NMDAR encephalitis presenting with "behavioral changes and some autistic features"

Anti N-methyl-D-aspartate (anti-NMDA) receptor encephalitis is yet again (see here) the blogging topic today, as I bring the case report published by Yasmin Khundakji and colleagues [1] to your attention. It's an important case report because, in keeping with the primary focus of this blog, the words 'autistic features' also appear in the Khundakji account. This follows quite a bit of other independent research where autism or autistic features has been mentioned in the context of NMDA receptor encephalitis (see here and see here).

The details? "The patient was a healthy girl" ('was' being the operative word). Some time before she was 2 years of age, she experienced some really quite sudden and stark behavioural changes "manifesting as bouts of irritability, aggression, inconsolable crying, and self-mutilatory behavior (self-biting)." A fever brought about various other somatic symptoms, as eye contact was lost and insomnia set in. "In addition, she developed a progressive regression in gross and fine motor skills and an inability to swallow" with seizures following. Things were getting really serious.

Various tests were carried out which in the most part came up within typical reference ranges (including a "brain MRI"). Someone had their suspicions that NMDA receptor encephalitis *might* fit with the presented profile. Lo and behold, following testing a positive result was received albeit "one month later" (samples had to be sent out of country for analysis). Interventions were put in place ("intravenous immunoglobulin (IVIg) and intravenous methylprednisolone... plasma exchange... rituximab") with some being more successful than others. Of particular note: "A dramatic improvement in her social skills and irritability appeared within hours following plasma exchange." Interesting. Things did eventually improve for the young girl at the centre of the Khundakji paper as we are told that: "Apart from mild speech delay, her neurological exam and developmental milestones are normal."

What lessons can be learned from such case reports? How about starting with the idea that rapid onset childhood regression that includes 'autistic features' should always be investigated as a sign of unmet medical need such as a response to infection (see here)? Perhaps also acknowledge that the presentation of autism or autistic features is not a life-long, immutable, set-in-stone scenario for some people (see here and see here and see here)? And as for the effects of plasmapheresis (plasma exchange) on this particular young child linked to a "dramatic improvement in her social skills and irritability", I'm wondering whether there is a research study or two to be designed and conducted on this topic (with due care)?

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[1] Khundakji Y. et al. Anti-NMDA receptor encephalitis in a toddler: A diagnostic challenge. International Journal of Pediatrics and Adolescent Medicine. 2018; 5: 75-77.

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The developmental correlates of asthma (again)

Can I just get it out of the way? May the 4th be with you.

OK. The results from Mark Strom & Jonathan Silverberg [1] caught my eye recently and further evidence of a 'correlation' between asthma and developmental and/or behavioural outcomes. This time around it was "caregiver-reported speech disorders in US children" and how the appearance of asthma, hay fever and/or food allergy might show some important relationships with something like speech disorder. This follows other, similar work from this research tag-team that has previously graced this blog (see here).

Based on the analysis of "cross-sectional data on 337,285 children aged 2-17 from 19 US population-based studies, including the 1997-2013 National Health Interview Survey and the 2003/4 and 2007/8 National Survey of Children's Health" researchers engaged in some number-crunching to ascertain how physiology and behaviour might be linked. When controlling for various other important variables such as age and a history of eczema, authors reported some interesting correlations based again on those household survey results. "Future prospective studies are needed to characterize the associations.

I've zoomed in on the specific condition called asthma as being tied into parent (caregiver) -reported speech disorders because I'm mighty interested in the behavioural correlates that might follow this inflammatory condition (see here and see here for example). As Strom & Silverberg mention: "In one study that assessed caregiver-reported asthma severity, mild (1.58 [1.20-2.08], P=0.001) and moderate (2.99 [1.54-3.41], P<0.0001) asthma were associated with increased odds of speech disorder, however severe asthma was associated with the highest odds of speech disorder (5.70 [2.36-13.78], P=0.0001)." The idea therefore that severity of asthma might correlate with the odds of reporting (caregiver-reporting) a speech disorder, is seemingly an important one.

I could speculate all-day as to what might be the important driver(s) in any association between asthma and speech disorder (genetics, immune function, gut bacteria, medication and/or pollutants) but I don't think it would be particularly helpful at this point. Not any more helpful than reiterating that we do need a lot more investigation into this proposed association and that preferential screening for one or other condition when the other has been diagnosed might be a rather good idea.

And while I'm on the topic of immune function and behavioural correlates, how about another recent paper from this research tag-team [2] and more scientific evidence for a possible important association between atopic dermatitis and ADHD...

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[1] Strom MA. & Silverberg JI. Asthma, hay fever and food allergy are associated with caregiver-reported speech disorders in US children. Pediatr Allergy Immunol. 2016 Apr 19.

[2] Strom MA. et al. Association between AD and attention deficit hyperactivity disorder in US Children and Adults. Br J Dermatol. 2016 Apr 23.

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Strom MA, & Silverberg JI (2016). Asthma, hay fever and food allergy are associated with caregiver-reported speech disorders in US children. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology PMID: 27091599

Toddler language and autism risk

I'm not going to keep you too long today as I introduce the paper by DeWayne Lazenby and colleagues [1] and some rather interesting data on whether early language use might help predict those toddlers who are at subsequent risk of being diagnosed on the autism spectrum.

Based on the prospective analysis of over 300 infants - "some of whom were at high risk for developing ASD [autism spectrum disorder]" - authors went about analysing various aspects of language using among other things, the MacArthur-Bates Communicative Developmental Inventories (CDI). They reported a few potentially interesting details including: "lower receptive and expressive language scores in infants who later were diagnosed with ASD" based on their testing round about 12 months of age. Further: "a Rasch analysis indicated that infants who later developed ASD had a higher degree of statistically unexpected word understanding and production." They concluded that there may indeed be more to see when it comes to language use in early childhood as a potential marker of subsequent autism diagnosis. Such findings accord with other data from some of the authors [2].

Accepting that within the very wide and heterogeneous autism spectrum probably better defined by the plural autisms (see here) there may be lots of factors influencing first presentation including the variable of regression (see here), these are important findings. Notwithstanding the notion that autism seems not to be protective against other language-related issues being potentially comorbid [3] and the effect that might have on early presentation of language, the idea that speech patterns might direct a child towards preferential early screening for autism is useful in light of the emphasis on early screening [4] and the 'clear benefits' of early intervention [5].

As part of the growing interest in aspects of telemedicine and mobile health, the recent news about ResearchKit being applied to autism (see here) might well provide something of an important platform whereby information about facial expressions is further combined with assessment of speech patterns and production (including aspects such as intonation [6] etc). This does not mean that every single early presentation of autism will be 'picked up' by such technology, but it does perhaps offer a way that technology can ease some of the significant pressures on clinical resources pertinent to identifying autism early and accurately.

And whilst we're on the topic of language and autism, I can recommend another article by Tager-Flusberg [7] worth a read...

Music: PJ Harvey - C'mon Billy.

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[1] Lazenby DC. et al. Language Differences at 12 Months in Infants Who Develop Autism Spectrum Disorder. J Autism Dev Disord. 2015 Oct 17.

[2] Talbott MR. et al. Diary Reports of Concerns in Mothers of Infant Siblings of Children with Autism Across the First Year of Life. J Autism Dev Disord. 2015 Jul;45(7):2187-99.

[3] Tager-Flusberg H. Defining language impairments in a subgroup of children with autism spectrum disorder. Sci China Life Sci. 2015 Sep 2.

[4] Zwaigenbaum L. et al. Early Screening of Autism Spectrum Disorder: Recommendations for Practice and Research. Pediatrics. 2015 Oct;136 Suppl 1:S41-59.

[5] Zwaigenbaum L. et al. Early Intervention for Children With Autism Spectrum Disorder Under 3 Years of Age: Recommendations for Practice and Research. Pediatrics. 2015 Oct;136 Suppl 1:S60-81.

[6] Nakai Y. et al. Speech intonation in children with autism spectrum disorder. Brain Dev. 2014 Jun;36(6):516-22.

[7] Tager-Flusberg H. Risk Factors Associated with Language in Autism Spectrum Disorder: Clues to Underlying Mechanisms. J Speech Lang Hear Res. 2015 Oct 20.

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Lazenby DC, Sideridis GD, Huntington N, Prante M, Dale PS, Curtin S, Henkel L, Iverson JM, Carver L, Dobkins K, Akshoomoff N, Tagavi D, Nelson CA 3rd, & Tager-Flusberg H (2015). Language Differences at 12 Months in Infants Who Develop Autism Spectrum Disorder. Journal of autism and developmental disorders PMID: 26476738

Does eczema increase the risk of childhood speech disorder?

Nativity Kylo?

The question posed in the title of this post reflects some interesting data published by Mark Strom & Jonathan Silverberg [1] who reported that: "Pediatric eczema may be associated with increased risk of speech disorder" on the basis of their analysis of data for some 350,000 children "from 19 US [United States] population-based cohorts."

Taking into account various variables such as "sociodemographics and comorbid allergic disease" authors determined that among the 19 cohorts, the majority (12) showed some kind of connection between eczema and elevated odds of speech disorder. Further, when pooled together, the prevalence of speech disorder among those children with eczema was 4.7% compared with a figure of 2.2% for those children without eczema.

One other detail to impart from the Strom/Silverberg study was how eczema plus other labels was also linked to risk of speech disorder as per the sentence: "children with both eczema and attention deficit disorder with or without hyperactivity or sleep disturbance had vastly increased risk of speech disorders than either by itself."

Allowing for the fact that correlation is not necessarily the same as causation and that as the authors admit: "Further, prospective studies are needed to characterize the exact nature of this association" these are interesting data strengthened by the large number of participants included for study. A quick trawl of the research literature in this area suggests that childhood speech disorders may very well be associated with additional health problems [2] although not necessarily just rooted in something like eczema.

The possibility that a physical ailment like eczema might have implications for a developmental condition like childhood speech disorder is a tantalising one. I've covered the preliminary idea of a 'skin-brain axis' before on this blog (see here) on the basis of data like that reported by Yaghmaie and colleagues [3] talking about atopic dermatitis and various developmental/psychiatric labels. More generally, allergic disease in infancy has been linked to various neurodevelopmental outcomes (see here) with again, the requirement for quite a bit more investigation of this possible association. Indeed, even the 'big data' of Taiwan has something to say on this topic (see here).

As to any mechanism, well, outside of the suggestion of shared genetic risk between something like eczema and speech (and language) issues, the idea that the immune function (a cardinal mechanism of eczema) might play a much greater role in our health and wellbeing than merely the somatic is becoming more mainstream in these days of immune system and psychiatry intersecting (see here). The more general idea that immune features such as inflammation might be able to 'interact' with psychology is a whole new frontier of medicine (see here) and one that should be incorporated into any future research strategy. The other potentially important question outside of any aetiological association is whether or not early treatment of eczema including attending to some of the possible triggers [3] might also have important implications for the risk of developing speech disorders?

Music: Blur - Trimm Trabb.

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[1] Strom MA. & Silverberg JI. Eczema Is Associated with Childhood Speech Disorder: A Retrospective Analysis from the National Survey of Children's Health and the National Health Interview Survey. J Pediatr. 2015 Oct 28. pii: S0022-3476(15)01140-3.

[2] Keating D. et al. Childhood speech disorders: reported prevalence, comorbidity and socioeconomic profile. J Paediatr Child Health. 2001 Oct;37(5):431-6.

[3] Yaghmaie P. et al. Mental health comorbidity in patients with atopic dermatitis. J Allergy Clin Immunol. 2013 Feb;131(2):428-33.

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Strom MA, & Silverberg JI (2015). Eczema Is Associated with Childhood Speech Disorder: A Retrospective Analysis from the National Survey of Children's Health and the National Health Interview Survey. The Journal of pediatrics PMID: 26520915