Non-coeliac gluten avoiding groups: autism included

"Nonceliac gluten-avoiding patients have higher prevalences of inflammatory bowel disease, irritable bowel syndrome, thyroid disease, lupus, and autism spectrum disorder, suggesting patients with these disorders have turned to a GFD [gluten-free diet] for perceived benefit, despite a scant evidence basis."

So concluded the study published by John Blackett and colleagues [1] who set out to "characterize the medical conditions and demographic backgrounds of hospitalized patients without celiac disease who adhere to a GFD." Coeliac (celiac) disease by the way, represents the archetypal autoimmune 'gluten is baddie' condition, where treatment via a gluten-free diet is (currently) primary.

Based on inpatient data - "inpatients at Columbia University Medical Center on a GFD in 2011-2016" - researchers reported on some 770 individuals. Most of them (~60%) did not have coeliac disease (CD) but were reported to have a range of diagnoses "compared with age-matched and sex-matched inpatients on a regular diet." Gluten-free dieters showed a higher prevalence of those conditions listed at the start of this post, with the diagnosis autism spectrum disorder (ASD) specifically providing the highest odds ratio (OR) of all of them for being on a GFD: "autism spectrum disorder (OR: 23.42; 95% CI: 5.29-103.73)." Interesting too that those on a GFD had a lower prevalence of hypertension (high blood pressure) and diabetes compared with those on a regular diet. I'm not saying that this was as a result of the GFD, but other independent data [2] has talked about "a lower prevalence of hypertension" for example, in those who avoid wheat/gluten.

Am I particularly surprised by the Blackett findings? No. Despite the need for more controlled studies on the use of a gluten-free diet 'for autism', there is a wealth of peer-reviewed evidence suggesting that (a) conditions are 'right' for the use of a GFD in relation to SOME autism (see here for example) outside of a separate diagnosis of CD (see here), and (b) there is SOME evidence that a GFD does seem to impact on some facets of autism (see here) both core and peripheral (see here). I know there are some out there who would disagree - and take great pleasure in disagreeing😁! - with such sentiments, but that's what the peer-reviewed science currently suggests and is not just speculation.

Oh, and following a gluten-free diet needn't be unhealthy either (see here) with no medical or clinical advice given or intended...

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[1] Blackett JW. et al. Characteristics and comorbidities of inpatients without celiac disease on a gluten-free diet. Eur J Gastroenterol Hepatol. 2018 Jan 8.

[2] Tavakkoli A. et al. Characteristics of patients who avoid wheat and/or gluten in the absence of Celiac disease. Dig Dis Sci. 2014 Jun;59(6):1255-61.

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Peripheral iron levels in autism: "available evidence is inconsistent"

Another blogging day, another meta-analysis; this time on the topic of peripheral iron levels and autism (in children) as per the paper published by Ping-Tao Tseng and colleagues [1]. Similar to another recent post on research published by this group (see here), I declare some personal interest in this paper in my role as part of the authorship group. But yet again, I want to reassure readers that this won't influence my hopefully critical musings on the paper and topic.

So, peripheral iron levels in autism was the name of the meta-analysis game "including iron, ferritin, or transferrin." This on the basis that iron is "an essential element in child development" and, at the time of submission, "no meta-analysis has evaluated peripheral iron levels in children with ASD [autism spectrum disorder]." I might add that iron and autism has been a topic previously covered on this blog from various perspectives (see here and see here).

From a starting number of publications in the hundreds, some 25 articles were eventually included in the meta-analysis. The cumulative number of participants - those diagnosed with autism vs. those not diagnosed with autism - were in the hundreds (~1700 vs. ~1800 respectively) bearing in mind important factors such as different measures related to iron were being assessed and different 'sample sources' (serum, plasma, hair, etc) were noted in the various studies included.

Results: "Our meta-analysis suggested that levels of serum ferritin in the children diagnosed with ASD (n = 391, mean age = 5.4, mean female proportion = 32.6%) did not differ significantly compared with the children without ASD." A similar trend was also observed when it came to hair levels of iron and food iron intake. Other measures - serum iron, plasma iron, blood transferrin - saw too few publications to make any valued judgements but were generally indicative of no significant differences between autism and not-autism groupings.

Of course such analyses are based on the available evidence at the time of meta-analysis so one has to be a little cautious not to assume that such findings are gospel. I might also add that our results say nothing about the possibility of critical periods (during pregnancy for example) where there may be a higher requirement for suitable iron levels when it comes to brain development or other important biological processes. To once again quote: "Further studies are needed to investigate iron storage during fetal development in ASD to elucidate more about the role of iron in the pathogenesis of ASD."

But as things currently stand, there is little to say that iron is a really, really important variable when it comes to childhood autism...

And whilst we're on the topic of iron and meta-analyses, another paper from Tseng and colleagues [2] has also been published with ADHD (attention-deficit hyperactivity disorder) in mind (with another small contribution from yours truly). The conclusion: "Our results suggest that ADHD [attention-deficit hyperactivity disorder] is associated with lower serum ferritin levels and ID [iron deficiency]." Perhaps I'll come back to this other study some other time, and how ADHD overlapping in a not insignificant number of people with autism (see here) might be something important to consider.

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[1] Tseng P-T. et al. Peripheral iron levels in children with autism spectrum disorders vs controls: a systematic review and meta-analysis. Nutrition Research. 2018; 50: 44-52.

[2] Tseng P-T. et al. Peripheral iron levels in children with attention-deficit hyperactivity disorder: a systematic review and meta-analysis. Sci Reports. 2018; 8: 788.

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Autistic traits occurring in Borderline Personality Disorder

The results published by Liliana Dell'Osso and colleagues [1] caught my attention recently and their observation that the: "Subthreshold autism spectrum may be relevant for subjects suffering from BPD [Borderline Personality Disorder]."

BPD is the "most commonly recognised personality disorder" with symptoms grouped into areas of emotional instability, disturbed thought patterns, impulsive behaviour and "intense but unstable relationships with others." It's generally not a stand-alone condition insofar as being present alongside other mental health issues too, such as anxiety, depression and/or bipolar disorder and eating disorders. Substance abuse disorders (alcohol, drugs of abuse, etc) can also be part of the clinical picture too.

Dell'Osso et al - whose other autism-linked research has appeared before on this blog (see here and see here) - detail findings in relation to their objective to "investigate the prevalence and clinical significance of autistic traits in subjects with BPD." This follows a growing trend in peer-reviewed research circles suggesting that 'autism-related dimensions' are not always 'autism-specific dimensions' (see here for an example); also following previous research talking about "overlap between autistic spectrum conditions and borderline personality disorder" [2].

Relying on data from some 50 participants with BPD and "69 healthy controls" (authors words not mine) researchers reported that those with BPD "reported higher autistic traits than healthy individuals" based on self-report using the Autism Spectrum Quotient (AQ) among other things. I'm not on this occasion going to go on about the various issues with the AQ as an 'autism screener' or anything else because (a) Dell'Osso and colleagues use results from the AQ in the context of autistic traits not diagnosis and (b) something called the Adult Autism Subthreshold Spectrum (AdAS Spectrum) schedule, I think developed by the current authors, was also part and parcel of their study methodology.

A few other important points are mentioned by Dell'Osso et al based on their results; perhaps most importantly: "Suicidality, lifetime exposure to physical/sexual abuse are impacted by autistic traits." I read this in the context that other independent research has, for example, talked about an autism diagnosis as a risk factor for suicidal behaviour(s) (see here) minus the important influences from *comorbid* conditions such as depression or other psychiatric labels (see here) to such extreme behaviour(s).

One of the primary messages to take from the Dell'Osso and other findings on this topic is once again, an example of how autistic traits and behaviours are not exclusively just part and parcel of a diagnosis of autism. I know this might sound a little counter-intuitive, but it does add to the argument that when autism is suspected, nothing, I repeat *nothing* can replace a thorough, professional assessment (see here).

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[1] Dell'Osso L. et al. Correlates of autistic traits among patients with borderline personality disorder. Comprehensive Psychiatry. 2018. Jan 5.

[2] Dudas RB. et al. The overlap between autistic spectrum conditions and borderline personality disorder. PLoS One. 2017 Sep 8;12(9):e0184447.

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A quarter of prison inmates screen positive for ADHD (and beyond)

This is not the first time that I've talked about neurodevelopmental diagnoses such as attention-deficit hyperactivity disorder (ADHD) in the context of the prison population (see here and see here) on this blog and I doubt that it will be the last.

Without making any excuses or condoning / justifying any behaviour(s), I believe it is important to talk about such labels in the context of offending and incarceration because, as in the case of ADHD, there seems to be some real risk(s) attached to such a diagnosis/behaviour(s) that may well be reduced by timely assessment and management/treatment. There may also be some intervention options to be instigated in prisons too [1] in light of other evidence (see here)...

This time around, the findings from Susan Young and colleagues [2] provide the starting research material and their analysis of nearly 400 male prison inmates who "underwent an assessment that included the Diagnostic Interview for ADHD in Adults 2.0, the Autism Quotient, the Learning Disability Screening Questionnaire, the Brief Symptom Inventory (BSI), and measures of disruptive behaviours and attitudes towards violence."

Researchers reported that a quarter of their prisoner population screened positive for ADHD. They also observed that nearly 10% of their population screened positive for autism and a similar percentage for intellectual disability (ID). As is the case in these days of overlapping labels (ESSENCE?), various diagnostic label combinations seemed to occur; some of these combinations also *correlated* with various behavioural patterns. So, for example: "the combined ADHD/ID group had significantly higher scores of behavioural disturbance than the ADHD-only group."

Whilst interested in the Young results, I do have one tiny issue with one of the instruments used: the Autism Quotient (AQ). It's quite a long running thing I have with regards to the AQ and the important question: what does it actually measure? (see here) I know for some, it's their 'go to' self-report 'are you autistic?' instrument (see here) but I'm rather less enthralled by it's specific autism diagnostic potential. Indeed, other (much more important) people have similarly voiced peer-reviewed concerns [3] about the utility of the AQ (see here too). In that respect, I don't think Young et al can conclusively claim that approaching 10% of their prison cohort had autism on the basis of the AQ screen alone. I might also at this point, refer you to a post I wrote some time back on whether autism was in fact under-diagnosed among prisoners that concluded 'probably not' (see here)...

Still, the ADHD findings are important and add to a growing body of work concluding that various long-term adverse events [4] are potentially over-represented when a diagnosis is given alone or in combination with other labels (see here and see here). And medication, whilst providing one important intervention option for ADHD (see here), may not be the only course available to potentially reduce symptoms and onward mitigate any heightened adverse risks (see here and see here)...

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[1] Gesch CB. et al. Influence of supplementary vitamins, minerals and essential fatty acids on the antisocial behaviour of young adult prisoners. Randomised, placebo-controlled trial. Br J Psychiatry. 2002 Jul;181:22-8.

[2] Young S. et al. Neurodevelopmental disorders in prison inmates: comorbidity and combined associations with psychiatric symptoms and behavioural disturbance. Psychiatry Res. 2017 Dec 15;261:109-115.

[3] Allely C. A systematic PRISMA review of individuals with autism spectrum disorder in secure psychiatric care: prevalence, treatment, risk assessment and other clinical considerations. Journal of Criminal Psychology. 2018; 8: 58-79.

[4] Luderer M. et al. Prevalence Estimates of ADHD in a Sample of Inpatients With Alcohol Dependence. J Atten Disord. 2018 Jan 1:1087054717750272.

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"maternal hypothyroidism is associated with an increased risk of ASD in children"

The quote heading this post comes from the findings reported by Darios Getahun and colleagues [1] who "used electronic medical records (EMRs) from the Kaiser Permanente Southern California (KPSC) system to evaluate whether maternal hypothyroidism is associated with increased risk of ASD [autism spectrum disorder] in children and whether this risk is modified by race–ethnicity, fetal sex, and timing of exposure."

Hypothyroidism by the way, refers to a clinical state where the thyroid gland is underactive and produces less thyroid hormone than is required. Symptoms such as fatigue/tiredness, depression, weight gain and constipation can follow. Pregnancy hypothyroidism can impact both mother and offspring health and development; at one extreme potentially leading to an increased risk of miscarriage, but also contributing to psychomotor issues and beyond in exposed offspring. Autism has been previously mentioned as a possible *outcome* linked to maternal hypothyroidism (see here) as part of a larger suite of research on the thyroid and offspring developmental outcomes (see here).

Based on a cohort number approaching 400,000 children with some 6,400 children diagnosed with an autism spectrum disorder (ASD), authors observed that: "Children of hypothyroid women had higher rates of ASD than children of women without the diagnosis (2.14 vs. 1.62‰; HR, 1.45; 95% CI, 1.25–1.68)." Maternal hypothyroidism was defined in this study as a formal (ICD-9) diagnosis together with reported details of medication used to treat said hypothyroidism. Researchers also had access to blood test results too: "Blood levels of TSH (>90.4 pmol/ml) and free thyroxine (fT4, <10.45 pmol/ml) obtained from women with a clinical diagnosis of hypothyroidism (99.4% of women with the diagnosis) were used to determine how biochemical hypothyroidism may affect the risk of ASD diagnosis." And as for the autism diagnosis in the current trial.. well, gold-standard springs to mind: "In the KPSC system, the clinical diagnosis of ASD was largely based on definitive diagnosis by a child/adolescent psychiatrist, developmental/behavioral pediatrician, child psychologist, or neurologist who adhered to a standard protocol (Autism Diagnostic Observation Schedule)."

There are a few other important details mentioned in the Getahun study: "Autism diagnoses occurred at younger ages for children born to mothers with hypothyroidism diagnosis than those born to mothers without the diagnosis" and: "Compared with white children, prenatal hypothyroidism was associated with an increased risk of ASD in children of Hispanics... and women of other/mixed race–ethnicity." These findings also require quite a bit more investigation, particularly the idea that there may be a difference in age of presentation of autism when hypothyroidism is potentially implicated.

And then the next question: how could hypothyroid exposure during pregnancy *cause* autism in offspring? The authors detail a few important points that could be relevant to such a question; many of which talk about a role for environmental (non-genetic) influences. So: "Hypothyroidism may be the result of a number of conditions such as inflammatory disease, autoimmune disorders, or iodine deficiencies." Various inflammatory and/or autoimmune conditions have been talked about in the context of autism risk (see here and see here for examples). The observation that most of the cases of hypothyroidism identified in the Getahun data were "because of autoimmune thyroiditis or iatrogenic ablation" adds to the feeling that the immune system / immune function could be an important variable with regards to aetiology. The iodine connection is based on the usefulness of this compound in the production of thyroid hormones.

Finally: "Management of maternal hypothyroidism may ameliorate the risk of ASD." I'm a little bit cautious about such a statement at the current time given (a) the relatively low rate of hypothyroidism picked up in the sample: "the prevalence of chronic hypothyroidism was 2.2%", and (b) the small (but significant) difference in autism rates in cases of maternal hypothyroidism vs. no diagnosis ("2.14 vs. 1.62%"). That's not to say that there may not be areas to look at, such as a role for vitamin D status on autoimmune disease (including that linked to thyroid status, see here) and/or how autoimmune thyroiditis *might* show some connection to depression (see here) which could be relevant to all that chatter about antidepressant medicine use during pregnancy might also impact on offspring autism risk (see here). But lots more research is indicated before any sweeping generalisations are made.

And, just before I leave you, how about the results of the systematic review and meta-analysis by Thompson and colleagues [2] concluding that whilst: "Maternal hypothyroxinaemia and subclinical hypothyroidism may be associated with intellectual disability in offspring" the "effect on the risk of autism in offspring was unclear"?

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[1] Getahun D. et al. Association between maternal hypothyroidism and autism spectrum disorders in children. Pediatric Res. 2018. Jan 3.

[2] Thompson W. et al. Maternal thyroid hormone insufficiency during pregnancy and risk of neurodevelopmental disorders in offspring: A systematic review and meta-analysis. Clin Endocrinol (Oxf). 2018 Jan 11.

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Pre- and peri-pregnancy use of folic acid and multivitamins and risk of offspring autism

The findings reported by Stephen Levine and colleagues [1] observing that: "Maternal exposure to folic acid and multivitamin supplements before and during pregnancy is associated with a reduced risk of ASD [autism spectrum disorder] in the offspring compared with the offspring of mothers without such exposure" provides the blogging fodder today.

Accompanied by media headlines such as 'Taking vitamins before and during pregnancy slashes autism risk by 75%, new study shows' the Levine paper adds to the growing research literature suggesting that certain nutrients taken during critical periods of pregnancy *might* be important when it comes to offspring development (see here).

"Epidemiologic studies report inconsistent associations between maternal supplementation with multivitamins or FA [folic acid] before and during pregnancy and the risk of ASD in offspring." I'm glad the authors have mentioned that the peer-reviewed literature on folic acid in relation to offspring autism risk is not all one-way. It's something that I've been particularly interested in on this blog for some time (see here and see here for examples) in terms of countering the often simplistic view that mothers-to-be should all be loading up on folic acid for example, to offset any enhanced risk of offspring autism. Yes, folic acid is a required supplement during pregnancy when it comes to something like reducing the risk of  neural tube defects (NTDs) in offspring, but with autism in mind, the evidence is not yet so clear-cut.

Levine et al report results based on Israeli children born between 2003 and 2007 and followed-up until early 2015. Their cohort included "all children with ASD and a randomly selected one-third of all children" born during their index dates including some 45,000 participants in total. When it came to exposure patterns (exposure to folic acid and/or multi-vitamins during pregnancy), the authors relied on a prescription register that included "drug names, prescription and dispensation dates, number of pills dispensed, and ATC codes." Importantly, this meant that researchers were able to classify some important details: "vitamin supplements were classified as FA and/or multivitamin supplements, an FA supplement, and a multivitamin supplement" and the timing of their dispensation: "before pregnancy (540-271 days before childbirth) and during pregnancy (270 days before childbirth up to the date of childbirth)." This is something rather different from some other previous research attempts that have for example, tended to rely on maternal recall of pregnancy supplements.

Results: "This study of 45 300 children revealed a decreased risk of ASD in children born to mothers who used FA and/or multivitamin supplements before and/or during pregnancy compared with those who had not." Among all supplement combinations - FA and/or Multivitamin Supplements, FA Supplements, Multivitamin Supplements - there was a reduced relative risk (RR) of offspring autism compared with 'unexposed' children that was present both before pregnancy and during pregnancy supplementation and took into account various covariates such as "sex, birth year, socioeconomic status (high vs low),17 a maternal and paternal psychiatric diagnosis by childbirth (present or absent), maternal and paternal age at childbirth, and parity." The sorts of risk reduction statistics being talked about - above 50% and even approaching that 75% risk reduction - are not to be sniffed at.

Although quite a good study design, the Levine results are to be treated with some caution. Not least that the authors noted: "causality cannot be inferred from observational epidemiologic studies such as this one" so one has to be careful.

But... yet again, this is further research talking about pregnancy folic acid and offspring autism. This is an area that requires further investigation in relation to possible mechanisms (or combinations of mechanisms) [2] potentially involved. Also, whether specific groups of women taking other important medicines during pregnancy, might benefit from something like folic acid supplementation in the context of enhanced offspring risk of autism [3].

To close, a musical choice to mark the passing of Mark E Smith: Mr Pharmacist (my favourite) or the more widely known, Hit the North?

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[1] Levine SZ. et al. Association of Maternal Use of Folic Acid and Multivitamin Supplements in the Periods Before and During Pregnancy With the Risk of Autism Spectrum Disorder in Offspring. JAMA Psychiatry. 2018. Jan 3.

[2] Goodrich AJ. et al. Joint effects of prenatal air pollutant exposure and maternal folic acid supplementation on risk of autism spectrum disorder. Autism Res. 2017 Nov 9.

[3] Bjørk M. et al. Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero. JAMA Neurol. 2017 Dec 26.

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Maternal tobacco smoking and offspring ADHD risk

"The results showed that either prenatal exposure to MSDP [maternal smoking during pregnancy] or smoking cessation during first trimester was significantly associated with childhood ADHD [attention-deficit hyperactivity disorder] after adjusting for parental psychiatric history and social socioeconomic status."

and:

"With our meta-analysis, we provide evidence for an association between maternal smoking and offspring ADHD but do not solve the causality issues concerning potential confounding by other risk factors."

Those quotes were taken from the findings reported by Tianyu Dong and colleagues [1] and Lan Huang and colleagues [2] respectively, both applying the 'top of the methodological tree' analysis that is a meta-analysis to the collected data looking at whether maternal smoking during pregnancy might impact on offspring risk of a diagnosis of ADHD. Their combined answer: very possibly but...

Having previously covered the non-association between maternal smoking during pregnancy and offspring autism before on this blog (see here), the recent results from Dong and Huang highlight how tobacco smoking during pregnancy is still something to be avoided for the sake of the child(ren). The fact that Huang et al also observed something of a dose-response relationship: "The risk of ADHD was greater for children whose mothers were heavy smokers (OR: 1.75; 95% CI: 1.51-2.02) than for those mothers were light smokers (OR: 1.54; 95% CI: 1.40-1.70)" kinda adds to the strength of their argument for an *association* between smoking during pregnancy and adverse offspring developmental outcome(s).

It's true that even with such meta-analytical prowess, it's still a little difficult to say conclusively that 'smoking causes offspring ADHD'. I'm also minded to state how "different assessment tools of ADHD and a lack of objective biological measures for maternal smoking" were picked up by the authors as other reasons to be cautious about their [collected] findings. I will also direct you to other research published not-so-long-ago that did not find such a strong connection between maternal smoking during pregnancy and offspring ADHD [3] (or at least "indicating that the association between maternal smoking during pregnancy and offspring ADHD is not directly causal, but confounded by unmeasured factors.")

Still, even if maternal smoking during pregnancy represents just one of a number of factors potentially impacting on offspring risk of ADHD, it is worth reducing that risk by nudging mums-to-be (and perhaps even dads-to-be) to quit smoking for the sake of their children. This on top of the myriad of other reasons that parental tobacco smoking during conception, pregnancy and offspring childhood is something that really needs to be stamped out once and for all...

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[1] Dong T. et al. Prenatal Exposure to Maternal Smoking during Pregnancy and Attention-deficit/hyperactivity Disorder in Offspring: A Meta-analysis. Reprod Toxicol. 2017 Dec 30. pii: S0890-6238(17)30599-3.

[2] Huang L. et al. Maternal Smoking and Attention-Deficit/Hyperactivity Disorder in Offspring: A Meta-analysis. Pediatrics. 2018 Jan;141(1). pii: e20172465.

[3] Gustavson K. et al. Smoking in Pregnancy and Child ADHD. Pediatrics. 2017 Feb;139(2). pii: e20162509.

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Mediterranean-style diet + fish oils = better diet quality and mental health in depression

"This is one of the first randomized controlled trials to show that healthy dietary changes are achievable and, supplemented with fish oil, can improve mental health in people with depression."

So said the findings reported by Natalie Parletta and colleagues [1] reporting results from a randomised-controlled trial investigating "the impacts of a Mediterranean-style diet intervention for mental health and quality of life (QoL) in people with depression."

Their study, called "HELFIMED (Healthy Eating for Life with a Mediterranean-style diet) Mood Study", drew on various data derived from a starting population of some 180 participants randomised to receive a Mediterranean diet plus fish oil (MedDiet) or a control social group who - "attended fortnightly social groups (e.g. sharing holiday stories, playing games, doing personality tests, watching a movie with discussion, book club)." The focus on 'social' noted in the control group was designed to "control for the social component of the cooking workshops that can help to improve depressive symptoms" used by the experimental (dietary) group. Having said that, I can't ever recall 'doing personality tests' as being something I've ever encountered in any social groups/outings down the years but hey-ho! We are also told that: "Assessments at baseline, 3 and 6 months included mental health, quality of life (QoL) and dietary questionnaires, and blood samples for erythrocyte fatty acid analysis" covering both groups over the intervention period.

Results: bearing in mind the numbers of completers at 3- and 6-months were quite a bit down on the starting numbers, a few important details were observed. So: "Compared to the social group, the MedDiet group reported significantly greater increase in their total Mediterranean diet score from baseline to 3 months... along with a significantly greater increase in consumption of vegetables, fruit, wholegrain foods, nuts and legumes, significantly lower consumption of unhealthy snacks and meat/chicken, and a greater diversity of vegetables." It appeared that quite a bit of 'nutrition education' and cooking classes et al seemed to do the trick in increasing the nutritional quality of participants food intake in this arm of the trial. Importantly too: "These dietary changes were maintained at 6 months" when intervention wasn't as intense as that given in the first 3-months.

Also: "Both the MedDiet and the social group reported significantly improved mental health on all outcome measures (DASS, PANAS, and AQoL-8D subscales) over 3 months (all P < 0.001) except for the AQoL-8D pain value." The authors speculate that this could be "attributed to the social component of the study as both groups were exposed to group workshops (either cooking or social group)." In other words, loneliness and/or lack of social support are important features when it comes to mental health in relation to depression (see here).

But... "Compared to the social group, the MedDiet group reported significantly greater improvement in their DASS depression score... and AQoL-8D mental health score over 3 months." The authors observed that transition to a Mediterranean diet plus fish oil supplement seemed to provide some value-added benefits when it came to self-reported depression scores. Whether it was the dietary change or the fish oil supplementation is not really clear from the data but the findings do invite further investigation.

Allowing for the fact that there were 'limitations' to this study (use of self-report, high attrition rate, single blind study design) I think it's fair to say that moves towards getting those with depression to eat healthier is a win-win situation on the basis of what the peer-reviewed evidence seems to point to [2]. Adding to the results of other similar trials in this area (see here) and there is a picture building up that alongside the physical health benefits a good diet (good insofar as containing fruit, vegetables, nuts, etc) can bring, there may be psychological benefits too [3]. It's not just about diet however, as the Parletta results show, but diet does seem to be quite a useful add-on.

The fish oil supplementing side of things is something else that requires some further investigation. I note that I've already covered other work by authors of this most recent study before on this blog with regards to their investigation on fatty acids and autism among other things (see here). In relation to depression (clinical depression), there is also evidence suggesting that certain types of fatty acid supplementation do seem to be able to act on presented symptoms (see here and see here) for some people at least. The problem, as I've mentioned in this study, is teasing apart fish oil/fatty acid supplements from the role played by the dietary changes.

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[1] Parletta N. et al. A Mediterranean-style dietary intervention supplemented with fish oil improves diet quality and mental health in people with depression: A randomized controlled trial (HELFIMED). Nutr Neurosci. 2017 Dec 7:1-14.

[2] Fowles ER. et al. Stress, Depression, Social Support, and Eating Habits Reduce Diet Quality in the First Trimester in Low-Income Women: A Pilot Study. Journal of the Academy of Nutrition and Dietetics. 2012; 112: 1619-1625.

[3] Opie RS. et al. Dietary recommendations for the prevention of depression. Nutr Neurosci. 2017 Apr;20(3):161-171.

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The heart and chronic fatigue syndrome

I'll freely admit that I'm no expert when it comes to the biology and physiology of the heart. I know roughly where one should find it in a human body and what it usually does but that's about the sum total of my knowledge. Having said that, such a lack of knowledge has not held me back before from talking about aspects of the heart on this blog (see here)...

I therefore approach the findings reported by Cara Tomas and colleagues [1] with a degree of trepidation such that I don't misrepresent their observations. Importantly because authors reported finding: "an association between reduced cardiac volumes and BNP [brain natriuretic peptide] in CFS [chronic fatigue syndrome]."

The heart and CFS? Well, much like another area of CFS science discussing a possible role for mitochondria (the cell's powerhouse) and some CFS (see here for example), there is good reason to assume that the heart might have some role to play for some. Y'know, the heart - the thing that pumps blood around the body and delivers important things like oxygen and nutrients - could be working sub-optimally in a condition that primarily manifests as fatigue and specifically, post-exertional fatigue and exhaustion (see here).

Indeed, it's worthwhile mentioning that quite a few of the authors on the Tomas paper have previously discussed cardiac issues in the context of CFS [2]. On that previous occasion, they talked about finding evidence to "support the role of cardiovascular physiology as an underpinning problem in those with CFS" on the basis of their finding "an association between reduced cardiac volumes and blood volume in CFS."

This time around BNP was a focus of study; a peptide that is "secreted by the ventricles of the heart in response to excessive stretching of heart muscle cells" and something that is typically elevated in cases of heart failure but can also be present under other clinical circumstances too. Thomas et al defined "a BNP value of >400 pg/mL as being consistent with moderate to severe cardiac disease" in their study based on data from some 42 people diagnosed with CFS and a smaller control group of 10 people who were described as 'sedentary'.

Results: based on analysis for BNP and other cardiac examinations, "BNP levels were significantly higher in the CFS cohort compared with the matched controls." Comparing group mean levels (I think!), the values came in at something like 500 pg/ml for the CFS group compared with about 300 pg/ml for controls. These findings are themselves notable in relation to existing guidance out there when it comes to BNP levels and their meaning in terms of heart health.

Further: "When we compared cardiac volumes (end-diastolic and end-systolic) between those with high BNP levels (BNP >400 pg/mL) and low BNP (<400 pg/mL), there were significantly lower cardiac volumes in those with the higher BNP levels in both end-systolic and end-diastolic volumes." The authors translate this finding in relation to "higher BNP levels are causing a diuresis (or natriuresis) and that this is depleting the plasma/blood volumes and leading to the smaller cardiac volumes."

Of course more investigations are needed in this area. I'd like to see a little more investigation of such BNP findings in the context of using other control groups (including those with diagnosed heart failure) to see where CFS 'ranks' on the basis of other heart tests too. The fact that BNP can be elevated in other conditions too (such as hyperthyroidism) is something else that needs to be analysed a little further [3] in the context that the broad spectrum of CFS might also include a number of other features/diagnoses too.

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[1] Tomas C. et al. Elevated brain natriuretic peptide levels in chronic fatigue syndrome associate with cardiac dysfunction: a case control study. Open Heart 2017; 4: e000697.

[2] Newton JL. et al. Reduced cardiac volumes in chronic fatigue syndrome associate with plasma volume but not length of disease: a cohort study. Open Heart. 2016 Jun 24;3(1):e000381.

[3] Tsai S-H. et al. Interpretation and Use of Natriuretic Peptides in Non-Congestive Heart Failure Settings. Yonsei Medical Journal. 2010;51(2):151-163.

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Meta-analysing risk factors for schizophrenia spectrum disorders

"Despite identifying 98 associations, there is only robust evidence to suggest that cannabis use, exposure to stressful events during childhood and adulthood, history of obstetric complications, and low serum folate level confer a higher risk for developing schizophrenia spectrum disorders."

So said the 'umbrella review of meta-analyses' published by Lazaros Belbasis and colleagues [1] looking at the current collected scientific literature on "risk factors and peripheral biomarkers for schizophrenia spectrum disorders." Their settling on only five factors reliably linked to schizophrenia spectrum disorder (SSD) did not mean that other associations may not be important, particularly in the context of pluralisation of labels (see here); merely that the current weight of robust evidence 'prefers' the five factors highlighted.

Having quite recently talked about 'symptom clusters' around one possible clinical sign of SSD: psychosis (see here), I continue to appreciate just how complicated an area that this is. Added to other recent-ish research upsetting the apple cart that is inflammatory markers and schizophrenia (see here) and you might see how one has to be quite careful that dogma does not take over in this area.

The mix of biological and social factors identified by Belbasis et al is important to mention. The link for example, between cannabis use and SSD perhaps ties into other chatter about how serious delinquency may potentially be linked to onset of schizophrenia (see here) if one assumes that such illicit drug use might be heightened where delinquency is a feature. That also goes for the idea that childhood and adulthood adversity (particularly trauma?) can and does seemingly impact on risk of schizophrenia or SSD.

Likewise the chatter about low serum folate levels being potentially relevant to SSD is intriguing and not something entirely new to this blog (see here). I've been particularly interested in at least one of the reason(s) why folic acid levels might not be what they should be with some schizophrenia in mind: MTHFR (methylenetetrahydrofolate reductase) (see here) or rather a point mutation potentially over-represented when it comes to schizophrenia (and seemingly other labels too).

More investigation is indicated.

Totally unrelated to today's topic, a few decades back a show called the Day Today began and 'fake news' has never been the same since...

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[1] Belbasis L. et al. Risk factors and peripheral biomarkers for schizophrenia spectrum disorders: an umbrella review of meta-analyses. Acta Psychiatrica Scandinavica. 2018. Dec 30.

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Yet more 'the label of autism rarely exists in a diagnostic vacuum' research

Two papers are served up for your reading delight today: the first is by Maj-Britt Posserud and colleagues [1] and concluded that: "Co-occurring problems were common in ASD [autism spectrum disorder] screen positive children and contributed strongly to both impairment and to contact with services." The second paper was by Anne-Katrin Kantzer and colleagues [2] and, in a similar vein, observed that: "The vast majority of children with ASD fitted the concept of “Autism Plus”."

The commonality between the two papers, aside from both including a notable researcher and author (see here), was the assertion once again, that the diagnosis of autism rarely exists in some sort of diagnostic vacuum.

Both papers are open-access so require only limited discussion from myself. Each research project followed a slightly different methodological track insofar as their participant numbers, how autism was assessed for and other, related details. There are also a few other nuggets of important information included in each paper.

Posserud et al relied on a pretty large participant group, all part of the Bergen Child Study (BCS). The aim of the study was to examine the "prevalence of co-occurring problems, impairment and service use in a population-based sample of children defined as screen positive on the Autism Spectrum Screening Questionnaire (ASSQ)." Of course 'screen positive' on the ASSQ does not necessarily mean 'diagnosed with autism' but there you go. Alongside, researchers also screened for a range of other behavioural and mental health issues in their cohort using both parents and teachers as informants.

Results: "A total of 226 children were defined as ASD screen positive (3.6%), 66 girls (2.1% of all girls) and 160 boys (5.1% of all boys)." A large proportion of those who screened positive for autism (over 90%) also screened positive for various other co-occurring issues including attention-deficit hyperactivity disorder (ADHD) and/or learning (intellectual) disability. Indeed: "Only 2% of children could be characterised as having “autism only”, i.e. having no other problems in this population-based sample."

Kantzer et al by contrast, relied on a data from a much smaller participant sample (N=96) who were prospectively 'followed' from first contact for assessment - having previously "been identified with autistic symptoms in a general population child health screening program" - for a further two years (T2). We are told that "assessment included a broad neurodevelopmental examination, structured interviews, a cognitive test and evaluations of the child́s adaptive and global functioning" across the different testing occasions.

Results: 76 of the 96 children included for study initially met the diagnostic criteria for ASD at initial assessment rising to 79 at T2. What this tells us is that not everyone referred for an autism assessment will hit autism diagnostic thresholds (something noted on a previous blogging occasions). Although diagnostic stability (i.e. maintaining a diagnosis at both time points) was pretty good across the study, that's not to say things were 100% consistent either (see here)...

"One, two or more ESSENCE related problems other than ASD were found in 98% (48/49) of the children with T2 AD [autistic disorder], in 87% (20/23) of the children with T2 PDD-NOS [pervasive developmental disorder - not otherwise specified] and in 71% (5/7) of the children with T2 Asperger syndrome." ESSENCE - Early Symptomatic Syndrome Eliciting Neurodevelopmental Clinical Examinations - is basically an umbrella term for the range of overlapping conditions that seem to accompany a diagnosis of autism. A bit more information about the concept can be found here.

To reiterate the observations from these collected data, the label of autism rarely exists in a diagnostic vacuum. Do you really need any more evidence? And, as one keen observer pointed out on social media (see here) the 'screening out' of these other 'autism plus' or ESSENCE traits to make various study results more 'autism-specific' might in fact, limit any research sample to something remarkably unlike 'real-life' autism if one assumes that autism plus or ESSENCE is the norm...

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[1] Posserud M. et al. Autism traits: The importance of “co-morbid” problems for impairment and contact with services. Data from the Bergen Child Study. Research in Developmental Disabilities. 2018; 72: 275-283.

[2] Kantzer A-K. et al. Young children who screen positive for autism: Stability, change and “comorbidity” over two years. Research in Developmental Disabilities. 2018; 72: 297-307.

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On coeliac disease and schizophrenia

"This systematic review and meta-analysis found a significantly higher risk of schizophrenia among patients with celiac disease."

So said the findings reported by Karn Wijarnpreecha and colleagues [1] examining whether "patients with celiac disease might be at an increased risk of schizophrenia" using everyone's favourite 'top of the methodological tree' analyses: the systematic review and meta-analysis.

Celiac (coeliac) disease (CD) represents the archetypal 'dietary gluten is baddie' autoimmune condition, where a certain type of immune system meets with everyone's 'love to hate' food group and biological and histological sparks begin to fly.

Authors identified a few studies (four studies that "compared the risk of schizophrenia among patients with celiac disease versus individuals without celiac disease") and came down on the side suggesting that yes, there is a higher risk of schizophrenia among those diagnosed with CD based on the currently available data. That all being said, there is quite a bit more to do in this research area.

Personally, I'm not too surprised by the Wijarnpreecha results. Enough times on this blog I've talked about the possibility of a *connection* between dietary gluten and various behavioural / psychiatric disorders including the possibility of a 'gluten-related subgroup of schizophrenia' (see here). I know not everyone is completely persuaded by the ideas espoused about by people such as the late Curt Dohan (see here) and the late Karl 'Tiny' Reichelt (see here) implicating gluten in the rise of [some] schizophrenia for example, but I've read enough on this topic to appreciate that an association is more than likely for some at least (see here).

With diagnosed CD in mind and not just the often nebulous term 'non-coeliac gluten sensitivity', the data is not however universally clear in relation to risk of schizophrenia. I say that on the basis that risk of various autoimmune conditions seemed to be elevated in relation to schizophrenia [2] of which CD is just one (see here). I could be really speculative and suggest that there may be some common mechanisms implicated in autoimmune conditions (gut barrier function, gut microbiota, HERVs, etc.) that could also be relevant to some schizophrenia too (see here for example). But at the moment, we just don't know enough, hence the need to screen and investigate further...

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[1] Wijarnpreecha K. et al. Association between celiac disease and schizophrenia: a meta-analysis. Eur J Gastroenterol Hepatol. 2017 Dec 26.

[2] Chen SJ. et al. Prevalence of autoimmune diseases in in-patients with schizophrenia: nationwide population-based study. Br J Psychiatry. 2012 May;200(5):374-80.

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Sleep duration and ADHD: a correlation across the years?

"Longer sleep duration (>10 hours per day) was associated with a lower ADHD [attention-deficit hyperactivity disorder] symptom score" was one of the findings reported by Gabriela Peralta and colleagues [1].

They sought to examine whether a particular set of activities (sleeping, physical activity, television watching, etc) might show some *correlation* to "(1) attention-deficit/hyperactivity disorder (ADHD) symptoms and (2) behavior problems, both assessed at 7 years, in ADHD-free children at baseline."

Drawing on a not-insignificant number of children participants (N=817) who were part of a research birth cohort previously discussed on this blog (see here and see here), authors relied on parental report via the Conners' Parent Rating Scales and the Strengths and Difficulties Questionnaire to ascertain ADHD and 'behaviour problem' scores respectively. This was carried out when the child was aged around 7 years old. A few years earlier - when the child was around 4 years old - parents had previously reported on a few other variables: "the time that their children spent sleeping, watching TV, engaging in cognitively stimulating activities, and engaging in physical activity." The two sets of data were married together for analysis.

Results: it's probably not escaped your notice that (a) parental report is a mainstay of the Peralta data and (b) data for a child at 4 years old and then again at 7 years old represents quite a large time frame during which lots can (and does) happen. With those factors firmly in mind, researchers provided some frequency data on activities at 4 years old. They then added in the data taken at 7 years old where that finding on longer sleep duration (at 4 years) seemed to be linked to lower ADHD scores (at 7 years) came from. Further: "Longer time spent in cognitively stimulating activities (>1 hours per day) was associated with lower scores of both ADHD symptoms... and behavior problems" and also rather interestingly: "Time spent watching TV and engaging in physical activity were not associated with either outcomes."

The quite fuzzy picture emerging from this data - with appropriate caveats - is that sleep and 'keeping the mind active' might be important factors when it comes to the presentation of something like ADHD (symptoms) and other 'behaviour problems' in childhood. The sleep side of things is particularly topical at the moment, given some research chatter about how a sleep intervention might be something to consider for at least some (diagnosed) cases of ADHD (see here). There are also seemingly lots of benefits from ensuring a regular bedtime routine for young children; assuming that is, that poor sleeping patterns are not an early marker for possible ADHD?

The whole 'cognitively stimulating activities' bit is slightly more fluffy in terms of what constitutes such activities and any relationship with ADHD or behavioural issues. I say this on the basis that whilst reading and writing for a 4-year old is likely to be cognitively stimulating, so are lots of other activities such as exploring nature for example or even spending time on the dreaded computer/tablet devices (depending on what activities are being done). Even time spent in front of the gogglebox could be considered cognitively stimulating if they're watching Blue Planet for example, and not just a re-run of Peppa Pig (sorry Peppa). And on the topic of television viewing or at least screen time in the context of ADHD risk, other data have suggested something *correlatively* different from the Peralta findings (see here) just to complicate matters further.

To close, it's been a while but here is some music... Elvin Bishop and a track brought back to life by the Guardians...

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[1] Peralta GP. et al. Sleeping, TV, Cognitively Stimulating Activities, Physical Activity, and ADHD Symptom Incidence in Children: A Prospective Study. J Dev Behav Pediatr. 2017 Dec 18.

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Vitamin D and autism... another double-take?

A quick-ish post today as I bring the results published by Dong and colleagues [1] to your attention and the [translated] observation that: "Serum 25-hydroxyvitamin D level in children with ASD [autism spectrum disorder] is obviously lower than that in the healthy control group, and there are negative correlations between vitamin D levels and core symptoms of ASD." 'Obviously' eh?

It's another study from China (see here) and yet again I find myself correcting language as per the authors' use of the term 'healthy control group' when describing not-autism. In much the same way that the word 'neurotypical' is a bit of a nonsense, so the insinuation that a diagnosis of of autism automatically means 'not healthy' is far too broad a sweeping generalisation.

Anyhow, vitamin D and autism was the name of the research game for these authors; something not altogether new and novel for at least some of the authorship group (see here and see here for examples). Indeed, my use of the term 'another double-take' in the title of this post refers to the observation that this group have really gone to town with their clinical trial registered research project in this area (see here for example).

"Serum vitamin D level in ASD children was significantly lower than that of the control group... and the between-group percentage difference of normal, insufficient and deficient levels of vitamin D was statistically significant." Bearing in mind that vitamin D levels were checked using a gold-standard technique (liquid chromatography-mass spectrometry, LC-MS), I'm inclined to accept these results as they stand. I'm not saying that other methods of vitamin D analysis are all bunk, but rather that LC-MS is a mighty powerful method for sample analysis with vitamin D in mind.

Further: "There were negative correlations between serum vitamin D level in ASD children and total ABC [Autism Behavior Checklist] score or ABC subscale scores (body behavior, self-care, language and social interaction). There were negative correlations between serum vitamin D level in ASD children and total CARS [Childhood Autism Rating Scale] score and CARS subscale scores (imitation, nonverbal communication and general impression). There were negative correlations between serum vitamin D level in ASD children and SRS [Social Responsiveness Scale] behavior subscale or ATEC [Autism Treatment Evaluation Checklist] social interaction subscale." In short, vitamin D  levels seemed to *correlate* with quite a few behavioural results, although I'm slightly less inclined to read too much into such findings given the relatively small participant group included for study and the 'snaphot' study methodology.

But yet again, this is another example illustrating that vitamin D metabolism should very much be a part of any assessment when it comes to autism (see here and see here)...

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[1] Dong HY. et al. Correlation between serum 25-hydroxyvitamin D level and core symptoms of autism spectrum disorder in children. Zhonghua Er Ke Za Zhi. 2017 Dec 2;55(12):916-919.

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"Meningitis is a significant risk factor for developing ADHD later in childhood"

The quote heading this post comes from the results published by Hadžić and colleagues [1] who sought to "examine the frequency of ADHD [attention-deficit hyperactivity disorder] in children who had had bacterial meningitis."

Bacterial meningitis by the way, reflects meningitis brought about by one of a number of bacteria (e.g. meningococcal, pneumococcal, TB, Group B Streptococcal, Hib) with treatment via timely use of antibiotics.

Comparing 60 children who "had had meningitis in the first year of their lives" with 60 control children who did not have meningitis, researchers looked at the frequency of ADHD - "assessed through the structural clinical interviews with parents according to the criteria set in DSM-IV." They observed that over 60% (37/60) of those with a history of meningitis had reported behaviours consistent with a diagnosis of ADHD compared with only 5% (3/60) of controls.

I might question the use of parental interviews outside that of the actual assessment of children as being one variable that puts the Hadžić results at something of a disadvantage. But, and it is an important 'but', this is not the first time that ADHD or behaviours that characterise ADHD have been talked about in the context of meningitis. Indeed, tuberculous meningitis (TBM) has been mentioned in the context of ADHD before [2] and on more than one research occasion [3] (albeit by the same research group).

The mechanisms / modes of action? Well, we're still left to speculate. Meningitis involves inflammation of the membranes (meninges) that protect the brain and spinal cord. The after-effects for some can involve brain damage but also a variety of other adverse outcomes have also been noted including issues such as epilepsy and/or seizure disorder. It's not inconceivable that one or more of these adverse effects *could* impact on the presentation of something like ADHD or at least, ADHD-related behaviours. Further research needs to be conducted on what follows from something like bacterial (and viral) meningitis in terms of 'brain symptoms' and onward what this might mean for risk of ADHD.

What this latest research does illustrate quite well is that, much like the debates in autism circles, not every single person diagnosed with ADHD or those presenting with clinically-relevant ADHD symptoms does so through some inborn process. Infection - or response/after-effects of infection - can seemingly play quite a big role for some; bearing in mind also that other, various types of infection, have been previously implicated in relation to ADHD (see here and see here) outside of just meningitis.

And whilst on the topic of infection potentially being related to *some* neurodevelopmental diagnoses, I note some conversations on social media have tried to (once again) poo-poo the idea that autism, or a diagnosis of autism, might not be a lifelong issue for some people. 'Masking' of autism is the new, universal idea emerging, which whilst important, probably doesn't cover every case of autism symptoms dissipating [4] (see here for my take)...

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[1] Hadzic E. et al. Is Bacterial Meningitis a Risk Factor for Developing Attention Deficit Hyperactivity Disorder. Isr J Psychiatry Relat Sci. 2017;54(2):54-57.

[2] Wait JW. & Schoeman JF. Behaviour profiles after tuberculous meningitis. J Trop Pediatr. 2010 Jun;56(3):166-71.

[3] Wait JW. et al. Tuberculosis meningitis and attention deficit hyperactivity disorder in children. J Trop Pediatr. 2002 Oct;48(5):294-9.

[4] Hacohen Y. et al. N-methyl-d-aspartate (NMDA) receptor antibodies encephalitis mimicking an autistic regression. Developmental Medicine & Child Neurology. 2016; 58: 1092-1094.

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Bowel issues over-represented in autism (and perhaps linked to some behaviours)

"Make it so Mr WORF"

Once again(!) more evidence emerges from the peer-reviewed science domain highlighting how functional gastrointestinal (GI) issues such as constipation and diarrhoea are very much over-represented when it comes to a diagnosis of autism (see here). The study providing the data this time was by Zhu and colleagues [1] and was carried out in China; thus illustrating how such bowel issues cross countries and ethnicity when it comes to autism.

There's little novelty in their findings that all-manner of functional bowel condition were more frequently present in their cohort of over 320 children diagnosed with an autism spectrum disorder (ASD) compared with some 200 not-autism controls. The authors' observation that almost 50% of their sample of children diagnosed with autism presented with at least one bowel issue is not as surprising in research-terms as it perhaps once might have been.

What is perhaps interesting is the growing focus on how such bowel issues may *correlate* with behaviour noted in children with autism, as per the results of other independent findings (see here). To quote from Zhu et al: "Compared with ASD children without GID [gastrointestinal disorders] (n=166), the ASD children with GID (n=162) got higher scores in the "Body and Object Use" of ABC [Autism Behavior Checklist] scale... and had more emotional problems. Moreover, the score of behavior problems questionnaire was higher in the ASD children with GID." This is not necessarily new news to many people (particularly to parents and caregivers) but should be a topic that is given more research and clinical consideration among professionals.

More needs to be done in this area, not least on:

• improving the ways of detecting and reporting on functional bowel issues in the context of autism (see here),
• ensuring that questions about bowel function are asked during autism assessments and exams,
• moving away from over-simple 'psychological' assumptions/explanations to potentially account for bowel issues in relation to autism (see here) without appropriate gastroenterological referral (also including ridding ourselves of the old-saying 'it's part of their autism'),
• ensuring that appropriate gastroenterological resources are available and timely referral is present (particularly for paediatric resources),
• following guidance that is out there in the peer-reviewed domain on screening and treating bowel issues in the context of autism (see here),
• not being afraid to look for signs of more serious bowel pathology as and when functional bowel symptoms are present (see here) and,
• embracing the idea that gut and brain might not be completely separate and independent in the context of autism and beyond (see here). 

'Nuff said I think.

But just before you go, some other study results [2] for you to mull over with regards to the question: what is the 'normal range' of bowel movements? Answer: anything from 3 a day to 3 a week apparently.

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[1] Zhu J. et al. Association between behavioral problems and gastrointestinal disorders among children with autism spectrum disorder. Zhonghua Er Ke Za Zhi. 2017 Dec 2;55(12):905-910.

[2] Mitsuhashi S. et al. Characterizing Normal Bowel Frequency and Consistency in a Representative Sample of Adults in the United States (NHANES). Am J Gastroenterol. 2018 Jan;113(1):115-123.

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Allergic disease and ADHD yet again...

Although words like 'first' and 'largest' were used in the paper by Chia-Feng Yang and colleagues [1] (open-access available here) observing that "AD [atopic dermatitis] and asthma with allergic sensitization are associated with ADHD [attention-deficit hyperactivity disorder] in children", I'm minded to be a little cautious with such 'we're the first/best' assertions.

Cautious because, on quite a few peer-reviewed research occasions (see here for example), a possible *link* between various allergic disease and ADHD has already been noted; even potentially extending to studies talking about how treatment for allergic disease might on some occasions also impact on presented ADHD symptoms (see here) (with no medical advice given or intended).

Yang et al relied on data from a research favourite country, Taiwan, derived from an initiative called the Childhood Environment and Allergic diseases Study (CEAS). The clue is in the name of the initiative in terms of what they were looking for/at, as per other publications derived from the initiative [2]. From the 3200-odd participants eligible for participation, researchers relied on data from over 2700 children. Questions about allergic disease history were asked to parents of said participants, alongside other 'environmental' factors such as family income, tobacco exposure and breastfeeding history. I note also a question about 'incensing at home' is also included relating to the use of burning incense typically linked to religious practices in certain cultures.

When it came to a diagnosis of ADHD, it's not entirely clear about how this was ascertained but it looks like diagnosis was given by a clinician: "The conditions of disease in children were confirmed by board-certified child psychiatrists or pediatric neurologists, according to the clinical evaluation." I should also mention that participants also received skin prick tests (SPTs) covering a range of potential allergens: "house dust mites (HDMs mix, including Der p, Der f, Der m, and Blot allergens), cockroaches, dog dander, milk, egg, and crab allergens" as way of defining allergic sensitisation.

Results: there was a "strong positive association between ADHD and allergic sensitization as diagnosed by positive SPTs." In other words, despite finding a fairly low level of ADHD in their sample (1%), those who 'reacted' to one or more of the allergens tested for via the skin prick test seemed to be at some increased risk of ADHD. Such an enhanced risk spanned both those presenting with "AD with allergic sensitization and asthma with allergic sensitization."

The authors provide some further results and details on the possible hows-and-whys of their results. Obviously the immune system figures quite strongly given what for example, they were testing for with the SPT and their focus on AD and asthma. The word 'inflammation' also figures quite heavily. I note too that the authors reiterate previous suggestions that: "Control of allergens exposure might be a critical factor influencing the development of ADHD."

There is a further scheme of work to follow in this area, not just dealing with mechanisms but also in relation to 'treating' allergies also potentially 'treating' [some] ADHD. I say this on the basis that other independent research has observed that before reaching for the antihistamine as a potential ADHD-modifier, there may actually be a connection between early antihistamine exposure and the development of ADHD [3] (albeit with potential confounders) to keep in mind. Other work also supporting a link between ADHD and atopic disease [4] provides some other 'clues' that may require further investigation; not least "cow's milk intolerance", which ties into similar findings (see here) and could also be one route from which ADHD heightens the risk of subsequent future psychiatric disorder (see here) in light of other 'milk' associations (see here).

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[1] Yang CF. et al. Association between allergic diseases, allergic sensitization and attention-deficit/hyperactivity disorder in children: A large-scale, population-based study. J Chin Med Assoc. 2017 Nov 24. pii: S1726-4901(17)30304-0.

[2] Wang IJ. et al. Allergens, air pollutants, and childhood allergic diseases. Int J Hyg Environ Health. 2016 Jan;219(1):66-71.

[3] Schmitt J. et al. Increased attention-deficit/hyperactivity symptoms in atopic dermatitis are associated with history of antihistamine use. Allergy. 2017 Oct 4.

[4] Hak E. et al. Association of childhood attention-deficit/hyperactivity disorder with atopic diseases and skin infections? A matched case-control study using the General Practice Research Database. Ann Allergy Asthma Immunol. 2013 Aug;111(2):102-106.e2.

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