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

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

Ear, ear and hyperactivity

The BBC headline - Inner ear disorders 'linked to hyperactivity' - caught my eye recently. Detailing a fascinating piece of research by Michelle Antoine and colleagues* published in the journal Science the suggestion is that issues with the inner ear that affect hearing and balance might also show some relationship with hyperactivity and in mice at least, might be amendable to treatment.

van Gogh @ Wikipedia  

Before going on, I'd like to point out that Science (the publishing journal) has produced some pretty interesting papers at a similar time to the publication of the Antoine research. I'm talking specifically about the gut bacteria from obese discordant twins producing obese mice research (see here) which discusses the 'transmissibility of obesity' among other things (see here for my previous blogging interest in this area of research). There was also that letter on MAR autism which I've covered recently....

Back to the ears - and no, not whale ears either. Apparently this is not the first time that the presence of inner ear disorders have been linked to behavioural issues as per the description from other media on this research (see here). The long-and short of the paper was the study of mice who were bred to carry a mutation in the Slc12a2 gene (see here for more information about the gene) involved with the transportation and reabsorption of sodium and chloride ions. Said mice with genetic mutation in the inner ear were observed to show "increased locomotor activity".

It was then a case of finding out why this genetic glitch produced such effects which eventually led to a part of the brain dealing with motor output: the striatum and the over-production of two proteins (pERK and pCREB) linked to the control of some important neurotransmitters: glutamate and dopamine (and GABA). Confirmation of these proteins as being involved also led to speculation that something could be done about the behaviours noted in their mouse model as per the use of a pERK inhibitor: SL327 wherein "Hyperactivity was remedied by local administration of the pERK inhibitor SL327".

I'll reiterate that as with many experimental studies these days involving knocking out genes and looking at the effects of genetic mutations, this was a study of mice and so one needs to be cautious about making too many sweeping generalisations to humans and the particular complexities that we have. I note that at least one quite prominent ADHD researcher (whose work has appeared previously on this blog) has cautioned against assuming that all ADHD is just a one gene disorder, much in the same light that autism is seemingly getting past that research hurdle too (see here).

A little light background reading on the Slc12a2 gene reveals some other interesting factoids. Schizophrenia for example, has more than one mention when it comes to looking at the expression of the gene; mainly tied back to that GABA link (see the paper by Hyde and colleagues** for example). Panichareon and colleagues*** (open-access) also detailed some potential connection between gene polymorphisms as being associated with cases of schizophrenia.

Taking into account one of the synonyms for the gene - NKCC1 - I note some mention of the drug bumetanide (see this previous post) as being involved (see here****) which 'potentially' suggests some cross-over into cases of autism too. That and the fact that hyperactivity as part of the diagnosis of ADHD may be part of the ESSENCE of at least some autism, although I hasten to add that the Antoine work did not explicitly mention autism. Ears and hearing, have been talked about previously on this blog with autism in mind though (see here and here).

I suppose the thing that really fascinates me about this work is the link between physical presentation and behavioural presentation not necessarily just exclusive to the brain in terms of origin. To me at least, it's of a similar ilk to other research; for example the observation that lower airway abnormalities might be linked with autism (see here) which still requires some follow-up. A real mind-body or body-mind connection you might say?

Some music. How about The Pixies and Here Comes Your Man.

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* Antoine MW. et al. A Causative Link Between Inner Ear Defects and Long-Term Striatal Dysfunction. Science. 2013; 341: 1120-1123.

** Hyde TM. et al. Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia. J Neurosci. 2011 Jul 27;31(30):11088-95.

*** Panichareon B. et al. Association of CTXN3-SLC12A2 polymorphisms and schizophrenia in a Thai population. Behav Brain Funct. 2012; 8: 27.

**** Lemonnier E. & Ben-Ari Y. The diuretic bumetanide decreases autistic behaviour in five infants treated during 3 months with no side effects. Acta Paediatr. 2010 Dec;99(12):1885-8.

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Antoine MW, Hübner CA, Arezzo JC, & Hébert JM (2013). A causative link between inner ear defects and long-term striatal dysfunction. Science (New York, N.Y.), 341 (6150), 1120-3 PMID: 24009395

Hears, ears and autism

It has been mentioned on quite a few occasions.

Parents or caregivers initially suspect that their young child presents with a hearing problem when, for example, the child seems non-responsive to their name being called or when their attention is sought (see item 14 of the M-CHAT). The child submits to a hearing test and some of the time, nothing untoward is found. The question is then asked: could it be autism?

Likewise, there have been occasions when parents have initially suspected autism and, following a hearing test, it has transpired that the child has hearing problems. You can see that there is some overlap here.
Like visual impairment, hearing impairment (deafness, hard-of-hearing, if you wish) moves across quite a bit of ground; ranging from the source of the problem, through to the extent of the loss. Also like sight, many people would describe hearing as probably being one of the more primary senses in terms of its importance to daily life - language and communication, social interaction, balance, etc (some of these sound familiar?).

Hearing is so important a sense that, certainly here in the UK, the day of (or day after) birth, newborns have a hearing screen complimentary of the NHS Newborn Hearing Screening Programme. From what I am aware, there is no equivalent programme offered for sight throughout infancy; allowing though, for the difficulties of objective vision testing in newborns.

Looking at the rates of hearing loss in autism and in the general population, the RNID estimate that 1 in 1,000 children (0.1%) in the UK are deaf at age 3. The figures for other age-groups are slightly more complicated but between the ages of 16-60 years, the estimated prevalence of all types of deafness is 6.6%.
In autism, the estimated occurrence of co-morbid hearing loss (all types) is round about 10% in children and adolescents (note that this is a study published in 1999 carried out in Sweden). Obviously the age ranges don't exactly match up with the RNID figures, but the general suggestion is that hearing loss may be more prevalent in autism compared with the general population figures.

Issues with hearing in autism are not solely confined to a loss of function. Some people with autism (and their parents / caregivers) report issues with the perception of hearing; that is things like hyperacusis. There is some good evidence to suggest that the perception of loudness might be perturbed in some cases of autism. Indeed, for some children, the option of ear defenders / ear plugs is a vital course of action to block out what can often be quite disturbing sensory input.

What causes such hyperacuity? I don't think anyone has an answer for that yet. There is some suggestion that it might be down to sensory gating or temporal processing in specific groups on the autism spectrum but much more research is required. Readers may remember my recent entry on vision and autism; perhaps there is some shared mechanism with the perceptual issues highlighted in that area too - whereby our senses are linked together?

What can be done about hyperacusis? Again, there are no universally 'right' answers to this. My first thought would be that adapting the environment to the child/person with autism should be key. It is however probably impossible to remove all sound altogether - also impractical for a person who might have to go to school, go outside, etc.

Like the various comments on vision processing in autism, one course of action proposed is to think about ambient noise and its potential effect. The humming of the lights; certain pitches in people's voices; singing; dogs barking etc - these are all things which have been suggested by people with autism to be a source of often, real irritation (obviously there are a lot of other things too).

I previously mentioned ear defenders as one option, and indeed this young lady found them to be useful for her (also her iPod - no advertisement intended). Various other options have also been suggested, including things like auditory integration therapy (AIT) - although make sure that you do your research first. One final point of information and help may also come from a referral for the child to their local audiologist.

Most guidelines for autism screening and diagnosis do include some reference to hearing assessment. Hopefully also this will be included in the upcoming NICE guidelines on autism, and indeed research also expanded on the important issue of how hearing and autism are connected.