Thursday, 23 November 2017

Yet more "lost their diagnosis" and autism research. Not for all but...

The question posed in the title of the paper by Solomon and colleagues [1] - "What will my child's future hold?" - examining the "phenotypes of autism spectrum disorder (ASD) based on trajectories of intellectual development from early (ages 2-3 ½) to middle (ages 5-8) childhood" - is an interesting one and a question that many parents/caregivers will probably ask or have asked at one point or another.

It's also an important question because throughout all the sweeping statements that have been made about the autism spectrum past and present, the generalisation that ALL autism is 'lifelong' is one of the more popular ones despite [peer-reviewed scientific] evidence pointing to the contrary (see here for example).

By saying all that I'm not trying to minimise the effect(s) that autism has on the lives of many, many people day-in and day-out throughout their lives and the varying requirements for suitable support. Just that, as per the notion 'if you've met one autistic person, you've met one person with autism' (or words to that effect), the experience(s) of continually hitting the diagnostic thresholds across the lifespan is likely to be different for different people as a function of many, many different factors. I say this acknowledging for example, the rise of 'compensation' in the context of autism recently (see here).

Solomon et al drew on data derived from the Autism Phenome Project including over 100 children "initially diagnosed with ASD." Researchers were particularly interested in cognitive trajectories as measured by IQ between 2 and 8 years of age and whether autistic and other related symptoms/traits were also affected by any changes to intellectual functioning. As it happens, they might be...

"A four class model best represented the data" meaning that participants typically fell into one of four 'patterns' with regards to their intellectual functions/trajectories. This included: "High Challenges (25.5%), Stable Low (17.6%), Changers (35.3%), and Lesser Challenges (21.6%) groups." As per the title of this post, I'm particularly interested in those described as 'Changers' or 'Lesser Challenges' who "demonstrated the most significant IQ change that was accompanied by adaptive communication improvement and declining externalizing symptoms" and "showed a significant reduction in ASD symptom severity" respectively. Indeed, within the Lesser Challenges group we are told that "by age 8, 14% of them no longer met ADOS-2 criteria for ASD." In other words, they did not reach cutoffs for the diagnostic criteria for an autism spectrum disorder (ASD) using a gold-standard assessment instrument and so could be considered not autistic by diagnostic standards.

Also important to the Solomon findings was the observation that: "Intervention history was not associated with group status." I'm not going to say too much more about this at the present time, but if replicated, the implications are pretty huge particularly where the current drive towards early intervention in autism is leading us (see here).

Although not always welcomed by everyone, the idea that a diagnosis of autism is permanent and immutable for all does not stand up well to scientific scrutiny. The best guess estimates currently suggest that somewhere between 9 and 12% of children/adults will 'lose their diagnosis' (see here and see here); also potentially affecting the presence of some important over-represented comorbidity too (see here). The old 'they weren't autistic in the first place' argument is a typical response from some nay-sayers on this topic; something which unfortunately contributes to the denigration of some important parts of the autism spectrum. Certainly a part of the autism spectrum that we can learn a lot from as the Solomon results are starting to show.

Indeed, given the other 'biological' focuses of the Autism Phenone Project [2] I'm hoping that we'll eventually see further results from this initiative providing important information on possible biological correlates linked to those who "no longer met ADOS-2 criteria for ASD". If ever there was a research study needed on autism, it is one including a little more biological and genetic information about those who move from autism to not-autism and what it could mean for the wider autism spectrum and particularly the concept of 'the plural autisms'...

To close, 'I want a deep fried turkey'....


[1] Solomon M. et al. What will my child's future hold? phenotypes of intellectual development in 2-8-year-olds with autism spectrum disorder. Autism Res. 2017 Oct 27.

[2] Onore CE. et al. Levels of soluble platelet endothelial cell adhesion molecule-1 and P-selectin are decreased in children with autism spectrum disorder. Biol Psychiatry. 2012 Dec 15;72(12):1020-5.


Wednesday, 22 November 2017

Antibodies against gluten in autism don't correlate with leaky gut markers

The paper by Jan Józefczuk and colleagues [1] provided some intriguing observations pertinent to quite a few topics previously discussed on this blog. Not only was there mention of anti-gliadin antibodies (AGA) and more specifically the finding that increased IgG-AGA was found in a quarter of their 77 participants with autism included for study, but also the important point: "An increased production of antibodies related to gliadin and neural TG6 [neural transglutaminase 6in ASD [autism spectrum disorder] children is not related to serological markers of an impaired intestinal barrier."

It's worthwhile breaking down some of the details of the Józefczuk findings and what they might mean. I'll warn you that this is likely to be a bit of a long-read blog post so please, get comfy and read on...

So, AGA and more specifically, IgG-AGA represent the immune system 'recognising' gliadin, an important part of the protein gluten. IgG-AGA are typically found in many people diagnosed with the archetypal gluten-related autoimmune condition called coeliac (celiac) disease (although this measure is not considered diagnostic) but also alongside other more 'non-coeliac' gluten sensitivity conditions too (see here). The finding of elevated IgG AGA in cases of autism is by no means a new one (see here) (yes, this data came from the AGRE program [2] so no quibbling about the diagnosis of autism or anything like that). Other data has indicated that the presence of such antibodies seems to be a good reason to attempt a gluten-free diet (see here) which is music to my autism research ears (see here) and a good evidence-based reason to quiet down those who might 'challenge' such dietary intervention in the context of [some] autism. Then also is the idea that the presence of IgG AGA in conditions not totally unrelated to autism (see here) *might* play an important role in something like 'peripheral' inflammation [3] and whether the same could be true for [some] autism...

Next: "antibodies against neural transglutaminase 6 (TG6)" described by the authors as present in about 5% of their cohort is also an important finding. Turning up in a variety of different conditions [4] (although not yet considered 'mainstream' in certain quarters), some of the most interesting, and potentially relevant, labels where TG6 might be present include something called gluten ataxia [5], a neurological 'sign' characterised by a 'lack of voluntary coordination of muscle movements that includes gait abnormality.' Again, the data is compelling insofar as the use of a gluten-free diet as an intervention option [6] where gluten ataxia is diagnosed. With specific regards to autism and TG6 antibodies, I think the Józefczuk paper provides the first research outing for the two together (at least in a PubMed search). Other transglutaminase antibodies however, have been reported in the context of autism (see here for example) with the need for lots more investigations including with reference to the overlap between autism and coeliac disease (see here). At this point, I'll also note that gluten ataxia has not yet been linked to autism despite ataxia potentially showing some connection to some cases [7].

Moving on and we have the finding that: "Mean levels of zonulin and I-FABP [intestinal fatty acid binding proteins] in ASD [autism spectrum disorder] patients were similar to those found in healthy controls." Further: "Serum concentrations of zonulin and I-FABP showed no statistically significant association with antibody positivity." OK, zonulin is another topic of interest to this blog particularly in light of other recent findings with autism in mind (see here). Still the topic of considerable debate, zonulin has been described as "a biomarker of impaired gut barrier function for several autoimmune, neurodegenerative, and tumoral diseases" [8]. The data so far seems to indicate that gliadin - that component of gluten - 'induces' zonulin release [9] hinting that diet may be an important variable when it comes to 'impaired gut barrier function' otherwise known as intestinal hyperpermeability (or more imprecisely, leaky gut). I-FABP is something I'm a little less sure about in any context. It has been mentioned in the peer-reviewed research arena with autism in mind [10] but I can claim not expertise on this specific marker.

The Józefczuk findings report that zonulin levels in their cohort with autism were similar to "to those found in healthy controls" which is contrary to those previous findings in autism published by Erman Esnafoglu and colleagues [11]. They (Esnafoglu et al) concluded that: "Serum zonulin levels were significantly higher in the patients with ASD (122.3 ± 98.46 ng/mL) compared with the healthy controls (41.89 ± 45.83 ng/mL). " Forgetting (but not excusing) the incorrect use of 'healthy controls' in that paper, there is something of a difference between the Esnafoglu and Józefczuk results. One could argue that this is simply reflective of 'conflicting' autism research more generally (see here) but one might also question things like the analytical ways-and-means of assaying for something like zonulin too (see here).

The observation that zonulin (and I-FABP) levels showed 'no statistically significant association with antibody positivity' whilst informative is something I've been thinking about quite a bit. I don't have any easy answers as to why they found what they found aside from assuming that such data is evidence for how "increased immune reactivity against gluten" might not be specifically related to "the effect of intestinal barrier abnormalities" in relation to autism. This relationship assumes that abnormal gut permeability is the route through which gluten fragments (peptides) gain access to the wider central nervous system (CNS) which then elicits that immune response. It is a little surprising that no relationship was found given that one of the ways that zonulin is released is ingestion of gliadin and the assumption that gluten needs to be present in the diet for antibodies to be formed against it. But there you go. I suppose one might entertain the possibility that zonulin as a biomarker of impaired gut barrier function might not be the optimal way of measuring gut barrier function and including other more direct measures [12] could be the way forward to resolving this issue further.

Either way, research on immunological responses to gluten and notions of atypical gut permeability in the context of 'some autism' are seemingly not going away any time soon. Indeed, even medical professionals are seemingly not adverse to prescribing a gluten-free diet in the context of [some] autism [13]...


[1] Józefczuk J. et al. The Occurrence of Antibodies Against Gluten in Children with Autism Spectrum Disorders Does Not Correlate with Serological Markers of Impaired Intestinal Permeability. J Med Food. 2017 Oct 26.

[2] Lau NM. et al. Markers of Celiac Disease and Gluten Sensitivity in Children with Autism. PLoS One. 2013 Jun 18;8(6):e66155.

[3] Kelly DL. et al. Anti Gliadin Antibodies (AGA IgG) Related to Peripheral Inflammation in Schizophrenia. Brain Behav Immun. 2017 Oct 23. pii: S0889-1591(17)30476-2.

[4] Gadoth A. et al. Transglutaminase 6 Antibodies in the Serum of Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2015 Jun;72(6):676-81.

[5] Hadjivassiliou M. et al. Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann Neurol. 2008 Sep;64(3):332-43.

[6] Hadjivassiliou M. et al. Dietary treatment of gluten ataxia. Journal of Neurology, Neurosurgery, and Psychiatry. 2003;74(9):1221-1224.

[7] Ahsgren I. et al. Ataxia, autism, and the cerebellum: a clinical study of 32 individuals with congenital ataxia. Dev Med Child Neurol. 2005 Mar;47(3):193-8.

[8] Fasano A. Zonulin, regulation of tight junctions, and autoimmune diseases. Annals of the New York Academy of Sciences. 2012;1258(1):25-33.

[9] Clemente MG. et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003 Feb;52(2):218-23.

[10] Pusponegoro HD. et al. Maladaptive Behavior and Gastrointestinal Disorders in Children with Autism Spectrum Disorder. Pediatr Gastroenterol Hepatol Nutr. 2015 Dec;18(4):230-7.

[11] Esnafoglu E. et al. Increased Serum Zonulin Levels as an Intestinal Permeability Marker in Autistic Subjects. Journal of Pediatrics. 2017; 188: 240-244.

[12] Bischoff SC. et al. Intestinal permeability – a new target for disease prevention and therapy. BMC Gastroenterology. 2014;14:189.

[13] Rubenstein E. et al. The prevalence of gluten free diet use among preschool children with autism spectrum disorder. Autism Res. 2017 Nov 20.


Tuesday, 21 November 2017

"Spending constraints" a.k.a austerity and a mortality gap?

I try not to be too political on this blog given the focus on peer-reviewed science and my notable lack of political interest or motivation. It is however difficult to completely separate science and politics from each other given the world that we live in. A world that still commonly uses the term 'austerity' quite a few years after 'the crisis', alongside a realisation that behind headlines on the continued drive(s) towards 'fiscal security' and 'balancing the books' there are inevitably going to be winners and losers.

The paper by Jonathan Watkins and colleagues [1] highlights some of the extreme 'not winners' potentially stemming from the "relative constraints in public expenditure on healthcare (PEH) and social care (PES)" here in Blighty over recent years. They concluded that: "Spending constraints between 2010 and 2014 were associated with an estimated 45 368 (95% CI 34 530 to 56 206) higher than expected number of deaths compared with pre-2010 trends." Further, that if current trends continue in relation to funding "approximately 150 000 additional deaths may arise between 2015 and 2020." Cue the sharp intake of breath as words such as 'economic murder' have been banded around in the popular press discussing this research (see here).

I'm not going to go into all the details of the Watkins findings on this occasion. The data for the study was derived from various public databases in relation to population mortality, spending on health and social care and related variables. I don't doubt that as per other debates on the 'weekend effect' for example, different people with different mindsets might arrive at different conclusions based on such data. 'Lies, damn lies and statistics' is a phrase that springs to mind. With my very rudimentary reading and understanding of the Watkins data, I can't however see any obvious flaws in their methods or logic behind their results; aside that is from remembering that correlation does not always equal causation. Others have voiced similar sentiments (see here).

"By setting, deaths at care homes and at home contributed most to the observed ‘mortality gap’, while hospital mortality was lower than expected." The authors specifically attribute such data to the gap between spending on social care vs. spending on health care; also noting that "the recent drive to move patients with poor prognoses and who have reached their ceiling of care away from the hospital environment to care homes or their own homes may have contributed to this." One interpretation of this is that those who are elderly and/or vulnerable placed outside of the hospital environment are perhaps disproportionately being burdened with the effects of austerity.  And one possible solution? Well: "Our study suggests that the number of NHS-qualified nurses is the strongest tested mediator of the relationships between spending, and care home and home mortality." One solution but not the only solution.

With a UK budget announcement set for later this week, I wonder if the Watkins findings might figure in relation to the suggestion that "a cumulative spending increase of approximately £25.3 billion would be required to close this gap across health and social care by 2020/2021, equating to around £6.3 billion annually." Yes, those are some quite staggering sums of money, but at the end of day what is to be valued more: balancing the books or plugging quite a significant mortality gap? (and even some of our elected officials seem to be interested in this debate).


[1] Watkins J. et al. Effects of health and social care spending constraints on mortality in England: a time trend analysis. BMJ Open 2017;7:e017722.


Monday, 20 November 2017

"the importance of considering how autism acceptance could contribute to mental health in autism"

The quote heading this post comes from the findings reported by Eilidh Cage and colleagues [1] (open-access) who sought to examine how "experiences and perceptions of autism acceptance could impact on the mental health of autistic adults."

Using an on-line survey "to test the relationship between perceived autism acceptance and mental health (specifically, depression, anxiety and stress)" findings are reported based on responses from over 110 people diagnosed as on the autism spectrum. I say 'diagnosed as on the autism spectrum' but as with any internet survey, there is always a degree of 'trust' that autism diagnoses are being reported faithfully just as it is with other labels that were under study: "a high proportion of participants reported additional diagnoses." Indeed, I also note that "11 participants reported that they did not currently have a formal diagnosis of autism" and were still included in some of the analyses...

No mind, the authors sought to 'quantify' autism acceptance given no measure currently exists by asking various questions including "whether they felt that society (specified as the general public, made up of people who did not personally know them) generally accepted them, with “yes”, “no”, “sometimes” and “prefer not to say” as response options." Responses were also sought to statements such as "over the past week, I have felt accepted by society as an autistic person/person with autism" and onward "perceptions of autism acceptance from different sources." This was complemented by responses to the Depression, Anxiety and Stress Scale (DASS-21).

Results: "depression was predicted by autism acceptance from external sources (society, family and friends) and personal acceptance" but anxiety was not seemingly *linked* to autism acceptance. Drilling down further into their results, researchers observed that "greater personal autism acceptance predicted lower depressive symptoms" indicating that variables such as self-esteem might mediate any risk of presenting with depressive signs and symptoms [2] (see here for my take). This is something that perhaps tallies with other research talking about autistic traits and wellbeing [3].

The author has also written a piece for The Conversation on her research study (see here).

I'm not quite sure why the ever-fluffy psychological concept of 'Theory of Mind' (ToM) needed to be introduced into the Cage paper given that no measure of ToM was actually included in the study. A quick search of other published research from these authors reveals that ToM is a feature there too [4]. The authors talk about how "Theory of Mind ability may impact on perceptions of autism acceptance" but I'm not so sure that this is particularly important. It's kinda like suggesting that society is completely autism aware and accepting/accommodating but those on the spectrum 'don't seem to understand it' as a result of any ToM issues, which is of course, a nonsense. ToM also still requires a bit more investigation into what it actually means and covers (see here) including the idea that issues with ToM might themselves be 'impaired' as a result of something like depression (see here). I'd also point out that quite a few other over-represented diagnoses potentially appearing alongside autism also seem to present with ToM issues [5] too...

"There is still a long way to go in understanding and tackling the high prevalence of mental health difficulties in autism, but we believe that the social model approach is a useful and positive lens through which mental health outcomes could be improved." That was the conclusion reached by authors on the basis of their findings. I would agree that there is still a long way to go on the topic of mental health and autism and the social model approach - "disability is caused by the way society is organised, rather than by a person’s impairment or difference" - is an option for further research of this kind. But I would also caution that one needs to balance such a perspective with others too (see here), and accept that the organisation of society is not always the most disabling aspect of a person's disability, particularly when it comes to something like depressive symptoms. Indeed, to say that depressive symptoms accompanying autism might merely be a facet of a 'lack of acceptance' or a lack of understanding from society or the individual themselves, risks plunging autism back into some pretty dark times (see here) and is likely to conflict with various other views. From a clinical point of view, it ignores some very serious research on the wide spectrum that is depression potentially present for all-manner of different reasons, being relevant to the equally wide spectrum that is autism (see here for a discussion on how depression might actually be something rather more fundamental to some autism over just being 'comorbidity'). At worst, it may even delay or put people off from seeking timely recognised treatments when depression becomes 'clinical', which could be a rather dangerous path to start down (see here).

Having said all that, I don't however think too many people would argue with the idea that personal perception(s) whether positive or negative are likely to impact on a person's mental (and physical?) health and wellbeing. If one is constantly feeling like an 'outsider' or excluded or feels that ones needs are not being met, added to a possible history of being bullied or loneliness or indeed, with other clinical labels also potentially being present for example, one is likely to build up a mindset appropriate to such a situation which probably includes some advanced risk for depressive signs and symptoms. From that point of view, much more needs to be done to look at the ways and means of impacting those personal perceptions; possibly taking into account other relevant research which has some [evidence-based] suggestions on things like societal inclusion and increasing access to it (see here) for those who want this option, alongside other complementary strategies where some [peer-reviewed] evidence is present (see here) and continues to be produced (Google the 'HUNT Cohort Study' to see what I mean). I say all this reiterating that something like chronic loneliness can very much be a major contributor to issues like depression.

I also understand the calls to make society more autism-accepting which I think most people would support as being pertinent across the ENTIRE autism spectrum (see here). I'm however, a little unsure of the real-life plan and details of the plan attempting to achieve this goal; particularly in the current climate when even getting a timely diagnosis seems to be an uphill struggle and when also many on the autism spectrum are seemingly left to fend for themselves post-diagnosis. Society it seems, is getting much more autism aware (for good or bad based on current media portrayals for example) but not necessarily getting more autism accommodating nor necessarily putting important words into actions. Indeed, one could argue that other societal factors like unemployment and financial hardship readily experience by those with autism are probably as, if not more, important to their experiences of something like depression yet little appears to be done to improve such issues for the vast majority...

As for the "experiences of “camouflaging” [that] could relate to higher rates of depression" also mentioned in the Cage article, I have quite a lot of time for this area of autism research (see here). Particularly the idea that camouflaging is not necessarily an all-female pursuit in the context of autism (see here) and how truly energy-sapping it can be for many, many people on the spectrum...


[1] Cage E. et al. Experiences of Autism Acceptance and Mental Health in Autistic Adults. J Autism Dev Disord. 2017. Oct 25.

[2] McCauley JB. et al. Self-Esteem, Internalizing Symptoms, and Theory of Mind in Youth With Autism Spectrum Disorder. J Clin Child Adolesc Psychol. 2017 Oct 19:1-12.

[3] Rodgers JD. et al. Brief Report: Personality Mediates the Relationship between Autism Quotient and Well-Being: A Conceptual Replication using Self-Report. J Autism Dev Disord. 2017 Sep 16.

[4] Cage E. et al. Reputation management: evidence for ability but reduced propensity in autism. Autism Res. 2013 Oct;6(5):433-42.

[5] Wang Y-Y. et al. Theory of mind impairment and its clinical correlates in patients with schizophrenia, major depressive disorder and bipolar disorder. Schizophrenia Res. 2017. Nov 7.


Saturday, 18 November 2017

Probiotics degrading gluten peptides - part 4

Here we go again. Probiotics degrading gluten peptides part 4 adds to previous posts on this topic (see part 1 here, part 2 here and part 3 here).

The difference this time around? People. People actually eating a a test meal containing gluten - "a porridge containing 0.5 g gluten" - and being given a potential gluten-degrading preparation - "Aspergillus niger-derived prolyl endoprotease (AN-PEP)" - or a placebo whilst their gastric and duodenal content was sampled for gluten concentrations over a 3-hour period after. So described the results published by Julia König and colleagues [1] continuing a research theme from this group [2].

AN-PEP was the product under the research spotlight following some previous scientific findings [3] suggesting that unlike various other digestive enzyme supplements, this stuff showed some pretty good actions/effects on immunogenic gluten peptides. Following a "randomized placebo-controlled crossover study" design, researchers followed 16 participants "with self-reported gluten sensitivity" (but not coeliac disease or wheat allergy) across 3 test days when on each day either a high dose of AN-PEP was given, or a low dose of AN-PEP was given or a placebo was given. Details of the high and low doses included: "The low dose tablets provided 83300 Protease Picomol International (PPI), and the high dose 166700 PPI of AN-PEP enzyme (1 PPI is the amount of enzyme that releases one picomole of p-nitroaniline per second under defined assay conditions)."

This was quite an invasive study as researchers had to gain access to parts of the gastrointestinal (GI) tract of participants and so: "Subjects attended each test day after an overnight fast, and a multi-lumen nasoduodenal catheter was placed with one lumen tip in the gastric antrum and one lumen tip 15 cm lower in the duodenum." It was then a case of drawing off stomach and duodenal samples and analysing for gluten content. Further: "success of AN-PEP in degrading gluten was defined as at least 50% gluten degradation compared to placebo, calculated as area under the curve (AUC) over 180 min."

Results: "It actually works" was a quote from one of the authors of the paper in previous media attention of this study before peer-reviewed publication. "In the stomach, gluten levels were reduced from 176.9 to 22.0 in the high dose and to 25.4 μg × min/ml in the low dose. In the duodenum, gluten levels were reduced from 14.1 in the placebo to 6.3 in the high dose and to 7.4 μg × min/ml in the low dose." AN-PEP appeared to be doing its designated job. Importantly too: "No severe adverse events were reported" over the course of the study period.

Scientific replication is the name of the game following the König results. Replication with larger sample numbers and also potentially looking at whether such a preparation might be useful for those diagnosed with something like coeliac disease or other accepted immune-related pathology linked to gluten consumption. I say that acknowledging that a gluten-free diet is the best that science and medicine currently has for the management of coeliac disease. The authors also note that they "did not perform a double-blinded placebo-controlled gluten challenge as sometimes suggested to confirm the diagnosis of gluten sensitivity" in their participants. This kinda intersects with the continuing discussions about what non-coeliac gluten/wheat sensitivity actually is (see here).

"In conclusion, our study showed that the AN-PEP enzyme is effective in degrading small amounts of gluten as part of a complex meal in the stomach. Even though the use of AN-PEP is not intended to replace a gluten-free diet in gluten-related disorders, it appears to be effective as a digestive aid protecting against the unintentional intake of gluten." I can't argue with that and look forward to seeing more on this topic in future.


[1] König J. et al. Randomized clinical trial: Effective gluten degradation by Aspergillus niger-derived enzyme in a complex meal setting. Sci Rep. 2017 Oct 12;7(1):13100.

[2] Salden BN. et al. Randomised clinical study: Aspergillus niger-derived enzyme digests gluten in the stomach of healthy volunteers. Aliment Pharmacol Ther. 2015 Aug;42(3):273-85.

[3] Janssen G. et al. Ineffective degradation of immunogenic gluten epitopes by currently available digestive enzyme supplements. PLoS One. 2015 Jun 1;10(6):e0128065.


Friday, 17 November 2017

On iron and vitamin D and autism

"This study suggests that deficiency of iron and Vitamin D as well as anemia were more common in autistic compared to control children."

'This study' refers to the findings reported by Abdulbari Bener and colleagues [1] (open-access available here) who set out to "investigate iron deficiency anemia and Vitamin D deficiency among autism children" in Qatar, a part of the world not renowned for its 'lack of sunshine' (a source material for the production of vitamin D).

Looking at some 300 children diagnosed with an autism spectrum disorder (ASD) and an equal number of controls, not-autism controls "who visited the primary health-care centers", researchers concluded that as a group, those with autism were more likely to present with low serum iron levels (and various related measures) and further that: "Vitamin D deficiency was considerably more common among autistic children." The authors provide some background details on what constitutes vitamin D deficiency and other 'levels': "Participants were classified into four categories: (1) severe Vitamin D deficiency, 25OHD <10 ng/ml; (2) moderate deficiency, 25OHD 10–19 ng/ml; (3) mild deficiency, 25OHD 20–29 ng/ml; and normal/optimal level is between 30 and 80 ng/ml."

When attempting to ascertain what factors might be important to the autism vs. not-autism participants, researchers reported that: "serum iron deficiency, serum calcium levels, serum Vitamin D levels; ferritin, reduced physical activity; child order, body mass index percentiles, and parental consanguinity can all be considered strong predictors and major factors associated with autism spectrum disorders." I might add that consanguinity defined as "unions between couples who share at least one common ancestor" is perhaps something more 'culturally-relevant' to autism in certain countries and societies [2] but not necessarily widely applicable...

What's more to say about the Bener findings? Well, given that issues with iron (see here) and issues with vitamin D (see here) are no strangers to the autism research landscape, there is little novelty in the conclusions reached even if being "the first report on an establishing level of iron deficiency in children with autism in Qatar and in Arabian Gulf Countries." The implication is again that preferential screening and treatment of such issues should be offered when a diagnosis of autism is received, save any further health inequalities arising. Whether or not treating something like iron deficiency and/or vitamin D issues will impact on behavioural presentation (see here) is perhaps an issue for another day. I say this bearing in mind the sentiments expressed in the recent paper by Philippe Autier and colleagues [3] examining the collected data on vitamin D supplementation "on non-skeletal disorders" and results seemingly "strengthening the hypothesis that low vitamin D status is a consequence of ill health, rather than its cause."


[1] Bener A. et al. Iron and vitamin D levels among autism spectrum disorders children. Ann Afr Med. 2017 Oct-Dec;16(4):186-191.

[2] Mahajnah M. et al. Clinical characteristics of autism spectrum disorder in Israel: impact of ethnic and social diversities. Biomed Res Int. 2015;2015:962093.

[3] Autier P. et al. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol. 2017 Oct 25. pii: S2213-8587(17)30357-1.


Thursday, 16 November 2017

Sleep and gut issues in autism: a clinically relevant subtype?

"Autistic children with gastrointestinal or/and sleep problems may represent clinically relevant subtypes of ASD [autism spectrum disorder], for which targeted treatments may be needed."

That was one of the conclusions reached by Xiao-Lei Yang and colleagues [1] looking at an interesting combination of symptoms/conditions that have featured before on this blog (see here and see here): gastrointestinal (GI) and sleep issues with autism in mind.

Surveying around 170 children diagnosed with an autism spectrum disorder (ASD) and a similar number of "healthy children" (authors words, most definitely not mine), researchers sought to estimate the prevalence of GI and sleep issues among their cohort(s). Perhaps unsurprisingly "GI and sleep problems were prevalent in Chinese ASD children." Interestingly too: "ASD children with GI symptoms reported more severe ASD core symptoms than others." Those with sleeping issues also showed "lower performance in daily living skills, social cognition, social communication and intellectual development" than the children with ASD who did not present with sleeping issues.

The implications of such observations? Several. Not least that when one talks about GI issues  - whether functional or more pathological - being over-represented in relation to autism, one has some confidence that such 'over-representation' seems to cross different ethnicities and different countries and is not just derived from or based on Western research findings. This adds further weight to the notion that at least some types/phenotypes of autism may have a significant bowel-related component to them for whatever reason(s).

Next, the suggestion that children with autism who also present with GI symptoms might present with a more 'severe ASD core symptoms' profile provides some truly tantalising clinical and research opportunities. Not least that said bowel symptoms might be able to affect some aspects of behaviour and onward the question: what happens when bowel symptoms are effectively treated? I know such sentiments are not necessarily welcomed in some quarters ('autism symptoms are lifelong and immutable' so the saying goes) but for others, particularly those suffering with bowel symptoms (yes, I did say suffering), there are some potentially interesting consequences following intervention. Assuming also that pain and discomfort are key parts of 'suffering' from bowel issues in autism as they are when present in not-autism, we arrive at a situation whereby certain autistic traits may be at least 'heightened' when pain is present. Such a proposition is not necessarily new news to the peer-reviewed autism research (see here and see here). And if one was to assume that something like 'inflammation' might be part and parcel of said GI issues and pain in relation to autism, we arrive at yet another testable hypothesis (see here)...

Finally, sleep issues in relation to the autism spectrum. What's more to say? They are pretty prevalent throughout children and adults on the autism spectrum and probably contribute to the various 'quality of life' disparities that have been shown in relation to autism (see here). There are things that can be 'tried' in relation to intervention (see here and see here for examples) but by no means is there some 'magic wand' that helps every single sleep issue for every single person. The idea that sleep issues, like GI issues, might also impact on certain behavioural aspects linked to autism is probably not unexpected but I would like to see a lot more research done in this area before any grand sweeping generalisations are made. Not least recognising that certain over-represented behavioural comorbidity such as attention-deficit hyperactivity disorder (ADHD) is rising through the sleep research ranks (see here) and what that might mean for autistic traits in these ESSENCE-like times...


[1] Yang X-L. et al. Are Gastrointestinal and Sleep Problems Associated with Behavioral Symptoms of Autism Spectrum Disorder? Psychiatry Research. 2017. Oct 24.


Wednesday, 15 November 2017

Loneliness --> low self-esteem ---> depression?

It was the findings reported by James McCauley and colleagues [1] that prompted today's post. Working on the basis that "there have been few comprehensive investigations of self-esteem in children and adolescents with autism spectrum disorder (ASD)" researchers set out "to assess how youth with ASD rate their self-esteem compared to age-matched TYP [typically developing] youth." Further, how levels of self-esteem (or not) might onward influence "internalizing psychopathology", the fancy phrase for issues such as depression and anxiety.

I don't typically go for grand theories and sweeping generalisations on this blog, particularly when referencing the very large and very diverse autism spectrum. I've not moved over to the 'dark side' of generalisation in this post but am particularly interested in the some of the *associations* talked about my McCauley et al.

Specifically how: "youth with ASD rated their self-esteem significantly lower than did TYP youth" and how self-esteem was "strongly related to depression." Add in the findings reported by Micah Mazurek [2] who observed that "loneliness was associated with increased depression and anxiety and decreased life satisfaction and self-esteem" and some potentially important processes emerge as per the equation titling this post: Loneliness --> low self-esteem ---> depression?

McCauley and colleagues do also talk about how Theory of Mind (ToM) also showed some possible *associations* to elements of their results but I'm not really minded to go into this part of their findings with any great detail. It's not that I don't believe that ToM might not be an issue for some on the autism spectrum, but rather as other results have suggested [3], questions still remain about what ToM actually means and whether other issues (i.e. alexithymia) might predominate in relation to some autism [4] (where the stress is on 'some').

I don't doubt that there are several other important elements potentially influencing things like self-esteem in relation to autism and how it can lead to issues such as depression (see here). Further studies are needed on this topic, including drawing on the autism-not-specifically-mentioned research literature [5]. But insofar as the simplistic relationship set out in the post, there is an obvious area ripe for intervention: loneliness. And on that point, there are options available (see here) if and when desired; accepting that not everyone wants (or needs) lots of people around them all of the time. This perhaps is also where the online world (in moderation) can also come into it's own [6] (I repeat 'in moderation').

Finally, I'll be coming to the findings reported by Cage and colleagues [7] in the not-too-distant-future talking about how "personal acceptance significantly predicted depression" in the context of autism and what role self-esteem might play here too (minus too much psychological fluff and ToM chatter)...


[1] McCauley JB. et al. Self-Esteem, Internalizing Symptoms, and Theory of Mind in Youth With Autism Spectrum Disorder. J Clin Child Adolesc Psychol. 2017 Oct 19:1-12.

[2] Mazurek MO. Loneliness, friendship, and well-being in adults with autism spectrum disorders. Autism. 2014 Apr;18(3):223-32.

[3] Oakley BF. et al. Theory of mind is not theory of emotion: A cautionary note on the Reading the Mind in the Eyes Test. J Abnorm Psychol. 2016 Aug;125(6):818-23.

[4] Trevisan DA. et al. Alexithymia, but not autism spectrum disorder, may be related to the production of emotional facial expressions. Mol Autism. 2016 Nov 11;7:46.

[5] Sowislo JF. & Orth U. Does low self-esteem predict depression and anxiety? A meta-analysis of longitudinal studies. Psychol Bull. 2013 Jan;139(1):213-240.

[6] Sundberg M. Online gaming, loneliness and friendships among adolescents and adults with ASD. Computers in Human Behavior. 2017. Nov 1.

[7] Cage E. et al. Experiences of Autism Acceptance and Mental Health in Autistic Adults. J Autism Dev Disord. 2017 Oct 25.


Tuesday, 14 November 2017

Breastfeeding and autism meta-analysed

"This meta-analysis provides evidence that breastfeeding (exclusively or including additional supplements) may protect against ASD [autism spectrum disorder]. Prospective longitudinal research is required to disentangle the complex relationships and to explore potential pathophysiological mechanisms."

So said the systematic review and meta-analysis published by Ping-Tao Tseng and colleagues [1] covering a [complicated] topic that has been discussed on this blog before (see here). I should mention that I was part of the 'and colleagues' bit to this latest paper; something that will in no way interfere with my hopefully critical musings on this latest publication.

Bearing in mind "a controversial relationship between ASD and breastfeeding" that exists in the peer-reviewed literature and the strong requirement not to make new mums feel bad just because they don't want to or can't breastfeed, the aim of the meta-analysing game was to synthesise the collected research literature into something like a coherent 'where we're at' statement. Seven studies out of a possible 20 were included for review, together including nearly 1500 children diagnosed with ASD and nearly 1200 not-diagnosed-with-autism controls.

Results: "Cumulatively, children with ASD, either in the form of clinical diagnosis or self-report, were significantly less likely to have been breastfed than children without ASD." I should add that 'self-report' refers to parents reporting on their child receiving a diagnosis of autism but not necessarily being independently confirmed by researchers or medical records. The strength of the association/effect was not to be sniffed at; with results even holding up when taking into account those "who were breastfed with additional supplementation."

Another important quote: "one should note the observational nature of these preliminary findings, whereby causation can clearly not be determined." What this means is that whilst variable A (breastfeeding) and variable B (autism or ASD) might be *associated* it is nigh on impossible to definitively say whether variable A *causes* or *protects against* variable B on the basis of the studies analysed. I might also suggest that the call for 'prospective longitudinal research' is also not likely to provide a definitive answer any time soon either, when taking into account how many other variables might be associated with risk of offspring autism and indeed, the plurality of the label and some related discussions on that topic (see here and see here). It's also noteworthy that autism rarely exists in some sort of diagnostic vacuum (see here) and how breastfeeding trends might be important there too [2] thus complicating any 'causative' picture.

Still, the Tseng results do provide some further information about this issue and a reiteration of the value of breastfeeding for many different reasons. Other studies have arrived at a similar conclusion insofar as the impact that breastfeeding *might* have on 'autistic traits' [3]; again, with more research to do.

Mechanisms of effect? Well, once again we're faced with a 'we don't know yet' scenario. Tseng et al speculated on various possible factors linked to breastfeeding and breast milk 'ingredients' that may be important (neurotrophic factors, oxytocin, fatty acid constitution, casomorphins) and could conceivably impact on risk of offspring autism. I'm also minded to add in the idea that the early presentation of autism in the first months of life [for some] could also potentially affect breastfeeding patterns; perhaps making breastfeeding practices more difficult and/or contributing to the early cessation of breastfeeding in some cases. Relevant mechanisms are likely to be complicated.

I appreciate that not everyone is going to be enthralled with this study or topic - no, it doesn't say that a lack of breastfeeding causes all autism - particularly when words like "protect against ASD" are also included in the text. All I can say is that we faithfully looked at the existing peer-reviewed research available to us in this area and went where the data instructed us to do so without fear or favour...


[1] Tseng P-T. et al. Maternal breastfeeding and autism spectrum disorder in children: A systematic review and meta-analysis. Nutritional Neuroscience. 2017. Oct 18.

[2] Bar S. et al. Long-term neurodevelopmental benefits of breastfeeding. Curr Opin Pediatr. 2016 Aug;28(4):559-66.

[3] Boucher O. et al. Association between breastfeeding duration and cognitive development, autistic traits and ADHD symptoms: a multicenter study in Spain. Pediatr Res. 2017 Mar;81(3):434-442.


Monday, 13 November 2017

Who speaks for who in relation to autism?

I'm probably stirring up a hornet's nest by writing this post around the findings reported by Karin Jongsma and colleagues [1] touching on the subject of 'who speaks for who' in autism advocacy, but thought it an important topic to approach. Not least because in some quarters, there are some quite heated discussions being had (mainly, and unsurprisingly, across social media and related platforms) concerning representation across various organisations and initiatives with a focus on autism. The question at the heart of such debates is: 'Who should be the primary voice(s)?' when it comes to things like decision-making about research and policy in the context of autism, both at an individual and group level? It's not a new debate by any means and such discussions will likely be part of the autism landscape forever more...


"The inclusion of people with a 'neuro-psychiatric' condition poses a particular challenge for the organizational processes and political representation of such collectives" was the starting point for Jongsma et al. I'm not very philosophically literate so can't really tell you too much about the use of 'epistemic injustice' as a framework by Jongsma, outside of it being an idea that includes 'testimonial injustice' meaning "prejudices that cause one to "give a deflated level of credibility to a speaker's word".

The authors conducted interviews with a number of patient organisation (PO) representatives and concluded that: "persistent stereotypes hamper the inclusion of affected members both within POs and on the health political level." Further: "Being affected causes distrust in having the 'capacity to know' in a two-fold way; it is assumed that those who can represent themselves are "not affected enough" to present valuable insights into the condition and those who have difficulties to express themselves due to their condition are excluded because of their affectedness."

That last sentence kinda hits the nail slap-bang on the head when it comes to many of the discussions around 'who speaks for who' in the context of autism. Remembering that autism is about as heterogeneous as it comes with regards to the huge range of abilities and disabilities covered under the spectrum label, many, if not all, arguments about representation stem from perspectives on whether the so-called 'able' are able/allowed/qualified to speak for the so-called 'not so able' and the apparent lack of the 'not so able' to have an appropriate voice, thus relying on proxy voices such as their parents and/or primary caregivers. The bold emphasis was added by me just in case you ask. Such issues are also positioned in the context of tenets such as: 'if you've met one person with autism, you've met one autistic person' (or words to that effect) and older adages about 'mother (or father) knowing [their child] best'. The fact that Jongsma et al also included dementia in their study - another condition/label/state where ability and disability is pretty heterogeneous - is also worth noting.

I'd advance the idea that there is no right or wrong answer in the debate on who speaks for who when it comes to autism. Certainly, further grand sweeping generalisations in relation to autism are not required. The moves to encourage greater participation by #actuallyautistic people are to be welcomed and reflect many factors such as the rise and rise of numbers of people being diagnosed with autism (some rather late in life) and how again, social media in particular, is providing an important tool to voice wants, needs, hopes, fears, concerns, vision and lots more when it comes to the lives of those on the autism spectrum. Various different sorts of group identities are emerging/have emerged as many, particularly adults with autism / autistic adults (see here), have come together. Sometimes this is under the banner of neurodiversity and the principles which it includes; other times not, or with more specific issues in mind. Without getting too 'reflective' on the topic, the autism/autistic group identities emerging probably also help fill an important gap, taking into account all the chatter down the years about how loneliness and isolation are very much over-represented and onward how the desire to 'belong' has been too long neglected in the context of autism.

It's also fair to say that not everyone diagnosed on the autism spectrum is 'part of the conversation' bearing in mind the 'nothing about us without us' mantra. There are many children and adults with autism for whom such debates on advocacy are probably not as big a concern as overcoming various day-to-day issues; be they based on the effects of core autism presentation or other important comorbidities such as epilepsy or gastrointestinal (GI) issues. For many of this group, their voice is their parents and/or primary caregivers and will be for the rest of their lives. By saying all that I'm not falling into the whole 'high' and 'low' functioning narrative about 'who's the more disabled'. I'm simply acknowledging that some people on the autism spectrum can't and probably won't ever participate in discussions about 'who speaks for them' and therefore their own voices are heard only through their parents/caregivers, siblings or significant others. I know some people will say that we aren't trying hard enough to give this section of the autism spectrum a voice, but right or wrong, that's where we currently stand.

What can be done to improve the situation and perhaps bridge any gulf between voices from the spectrum and proxy voices from the spectrum? Well, there's no easy fix because yet again, heterogeneity rules. It would be unwise to assume that every actually autistic adult who can vocalise or communicate wants the same thing for themselves or any group they feel allied to, just as any sweeping generalisations that every non-communicating person with autism (I don't know how else to describe this group) or parent/primary caregiver wants the same thing are likely untrue. I think this is an important point to raise particularly when for example, the social model of disability - "disability is caused by the way society is organised, rather than by a person’s impairment or difference" - can too often be assumed to be a significant part of the vocal autism agenda, seemingly at the expense of acknowledging some very real disabilities. It's not, for example, difficult to imagine how such an extreme sentiment might sound to the parent or caregiver of a child/adult who requires significant day-to-day care and is very much disabled as a result of their autism and the issues it brings, irrespective of societal organisation. This also goes for those 'autism as a superpower' and related statement(s) which have been mentioned down the years. How such sweeping generalisations, seemingly contrary to the diagnostic tenets of autism, may well reflect individual perceptions and abilities of autism, but often do very little to forward the agenda of those severely impacted by their autism and their representation (including in the lay media).

There are substantial benefits to be had from listening to the many voices from the autism spectrum particularly when it comes to outcomes and events that will likely impact them as individuals and/or other groups on the spectrum. Similar sentiments are being discussed with other labels in mind too. I note for example, there are quite a few autistic voices that provide both informative and compassionate 'middle-ground' on many topics related to the details included in this post and the Jongsma paper. Importantly too that some are also not afraid to critique some of the tenets of neurodiversity (and by virtue, the misnomer of 'neurotypical' that has seemingly pervaded autism science and practice). These are important voices not just because of the accounts and experiences they provide, but also because theirs provides a hint of what challenges/successes might be 'more likely to occur' when a person is diagnosed with autism. Further, they do to some extent, provide an opportunity to positively act on such issues for the benefit of the person themselves and others who may not be in such a fortunate [communicative] position.

But also there is no reason why autistic voices cannot be complemented by hearing the equally important messages that parents and primary caregivers - the people who raise and mould children - can bring to the discussion table too. This also includes the 'teachings' of a rapidly emerging group who offer a really unique perspective: the rise and rise of autistic parents raising children with autism.

I suppose the bottom line is that everyone deserves to be heard no matter what section of the autism community they are allied to, and autism research and practice is all the richer for have such a diverse set of voices on the topic of autism. But this does not mean that conflict(s) are going to be so easily solved given the multitude of opinions, viewpoints and experiences included with autism in mind. How, the very individual nature of autism, is probably never going to lend itself particularly well to favouring one specific viewpoint over any others...


[1] Jongsma K. et al. Epistemic injustice in dementia and autism patient organizations - an empirical analysis. AJOB Empir Bioeth. 2017 Nov 8:0.


Saturday, 11 November 2017

Relative age and ADHD continued

"In a health service system with low prescribing rates for ADHD [attention-deficit hyperactivity disorder], a younger relative age is associated with an increased likelihood of receiving a clinical diagnosis of ADHD."

So said the findings published by Kapil Sayal and colleagues [1] (open-access available here) adding to an important body of peer-reviewed research evidence suggesting that younger relative age - relative age compared with other children in the same school year - does seem to be a factor in both receipt of a diagnosis of ADHD (see here) and use of medication purposed for ADHD (see here). I might also direct your attention to another paper also recently published by Sayal and colleagues [2] discussing ADHD in a more general sense.

The Sayal study represents yet another large population being used to analyse any such link; this time relying on "nationwide population-based registers to identify all Finnish children born between Jan 1, 1991, and Dec 31, 2004, who were diagnosed with ADHD from age 7 years onwards (age of starting school)." They found over 6000 children diagnosed with ADHD, and as well as looking at relative age compared to other children in the school year, also examined the important variable of year of diagnosis - "(1998-2003 vs 2004-11)" - to ascertain whether changes in diagnostic practices might be contributory to this issue.

As per the opening line, there was consistency in the Sayal findings with the other occasions that this issue has been examined. So: "Compared with the oldest children in the school year (ie, those born between January and April), the cumulative incidence of an ADHD diagnosis was greatest for the youngest children (ie, those born between September and December)." Sex/gender did not seem to show any differences in this trend. Also relevant: "This effect has increased in recent years."

If all that wasn't enough, the results published by Boland and colleagues [3] (open-access available here) also add to the data on relative age and ADHD by observing that: "Attention deficit hyperactivity disorder was the only identified relative age association" in their study utilising "electronic health record data from 6 sites representing 10.5 million individuals in 3 countries (United States, South Korea, and Taiwan)." The more general research brief for Boland et al to examine "Birth month and climate impact lifetime disease risk" took into account lots and lots of diagnoses not just ADHD concluding that: "children younger than their peers [are] experiencing greater ADHD risk."

Other coverage of the Sayal study (see here) caution about the 'applicability' of the results particularly in the context of school and ADHD here in Blighty. I agree that the study does not 'prove' relative age is directly linked to ADHD diagnosis (and/or medication use for ADHD) but in the context of this not being the first time that such a link has been made and the strength of the accumulating evidence, I find it difficult to suggest that any relationship is just a spurious one.

Finally, to quote from Sayal: "In terms of clinical and educational implications, these findings suggest that key adults (teachers and parents) might interpret behaviour differently of children who are younger than their classmates." Translation: one should be careful not to mis-classify 'developmental immaturity' with a diagnosis of ADHD [4] and that ideas discussing greater flexibility on school age start dates perhaps come into their own...

To close, lest we forget today of all days...


[1] Sayal K. et al. Relative age within the school year and diagnosis of attention-deficit hyperactivity disorder: a nationwide population-based study. Lancet Psychiatry. 2017 Oct 9. pii: S2215-0366(17)30394-2.

[2] Sayal K. et al. ADHD in children and young people: prevalence, care pathways, and service provision. Lancet Psychiatry. 2017 Oct 9. pii: S2215-0366(17)30167-0.

[3] Boland MR. et al. Uncovering exposures responsible for birth season - disease effects: a global study. J Am Med Inform Assoc. 2017 Sep 28.

[4] Efron D. The role of schools in the diagnosis of ADHD. Lancet Psychiatry. 2017 Oct 9. pii: S2215-0366(17)30406-6.


Friday, 10 November 2017

"abnormalities in mitochondrial activity in the lower GI tract of children with ASD"

The findings reported by Shannon Rose and colleagues [1] (open-access) continue a research theme by [some of] this authorship group looking at how mitochondrial dysfunction seems to be part and parcel of at least some autism (see here). Indeed, how when one talks about mitochondrial issues potentially accompanying [some] autism, one really needs to look at it in the context of other issues potentially also 'over-represented' in relation to autism (see here).

This time around, Rose et al set out to "determine whether mitochondrial dysfunction may contribute to GI [gastrointestinal] symptoms in children with ASD [autism spectrum disorder]" on the basis that GI symptoms (whether functional or more pathological) are no stranger to autism (see here). With this in mind, I note the name Tim Buie is included as part of the Rose paper authorship team and so should reference some of the sterling work he and his team have done on the topic of GI issues and autism and its importance down the years.

Researchers analysed mitochondrial function(s) in rectal and cecum mucosal biopsies in a small sample of children diagnosed with ASD (n=10) and compared results with those from "10 children with Crohn’s disease and 10 neurotypical children with nonspecific GI complaints." There are two points for me to make here: first, although it is an invasive procedure to collect them, those biopsies used for study were extracted on a clinical basis as part of "elective diagnostic colonoscopy." This was not a case of 'experimenting' on children for the sake of an experiment; rather that children were already undergoing investigations for their significant bowel issues, save any health inequalities appearing "just 'cos they were autistic" for example. Second, although the authors have chosen to use the term 'neurotypical' to reflect not-autism, I myself still find this terminology to be scientifically problematic (see here) in the context that no brain is seemingly typical or atypical according to current scientific evidence. Not least also on the basis that immune-based conditions such as inflammatory bowel diseases do seem to carry an increased 'risk' of psychiatric issues (see here) and what that might [eventually] mean for those children diagnosed with Crohn's disease (an inflammatory bowel disease) for example. Anyhow, two approaches are described in connection with the study of mitochondria in those biopsy samples looking at both the quantity and activity of various electron transport chain (ETC) complexes. Yet again, I can profess no serious expertise on the various elements of mitochondria but there is some good reading out there in the peer-reviewed science domain on the topic.

Results: "Differences in mitochondrial function were found in children with ASD as compared to the other control groups across several ETC complexes suggesting a difference in overall mitochondrial function rather than a change in one specific mitochondrial enzyme." Accepting the small participant numbers included for study, these are potentially important results. Not least because other work looking at such mitochondrial issues in relation to [some] autism has been predominantly based on activity in muscle; now it appears extending "this observation to altered ETC complex activity in the GI mucosa" too.

Then to some speculation: "The fact that increased ETC complex protein content was primarily seen in the cecum, an area where enteric microbiome fermentation products such as PPA [propionic acid] and BUT [butyrateare abundant, suggests a role for the enteric microbiome in the evolution of mitochondrial abnormalities in children with ASD." An interesting perspective indeed and in need of some further investigation. Butyrate has, in recent years, been elevated to almost scientific sainthood (see here for example) so one has to perhaps be a little cautious about sweeping statements in the context of autism or any other label. I say this with particular relevance to an 'autism colon' discussed by the authors (see here) which I also think is perhaps a little premature to speculate on.

No mind, the results are what they are and add to the growing literature discussing mitochondria in the context of [some] autism. The implication once again is to screen for such issues within the context that a diagnosis of autism should represent a starting point for further investigations not the finishing line.

And finally, to another author on the Rose paper, I'm still waiting to read about some of your results...


[1] Rose S. et al. Mitochondrial dysfunction in the gastrointestinal mucosa of children with autism: A blinded case-control study. PLoS One. 2017 Oct 13;12(10):e0186377.


Thursday, 9 November 2017

On antipsychotic treatment failure when both psychosis and autism present together

"Children with first-episode psychosis and comorbid autism spectrum disorders at first presentation are less likely to have a beneficial response to antipsychotics."

So said the results reported by Johnny Downs and colleagues [1] based on their analysis of historical health records for over 630 children and young adults "referred to mental health services in South London, United Kingdom" between 2008 and 2014. Researchers looked for evidence of "multiple treatment failure" (MTF) - defined as "the initiation of a third trial of a novel antipsychotic due to insufficient response, intolerable adverse effects, or nonadherence to prior antipsychotic treatment" - among their cohort as a function of a diagnosis of an autism spectrum disorder (ASD) and other neurodevelopmental labels such as "hyperkinetic disorders (ICD-10 F90) and intellectual disability (ICD-10 F70–9)." The hypothesis being that those with at least one mention of psychosis in their health records alongside comorbid ASD "would be more likely to experience treatment failure" as a consequence of other findings talking about "psychopharmacologic effectiveness [being] lower in populations with coexisting ASD." The reasoning for that hypothesis seemingly comes from other research such as that from Politte and colleagues [2] and is set in the context of the NICE guidance here in Blighty on the subject of antipsychotics and 'core' autism (see here).

Results: 114 of the 638 participants (~18%) studied also had a diagnosis of ASD. This kinda reiterates that psychosis and other conditions characterised by psychosis are probably not strangers when it comes to the clinical profile of [some] autism (see here and see here). Some 20% of their total cohort developed MTF during the study follow-up period. After adjusting for various potentially confounding variables researchers observed that: "ASD comorbidity was associated with a 2-fold increased risk of MTF" and further: "28% of those with comorbid ASD compared to 11% of non-ASD children had a persistently insufficient response to antipsychotics." Autism or possibly something about autism or linked to autism, seemed to potentially affect response to antipsychotics where psychosis was present.

There are a couple of other observations to make about the Downs data. When comparing the ASD - first episode psychosis (FEP) group with the not ASD - FEP group, the former showed an increased frequency of both hyperkinetic disorders a.k.a attention-deficit hyperactivity disorder (ADHD) and intellectual (learning) disability. This tallies with quite a bit of other research looking at other over-represented labels in the context of autism (see here and see here respectively). Also: "Children with ASD showed higher rates of the “persistent insufficient response” or the “insufficient response–adverse effect” trajectory but lower rates of adherence-related reasons relative to those without ASD." The adherence bit kinda suggests that for example, not taking the antipsychotic medicine when required to, was not a core reason for MTF where ASD is mentioned.

Insofar as the important questions of 'how and why' in relation to the Downs results, the authors pop into 'speculating mode'. They talk for example, about how findings "may be explained by specific neurobiological profiles related to psychosis-ASD comorbidity" mentioning things like dopamine as being important. Equally as speculative, I might add in a few ideas that could also be pertinent. The first is that some effect on immune function could be a complementary pathway in relation to the action of specific antipsychotics (see here). The second is another 'sexy' area of research with a proposed 'epigenetic' action (see here); antipsychotics potentially acting on targets linked to gene expression for example. Both areas - immune function and/or epigenetics - have some 'research form' in both psychosis and autism investigations (see here for example). Both areas require a lot more investigation in this context.

I'm going to finish with another important quote from the Downs paper: "Our results are consistent with the evidence that shows psychotic illness experienced by children and adults with ASD may be different from non-ASD samples." I think the authors might be on to something here as per other observations on important psychiatric comorbidity in relation to autism such as the presentation of bipolar disorder (see here) for example. The idea being that such 'atypical' psychosis presentation and seemingly poor(er) response to recognised treatments for such psychiatric issues could denote that either a novel phenotype may be at work or indeed, that alongside anxiety and depression (see here and see here) being present in cases of autism, psychotic and other symptoms might be seen as more 'core' features of some autism? Once again, I hark back to the [sadly forgotten] writings of Mildred Creak and colleagues [3] as a possible framework for further study...


[1] Downs JM. et al. The Association Between Comorbid Autism Spectrum Disorders and Antipsychotic Treatment Failure in Early-Onset Psychosis. Journal of Clinical Psychiatry. 2017.

[2] Politte LC. et al. Psychopharmacological interventions in autism spectrum disorder. Harv Rev Psychiatry. 2014 Mar-Apr;22(2):76-92.

[3] 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.