autism: n=4164, matched controls: n=16,582); all born in Finland.
• Result: "This study showed no increased risk of ASDs in children born after IVF" as per other studies in this general area.
• But...  and it is a but, the connection in particular between IVF and boys with Asperger syndrome (AS) might need to be looked at with greater assiduity. Having said that, any study had better be done sooner rather than later since AS as an independent diagnostic entity is due to be phased into ASD in the latest DSM revision in May (2013). Please note: this does not mean that people will lose their AS diagnosis though.

Combined, these papers add quite a bit to the literature on birth factors in relation to autism bearing in mind risk is risk and not proof. Although events in-utero and during childbirth have always been on the autism research radar, I am noting a renewed interest in all things early development with autism in mind in recent years as per areas like maternal immune activation and autism risk (think Paul Patterson and mice) and some continued interest in the environment (think pollution and correlation for a start). The suggestion that the placenta for example may play a "potent role in autism risk" represents quite an exciting research opportunity, mirroring research on other health-related conditions. Thin-fat body anyone?  

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* Langridge A. et al. Maternal conditions and perinatal characteristics associated with autism spectrum disorder and intellectual disability. PLoS ONE. 2013; 8: e50963.

** Lehti V. et al. Autism spectrum disorders in IVF children: a national case-control study in Finland. Hum Reprod. 2013 Jan 4.

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Amanda T. Langridge, Emma J. Glasson, Natasha Nassar, Peter Jacoby, Craig Pennell, Ronald Hagan, Jenny Bourke, Helen Leonard, & Fiona J. Stanley (2013). Maternal Conditions and Perinatal Characteristics Associated with Autism Spectrum Disorder and Intellectual Disability PLoS ONE : 10.1371/journal.pone.0050963

The continuous nature of autism symptoms

The proposed revisions to the DSM re-definition of autism becoming an actuality are fast approaching over the clinical horizon as we are told that the die has now been cast. Although there is still considerable debate about what the changes will do to the numbers of people eligible to receive a formal diagnosis of the label autism as per previous revisions, one of the more well-received changes to the criteria is the formal acceptance that autism is a spectral condition, and that the severity of presentation of the soon-to-be dyad of core symptoms, reflects as much.

Prisms @ Wikipedia  

The spectrum concept, whilst not wholly supported by everyone, provides an intellectually satisfying description of the heterogeneity present in autism but also implies a few important principles must be accepted.

One of them is the assumption that for autistic traits to become clinically relevant, there must be a start point in the same way that the visible light spectrum has a very fuzzy beginning. Following this argument, and accepting that diagnosing clinicians are still as much artists as they are physicians when it comes to autism and other developmental disorders solely reliant on observation and developmental history, the question is: where do the symptoms of autism begin?

A recent paper by Kamio and colleagues* (open-access) looked at this question and came to some very interesting conclusions.

• The name of the Kamio game was to look at the quantitative distribution of autistic traits in a rather large normative population sample of children (N=22,529) in Japan aged 6-15 years based on parental ratings of the Social Responsiveness Scale (SRS). There were also other data included in the results based on child psychiatric patients with an autism spectrum disorder (ASD) (n=257) and without (n=157) but receiving other diagnoses such as ADHD, schizophrenia and learning disability. And also a typically developing group (n=61) with no neuropsychiatric history. These latter groups were included primarily to validate and calibrate the Japanese version of the SRS. Normative data from a US sample used to validate the US version of the SRS were also included as some points.
• Results: there were quite a few of them. The main message is, as per the title of this post, that results "add substantial evidence in support of the continuous nature of autistic traits in the general population" and specifically "there was no evidence of a natural cutoff that differentiated children categorically affected from those unaffected by ASD".
• The male : female differences were also confirmatory that boys exhibit quantitatively higher autistic trait scores than girls as per other findings.
• An interesting thought is entertained based on the capability of the SRS to distinguish autism from other conditions, "autistic traits, when present, exacerbate other types of psychopathology when they cooccur with autistic traits as comorbid conditions". In effect autism might magnify the symptoms of other comorbid conditions such as ADHD.

Some of this data takes me back to my Ph.D write-up days, and what I was once told by someone involved in my studies. It went something like this: autism is a distinct condition diagnosable on the basis of that triad (soon to be dyad) of symptoms, but most if not all of the traits present in autism are to some extent also present during typical development at specific periods. I must admit that at the time I had some trouble believing this, after all autism can be associated with some very extreme characteristics and symptoms.

As the years have gone on however, I've understood that those lining up of toys, spinning of wheels, flicking of fingers, even pronoun reversal and other communicative features, are present in typically developing children too at specific times of development; autism merely describes the unusual persistence of these behaviours or quantitative differences in their presentation. Of course this takes no account of symptoms which might not necessarily be totally psychological in nature, as per what can happen when gastrointestinal symptoms are present and potentially exert an effect on behaviour for example.

With all that in mind, it's not so surprising that there is no distinguishable natural cut-off point when it comes to autism or not-autism in those border regions outside of the lines in the sand that we draw, or rather our diagnosing clinicians and clinical symptom makers impose. I assume that's why we also have the concept of the broader phenotype further illustrating these fuzzy boundaries.

That being said Kamio and colleagues do suggest that "segments of the autistic continuum may be comprised of small clusters of discrete disorders". This point really intrigues me, in that they are in effect talking about more than one type of autism; a spectral type which basically runs from typical development through to autism, and a second type which includes a number of known conditions which manifest autism, such as Fragile X syndrome and indeed, that recent in-born error of branched chain amino acid condition. The rise of the autisms indeed.

I must finally pass some comment on that comorbidity suggestion which basically theorises that autism might magnify the effects of certain comorbidities. It really is an interesting finding which is deserving of a whole lot more study, particularly in light of how much increased risk of other comorbidity such as ADHD a diagnosis of autism can convey. Readers might know that I have a bit of a thing for comorbidity and autism on this blog, and indeed how tackling comorbidity - however this manifests - can sometimes impact on core presentation. Think dietary intervention as one example.

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* Kamio Y. et al. Quantitative autistic traits ascertained in a national survey of 22 529 Japanese schoolchildren. Acta Psychiatr Scand. November 2012.

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Kamio, Y., Inada, N., Moriwaki, A., Kuroda, M., Koyama, T., Tsujii, H., Kawakubo, Y., Kuwabara, H., Tsuchiya, K., Uno, Y., & Constantino, J. (2012). Quantitative autistic traits ascertained in a national survey of 22 529 Japanese schoolchildren Acta Psychiatrica Scandinavica DOI: 10.1111/acps.12034