Facial phenotypes of autism continued

Quite a few years back, I talked on this blog about research suggesting that the structure of faces might be an important research area when it comes to at least some autism (see here). As per that blogging occasion, I cautioned that one has to be a little careful in this area of science so as not to make too many sweeping generalisations from any findings, but that there may some important *associations* to be noted. Such associations may, for example, be particularly important in the context of various genetic syndromes manifesting specific facial features as well as expressing autism or autistic traits.

In recent times I've noticed a couple of articles emerging on this topic from the University of Western Australia under the guidance of Prof. Andrew Whitehouse. Research from Prof. Whitehouse has been discussed before on this blog (see here and see here for examples) and I have to say I'm quite a fan of some of his, and his teams, efforts.

This time around I'm blogging about the papers by Maryam Boutrus and colleagues [1] and Diana Weiting Tan and colleagues [2] who talked about applying "a hypothesis-driven approach" to the study of facial phenotypes when it comes to autism and then offered up one such hypothesis: "comparing the facial masculinity/femininity of boys and girls with ASD [autism spectrum disorder] to that of typically-developing children" in the context of elevated prenatal testosterone exposure being *associated* with autism (albeit probably not universally so). I yet again hasten to add that the term 'typically-developing' is the authors' choice not mine.

The Tan paper talks about 3D imaging of faces from "a normative sample of 48 boys and 53 girls" which built up a kind of composite image to differentiate boy faces from girl faces. Some 21 facial landmarks were initially used but eventually this was boiled down into 11 selected facial features: "three linear distances (alar-base width, nose height and upper lip height) and eight geodesic distances (outer-canthal width, forehead width, forehead height, right upper cheek height, nasal tip protrusion, nose height, upper lip height, and nasal bridge length)."

The second part of the study then applied these 11 parameters deemed useful for differentiating "the faces of typically-developing boys and girls" and used them to compare faces of children diagnosed with ASD compared with those with no diagnosis - "54 autistic and 54 control boys... and also for 20 autistic and 60 control girls." This involved the application of "an overall facial masculinity/femininity index" providing a scale scoring between extreme masculinity and extreme femininity.

Results: "autistic boys had significantly lower gender scores for their faces (i.e., more masculine) when compared to the control boys." Also: "For girls, ANOVA showed that gender scores were significantly lower (i.e., less feminine) for the ASD group compared to the control group." These findings were accompanied by some equally interesting observations in relation to how the gender context of facial features seemed to tie into aspects of autistic presentation. Specifically: "increased facial masculinity in the ASD group correlated with more social-communication difficulties based on the Social Affect score derived from the Autism Diagnostic Observation Scale-Generic (ADOS-G)." No such relationship was reported in relation to the other part of the diagnostic dyad currently used to diagnose autism - Restricted and Repetitive Behaviours (RRBs).

Obviously, more needs to be done in this area. The sample size for both parts of the study reported by Tan et al is preliminary at best and replication is most definitely the name of the research game. I have to say that outside of the sexing/gendering of faces with autism in mind, I'm particularly interested in how facial masculinity might be linked to greater issues with social affect. One wonders whether this might for example, extend to the more general population and indeed, sub-clinical signs and symptoms of autism such as that noted in the broader autism phenotype (BAP)?

To close, although unrelated to the material covered today, facial phenotyping is starting to ask some other interesting questions too...

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[1] Boutrus M. et al. Investigating facial phenotype in autism spectrum conditions: The importance of a hypothesis driven approach. Autism Res. 2017 Aug 17.

[2] Tan DW. et al. Hypermasculinised facial morphology in boys and girls with Autism Spectrum Disorder and its association with symptomatology. Sci Rep. 2017; 7: 9348.

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On drinking water lithium content and dementia risk

"Lithium in tap water may cut dementia" went the BBC website headline reporting the study results published by Lars Vedel Kessing and colleagues [1]. The authors relied on some of those oh-so important Scandinavian population registries and other data to examine a possible connection between drinking water lithium levels and risk of "diagnosis of dementia in a hospital inpatient or outpatient contact."

Alongside looking at data for some 70,000 people diagnosed with dementia and nearly three-quarters of a million non-diagnosed controls, researchers estimated lithium exposure via drinking water based on data from over 150 waterworks. The relationship they observed between lithium in drinking water and risk of dementia diagnosis was not altogether straight-forward as "higher long-term lithium exposure from drinking water may be associated with a lower incidence of dementia" but the relationship was described as "nonlinear." Nonlinear meant that those with drinking water levels of lithium at moderate levels - between 5.1 and 10 micrograms per litre - actually showed an increased risk of dementia compared to those who had low levels of lithium (below 5 micrograms per litre) in their drinking water. The authors add: "Nonlinear dose-response associations are often found in medicine, with a gradual increase in drug response at the lower doses and gradual leveling off in response at the highest doses."

The authors do caution about their results and the various limitations attached to the findings. Not least is their reliance on a diagnosis of dementia as a starting point and how factors such as "accessibility to health care services that vary geographically" may have influenced such results. Indeed they note: "accessibility to health care services is increased in eastern regions of Denmark, where lithium levels generally are higher, and decreased in western regions, specifically in Jutland, where lithium levels generally are lower." They also found: "a direct inverse association with increasing risk of dementia in rural areas" as part of a sensitivity analysis, and as noted in some other studies [2]. More investigation is definitely required.

But these remain interesting results. Lithium is a treatment of choice when it comes to conditions such as bipolar disorder (see here). I've also talked about this stuff in connection to some other important research looking at suicide reduction too (see here) based on quite a body of research [3] (and growing all the time [4]) but minus simplifying something like suicide ideation, attempts or completion all down to lithium 'deficiency'. In relation to the possible effects on dementia risk, this is not the first time that lithium has been discussed as per findings looking at dementia risk in cases of lithium treated bipolar disorder [5] (something else that has been discussed on this blog - see here).

Questions still however remain. The mechanism of effect(s) is still to be suitably deciphered and one also needs to keep in mind the safety profile of lithium [6] as a balance to any risk-reduction effects on dementia or anything else. This is particularly relevant to those who might be at particular risk for dementia [7]. I'll also add that any focus on lithium intake and dementia also needs to keep in mind other *associations* that have been previously discussed in the peer-reviewed research literature such as that talking about vitamin D deficiency and dementia risk for example (see here) as part of a wider research interest in vitamin D and cognitive functions in the context of ageing (see here).

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[1] Kessing LV. et al. Association of Lithium in Drinking Water With the Incidence of Dementia. JAMA Psychiatry. 2017 Aug 23.

[2] Contador I. et al. Childhood and Adulthood Rural Residence Increases the Risk of Dementia: NEDICES Study. Curr Alzheimer Res. 2015;12(4):350-7.

[3] Cipriani A. et al. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013 Jun 27;346:f3646.

[4] Kanehisa M. et al. Serum lithium levels and suicide attempts: a case-controlled comparison in lithium therapy-naive individuals. Psychopharmacology (Berl). 2017 Aug 28.

[5] Gerhard T. et al. Lithium treatment and risk for dementia in adults with bipolar disorder: population-based cohort study. Br J Psychiatry. 2015 Jul;207(1):46-51.

[6] Albert U. et al. Lithium treatment and potential long-term side effects: a systematic review of the literature. Riv Psichiatr. 2014 Jan-Feb;49(1):12-21.

[7] Holroyd S. & Rabins PV. A Retrospective Chart Review of Lithium Side Effects in a Geriatric Outpatient Population. Am J Geriatr Psychiatry. 1994 Autumn;2(4):346-351.

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School refusal is 'pervasive' in students with autism

The findings reported by Ellen Kathrine Munkhaugen and colleagues [1] make for worrying reading when it comes to the concept of school refusal in the context of autism spectrum disorders (ASD). Detailing how school refusal - where a child/young adult refuse to attend school because of the anxiety or distress it causes - was quite a bit more common among students with ASD compared with non-ASD students over a 20-day inspection period, the authors highlight an important issue. Indeed, an issue that has already been noted in the peer-reviewed literature [2] and has accompanying advice from the one of the larger autism organisations here in Blighty (see here).

As I've mentioned a few times on this blog, school can be a significant source of stress for many children on the autism spectrum (see here). We can for example, um-and-ah about the merits of inclusive vs. specialised education settings in the context of autism or how bullying seems to be something that quite a few children unfortunately, have to contend with (see here), but the bottom line is that stress is a likely passenger for many children with autism as they navigate the complicated world that is the childhood education system. And it is therefore perhaps unsurprising that for some children/young adults with autism, school might not be a place they necessarily want to spend a lot of time in.

One of the worries (among the many) that I have about results such as the ones from Munkhaugen et al is how, in these days of real focus on 'bottoms on seats' in school at least here in Blighty, such findings have the potential to single out families. If one reads the guidance from the UK Department of Education on the topic of school attendance (see here) for example, it's not difficult to see how tools like 'parenting contracts' and even 'parenting orders' might be something not unfamiliar in the context of school refusal. I say this bearing in mind that quite a few parents are already having to fight their child's corner when it comes to schools and local authorities providing appropriate school resources and allowances (see here) also potentially impacting on school refusal.

There are no easy or universal solutions to the issue of school refusal in the context of autism. Yes, schools can perhaps make provisions to help a child, but this needs to be set in the context that they have a school full of children who are similarly relying on them to provide the best educational experience that they can. The current cash-flow situation that many schools are faced with is also pertinent (see here). The other option is to try to manage school refusal behaviours particularly when chronic. This might first include investigations relevant to comorbid conditions that might also impact on school refusal [3] and then looking to strategies to help minimise the possible causes of school refusal [4] (tailoring them to the individual of course). Anxiety seems to be a key feature of school refusal (see here) and hence, moves to address this issue - and the core symptoms that seemed to be linked to it - should probably be part of any intervention strategy (see here). I hold back from making a big case for moving a child to a new school or into home education because this should really be a very last resort and come with their own potential issues.

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[1] Munkhaugen. EK. et al. School refusal behaviour: Are children and adolescents with autism spectrum disorder at a higher risk? Research in Autism Spectrum Disorders. 2017; 41-42: 31-38.

[2] Kurita H. School refusal in pervasive developmental disorders. J Autism Dev Disord. 1991 Mar;21(1):1-15.

[3] Egger HL. et al. School Refusal and Psychiatric Disorders: A Community Study. Journal of the American Academy of Child & Adolescent Psychiatry. 2003; 42: 797-807.

[4] Kearney CA. & Silverman WK. A Preliminary Analysis of a Functional Model of Assessment and Treatment for School Refusal Behavior. Behavior Modification. 1990; 14: 340-366.

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On puzzle pieces and autism

At first reading I was a little confused by the paper published by Morton Ann Gernsbacher and colleagues [1] talking about how puzzle pieces used as part of various organisations insignia concerned with autism might stir up the wrong kind of sentiments about the diagnosis. Confused because, with all the pressing needs related to autism research and practice - diagnosis, services, comorbidities, quality of life, happiness! - it seemed a little trivial to publish a research paper on what symbols an organisation might wish to choose and their subsequent connotations.

With a little more thought, my opinion of this research softened slightly as I can see how there might be some important psychological forces at work based on the imagery used to represent autism. Indeed, the puzzle piece and autism has been the topic of quite a few discussions in various quarters (see here) reflective of how some views and opinions about autism have changed down the years.

On this particular research occasion authors questioned some 400 people about the associations the general public might make regarding the use of the puzzle piece in the context of autism. They concluded that: "Puzzle pieces, both those used as autism logos and those used more generically, evoked negative implicit associations... and negative explicit associations" onward to associations with words like "incompleteness, imperfection, and oddity." Authors even concluded that: "If an organization's intention for using puzzle-piece imagery is to evoke negative associations, our results suggest the organization's use of puzzle-piece imagery is apt." Whoa. Where did that come from I wonder?

I've kinda approached this topic before on this blog in the context of how associations between organisations here in Blighty and brands such as Thomas the Tank Engine might have similar connotations when it comes to the perception of autism (see here). I suppose one could equally suggest that whilst something like Thomas the Tank Engine is enjoyed by many children on the autism spectrum (as well as many children not on the autism spectrum!) there is always a risk that it might feed into a stereotype. In the case of trains, one can see the old 'systemising' link coming through and onward the shadow of the 'extreme male brain' thingy-majig that has, I think, been rather overplayed in the context of autism (see here). Indeed, with the classical association between trains and boys ('boys and their toys') one might be inclined to ask what such an association might mean for the the perception of the presentation of autism in females for example? And onward what imagery/association would be most appropriate in the context of female autism minus any sweeping generalisations?

Of course, one can find meaning in any imagery used in the context of any organisation linked to a specific diagnosis or condition. At least some opinions on this topic are likely also to reflect specific viewpoints about the organisation in question as per the MSSNG project funded by Autism Speaks (who coincidentally use a puzzle piece in their logo) and how that has been interpreted in some quarters. I do think we have to be quite careful in this area not to slide from one extreme to another in relation to how wide the autism spectrum is and indeed, ensuring representation of the entire autism spectrum when it comes to public perceptions (see here). I have one suggestion: with all the creative talent out there on the autism spectrum, perhaps organisations linked to autism should ask their members with autism to help design new logos...

To close, some artwork from a rather talented chap who might be able to help.

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[1] Gernsbacher MA. et al. Do puzzle pieces and autism puzzle piece logos evoke negative associations? Autism. 2017 Aug 1:1362361317727125.

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Epilepsy (or comorbidity?) impacts on academic achievement

The results of the systematic review from Wo and colleagues [1] highlight something of an important trend in the peer-reviewed science domain looking at how epilepsy may have various important implications for all manner of different issues outside of just the presence of seizures. This time around the focus was on academic achievement.

Drawing on data from 20 studies that "assessed the prevalence of academic difficulties in children with epilepsy (CWE) of normal intelligence, and its associating factors" researchers concluded that nearly three-quarters of studies found that CWE "had significantly lower academic achievement scores" compared with controls or population norms. The authors added that despite improvements in seizure frequency for some, issues with academic achievement still remained.

There were also some more positive points to take from the Wo findings: "Higher parental education and children with higher IQ, and [who] had better attention or had a positive attitude towards epilepsy, were associated with higher academic achievement score." I can't readily explain how (and indeed whether) a 'positive attitude' towards ones epilepsy might influence academic achievement but one might see how children with a high IQ, nurtured under the right circumstances, might have somewhat more protection against 'lower academic achievement scores'.

I think it is important to take a step back here before any sweeping generalisations are made. Not every study included for review by Wo et al indicated a relationship between epilepsy and academic achievement. This is an important point, and stresses how under the very heterogeneous label of epilepsy - some types more readily associated with conditions such as learning (intellectual) disability - not everyone is going to be potentially 'disadvantaged' in an academic sense as a result. This also bearing in mind that academic achievement is not always a great 'marker' when it comes to what one might define as a successful life; plenty of people do alright / make it big without great academic achievement scores.

Added to the Wo study, I also want to introduce the findings reported by Gillberg and colleagues [2] providing something of an example of how many other factors might potentially affect academic achievement in the context of epilepsy. Gillberg et al once again refer to their ESSENCE description - early symptomatic syndromes eliciting neurodevelopmental clinical examinations - to denote how diagnoses affecting behaviour and development rarely appear in isolation to one and another. They observed that: "The rate of ESSENCE in febrile seizures and epilepsy was significantly higher than in the total population without seizures" based on the examination over 27,000 parent reports of twins. I might venture further into their suggestion that: "Febrile seizures alone could be seen as a marker for a broader ESSENCE phenotype in some cases" specifically in the context of autism on a separate blogging occasion (see here) but for now, the message is that epilepsy probably does not appear (diagnostically) alone and said comorbidity *might* also be important to academic achievement and no doubt, other outcomes too.

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[1] Wo SW. et al. The impact of epilepsy on academic achievement in children with normal intelligence and without major comorbidities: A systematic review. Epilepsy Res. 2017 Jul 20;136:35-45.

[2] Gillberg C. et al. Febrile Seizures and Epilepsy: Association With Autism and Other Neurodevelopmental Disorders in the Child and Adolescent Twin Study in Sweden. Pediatr Neurol. 2017 Jun 8. pii: S0887-8994(17)30178-9.

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Metformin to tackle medication induced weight gain in autism continued

The results of the open-label extension trial on the use of "Metformin for the Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism" reported by Benjamin Handen and colleagues [1] is blogging fodder for today. Continuing a research interest from this group (see here), the idea that weight and related side-effects from certain antipsychotic medicines can be managed by a drug readily used to treat type 2 diabetes receives yet more support.

Last time around [2] researchers showed that under double-blind, placebo controlled conditions, metformin was fairly well-tolerated and did aid in "decreasing weight gain associated with atypical antipsychotic use" in children and young adults diagnosed with an autism spectrum disorder (ASD). This latest publication detailed what happened when everyone - well, 85% of the original cohort - went on metformin in terms of their body mass index (BMI) and "additional body composition and metabolic parameters" for an additional 16 weeks.

Results: well, as would probably be expected, "participants initially taking placebo during the RCT [randomised controlled trial] had reduced BMI z-scores" when metformin was introduced. For those who were already taking metformin during the original trial, prior reductions in BMI were maintained but they "did not experience additional weight loss." I might also add that 'fairly well-tolerated' meant that: "Three participants discontinued treatment due to an adverse event."

These are important findings and add to other preliminary research findings in this area [3]. I know many people (including myself) have some reservations about adding in medicines to treat the side-effects of other medicines (as well as the conditions for prescribing antipsychotics in the first place [4]), but given what elevated BMI scores can mean to physical health and associated health risks, this is one occasion where intervention might be truly life-saving (with appropriate clinical monitoring assumed). Further studies are indicated.

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[1] Handen BL. et al. A Randomized, Placebo-Controlled Trial of Metformin for the Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorder: Open-Label Extension. Journal of the American Academy of Child & Adolescent Psychiatry. 2017. Aug 19.

[2] Anagnostou E. et al. Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder: A Randomized Clinical Trial.  JAMA Psychiatry. 2016 Sep 1;73(9):928-37.

[3] Wink LK. et al. Brief Report: Metformin for Antipsychotic-Induced Weight Gain in Youth with Autism Spectrum Disorder. J Autism Dev Disord. 2017 Jul;47(7):2290-2294.

[4] Jackel C. et al. Factors Associated with Developmental Behavioral Pediatricians Prescribing Psychotropic Medication to Children with Autism Spectrum Disorder: A Study of Three DBPNet Sites. J Dev Behav Pediatr. 2017 Aug 10.

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