Middle ear infection and autism (again)

"Autism was more common in children who had had an otitis media infection or who had been treated with antibiotics."

Minus any sweeping generalisations, that was the conclusion reached in the study by Theresa Wimberley and colleagues [1] continuing some important research themes (see here and see here) examining any "interplay among otitis media, antibiotics, and the subsequent risk of developing autism."

Just in case you don't already know, otitis media infection refers to an infection of the middle ear that "causes inflammation (redness and swelling) and a build-up of fluid behind the eardrum." Aside from the use of painkillers, the seriousness of certain otitis media infections can sometimes mean that antibiotics are prescribed to combat any underlying bacterial infection or even in some cases, grommets inserted as treatment.

Wimberley et al report results based on "the entire Danish population", well, over three-quarters of a million children "followed from birth (January 1, 1997 to December 31, 2008) until December 31, 2012." They calculated various 'risk of autism' statistics as a function of a previous medical diagnosis of otitis media and "antibiotic prescriptions redeemed at Danish pharmacies." Yes folks, yet again those big data Scandinavian population registries have been used to good research effect.

Results: "The absolute risk of autism before age 10 was increased among children with otitis media (1.2% for females and 3.3% for males) and in children who had redeemed an antibiotic prescription (0.6% and 2.7% for females and males) compared to children without a history of otitis media and antibiotics usage (0.4% for females and 1.9% for males)." Researchers also reported finding "little evidence of a synergistic effect between otitis media infections and treatment with antibiotics" despite them being over-represented in relation to autism. They also caution that cause-and-effect cannot be inferred from their observational results.

What more can one say about the Wimberley findings? Well, echoing the idea that correlation is not the same thing as causation, I'd say that there is quite a bit more research to do on this topic. Further investigations are required into the possible mechanisms through which autism may manifest at least partially as a result of a history of ear infection (or indeed vice-versa). Mention of antibiotics also brings in areas of additional research interest such as the gut microbiome and what antimicrobials might 'be doing' to the trillions of passengers that are carried in the deepest, darkest recesses of the human body. I'm also minded to suggest that alongside antibiotic use to potentially treat infections like otitis media, researchers might also want to focus in on other medicines that might be accessed in such case such as over-the-counter pain relief in light of other *associations* that have been made (see here).

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[1] Wimberley T. et al. Otitis media, antibiotics, and risk of autism spectrum disorder. Autism Res. 2018 Oct 3.

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Adenotonsillectomy for obstructive sleep apnea and autistic behaviours?

Adenotonsillectomy refers to the surgical removal of the tonsils and adenoids and is typically indicated for a variety of reasons, not least in cases of obstructive sleep apnoea (OSA) (where breathing is interrupted during sleep). It's not an unfamiliar operation and is generally categorised as low-risk surgery. The positive outcomes following surgery have been described as 'dramatic' both in clinical terms and also related to quality of life [1].

A recent study published by Emi Murata and colleagues [2] (open-access available here) adds a further dimension to the use of adenotonsillectomy (AT) for obstructive sleep apnoea specifically with the autism spectrum in mind. They concluded that: "Behavioral problems were significantly improved following AT in ASD [autism spectrum disorder] children with OSA."

First off, I'll direct you to a previous post that I wrote about sleep apnoea and autism (see here) based on the findings reported by Hirata and colleagues [3]. They concluded that within their research cohort: "sleep problems, especially obstructive sleep apnea, are more common in ASD preschoolers than in community preschoolers." Then there are the study results by Malow and colleagues [4] who detailed a case report of treating sleep apnoea in a child with autism via use of AT. Bearing in mind this was an N=1, they observed that treatment coincided with "improvements in sleep, social communication, attention, repetitive behaviors, and hypersensitivity" based on use of the ADOS among other measures.

Set within this context, the Murata paper detailed the results of a study including some 54 children diagnosed with ASD. Their aims were two-fold: "to determine whether AT for the treatment of OSA improves the behavior of Japanese children with ASD using the Child Behavior Checklist (CBCL)" and "to identify characteristics for behavioral improvement following the treatment of OSA in these children with ASD." Thirty of the study participants were diagnosed with OSA and all underwent surgery for AT. I must also stress that said surgery was a clinical decision: "Because hypertrophy of the adenoids and/or palatine tonsils was observed." The rest of the cohort served as a control group used "to establish whether observed changes in CBCL scores were due to the natural course or a result of the experimental intervention."

The results are pretty interesting: "After AT, T-scores of the CBCL scales were significantly improved in the OSA group, but no change was observed in the control." This was based on before and after inspection at 0 months (before surgery) and 6 months after surgery. The sorts of things seemingly improved in the AT group were aspects of behaviour and functioning linked to being withdrawn, social problems. attention issues and aggressive behaviour. Authors noted that: "The domain of “thought problems” showed the largest decrease... in the OSA group."

When it came to the 'characteristics for behavioural improvement' side of their study, authors noted that: "the improved group show[ed] significantly higher scores on the CBCL at pre-AT than the unchanged/deteriorated group in ASD children with OSA after OSA treatment". This implies that baseline presentation might be important when it comes to behavioural outcomes following the use of AT and also that not every child with ASD and sleep apnoea undergoing AT will show the same pattern of behavioural changes.

I find these results to be fascinating. Not least because they offer a roadmap for (a) screening for sleep apnoea in cases of autism and (b) details of how a treatment for one cause of sleep apnoea in such cases might have effects well beyond just related to breathing patterns. Then also, there is the question of why such surgery might impact on presented behaviour? I'm afraid I don't know enough about such issues to offer any definitive explanations. I might refer you back to some other discussions on this blog about middle ear infections and autism (see here) in the context of ear, nose and throat being linked on several levels but further investigations are very much required on the biological parameters potentially important to findings such as those described by Murata et al. That being said [5] there may already be some clues in the peer-reviewed science literature...

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[1] Mitchell RB. Adenotonsillectomy for obstructive sleep apnea in children: outcome evaluated by pre- and postoperative polysomnography. Laryngoscope. 2007 Oct;117(10):1844-54.

[2] Murata E. et al. Evaluation of behavioral change after adenotonsillectomy for obstructive sleep apnea in children with autism spectrum disorder. Res Dev Disabil. 2017 May 14;65:127-139.

[3] Hirata I. et al. Sleep problems are more frequent and associated with problematic behaviors in preschoolers with autism spectrum disorder. Research in Developmental Disabilities. 2016; 49-50: 86-99.

[4] Malow BA. et al. Impact of treating sleep apnea in a child with autism spectrum disorder. Pediatr Neurol. 2006 Apr;34(4):325-8.

[5] Mitchell RB. & Kelly J. Behavioral changes in children with mild sleep-disordered breathing or obstructive sleep apnea after adenotonsillectomy. Laryngoscope. 2007 Sep;117(9):1685-8.

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Murata E, Mohri I, Kato-Nishimura K, Iimura J, Ogawa M, Tachibana M, Ohno Y, & Taniike M (2017). Evaluation of behavioral change after adenotonsillectomy for obstructive sleep apnea in children with autism spectrum disorder. Research in developmental disabilities, 65, 127-139 PMID: 28514706

Antibiotic brain part 3

"This study demonstrates an association between antibiotic use in the first year of life and subsequent neurocognitive outcomes in childhood."

So said the findings reported by Slykerman and colleagues [1] who relied on data from the Auckland Birthweight Collaborative Study (an initiative set up to determine whether "internationally recognized risk factors for small-for-gestational-age (SGA) term babies were applicable in New Zealand") to examine the suggestion that early life antibiotic use might be associated with a "detrimental effect on later neurocognitive outcomes."

Relying on maternal report of antibiotic use among offspring "between 12 months and 3.5 years of age" researchers compared data with that derived from "Intelligence test scores and measures of behavioural difficulties" when children were 3.5, 7 and 11 years of age. They found that antibiotic use during the first 12 months of life was high in their cohort (70%) and that: "Those who had received antibiotics had more behavioural difficulties and more symptoms of depression at follow up." I've highlighted the 'relying on maternal report' bit because although parents are typically the experts on their own children (yes, they are), the reliance on parental report is not the same as reliance on objective medical or prescribing records for antibiotic use and important information on antibiotic type, dose and reason for such use that they typically contain. Indeed, I might also stress that correlating antibiotic use and developmental outcome whilst interesting should also be mindful of the myriad of other variables that might play a role, including the idea that 'behavioural difficulties' often don't present until later infancy for whatever reason. Be careful with single associations.

But... I've labelled this post 'Antibiotic brain part 3' because I feel that the Slykerman findings are another important piece of evidence potentially pertinent to the idea that antibiotics may be pretty good at tackling bacterial infection but that also that they may have some quite potent effects on behaviour and development as well as physiology (see here for antibiotic brain part 1 and antibiotic brain part 2).

What's the possible mode of action linking [early] antibiotic use and behaviour and development? Well, far be it from me to speculate too much but I'm minded to bring in the idea that those trillions of wee beasties that inhabit our deepest, darkest recesses (the gut microbiome) might play some role in any process. Minus hype [2] we're for example, already finding out how gut bacteria 'might' show some important behavioural connections (see here for example) and specifically how certain strains of bacteria might link to important states such as depression (see here and see here). It's not outside the realms of possibility that 'swallowing a grenade' (although not literally) designed to kill bacteria rather willy-nilly, might influencing either bacterial diversity in the gut or impact on specific strains that could be consider more rather than less beneficial.

One more idea for science to perhaps consider relates to why antibiotics were given in the first place. If for example we assume that ear infection might be a common reason, could it not be that the actual symptoms over and above the [antibiotic] treatment might be the more important variable in relation to 'behavioural difficulties'? [3]

There is much more to do in this area, but alongside the dangers of antibiotic resistance perhaps science might also be more open to the idea that antibiotics might do so much more than just impact on physiology?

To close, for those in Blighty who might remember Hastings, 1066 and a certain Tapestry, things were a whole lot more complicated/gory that you might have expected...

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[1] Slykerman RF. et al. Antibiotics in the first year of life and subsequent neurocognitive outcomes. Acta Paediatr. 2016 Oct 4.

[2] Bik EM. The Hoops, Hopes, and Hypes of Human Microbiome Research. Yale J Biol Med. 2016 Sep 30;89(3):363-373.

[3] Niclasen J. et al. Associations between otitis media and child behavioural and learning difficulties: Results from a Danish cohort. Int J Pediatr Otorhinolaryngol. 2016 May;84:12-20.

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Slykerman RF, Thompson J, Waldie KE, Murphy R, Wall C, & Mitchell EA (2016). Antibiotics in the first year of life and subsequent neurocognitive outcomes. Acta paediatrica (Oslo, Norway : 1992) PMID: 27701771

Middle ear infections and autism

I'm gonna be fairly brief today in drawing your attention to the paper published by Daniel Adams and colleagues [1] reporting that: "Children with ASD [autism spectrum disorders] are more likely to have middle ear infections and otitis-related complications."

The results, which we've known were coming (see here), detail findings based on a retrospective case-cohort study where the health insurance records of children of US military families were initially screened for the presence of autism or an ASD and then further screened for ICD-9-CM diagnostic codes relevant to acute otitis media and related diagnoses. The supplementary material provided alongside the article gives further details (see here).

Alongside the findings of an elevated rate of acute otitis media (AOM) among children diagnosed with autism were various other details including a higher rate of complications following AOM such as mastoiditis - affecting the mastoid bone behind the ear - and the requirement for a mastoidectomy. The surgical reconstruction of the eardrum (tympanoplasty) was also more frequently noted for the autism group versus the non-autism controls. The authors conclude that quite a bit more research is required in this area alongside "highlighting the importance of routine middle ear examinations and close attention to hearing impairment in this population."

This is interesting work. For many years I've heard about how quite a few children on the autism spectrum had a history of early ear infections that were typically followed by quite an aggressive schedule of antibiotic use. Indeed, on one of the previous blogging occasions when I've mentioned ear infections and autism it was to speculate on the double-edged sword that might be the [early repeated] use of antibiotics with [some] autism in mind (see here). That 'association' remains as relevant today as it did during earlier descriptions [2] playing into the various emerging gut bacteria studies of autism.

I have only a few more things to add. First is the idea that screening for middle ear infections might be an important issue for children on the autism spectrum. I can't argue with that; and indeed added to the requirement for screening other sensory gateways such as the eyes (see here), the evidence is accumulating for preferential services to be offered. Second is the idea that recurrent otitis media might show some connection with aspects of sleep too [3] such that issues such as sleep apnoea occurring alongside autism (see here) might also be something to look out for. Finally is the need for quite a bit more research on what happens to autistic symptoms when ear infections are finally diagnosed and treated. Take for example the case report detailed by Kazuhiro Tajima-Pozo and colleagues [4] and the suggestion that surgical correction of the "middle ear for repetitive otitis" correlated with "an improvement in autistic behaviours". One wonders how many other children have shown or might show similar effects and what the possible mechanism(s) could be...

Music: Alanis Morissette - Ironic.

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[1] Adams DJ. et al. Otitis Media and Related Complications Among Children with Autism Spectrum Disorders. J Autism Dev Disorders. 2016. Jan 6.

[2] Bolte ER. Autism and Clostridium tetani. Med Hypotheses. 1998 Aug;51(2):133-44.

[3] Gozal D. et al. Prevalence of Recurrent Otitis Media in Habitually Snoring School-Aged Children. Sleep medicine. 2008;9(5):549-554.

[4] Tajima-Pozo K. et al. Otitis and autism spectrum disorders. BMJ Case Rep. 2010 May 6;2010. pii: bcr1020092351.

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Adams, D., Susi, A., Erdie-Lalena, C., Gorman, G., Hisle-Gorman, E., Rajnik, M., Elrod, M., & Nylund, C. (2016). Otitis Media and Related Complications Among Children with Autism Spectrum Disorders Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-015-2689-x