Injury risk and ADHD

"The results indicate that there is an elevated injury risk among Swedish schoolchildren with ADHD [attention-deficit hyperactivity disorder] but not for children with ASD [autism spectrum disorder]."

So went the findings reported by Carl Bonander and colleagues [1] providing yet more important data on how a diagnosis of ADHD might be something that confers quite a bit of additional risk for all-manner of different negative outcomes.

I've hinted at this important topic before as per some discussion a few years back on how road crossing behaviour might be 'affected' by a diagnosis of ADHD (see here). This time around Swedish researchers compared the risk of injury for those diagnosed with autism vs. risk of injury for those diagnosed with ADHD based on school nurse collected- and school-based data (survey A and B respectively). "After adjusting for confounders, ADHD was associated with a 65% increased risk of injury... in Survey A, and a 57% increased risk of injury... in Survey B" relative to data derived from "unaffected controls."

A quick look through the other peer-reviewed material on this topic reveals the extent to which a diagnosis of ADHD might increase the risk of various injuries. Take the paper by Silva and colleagues [2] who noted that in "young children who are subsequently diagnosed with attention deficit hyperactivity disorder (ADHD)" there was an increased risk of hospitalisation for all manner of different things: "head injuries, burns, poisons, all other injuries." Other studies have reported similar findings [3] including that relying on 'big data' from the big data capital that is Taiwan [4] (see here for more chatter on Taiwan).

Whilst no-one is suggesting that every visit to accident and emergency (the emergency room) is somehow the product of ADHD, there are some potentially important lessons to learn from such collected data. Timely diagnosis and appropriate management of ADHD symptoms when they affect quality of life are two points raised, bearing in mind 'management' might include several strategies (see here and see here and see here). Where also hospitals or other medical professionals are presented with children or young people who are 'regular visitors', one might also look to the possibility of preferential screening for something like ADHD too as part of additional enquiries. I might add that whilst Bonander and colleagues looked at ADHD vs. autism when it comes to injury risk, one must not forget that ADHD and autism occurring together is not an uncommon finding (see here) and accident and emergency is not necessarily an unfamiliar place to some of those on the autism spectrum (see here). There is more to do in this important area of research.

Finally, I'm also minded to reiterate that hosptial admissions for certain chronic somatic issues might also flag up preferential ADHD screening as well (see here)...

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[1] Bonander C. et al. Injury risks in schoolchildren with attention-deficit/hyperactivity or autism spectrum disorder: Results from two school-based health surveys of 6- to 17-year-old children in Sweden. J Safety Res. 2016 Sep;58:49-56.

[2] Silva D. et al. Children diagnosed with attention deficit disorder and their hospitalisations: population data linkage study. Eur Child Adolesc Psychiatry. 2014 Nov;23(11):1043-50.

[3] Hurtig T. et al. The Association Between Hospital-Treated Injuries and ADHD Symptoms in Childhood and Adolescence: A Follow-Up Study in the Northern Finland Birth Cohort 1986. J Atten Disord. 2016 Jan;20(1):3-10.

[4] Kang JH. et al. Attention-deficit/hyperactivity disorder increased the risk of injury: a population-based follow-up study. Acta Paediatr. 2013 Jun;102(6):640-3.

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Bonander C, Beckman L, Janson S, & Jernbro C (2016). Injury risks in schoolchildren with attention-deficit/hyperactivity or autism spectrum disorder: Results from two school-based health surveys of 6- to 17-year-old children in Sweden. Journal of safety research, 58, 49-56 PMID: 27620934

The Adult Psychiatric Morbidity Survey (APMS) 2014 and autism

They've finally arrived. The results of the English Adult Psychiatric Morbidity Survey 2014 have been published by NHS Digital (yes, our Nation's healthcare services has a digital arm) and when it comes to autism (adult autism 18 years+), some rather peculiar statistics have been produced.

OK, for those who want/need a quick heads-up on all-things Adult Psychiatric Morbidity Survey (APMS), I'll refer you to a previous post I wrote covering this prevalence survey with autism in mind (see here). APMS provides estimates of the numbers of various mental health diagnoses among adults living in private households in England.

The 2014 data report some key facts, not least that: "One in three adults aged 16-74 (37 per cent) with conditions such as anxiety or depression, surveyed in England, were accessing mental health treatment, in 2014." This figure is an increase on the 2007 APMS data (24%). There are also some other important data derived from the 2014 survey too with regards to sex differences in relation to "common mental disorder (CMD)" in diagnosis and in symptoms. Lessons need to be learned.

It is however with autism in mind (see here for the section covering autism), that I'm concentrating on in this post and the observation that: "The estimated prevalence of autism in 2014, using the threshold of a score of 10 on the ADOS [autism diagnostic observation schedule] to indicate a positive case, was 0.7% of the adult population in England (equivalent to a rate of 7 per thousand). The estimated prevalence of autism in the 2007 data (1.0%) was similar to the 2014 estimate; with largely overlapping confidence intervals." A separate 'additional notes' document accompanies the APMS 2014 autism findings (see here).

1% in 2007 and 0.7% in 2014? Accepting that when it comes to prevalence estimates there is always a degree of 'error' expected (as per the comment on 'overlapping confidence intervals') I'm a little bit puzzled by this latest data and the idea that the figures are described as 'similar'. Puzzled because as well as suggesting that adult autism prevalence estimates might have actually dipped between the years, the authors note that their search of 3 quite populous areas of England ("Leicestershire, Lambeth and Sheffield") across both the 2007 and 2014 data combined only found "31 participants identified with autism."

So what's going on with the APMS and autism?

A question indeed and I assume that the 'combining' of the 2007 and 2014 datasets reveals quite a bit more than just the very small number of participants identified in the studies. I have to say that my brow is furrowing a little at the sight of the Autism Spectrum Quotient (AQ) as retaining an 'autism screener' role in the APMS 2014. If I've learned anything about the AQ in recent times it is that whilst measuring something, it may not be a particularly great exclusive screen for autism (see here). Even the authors attached to the APMS 2014 autism data have said so [1]: "The AQ-20 was only a weak predictor of ADOS-4 cases." I've also mentioned about the ADOS module situation and the whys and wherefores with APMS in mind in that previous post on the topic (see here again).

So we're left with a quandary. The much heralded '1% of adults may have autism' statistic is replaced by a lower value (with appropriate caveats on confidence intervals) of 0.8% when the APMS 2007 and 2014 data are combined. Is this a true reflection of adult autism in England in recent times? How does this tally with the suggestion that child and adolescent rates of autism are on the increase as per that seen in other parts of the UK (see here)?

Or, are the processes pertinent to estimating adult autism used by the APMS not really cutting the statistical/methodological mustard?

Which one is it?

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[1] Brugha TS. et al. Validating two survey methods for identifying cases of autism spectrum disorder among adults in the community. Psychol Med. 2012 Mar;42(3):647-56.

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Brugha TS, McManus S, Smith J, Scott FJ, Meltzer H, Purdon S, Berney T, Tantam D, Robinson J, Radley J, & Bankart J (2012). Validating two survey methods for identifying cases of autism spectrum disorder among adults in the community. Psychological medicine, 42 (3), 647-56 PMID: 21798110

On "socially successful elementary school-aged children with autism"

"School-based interventions should address malleable factors such as the number of peer connections and received friendships that predict the best social outcomes for children with ASD [autism spectrum disorder]."

So said the study findings reported by Jill Locke and colleagues [1] looking at "the stable (unlikely to change) and malleable (changeable) characteristics of socially successful children with ASD."

Mindful that the phrase 'socially successful children' is perhaps not one that I'm particularly enamoured with, and certainly not one that necessarily opens the doors to 'successful' academic outcomes in childhood for example (see here), the Locke paper makes for interesting reading.

Looking at nearly 150 "elementary-aged children with ASD" authors listed a number of factors linked to 'playground peer engagement' and 'social network salience ' a.k.a playing with other children in the school yard and "inclusion in informal peer groups." The severity of autistic symptoms was unsurprisingly a key feature as was those numbers of 'peer connections' and 'received friendships'.

What do these results mean? Well, minus sweeping generalisations, there may be some pretty easy ways that 'social outcomes' can be positively influenced for at least some children on the autism spectrum; not least one important variable: friends. Yes, a shocker I know.

I've used the term 'easy ways' and 'friends' in that previous sentence to denote how [sometimes] complicated and expensive/resource intensive interventions to 'increase social outcomes' when it comes to the label of autism really might not be the most effective use of resources. I however understand that friends, real friends, are not just something that can be magically produced on demand and that also friendships, whilst in the end generally worthwhile, are not without their own stresses and strains (some of which might be even more stressful and strainful(!) for a child on the autism spectrum).

One approach that does seem to be finding some favour in the peer-reviewed domain at least is that of employing a buddy system. The findings reported by Laushey & Heflin [2] whilst not without their methodological issues, provide some important assertions that a peer buddy approach might be something for schools to consider for some pupils with autism. I know some people might argue that a buddy is not the same as a friend but I'm not one of the them: opportunity (not necessity) is the mother of invention. Visit most schools (at least in here in the UK) and you will see similar arrangements being made for pupils whether diagnosed with autism or not. That and use of 'buddy/friendship stops' in certain parts of the playground and you'll see how important socialisation is viewed for all school pupils.

I'm also a greater believer that sport and exercise can be an important part of inclusion practices when it comes to autism - something equally applicable to school. Y'know, those team games that help build and forge important bonds between children particularly when it comes to competitive team games, also introducing the important concept of 'belonging'. I appreciate that finding the right sport is important in terms of likes/dislikes and ability but there are quite a few options out there. Indeed, drilling further down into the concept of 'belonging', one can perhaps see how even at elementary school age, finding your social niche can open up a whole world of new friends/associates thus implying that school clubs (e.g. Lego club, ICT club) might also be an important intervention tool too.

I don't want to come across too formulaic or mechanical when it comes to how to improve social outcomes for children on the autism spectrum because there is not one-size-fits-all 'flowchart' to this issue. Appreciating also that some children on the autism spectrum might not necessarily want to be 'social butterflies' there has to be some indication from the child as to the extent of their wants and wishes when it comes to social interaction also taken into account.

I should also remind readers that when it comes to friendships, children can be a rather fickle bunch...

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[1] Locke J. et al. Characteristics of socially successful elementary school-aged children with autism. J Child Psychol Psychiatry. 2016 Sep 13.

[2] Laushey KM. & Heflin LJ. Enhancing social skills of kindergarten children with autism through the training of multiple peers as tutors. J Autism Dev Disord. 2000 Jun;30(3):183-93.

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Locke J, Williams J, Shih W, & Kasari C (2016). Characteristics of socially successful elementary school-aged children with autism. Journal of child psychology and psychiatry, and allied disciplines PMID: 27620949

Postural tachycardia syndrome and gluten?

Please use your full stops wisely.

I believe that this is the first time that I've talked about postural tachycardia syndrome (PoTS) on this blog as I bring to your attention some rather intriguing findings reported by Hugo Penny and colleagues [1] on how PoTS and gluten-related disorders might not be unstrange diagnostic bedfellows.

PoTS by the way, describes symptoms where standing upright / sitting down induces dizziness, fainting and other symptoms. As well as being quite prevalent in a certain condition called Ehlers-Danlos syndrome (see here), PoTS is also described fairly frequently in cases of chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME) too.

Describing how "patients with postural tachycardia syndrome (PoTS) were placing themselves on a gluten-free diet without medical consultation" the authorship team (mentioned previously on this blog) residing in the great city of Sheffield decided to look-see whether there may be underlying medical reasons why such gluten-free moves seemed to be used in cases of PoTS. They screened their 100 participants with PoTS "for gluten sensitivity, related symptoms and dietary habits" as well as assessing for coeliac disease, the archetypal gluten-related autoimmune condition.

Results: compared with a couple of control groups numbering in total above 1500 local participants, coeliac disease (CD) seemed to be more common in the PoTS groups - "serology and biopsy-proven coeliac disease." Alongside: "PoTS patients also had a higher prevalence of self-reported gluten sensitivity... compared with age-matched and sex-matched controls." The authors conclude that there may be more to see when it comes to the presence of classical and non-classical gluten-related disorders in relation to PoTS.

This is potentially important stuff. Accepting that outside of the immediate dizziness and fainting symptoms associated with PoTS there may be other 'gastrointestinal' involvement [2] the intriguing idea that [certain] symptoms might be to some degree alleviated by use of a dietary change is worthy of greater inspection. Indeed, set within the context of an associated diagnostic label, orthostatic intolerance, where an upright posture provokes related symptoms, also being potentially linked to gastrointestinal issues [3] one has an interesting template as to how gut and brain might show some important links. That a gluten-free diet will most likely target both gut and brain (yes, it might) provides plenty of food for thought as to possible mechanisms.

I'm also pretty interested in the growing research base looking at a possible autoimmune component to at least some cases of PoTS [4]. I know this takes us into some 'brow-furrowing' areas of peer-reviewed science [5] (indeed, complicated science) but the potential importance of cases of autoimmune PoTS intersecting with cases of autoimmune coeliac disease provides yet another example of how birds of an autoimmune feather tend to flock together (see here). The implication being that cases of PoTS should perhaps be screened for CD and other autoimmune disease/features and perhaps treated accordingly, offers some new directions for research and clinical practice.

And just in case you are still convinced that use of a gluten-free diet outside of CD is all bunk, the worm still continues to turn...

To close, 'Shatner's Bassoon'. That is all.

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[1] Penny HA. et al. Is there a relationship between gluten sensitivity and postural tachycardia syndrome? Eur J Gastroenterol Hepatol. 2016 Sep 7.

[2] Wang LB. et al. Gastrointestinal dysfunction in postural tachycardia syndrome. J Neurol Sci. 2015 Dec 15;359(1-2):193-6.

[3] Sullivan SD. et al. Gastrointestinal symptoms associated with orthostatic intolerance. J Pediatr Gastroenterol Nutr. 2005 Apr;40(4):425-8.

[4] Thieben MJ. et al. Postural orthostatic tachycardia syndrome: the Mayo clinic experience. Mayo Clin Proc. 2007 Mar;82(3):308-13.

[5] Blitshteyn S. & Brook J. Postural tachycardia syndrome (POTS) with anti-NMDA receptor antibodies after human papillomavirus vaccination. Immunol Res. 2016 Aug 25.

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Penny, H., Aziz, I., Ferrar, M., Atkinson, J., Hoggard, N., Hadjivassiliou, M., West, J., & Sanders, D. (2016). Is there a relationship between gluten sensitivity and postural tachycardia syndrome? European Journal of Gastroenterology & Hepatology DOI: 10.1097/MEG.0000000000000740

Neurotensin, intestinal inflammation and autism?

"Elevated peripheral pro-NT [neurotensin] levels reflect more severe forms of active celiac disease, indicating a potential role of NT in intestinal inflammation."

The suggestion, from Caroline Montén and colleagues [1], that the neuropeptide called neurotensin might play a role in paediatric coeliac disease is an interesting one that caught my eye recently. Interesting not only because of the potential implications for the archetypal 'gluten-causing' autoimmune condition called coeliac disease, but also because neurotensin might have some rather important links to [some] autism too [2].

OK, a quick recap is perhaps useful. Neurotensin when it comes to autism typically means one name, Theoharis Theoharides, he of mast cells fame (see here). The idea is that neurotensin (NT) is, among other things, quite a 'potent trigger' of mast cells and when activated these mast cells can release their inner contents that include quite a few substances linked to allergic inflammation. At least some of the talk linking 'inflammation' and autism might include a role for mast cells [3]  and so hey presto, a potentially important chain of biological events might therefore be linked.

Going back to the original Montén paper on NT and coeliac (celiac) disease, researchers set about investigating "if plasma pro-NT levels correlated with the degree of intestinal mucosal damage and tissue transglutaminase autoantibody (tTGA) levels in children with celiac disease." They did find elevated levels of one of the NT precursor fragments in a coeliac disease group (n=96) compared with controls (n=89) and there did seem to be something of a possible connection between pro-NT levels and tTGA. On these basis, they concluded that NT might indeed be linked to the intestinal inflammation noted in cases of coeliac disease. Mast cells might also be important to coeliac disease too according to recent findings.

Accepting that coeliac disease is not autism (even though in some individual cases they may be linked [4]), there are a few further studies that might be required on this topic with autism in mind. As I've already mentioned, inflammation - particularly inflammation of the gastrointestinal (GI) tract - is not something unheard of in autism research/practice circles (see here). I know furrowed brows can be associated with this area of discussion but I'm talking about peer-reviewed science not anecdote and speculation. One might for example, see an investigation whereby those with autism and GI-related issues (including an inflammatory component) might be more closely inspected for something like NT to see if it is something important. You could even include those potentially falling into the grey area of non-coeliac gluten sensitivity (NCGS) if you so wished (see here). Given also related findings for some on the autism spectrum in relation to tTGA too (see here) and the possibility of another link there with NT, some brave research team might also wish to inspect this parameter. I might also suggest that looking at gut motility patterns in relation to NT levels could be another area ripe for further investigation with autism in mind (see here) given some previous discussions on the effects of NT.

Just a few suggestions for how a little more work in this area might prove illuminating.

Insofar as what to do about a possible link between NT and autism, well someone it seems has already started that conversation [5] and discussions are seemingly continuing in the peer-reviewed domain [6]...

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[1] Montén C. et al. Role of pro-neurotensin as marker of paediatric celiac disease. Clin Exp Immunol. 2016 Sep 10.

[2] Angelidou A. et al. Neurotensin is increased in serum of young children with autistic disorder. J Neuroinflammation. 2010 Aug 23;7:48.

[3] Theoharides TC. et al. Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders. Transl Psychiatry. 2016 Jun 28;6(6):e844.

[4] Genuis SJ. & Bouchard TP. Celiac disease presenting as autism. J Child Neurol. 2010 Jan;25(1):114-9.

[5] Ghanizadeh A. Targeting neurotensin as a potential novel approach for the treatment of autism. Journal of Neuroinflammation. 2010; 7:58.

[6] Patel AB. et al. Neurotensin stimulates sortilin and mTOR in human microglia inhibitable by methoxyluteolin, a potential therapeutic target for autism. Proc Natl Acad Sci U S A. 2016 Sep 23. pii: 201604992.

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Montén C, Torinsson Naluai Å, & Agardh D (2016). Role of pro-neurotensin as marker of paediatric celiac disease. Clinical and experimental immunology PMID: 27612962

On HERV-H, autism, ADHD and methylphenidate?

Today's post is a bit of a mash-up including two paper: the first from Emanuela  Balestrieri and colleagues [1] (open-access available here) talking about "increased HERV-H [Human Endogenous Retroviruses - H] transcriptional activity in all autistic patients" included in their cohort (author's words not mine) and the second from D'Agati and colleagues [2] (open-access available here) describing "the reduction of HERV-H expression and the significant improvement of ADHD [attention-deficit hyperactivity disorder] symptoms after 6 months of methylphenidate treatment."

Taken together, both papers provide some potentially important information on how those fossil viruses that litter the human genome might not be as redundant as we might have first thought. Also how some of the commonly used medications to treat/manage certain psychiatric labels might have quite a few more effects than those listed on the package insert. A shocker indeed.

I've covered HERVs a few times on this blog in relation to quite a few labels (see here and see here and see here). If you've clicked on that first link, you'll know that this is not the first time that Balestrieri et al have talked about HERVs with autism in mind [2]. On that first occasion, they even went as far as proposing that "HERV-H expression be explored in larger samples of individuals with autism spectrum in order to determine its utility as a novel biological trait of this complex disorder." This time around "the transcriptional activity of three human endogenous retrovirus (HERV) families, in peripheral blood mononuclear cells (PBMCs)" was examined in 30 children diagnosed with autism spectrum disorder (ASD) and 30 asypmtomatic controls. Quantitative real-time PCR was the analytical weapon of choice, as "transcriptional levels of env of HERV families were quantitatively evaluated." As I've already mentioned, HERV-H expression showed some interesting trends compared to the not-autism controls. The authors note that this data from Albanian children is pretty much the same as what they found in Italian children diagnosed with autism.

The D'Agati findings - also including Balestrieri on the authorship list - although discussing a case report on what happened to HERV-H expression following use of methlyphenidate (MPH) in relation to ADHD, might also have some implications for [some] autism. Reiterating that this was a case report where both before and after HERV-H expression levels were measured, it potentially offers a road map for how HERV-H expression might be 'affected' by the use of certain medicines. Yes, I know that researchers only measured one variable (HERV-H) and one variable/measurement does not a link make. But given the quite significant overlap between ADHD and autism (see here) and the insinuation that over-expression of HERV-H might not necessarily be a 'good thing', one could see how further [independent] studies might be informative in this area.

Although slightly complicated by the fact that we are only beginning to realise how important HERVs might be to things like stem cells for example or even potentially being involved in the process of genetic deletion (see here), what is becoming clear is that these fossil viruses might be something to watch when it comes to health and wellbeing at different times of development. I've tried not to be too enthusiastic about HERVs and autism / ADHD / other (delete as appropriate) on this blog given our lack of understanding on any connection, specifically the hows and whys of any effect on either aetiology or symptoms. But it is getting harder not to wonder what role these and other mobile elements might play in development and behaviour, particularly in the context of HERVs being implicated in autoimmunity [3] (yes, that might also show a connection to some autism) and a possible role for the still emerging science of epigenetics in both HERV expression [4] and also [some] autism. There is lots more research to be done on this topic.

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[1] Balestrieri E. et al. Transcriptional activity of human endogenous retrovirus in Albanian children with autism spectrum disorders. New Microbiol. 2016 Sep;39(3):228-31.

[2] D'Agati E. et al. First evidence of HERV-H transcriptional activity reduction after methylphenidate treatment in a young boy with ADHD. New Microbiol. 2016 Sep;39(3):237-9.

[3] Tugnet N. et al. Human Endogenous Retroviruses (HERVs) and Autoimmune Rheumatic Disease: Is There a Link? The Open Rheumatology Journal. 2013;7:13-21.

[4] Lavie L. et al. CpG methylation directly regulates transcriptional activity of the human endogenous retrovirus family HERV-K(HML-2). J Virol. 2005 Jan;79(2):876-83.

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Balestrieri E, Cipriani C, Matteucci C, Capodicasa N, Pilika A, Korca I, Sorrentino R, Argaw-Denboba A, Bucci I, Miele MT, Coniglio A, Alessandrelli R, & Sinibaldi Vallebona P (2016). Transcriptional activity of human endogenous retrovirus in Albanian children with autism spectrum disorders. The new microbiologica, 39 (3), 228-31 PMID: 27602423


D'Agati E, Pitzianti M, Balestrieri E, Matteucci C, Sinibaldi Vallebona P, & Pasini A (2016). First evidence of HERV-H transcriptional activity reduction after methylphenidate treatment in a young boy with ADHD. The new microbiologica, 39 (3), 237-9 PMID: 27602426

Correcting ophthalmic problems in autism

'Does Correction of Strabismus Improve Quality of Life in Children with Autism Spectrum Disorder?' went the title of the paper by Pinar Ozer and colleagues [1]. Yes, it may very well do was the answer (but with certain caveats and the requirement for a lot more research in this area).

Strabismus, a condition where the eyes don't line up in the same direction, can sometime have some quite noticeable effects on a person's vision and indeed, has been linked to various other non-vision related symptoms and outcomes.

Ozer et al looked to identify "the impact of optical or surgical correction of the strabismus on the child using a questionnaire for parents." The published research of this team has been previously discussed on this blog (see here) with ophthalmic findings in mind, and the requirement for quite a few more resources to be put into eye examinations when autism is diagnosed (see here). This time around they were discussing what happens when such eye issues are resolved.

I'm not completely convinced that the Ozer findings this time around reporting 'significant improvements' in areas of "psychosocial interactions" is as it stands, a methodologically firm finding just pertinent to autism. Although no expert on strabismus, from what I gather, the 'cosmetic' side of the condition can have some far-reaching effects on 'psychosocial' functions. I daresay that such effects would be just as prevalent in autism as they are in the general population and hence, correction would likely have similar outcomes.

I am more open to the idea that if strabismus is affecting vision, as in causing something like blurred or double vision, correction of the issue may in some cases have some important 'effects' in relation to autism. Accepting that structural issues with the eye are not necessarily the same as or causative of visual perceptual issues that seem to crop up quite often in the autism research arena, it is not outside the realms of possibility that something like strabismus could be part and parcel of visual effects for some people.

I suppose to reiterate, screening for structural eye/vision issues when it comes to autism remains a pretty important area.

To close, karate gradings for one of my brood today and this is what they will be attempting...

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[1] Ozer PA. et al. Does Correction of Strabismus Improve Quality of Life in Children with Autism Spectrum Disorder: Results of a Parent Survey by Ophthalmologists. Semin Ophthalmol. 2016 Sep 6:1-6.

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Ozer PA, Kabatas EU, Bicer BK, Bodur S, & Kurtul BE (2016). Does Correction of Strabismus Improve Quality of Life in Children with Autism Spectrum Disorder: Results of a Parent Survey by Ophthalmologists. Seminars in ophthalmology, 1-6 PMID: 27599387

Epilepsy and systemic autoimmune diseases: birds of a feather?

A couple of years back on this blog I talked about some rather intriguing research suggesting that epilepsy and autoimmune disease might not be unstrange diagnostic bedfellows (see here) and that a "potential role of autoimmunity must be given due consideration in epilepsy." [1]

Today, I'm continuing that research theme as the findings from Zhang Lin and colleagues [2] caught my eye concluding that: "There is an association between epilepsy and SAD [systemic autoimmune diseases], which was shown to be stronger at a young age."

Relying on that rather important methodological tool called a meta-analysis, where various study findings are lumped together and conclusions (hopefully) derived from the whole, Lin et al included data from some 25 studies where epilepsy and SAD had been examined together "which included 10,972 patients with epilepsy (PWE) and 2,618,637 patients with SAD."

Aside from those with epilepsy showing "more than a 2.5-fold increased risk of SAD" the authors also observed the opposite too: "patients with SAD were also shown to have a more than 2.5-fold increased risk of epilepsy." When it came to specifics, those diagnosed with epilepsy were observed to show "a 2.6-fold increased risk of celiac disease" and those "patients with systemic lupus erythematosus had a 4.5-fold increased risk of epilepsy."

I remain intrigued about this topic. Appreciating that within the peer-reviewed literature there is such a thing as autoimmune epilepsy [3] and that even in cases of epilepsy seemingly without the autoimmune encephalitis element to it, there may be antibodies to neuronal tissue involved [4], there are perhaps some further important clinical studies to be done in this area. It is for example, not uncommon to see more than one autoimmune condition appearing at the same time (see here) as various autoimmune overlaps have been noted in the quite voluminous science literature on this topic. The implications perhaps being that if one could find some of the 'causes' behind such autoimmune issues (be that related to molecular mimicry or the presence of a superantigen for examples) one may potentially be able to treat/manage quite a few conditions.

Wearing my autism research blogging hat and extending the possibility of an 'autism link' discussed on my previous post on this topic, I'd like to think there may be some scope for further inquiry with autism in mind too. Not only because epilepsy is one of the prime comorbidites attached to a diagnosis of autism (see here) but also that for some people on the autism spectrum, autoimmunity is also potentially something to contend with (see here). Should we therefore be so surprised at the possibility that autism, epilepsy and autoimmunity could form an important clinical triad for some?

And with full caveats in action about not giving medical or clinical advice on this blog, there is a body of evidence out there supporting immunotherapy for certain types of epilepsy [5] where other interventions have failed. Mmm, I also wonder...

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[1] Ong MS. et al. Population-level evidence for an autoimmune etiology of epilepsy. JAMA Neurol. 2014 May;71(5):569-74.

[2] Lin Z. et al. Association between epilepsy and systemic autoimmune diseases: A meta-analysis. Seizure. 2016 Aug 23;41:160-166.

[3] Britton J. Autoimmune epilepsy. Handb Clin Neurol. 2016;133:219-45.

[4] Wright S. et al. Neuronal antibodies in pediatric epilepsy: Clinical features and long-term outcomes of a historical cohort not treated with immunotherapy. Epilepsia. 2016 May;57(5):823-31.

[5] Bello-Espinosa LE. et al. Efficacy of intravenous immunoglobulin in a cohort of children with drug-resistant epilepsy. Pediatr Neurol. 2015 May;52(5):509-16.

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Lin Z, Si Q, & Xiaoyi Z (2016). Association between epilepsy and systemic autoimmune diseases: A meta-analysis. Seizure, 41, 160-166 PMID: 27592469

"Paediatricians are seeing more children with developmental-behavioural conditions"

The findings reported by Harriet Hiscock and colleagues [1] are brought to the blogging table today, specifically that suggestion that paediatricians, at least in Australia, might be encountering an increased number of "developmental/behavioural conditions" as part of their workload.

Looking at the clinical experiences of some 180 paediatricians who took part in the study in late 2013 and comparing them with data from 2008, researchers probed a number of practices relating to "(i) conditions seen; (ii) consultation duration; (iii) imaging and pathology ordered; and (iv) prescribing." The details associated with seeing an increasing number of children "with developmental-behavioural conditions" included: "More paediatricians reported diagnoses of autism spectrum disorder... attention-deficit/hyperactivity disorder... and intellectual disability... in first consultations."

Whilst being slightly careful that 'seeing more children with developmental-behavioural conditions' is not necessarily equated with there 'being' more children with such issues, I'm inclined to suggest that such data is important. Quite a few times in the British media at least, stories have emerged about long waiting times for developmental assessments (see here for one example) and how an already stretched National Health Service (NHS) is seemingly struggling in some parts, to cope with the number of referrals coming through (see here).

As part of a wider peer-reviewed and 'other' evidence base suggesting that (a) the estimated prevalence rates for autism have increased (see here) and (b) there may be a 'real' increase in 'rates of behaviour' associated with an autism spectrum disorder (ASD) (see here) I am becoming more and more convinced that old arguments about 'better awareness' or 'diagnostic switching' are becoming less relevant to the debate about the increasing numbers of cases of autism (see here for example).

I don't doubt that as a society we are far more aware of autism than we ever were (we've even started 'screening for it' during early infancy here in Blighty) and where decades ago someone for example, might have been diagnosed with a learning disability even though they presented with autistic features so things are a little different nowadays. But the sorts of stresses and strains being placed on developmental screening and diagnostic services (particularly paediatric services) in comparison to times gone by are seemingly not comparable anymore. Even taking into account population increases and changes to the organisation of screening and diagnostic services, talk of a growing tide of children being diagnosed, or waiting to be assessed, as being on the autism spectrum is something that really should be prompting a lot more urgency and action. I might also add that arguments about better clinical awareness - did they really miss all those children? - really do a disservice to those who have been skillfully diagnosing autism for many years. Value our experts!

And alongside the talk about children being diagnosed, adult services too are also under a lot more pressure these days...

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[1] Hiscock H. et al. Trends in paediatric practice in Australia: 2008 and 2013 national audits from the Australian Paediatric Research Network. J Paediatr Child Health. 2016 Sep 4.

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Hiscock H, Danchin MH, Efron D, Gulenc A, Hearps S, Freed GL, Perera P, & Wake M (2016). Trends in paediatric practice in Australia: 2008 and 2013 national audits from the Australian Paediatric Research Network. Journal of paediatrics and child health PMID: 27594610

Respite care and parent stress with autism in mind

"While most studies found that respite care was associated with lower stress, several found that respite care was associated with higher stress."

That sentence is perhaps the most important finding recorded in the 'integrative review' published by Kim Whitmore [1] looking at "the relationship between respite care and stress among caregivers of children with ASD [autism spectrum disorder]."

Covering a "final sample of 11 primary research reports" the author provides yet another example of how sweeping generalisations in relation to autism really do no-one no good and how "tailoring respite care services to the unique family needs" is most definitely the way forward.

This is important stuff [2]. I've previously talked about how - again, minus any sweeping generalisations - parental stress in relation to raising a child with autism is one of the more pressing issues when it comes to the health and wellbeing of carers (see here). A steady flow of firsthand accounts also substantiate this finding even in some instances talking about "trauma-related symptomatology" [3]. Respite as one tool in the arsenal to care for the carers is something important; not least because of how such stress can sometimes severely impact on parental quality of life (see here) and potentially onward parent-child (and other) relationships. In amongst all the discussions about autism - how we view it and the implications for the person diagnosed - the effect of a diagnosis on parents/carers can sometimes get a little lost in all the noise.

What's more to say on this topic? Well, I think it is perhaps important to bring in the paper by Southby [4] who brought up an interesting point about how: "Residential respite appears to be the default conceptualization of 'respite' for carers, service users and stakeholders." It's not, and as per the organisation that I'm linked to, something like domiciliary support (otherwise known as home care) can sometimes provide a viable alternative to residential respite/placement. The knowledge that a person does not have to leave the family home, for example, can in some instances have a more positive impact on carer stress, and indeed, most probably will be less cost- and resource-intensive too. I don't also doubt that when it comes to stress for the person diagnosed with autism (an important consideration), for some the familiarity of the home environment is something not to be tinkered with by thoughts of residential respite. But again as per the idea of 'tailoring' resources to individual needs, for some families [5], residential respite every now-and-again should not be discounted.

Finally, it's all well and good talking about the benefits of respite and tailoring respite to meet individual needs, but the cold, hard reality of providing respite in these austere times should not also be forgotten. Indeed, as social purse strings are tightened alongside criteria for eligibility for such services, the factors associated with use and non-use of such services present some difficult choices [6] and are only likely to become even more narrow in future...

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[1] Whitmore KE. Respite Care and Stress Among Caregivers of Children With Autism Spectrum Disorder: An Integrative Review. J Pediatr Nurs. 2016 Aug 31. pii: S0882-5963(16)30150-6.

[2] Dyches TT. et al. Respite Care for Single Mothers of Children with Autism Spectrum Disorders. J Autism Dev Disord. 2016 Mar;46(3):812-24.

[3] Stewart M. et al. Through a trauma-based lens: A qualitative analysis of the experience of parenting a child with an autism spectrum disorder. Journal of Intellectual and Developmental Disability. 2016. Sep 16.

[4] Southby K. Barriers to non-residential respite care for adults with moderate to complex needs: A UK perspective. J Intellect Disabil. 2016 Jul 20. pii: 1744629516658577.

[5] Harper A. et al. Respite care, marital quality, and stress in parents of children with autism spectrum disorders. J Autism Dev Disord. 2013 Nov;43(11):2604-16.

[6] Preece D. & Jordan R. Short breaks services for children with autistic spectrum disorders: factors associated with service use and non-use. J Autism Dev Disord. 2007 Feb;37(2):374-85.

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Whitmore KE (2016). Respite Care and Stress Among Caregivers of Children With Autism Spectrum Disorder: An Integrative Review. Journal of pediatric nursing PMID: 27592275

First trimester maternal vitamin D status and offspring autism risk?

Vitamin D - the sunshine vitamin/hormone - is seemingly everywhere these days in research terms. At the time of writing this post we have news that vitamin D might cut the risk of severe asthma attacks if taken alongside prescribed asthma medication. The week before that it was the suggestion that vitamin D might be part of the explanation as to why childhood learning difficulties were more commonly found in children conceived during the winter months. Vitamin D is seemingly shouldering quite a bit of responsibility when it comes to health and wellbeing.

Today I'm adding to that research responsibility by introducing the paper by Jianzhang Chen and colleagues [1] who suggested that: "Lower first trimester maternal serum levels of 25(OH) D were associated with increased risk of developing autism in offspring." 25(OH)D by the way, is calcifediol, and refers to the typical metabolite assayed for to provide a measure of ones vitamin D status.

Chen and colleagues accessed archived maternal blood samples taken during the first trimester of pregnancy - "11–13 weeks gestational age" - for some "68 children diagnosed with ASD [autism spectrum disorder] and 68 sex and age matched typically-developing children." Not only was vitamin D status examined in those samples but various other potentially useful metabolites: "unmetabolized folic acid (FA), vitamin B12, homocysteine (HCY) and High Sensitivity C Reactive protein (CRP)" that may have some important autism-related links for some (see here and see here for example).

Their report on this occasion focused on the vitamin D results and the finding that mums of children diagnosed with autism/ASD were as a group more likely to present with lower levels of 25(OH)D than control (not-autism) mums. Indeed, when it came to the percentages of who were and weren't vitamin D deficient, some 55% of mums with a child with autism fell into this category compared with less than 30% of control mums. I might add that vitamin D deficiency is typically only one 'banding' when it comes to looking at vitamin D status. With the caveats that this was a study of maternal vitamin D and autism offspring risk in China (so not necessarily translatable to other parts of the world; see discussions shortly) authors also observed a possible correlation between maternal vitamin D status and autism 'severity' in their cohort.

Bearing in mind my recent discussions on the maternal body as 'an environment in autism science' (see here) and the potential pitfalls this presents, the data from Chen et al are interesting. Accepting also that I have a bit of a research 'thing' for vitamin D when it comes to autism on this blog (see here and see here for examples), this work seemingly fits in pretty well with the idea that nutritional factors at critical periods may indeed play a role in the development of at least some autism. Indeed, when one talks about season of conception as potentially being associated with offspring risk of behavioural or developmental issues [2], vitamin D levels look like an attractive research target. The next stage in this research process would be independent replication and perhaps, looking at other populations too.

In fact, on the topic of other populations similarly studied with maternal vitamin D status and offspring autism or autistic traits in mind, the research path previously trodden might not be all one-way. Take for example research coming out of Australia [3] a few years back that observed little in the way of connection between maternal vitamin D levels and offspring development (see here). OK, they used the Autism Spectrum Quotient (AQ) as their behavioural diagnoser (something that might not be cutting the appropriate mustard in recent times) but all-in-all they found little in the way of any relationship in contrast to the Chen findings. The fact that the Raine study data used in the Australian paper also included quite a few more participants also offers a significant advantage to the smaller Chen study.

But I don't think we can just discount the Chen results as they stand, as more and more vitamin D is thrust onto the [autism] research stage. Combined with the recent guidance from the Government here in Blighty suggesting that vitamin D supplementation perhaps needs to be a lot more widespread than it is (see here and see here) throughout the population as a whole, research opportunities aplenty present themselves in this area of growing importance...

Oh, and that includes with regards to the genetics of vitamin D metabolism too (see here).

To close, if you are easily offended by bad language, please stay away from this advert for a cookbook (probably not the language you're likely to hear on Bake Off whatever channel it's on).

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[1] Chen J. et al. Lower maternal serum 25(OH) D in first trimester associated with higher autism risk in Chinese offspring. Journal of Psychosomatic Research. 2016; 89: 98-101.

[2] Zerbo O. et al. Month of conception and risk of autism. Epidemiology. 2011 Jul;22(4):469-75.

[3] Whitehouse AJ. et al. Maternal vitamin D levels and the autism phenotype among offspring. J Autism Dev Disord. 2013 Jul;43(7):1495-504.

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Chen, J., Xin, K., Wei, J., Zhang, K., & Xiao, H. (2016). Lower maternal serum 25(OH) D in first trimester associated with higher autism risk in Chinese offspring Journal of Psychosomatic Research, 89, 98-101 DOI: 10.1016/j.jpsychores.2016.08.013

Constipation in schizophrenia

"Constipation and dyspepsia are disturbing gastrointestinal symptoms that are often ignored in research on physical comorbidities of schizophrenia."

Go on.

"The prevalence of constipation was 31.3%, and of dyspepsia 23.6%."

So said the findings reported by Tomi Virtanen and colleagues [1] who assessed "dyspepsia and constipation in a sample of outpatients with schizophrenia spectrum psychoses." Alongside the general practitioner assessment of such functional bowel complaints, researchers also "assessed the possible contribution of several sociodemographic, lifestyle, and clinical variables" including gender/sex and medication use.

As per the sentence above, functional bowel issues such as constipation and dyspepsia might not be unstrange bedfellows alongside a diagnosis of schizophrenia spectrum disorders. There were however some important potential 'correlates' associated with such bowel issues, not least that certain types of medication might exert some effect(s). So for example: "Clozapine use markedly increases the risk of constipation and may lead to life-threatening complications." Even something like the (not-so) humble medicine called paracetamol might also show some relationship to bowel symptoms according to the Virtanen data.

Glancing through the other peer-reviewed literature on the topic of bowel issue prevalence and schizophrenia, I was struck by how little there seems to be at present. Yes, there are various papers talking about the comorbidity of certain bowel diseases and schizophrenia [2] but when it comes to the question of 'how prevalent are functional bowel disorders (i.e. constipation, diarrhoea, etc) in cases of schizophrenia?' there appears to be something of a bit of a research gap. This is perhaps a more important topic than many might realise given the suggestion that 'the gut might matter' when it comes to at least some schizophrenia [3]. Yet another example of the gut-brain axis at work eh?

The very important effect that something like medication might have on the presentation of bowel issues in schizophrenia is not to be sniffed at either. When words like: "Constipation associated with antipsychotic treatment is frequent in patients with schizophrenia. It can be severe when early detection fails." one really would think that a lot more would be done to further quantify such risk and importantly, start providing viable options to reduce any risk from such potentially severe functional bowel effects. On this matter, and minus any charges of me providing clinical and/or medical advice (I'm not), I might draw your attention to the data suggesting that the use of probiotics in cases of schizophrenia with bowel issues [4] (see here for further discussion) might be something to look further at. More so if one assumes that such something like constipation might be more readily described in terms of irritable bowel syndrome (IBS) for some, and the growing moves towards using probiotics as an intervention aid with that label in mind (see here). Dietary advice could also be something that could be utilised a lot more assuming that a diagnosis of schizophrenia (spectrum disorder) might confer some enhanced risk for a poor diet and nutrition [5].

Who knows, treating such bowel issues as and when they present might also have some interesting knock-on effects for other areas of functioning too...

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[1] Virtanen T. et al. Dyspepsia and constipation in patients with schizophrenia spectrum disorders. Nord J Psychiatry. 2016 Aug 26:1-7.

[2] Mäkikyrö T. et al. Comorbidity of hospital-treated psychiatric and physical disorders with special reference to schizophrenia: a 28 year follow-up of the 1966 northern Finland general population birth cohort. Public Health. 1998 Jul;112(4):221-8.

[3] Severance EG. et al. Gastroenterology issues in schizophrenia: why the gut matters. Curr Psychiatry Rep. 2015 May;17(5):27.

[4] Dickerson FB. et al. Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. Prim Care Companion CNS Disord. 2014;16(1). pii: PCC.13m01579.

[5] Teasdale SB. et al. A nutrition intervention is effective in improving dietary components linked to cardiometabolic risk in youth with first-episode psychosis. Br J Nutr. 2016 Jun;115(11):1987-93.

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Virtanen T, Eskelinen S, Sailas E, & Suvisaari J (2016). Dyspepsia and constipation in patients with schizophrenia spectrum disorders. Nordic journal of psychiatry, 1-7 PMID: 27564411

Comorbidities surrounding paediatric chronic fatigue syndrome / myalgic encephalomyelitis (CFS / ME)

"This large nationwide registry linkage study confirms that the clinical picture in CFS/ME [chronic fatigue syndrome / myalgic encephalomyelitis] is complex."

That sentence, taken from the paper by Inger Bakken and colleagues [1] (open-access available here), is perhaps the under-statement of the year as authors sought to "describe comorbidities diagnosed in primary care in children diagnosed with CFS/ME in specialist health care" and "describe the timing of the diagnoses from primary care in relation to the timing of the CFS/ME diagnosis."

I grow tired of saying this but yet again, one of those very useful Scandinavian population registries was the starting point for the study - this time based in Norway - as some 1600 children diagnosed with CFS/ME were identified. Their data were compared against nearly 5000 children diagnosed with type 1 diabetes (T1DM) and a little over 1.3 million control - general child population - children. You could say that this was an adequately powered study.

A couple of important points were identified from the analysis of patient records. First: "Among children with CFS/ME, the most frequently observed primary care diagnosis was “weakness / general tiredness”." This is probably not unexpected given the nature of CFS/ME. Despite such weakness/general tiredness being initially identified in the vast majority of those with CFS/ME, sleep disturbances were also found more commonly among this group compared to other participants. Rather interestingly, asthma was also reported to be more common in the CFS/ME group than either of the control groups potentially reinforcing a role for atopy in the course/onset of at least some CFS/ME [2].

Next: "we found higher frequencies of depression and anxiety in the CFS/ME group." This is an important point that one has to be slightly careful with in terms of the introduction of psychological/psychiatric elements to a diagnosis of CFS/ME. I'll come back to this shortly.

Next: "Elevated frequencies of all diagnoses related to infection were observed in the CFS/ME group. In particular, infectious mononucleosis was far more frequent in this group (17.2 %) than in the control groups (T1DM: 3.7 %, general child population: 2.9 %). Influenza, acute tonsillitis, “strep throat”, and pneumonia were also more frequent in the CFS/ME group." Minus any sweeping generalisations, the suggestion that an infection illness might be part and parcel of at least some cases of CFS/ME is potentially borne out by this data. Infectious mononucleosis a.k.a glandular fever as a 'trigger' for CFS/ME is not unknown to the research [3] and other literature for example.

Finally: "The time span from the first primary care diagnosis of weakness / general tiredness to the specialist health care diagnosis of CFS/ME was 1 year or longer for 47.8 %." Whilst everyone would love to see a timely diagnosis of CFS/ME made, particularly when it comes to children, this data kinda suggest that diagnosis in Norway can still a long and drawn out process. Yes, I understand that many of the numerous diagnostic criteria used to diagnose CFS/ME rely on symptoms being present for an extended period of time but this does little to aid the child and their family and the important effects of such symptoms on things like schooling and other important facets of childhood.

The Bakken findings provide an important research snapshot of CFS/ME in children. The themes of (i) infection being potentially important to quite a few cases and (ii) the quite long time lag between primary care (i.e. General Practitioner, GP) diagnosis of weakness / general tiredness and specialist diagnosis of CFS/ME are important ones that research and practice can/should perhaps learn some lessons from.

Insofar as the observation of depression and/or anxiety being more frequently present in cases of CFS/ME, the authors make reference to the paper by Winger and colleagues [3] (see this post for more information). Winger et al reported that depressive symptoms in their group did not seemingly link/explain the reduction of health-related quality of life scores they reported for their cohort of adolescents with CFS. Taken together with the Bakken results, the implication is that whilst more commonly reported in CFS/ME, depression (and anxiety) issues are important to cases. They cannot however at this point be described as anything more than comorbid. I say this because, unfortunately, there are still opinions out there that might see depression, anxiety and other psychiatric manifestations as 'causative' of CFS/ME rather than, as I see it, being a symptom stemming from the effects of CFS/ME. If you are bed-bound, not able to go to school, not able to socialise properly and not able to do all the things your peers are doing, it is highly likely that your psychology will eventually be affected to some degree.

"The long time spans observed from the first diagnosis of weakness / general tiredness in primary care to a specialist health care diagnosis of CFS/ME might indicate that the treatment of these patients is sometimes not optimal." I also struggle to disagree with that sentence.

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[1] Bakken IJ. et al. Comorbidities treated in primary care in children with chronic fatigue syndrome / myalgic encephalomyelitis: A nationwide registry linkage study from Norway. BMC Fam Pract. 2016 Sep 2;17(1):128.

[2] Yang TY. et al. Increased Risk of Chronic Fatigue Syndrome Following Atopy: A Population-Based Study. Medicine (Baltimore). 2015 Jul;94(29):e1211.

[3] Winger A. et al. Health related quality of life in adolescents with chronic fatigue syndrome: a cross-sectional study. Health Qual Life Outcomes. 2015 Jul 3;13:96.

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Bakken IJ, Tveito K, Aaberg KM, Ghaderi S, Gunnes N, Trogstad L, Magnus P, Stoltenberg C, & Håberg SE (2016). Comorbidities treated in primary care in children with chronic fatigue syndrome / myalgic encephalomyelitis: A nationwide registry linkage study from Norway. BMC family practice, 17 (1) PMID: 27590471