Low grade intestinal inflammation and autism

The suggestion that low grade intestinal inflammation might be related to some autism comes from the findings reported by Katarina Babinská and colleagues [1] (open-access available here).

Researchers set out to "assess the concentrations of fecal calprotectin in a sample of children with ASD [autism spectrum disorder] and to investigate the correlations of this inflammatory marker with the core behavioral symptoms of ASD."

Faecal calprotectin (FC) is a measure of the amount of calprotectin in a stool (poo) sample. It's typically released in response to the presence of inflammation and, here in Blighty at least, is indicated as "an option to support clinicians with the differential diagnosis of inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS) in adults with recent onset lower gastrointestinal symptoms for whom specialist assessment is being considered." 

In terms of research history looking at autism and FC, there is some peer-reviewed science on the topic; also having been included as a parameter in the important paper by Laura de Magistris and colleagues [2] talking about 'leaky gut' in the context of some autism (see here) and how "FC was elevated in 24.4% of patients with autism and in 11.6% of their relatives." Such research is set in the more general context that bowel or gastrointestinal (GI) issues are absolutely no stranger to a diagnosis of autism (see here).

This time around Babinská et al measured FC (via ELISA) in some 87 children diagnosed with an autism spectrum disorder (ASD) aged between 2 and 17 years of age. The authors use the term 'low functioning' to describe this portion of their participant group but I'm rather less enamoured with such labels (see here) despite the well-deserved focus on a group very much under-represented in autism research and other areas. Alongside, over 50 age-matched controls (not-autism) and 29 siblings of children with ASD also provided samples for analysis and comparisons.

Results were not exactly as cut-and-dried as one might have expected. So: "In non-relatives significantly lower values of fecal calprotectin were observed than in both subjects with ASD and their siblings." What this means is that based on group results, those with autism and the siblings of those with autism seemed to manifest higher levels of FC than non-related controls. Based on individual results, where elevated levels of fecal calprotectin was set at 50 µg/g of feces or higher according to test producers guidance as being a level of concern, the frequency of such a finding was greater in those with autism (22%) and their siblings (20%) than in non-related controls (9%) but this difference was reported as 'non-significant'.

Authors also did a little work on another important area in relation to bowel symptoms/pathology and autism: how *might* something like intestinal inflammation 'interact' with the behavioural signs and symptoms of autism? Well, we are told that those diagnosed with autism "had to meet criteria for ASD" on two gold-standard diagnostic tools: the Autism Diagnostic Observation Schedule – second edition and the Autism Diagnostic Interview-Revised (ADI-R). Data from the ADI was examined in the context of the FC findings and lo and behold: "In the group with ASD significant correlations of fecal calprotectin with all domains of the ADI-R diagnostic tool were found: qualitative abnormalities in reciprocal social interaction and communication, restrictive and repetitive patterns of behavior." I say this bearing in mind that similar analyses between FC values and ADOS ratings do not seem to have been either done or reported on for some reason.

When the authors talk about low grade intestinal inflammation as potentially being relevant to some autism, they seem to be accurate insofar as the measured levels of FC in some participants and the *correlation* with autism scores on one of the gold-standard assessment instruments. That being said, there is quite a bit more to do in this area before anyone gets too carried away with the results as they stand. So for example, all that chatter about inflammatory bowel disease (IBD) being related to some autism (see here and see here) did not seem to register in this particular study insofar as the guidance on FC being a marker for possible IBD, albeit based on higher levels of FC being detected: "Active, symptomatic inflammatory bowel disease 200 – 40,000 mg/kg."

I also note that the authors report an important limitation when it came to their research: "Additional factors that might have been a cause of elevated FC levels, such as nutritional or gastrointestinal factors were not analysed." Nutritional factors eh? Y'mean like milk type for example [3] or other dietary and/or environmental factors such as the implementation of a gluten-free diet [4] positively affecting FC levels? Indeed, there are lots of potential factors that could cause a 'false-positive' when it comes to elevated FC such as infections like C. diff or gastrointestinal conditions such as coeliac disease, many of which have shown some important connections to autism (see here for example).

It looks like there is still much more research to do in this area but investigations should definitely continue.

To close, my brood have just discovered the brilliant film 'The Great Escape'. As well as setting up many, many discussions about war, bravery and captivity, they've also commented on the theme tune...

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[1] Babinská K. et al. Fecal calprotectin levels correlate with main domains of the autism diagnostic interview-revised (ADI-R) in a sample of individuals with autism spectrum disorders from Slovakia. Physiol Res. 2017 Dec 30;66(Supplementum 4):S517-S522.

[2] de Magistris L. et al. Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives. J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24.

[3] Ho S. et al. Comparative effects of A1 versus A2 beta-casein on gastrointestinal measures: a blinded randomised cross-over pilot study. Eur J Clin Nutr. 2014 Sep;68(9):994-1000.

[4] Balamtekın N. et al. Fecal calprotectin concentration is increased in children with celiac disease: relation with histopathological findings. Turk J Gastroenterol. 2012;23(5):503-8.

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Once more... listen to parents: on the identification of the early behavioural signs of autism

"The results suggest that parents may detect some clinically informative behaviors based on their day-to-day observations more readily than do clinicians during brief clinical assessments."

So said the findings reported by Lori-Ann Sacrey and colleagues [1] who compared the views of parents "of children at high-risk of autism spectrum disorder (ASD; have an older sibling with ASD)" with clinicians opinions when it came to reporting on around 20 clinical signs that could indicate the presence of autism.

Clinicians relied on the Autism Observational Scale for Infants (AOSI) to make their judgements and parents used the Autism Parent Screen for Infants (APSI) (a sort of parent-version of the AOSI) for theirs when infants were between 12 and 18 months of age. Infants being 'observed' subsequently underwent "a blind independent diagnostic assessment for ASD at 36 months of age" to see how accurate those earlier parent and clinician observations were.

The old adage that 'parents generally know their children best' shines through in the Sacrey results with "parent-reported symptoms being better able to differentiate between children with and without ASD at both 12 and 18 months of age compared to clinician observations during a brief office visit." No, most parents aren't experts when it comes to child development and no, typically they aren't seeing lots of children on a day-to-day basis who may present with various developmental issues including autism. But... compared with an often "brief clinical assessment", all those day-in day-out observations that are made - particularly when autism is 'already a part of the family' - do seem to count for quite a bit. Once again, we would all do well to listen to parents (see here) and any concerns they have about their child's development. I might add that combined with the recording technology available to most people these days and the tendency for many parents to document their child's every developmental move, there is potentially plenty of data available for further analysis (see here).

There are a few other issues that could come into play as a result of the Sacrey and other, related but independent findings. I tend to go on quite a bit on this blog about how various 'comorbidities' (if I can still call them that) seem to be over-represented when it comes to a diagnosis of autism. One of the more prevalent ones is that of bowel / gastrointestinal (GI) issues (see here) which is becoming more readily accepted in various circles as being a part of the clinical picture for quite a few people on the autism spectrum. I've talked before about how parents were/are typically the first ones to pick up the bowel-side of things and how, their observations of their own child's bowel symptoms, can on many occasions, provide some important 'pointers' to the professionals (see here). I see the Sacrey work as an extension of this other research, as the message 'listen to parents' continues to be a consistent theme.

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[1] Sacrey LR. et al. Parent and clinician agreement regarding early behavioral signs in 12- and 18-month-old infants at-risk of autism spectrum disorder. Autism Res. 2018 Jan 22.

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Methylphenidate affecting academic performance meta-analysed

When first tweeting about the paper by Anne Fleur Kortekaas-Rijlaarsdam and colleagues [1] I kinda made a mistake. The text of the tweet read something like: "Does methylphenidate improve academic performance? A systematic review and meta-analysis... Pretty much so, but only in relatively small amounts."

Reading that tweet back to myself I realised that by saying 'but only in relatively small amounts' it's highly likely that any readers might have thought that I was talking about the dose of methylphenidate (MPH) rather than the [intended] effect on things like "math productivity (7.8% increase, p < .001); math accuracy (3.0% increase, p = .001); [and] increased reading speed (SMD .47, p < .001)." I apologise, and once again reiterate my blogging (and social media) caveat about not giving anything that looks, sounds or smells like medical or clinical advice.

I did think it worthwhile to write a short post about the Kortekaas-Rijlaarsdam findings given that (a) ADHD (attention-deficit hyperactivity disorder) is something that turns up quite a bit on this blog (see here for example), and (b) pharmacotherapy 'for ADHD' is an important intervention area which has also, unfortunately under some circumstances, been 'hijacked' for other purposes (see here). On that last point, I specifically refer to the idea that for some people, striving for a diagnosis of ADHD is merely a route to either better academic accommodations or perhaps more worryingly, to gain access to a class of medicines with some potentially significant 'cognitive-enhancing' qualities...

What sets the Kortekaas-Rijlaarsdam findings apart from other reviews of the potential nootropic (cognitive enhancing) abilities of something like MPH is their focus on resolving the issue of "whether there are improvements in core academic skills or just improvements in academic productivity" in the context of "the mediating or moderating effects of symptom improvements, demographic-, design- and disorder-related variables."

From a starting number of 148 full-text research articles, the collected texts were screened for eligibility and some 34 were eventually included for meta-analysis ("quantitative synthesis"). These articles were included because they "provided information about either accuracy or productivity scores for math, reading or spelling, or a combination of these" or could at least be calculated on the basis of their included data. Various mediating and moderating variables were also thrown into the statistical mix - "age, gender, percent diagnosed with ADHD-inattentive subtype, and study characteristics: release system, trial duration, and titration method" - and results reported.

As per previous sentences, various aspects of maths performance showed an improvement that correlated with MPH use, and reading speed but not accuracy also came out as potentially showing a relationship with medicine usage. Important too was the information that: "None of our mediators or moderators influenced MPH effects on math and reading accuracy or productivity."

So, following meta-analytic scrutiny of some 1700 children, it looks like there is a small but potentially relevant effect from MPH use of some academic abilities, at least in the short-term ("between 1 and 7 days"). The authors do well not to stray too much into speculating mode when it comes to the cause of any nootropic effect but instead to include the need for more research "to isolate groups of patients who may benefit more or less from MPH and to reveal its mechanism of action." Can't argue with that.

And going back to the topic of cognitive enahncers, an interesting article from a few years back on what they may or may not be doing to elements of our University student body...

Music to close... Sia and Chandelier. Seemingly always playing outside my dojo....

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[1] Kortekaas-Rijlaarsdam AF. et al. Does methylphenidate improve academic performance? A systematic review and meta-analysis. Eur Child Adolesc Psychiatry. 2018 Jan 20.

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The latest CDC figures on ADHD medication trends among women aged 15-44

The report published by Kayla Anderson and colleagues [1] has made quite a few media headlines (see here for example) based on their observations that: "The percentage of privately insured reproductive-aged women who filled a prescription for an ADHD [attention-deficit hyperactivity disorder] medication increased 344% from 2003 (0.9%) to 2015 (4.0%). Further: "ADHD medication prescriptions increased across all age groups and U.S. geographic regions, and the increase was confined to stimulant medications."

"The new report raises questions about the increasing use of a diagnosis that once was reserved for children and adolescents" was one of the issues discussed following the publication of the Anderson report. This continues a theme in psychiatric circles on whether the diagnosis of ADHD is being 'over-used' across many different age groups [2]. Another issue - that of the potential performance-enhancing abilities of certain medicines commonly indicated for managing ADHD (see here for a recent review [3]) - has also come into the media spotlight too as a result of these latest findings.

A further point of discussion has also been noted by Anderson et al: "ADHD medication prescriptions are increasingly common among privately insured, reproductive-aged women. Additional research on ADHD medication safety among this population, including safety before and during pregnancy, could help women and their health care providers make evidence-based decisions concerning the risks and benefits of pharmacologic and behavioral treatment options for common conditions, including ADHD." The question raised is whether use of something like "a prescription for mixed amphetamine salts... for lisdexamfetamine.. for methylphenidate" is 'safe' before and during pregnancy when it comes to offspring health, wellbeing and development?

The area of pregnancy medicine use is a particularly complicated issue. Not least because various medicines used before and during pregnancy have come under the spotlight in recent times, in terms of their potential effects on the unborn child. Ranging from the pretty convincing valproate story (and guidance) (see here) to the *possible* effects of various anti-depressants (see here) to that of over-the-counter pain relief medicines (see here), the research literature is quite 'lively' when it comes to pregnancy pharmacotherapy. Of course there are gaps in the literature as it stands, and one should never forget that many of the prescription medicines under the research spotlight are not typically prescribed and dispensed willy-nilly, but...

In relation to 'stimulant medication' indicated for ADHD and any effect(s) on the unborn child, we're not yet in any position to make any valued judgements just yet. There is some research out there [4] and it's not all positive [5] but a lot more investigations are indicated. I say that bearing in mind that: (a) ADHD might not be the only condition/label given to some mothers, which will likely affect their medication profile too (see here for example), and (b) much like other work looking at medicines and risk of 'adverse' childhood issues, there's always the possibility that the risk to offspring *might* be elevated as a result of the underlying condition being treated/managed (i.e. ADHD) or some related comorbidity irrespective of any medication influences.

I'm not coming out as any sort of 'champion' for ADHD medications (despite their quite impressive safety and efficacy profiles) but neither am I going to demonise a whole class of medicines based on a currently pretty scant evidence base. Understanding also how much of an effect a diagnosis of ADHD can have on a person (see here and see here for examples), further investigations are indicated before hype and sweeping generalisations take hold.

And this is not the first time that research has indicated that ADHD medication use is on the up (see here)...

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[1] Anderson KN. et al. Attention-Deficit/Hyperactivity Disorder Medication Prescription Claims Among Privately Insured Women Aged 15-44 Years - United States, 2003-2015. MMWR Morb Mortal Wkly Rep. 2018 Jan 19;67(2):66-7

[2] Danielson ML. et al. Prevalence of Parent-Reported ADHD Diagnosis and Associated Treatment Among U.S. Children and Adolescents, 2016. J Clin Child Adolesc Psychol. 2018 Jan 24:1-14.

[3] Kortekaas-Rijlaarsdam AF. et al. Does methylphenidate improve academic performance? A systematic review and meta-analysis. Eur Child Adolesc Psychiatry. 2018 Jan 20.

[4] Nörby U. et al. Perinatal Outcomes After Treatment With ADHD Medication During Pregnancy. Pediatrics. 2017 Dec;140(6). pii: e20170747.

[5] Bro SP. et al. Adverse pregnancy outcomes after exposure to methylphenidate or atomoxetine during pregnancy. Clin Epidemiol. 2015 Jan 29;7:139-47.

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"ASD characteristics in adulthood are differently perceived across age, sex, and informants"

The research tag-team that is Anne Lever and Hilde Geurts have provided peer-reviewed fodder for this blog before (see here and see here). Without wishing to cajole their research interests into a specific box, quite a bit of their time seems to be taken up by looking at autism in the context of ageing, alongside how the label of autism does not seem to have a monopoly on the presentation of certain autistic traits.

A recent paper published by this team [1] provides yet more blogging material, specifically focused on testing "the association between age and ASD [autism spectrum disorder] characteristics, including empathy and sensory sensitivity, in adults aged 19–79 years." A scientific hat-tip is offered to other research in this area [2] that previously observed that: "older age was associated with higher ratings of ASD traits and better cognitive performance."

Drawing on data derived from a participant group numbering above 400 (N=237 with autism and N=198 without autism) spanning the age ranges, a variety of self-report and informant-report (family members, friends, other significant others) were utilised. I should point out that the autism participant group seemed to be represented by the 'more able' part of the autism spectrum (I don't use the term 'functioning') insofar as most either being diagnosed with Asperger syndrome or PDD-NOS (pervasive developmental disorder - not otherwise specified), being predominantly independent or living with a partner or housemate in residential status terms and also with that reliance on self-report used throughout the study kept in mind. This is worth knowing given other discussions on under-represented groups when it comes to scientific study (see here) and how representative autism research may or may not be to the entire spectrum.

Among the measures included for analysis we have an old favourite - the Autism-Spectrum Quotient (AQ) - as well as the Interpersonal Reactivity Index (IRI) (measuring various aspects of empathy) and the Sensory Sensitivity Questionnaire (SSQ) (examining sensory hyper- or hyposensitivity). Obtained results were collated and subjected to quite a few statistical analyses.

Results: noted as a 'group difference' findings were reported observing that: "Adults with ASD reported higher scores on the SSQ and on all subscales of the AQ than adults without ASD." This is pretty much what would be expected, despite any qualms I might have about what the AQ actually measures (see here for more of them). Sensory issues being reported as being greater in those with a diagnosis of autism also ties in well with their inclusion in the DSM-5 schedule for diagnosing autism or ASD (see here).

Then: "Within the ASD group, age-related differences were observed in self-reported ASD traits and sensory sensitivity, with a peak among middle-aged adults." Alongside that previously 'hat-tipped' study, the authors conclude that "ASD characteristics are more heavily experienced in middle adulthood than in younger or older adults." This is interesting from quite a few perspectives; bearing in mind that such findings say nothing about the expression of autism in childhood and early adulthood. Appreciating that the self-report of autism or sensory traits may not be the same as everyday autism expression, such findings *might* have some relevance to various issues such as the rise and rise of adult autism diagnoses being given and indeed, how a diagnosis of autism for some (a few?) might not be a 'lifelong' issue (see here). I know that last point raises blood pressure in some quarters as words like 'masking' are banded around (with the need for far greater study), but there is good reason to think that like many other conditions/labels, autistic behaviours and/or traits ebb and flow according to environment and perhaps other factors, such as the presentation of comorbidity for example (as per the author's other work [3] already mentioned). In short, the presentation of autism is probably dynamic and fluidic, rather than just a static thing.

Onward: "we replicated earlier findings that females with ASD had more sensory issues and reported more ASD characteristics than males... whereas females without ASD manifested fewer ASD traits than non-ASD males.". Females with ASD (74 females vs. 163 males) 'reported more ASD characteristics than males'? Intriguing - "ASD females reported higher scores than ASD males on the AQ total score" - to say the least in light of other [childhood] findings [4] but not without cautions. I go back once again the question of what the AQ is actually measuring and whether for example, the typically higher rate of mood disorders generally noted in females could be a potential confounder when it comes to AQ scores in the context of that previous reference [3] from the authors. This area requires further investigation.

Finally: "Overall, the current results show poor to fair agreement between self- and other-reports of well-known proxies, even though the agreement of the overall group was similar to those previously reported for social responsiveness." Again, some potentially important lessons to be learned here insofar as the 'meaning of autism' to a person and those around them. Indeed I note the authors' offer one explanation: "the self may be more accurate about traits that describe unobservable thoughts and feelings due to privileged access (e.g. feelings of empathy and sensory sensitivity), whereas an informant would be more accurate about observable behavior (e.g., ASD traits)." Again, jumping back into 'hot potato' territory, such a finding may have implications for the whole 'self-diagnosed vs. formal diagnosis' debate that still continues at a pace (see here).

There is quite a bit more to take in from this latest paper from Lever & Geurts and definitely some food for thought. I'll leave you however with one final quote from the authors that is perhaps one of the more important take-away points from their study: "it is important to repeatedly assess self-reported ASD characteristics during adulthood." Who would argue with that in terms of getting wants, wishes, needs and requirements accurate and up-to-date?

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[1] Lever AG. & Geurts HM. Is Older Age Associated with Higher Self- and Other-Rated ASD Characteristics? Journal of Autism & Developmental Disorders. 2018. Jan 18.

[2] Happé FG. et al. Demographic and Cognitive Profile of Individuals Seeking a Diagnosis of Autism Spectrum Disorder in Adulthood. J Autism Dev Disord. 2016 Nov;46(11):3469-3480.

[3] Geurts HM. et al. Autism Characteristics in Older Adults with Depressive Disorders. The American Journal of Geriatric Psychiatry. 2016; 24: 164-169.

[4] Øien RA. et al. Sex-Differences in Children Referred for Assessment: An Exploratory Analysis of the Autism Mental Status Exam (AMSE). J Autism Dev Disord. 2018. Feb 8.

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Maternal diabetes and offspring autism risk meta-analysed

"Maternal diabetes, especially gestational diabetes mellitus, is associated with ASDs [autism spectrum disorders] in offspring based on a limited number of convincing case-control studies. More large-scale population-based prospective studies are still needed to draw firm conclusions."

So concluded the systematic review and meta-analysis by Hongquan Wan and colleagues [1] taking on an important question: does maternal diabetes confer an enhanced risk of offspring autism? Diabetes by the way, covers quite a bit of diagnostic ground, but is typically characterised by elevations in blood sugar levels and the various ways that this can (and does) affect biology and risk of some important adverse conditions.

Yes, appears to the answer based on the peer-reviewed research literature so far (until June 2017) with regards to maternal diabetes affecting offspring autism risk; although with it, a greater need to confirm such findings and also elucidate possible genetic and biological pathways linking diabetes exposure and offspring autism risk is required. I might add that having covered this topic a few times on this blog (see here and see here), including discussing other meta-analysis results [2], I'm not all that surprised by the findings.

Wan et al report results based on 12 articles - "7 were case-control studies... and 5 were cohort study." Combining results in a meta-analytic fashion produced some important observations: "The overall analysis demonstrated that gestational diabetes increased the risk of ASD by 48%" and when reliant on "case-control studies with moderate... or high quality [standing]", the risk increased to over 60%. In short, maternal diabetes exposure does seem to have something of an important effect on offspring risk of autism.

Mechanism(s) of effect? Well, the authors do provide some summary of hypotheses previously put forward. Diabetes exposure causing "brain malformation and aberrant neurodevelopment" is one theory; with words such as "enhanced cell apoptosis and activated oxidative stress" also included. Even possible immune system effects gets some airtime; as the discussion also turns to "the presence of autoantibodies" as a potentially important variable. Autoantibodies, I might add, are part and parcel of at least one type of diabetes. I might also throw in the idea of foetal programming as an over-arching concept to perhaps keep in mind and with it, the implication that early and timely diagnosis and management of maternal diabetes both before and during pregnancy *could* potentially affect offspring autism risk. *Could* is the operative word there...

But... alongside all the 'we need more and better research in this area' sentiments, I'm also minded to highlight how maternal diabetes - in all it's forms - is not necessarily a stand-alone condition. Indeed, it's an important point to remember that when talking about pregnancy factors in the context of something like offspring autism risk, there could be a range of separate but overlapping issues to contend with (see here and see here for examples) which complicate any attempts to single out particular variables as being more or less important when it comes to offspring outcomes.

It's also unwise to assume that 'all autism' is somehow conception or pregnancy-associated either (see here and see here)...

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[1] Wan H. et al. Association of maternal diabetes with autism spectrum disorders in offspring: A systemic review and meta-analysis. Medicine. 2018' 77: e9438.

[2] Xu G. et al. Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis. J Autism Dev Disord. 2014 Apr;44(4):766-75.

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