"Maternal infection during pregnancy may be responsible for some portion of autism..."

The quote heading this post - "Maternal infection during pregnancy may be responsible for some portion of autism..." - comes from the paper published by Benjamin al-Haddad and colleagues [1]. They continue a research theme observing that pregnancy infection may have some quite far-reaching effects on the unborn child and their subsequent risk for various conditions / labels / diagnoses (see here for example).

So: "A total of 1 791 520 Swedish children born between January 1, 1973, and December 31, 2014, were observed for up to 41 years using linked population-based registries." As per use of the term 'population-linked registries', this was another study originating in Scandinavia (this time in Sweden) and their important research registries (see here). The important variables being analysed were the presence of "fetal exposure to any maternal infection while hospitalized during pregnancy" and "diagnosis of autism, depression, bipolar disorder, or psychosis among offspring."

Results: "fetal exposure to any maternal infection increased the risk of an inpatient diagnosis in the child of autism... or depression" but not seemingly for bipolar disorder or psychosis. The magnitude of the risk could be described as 'notable' but perhaps not exceptional. 'Urinary tract infection' (UTI) is mentioned as one infection that seemed to increase the risk of offspring diagnosis; something that has been kinda hinted at in other research literature [2] outside of the classic 'acute psychosis and UTI' research that appears in the peer-reviewed literature (see here).

Mechanisms? Well, it doesn't take a genius to figure out that most infection has a bearing on immune system functions and onward concepts like inflammation. There's quite a long history of immune system 'issues' and inflammatory processes being potentially connected to labels like autism and depression (see here and see here respectively) that provide a template for further investigation. This, bearing in mind, that pregnancy is already a time of 'reprogrammed' immune function so that a mothers body can 'tolerate' the developing fetus. As good as any place to start for further investigations...

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[1] al-Haddad BJS. et al. Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero. JAMA Psychiatry. 2019. March 6.

[2] Hadjkacem I. et al. Prenatal, perinatal and postnatal factors associated with autism spectrum disorder. J Pediatr (Rio J). 2016 Nov - Dec;92(6):595-601.

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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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Autism: a spectrum, dimensions or clusters? How about a multi-dimensional cluster of spectrums?

A write-up (see here) of the paper by Hyunsik Kim and colleagues [1] was the initial impetus for formulating this blog post, but it quickly escalated into something a little larger when the findings from Frank Duffy & Heidelise Als [2] also popped up.

The question at hand: how should one conceptualise autism? Is it truly a spectrum as per the Lorna Wing proposition, or is it something a trifle more complicated? As per the title of this post, should we perhaps be thinking about autism as some sort of "multi-dimensional cluster of spectrums?" I'll come back to that idea shortly.

Well, it's not for me to make definitive conclusions on this blog. Science rarely, if at all, provides an absolute 'truth' but rather the probability that something is approaching truth. Such a notion goes double when you consider the singular label of autism and the huge heterogeneity that it encompasses. There are no easy answers and probably little or no truths.

Starting with the Kim paper (including some notable names such as the surname 'Gadow') and the name of the research game was modelling, modelling in a computational sense. So: "The sample comprised 3,825 youth, who were consecutive referrals to a university developmental disabilities or child psychiatric outpatient clinic." The CASI-4R - formulated by Prof. Gadow - was the schedule administered, which includes "an ASD [autism spectrum disorder] symptom rating scale" among other things. Some nifty statistics were applied to the data and the initial findings were 'tested' on a further group of over 2500 children.

Results: "Based on comparison of 44 different models, results indicated that the ASD symptom phenotype is best conceptualized as multi-dimensional versus a categorical or categorical-dimensional hybrid construct." And the dimensions mentioned in that 'multi-dimensional' statement? Well, lucky for us they were something familiar: "social interaction, communication, and repetitive behaving."

Then to the Duffy/Als paper (again, these authors are no stranger to autism research) and a similar starting point: "The authors postulate that the broad definition of an omnibus 'spectrum disorder' may inhibit delineation of meaningful clinical correlations." Indeed, very familiar (see here). The conclusion: "evidence that an objectively defined, EEG [electroencephalogram] based brain measure may be helpful in illuminating the autism spectrum versus subgroups (clusters) question." The tool used by Duffy/Als in their study was something called NbClust "specifically designed to provide an objective means, i.e. independent of investigator choice, to identify the ‘optimal’ cluster number within a population." Said tool was applied to EEG data derived from 400 participants diagnosed with an ASD. Statistics and more statistics applied to the data revealed that: "430 subjects diagnosed as being on the autism “spectrum” and represented by 40 EEG coherence factors..., fell into two distinct clusters." These autism spectrum clusters differed from each other and importantly, from "554 subject neuro-typical control group subjects, not involved in the clustering process." Interesting results but an unfortunate use of the term 'neurotypical' (see here). Duffy & Als conclude that their data support a view whereby "autism disorder should not be seen as a continuous spectrum." So Kim & Duffy/Als arrive at similar conclusions: a singular 'spectrum' idea of autism is probably not the best way of conceptualising the essence of the label.

I would perhaps add in a little more evidence for the idea that 'multi-dimensional clusters of spectrums' is a potentially better fit. I used the words 'spectrums' (plural) because there is a growing body of evidence to support the idea of more than one 'type' of autism. I say that from the perspective of evidence for autism being 'acquired' under several different circumstances (e.g. accompanying inborn errors of metabolism, linked to exposure to certain infections or diseases, etc). There's also evidence that clinical profiles under the umbrella term autism are not uniform (e.g. regressive autism, the so-called 'optimal outcomers', differing developmental trajectories, etc). And when one looks at something like the success (or not) of intervention, it's plain to see that there is no universally shared genetics and/or biology of autism in the singular either (see here and see here for examples). Add in the idea that autism rarely appears in a diagnostic vacuum (see here) and that said comorbidity might 'cluster' in some subgroups of autism (see here), and I hope you can see why 'plural' might be a good addition to any attempt to re-conceptualise autism: spectrum, dimension, tapestry, cluster or however you think it should be defined...

Oh, and since we're on the topic of trying to conceptualise autism, a new book out recently has been reviewed in Nature (see here). It talks about how "conclusive findings about sex-linked brain differences have failed to materialize" which is particularly apt in relation to previous talk about 'extreme male brains' as a way of conceptualising [some] autism (see here). One quote I particularly liked from the review is this one: "The brain is no more gendered than the liver or kidneys or heart."

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[1] Kim H. et al. Quantifying the Optimal Structure of the Autism Phenotype: A Comprehensive Comparison of Dimensional, Categorical, and Hybrid Models. J Am Acad Child Adolesc Psychiatry. 2018 Oct 29. pii: S0890-8567(18)31894-X.

[2] Duffy FH. & Als H. Autism, spectrum or clusters? An EEG coherence study. BMC Neurol. 2019 Feb 14;19(1):27.

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"The most common peri-onset events reported by subjects were infection-related episodes (64%)"

The quote titling this post - "The most common peri-onset events reported by subjects were infection-related episodes (64%)" - comes from the (open-access) findings reported by Lily Chu and colleagues [1] continuing something of a research theme from this authorship group examining myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) (see here).

Indeed, it's probably no coincidence that the Chu cohort of "150 subjects fitting Fukuda 1994 CFS criteria" is the same as that used in their other research [2] when discussing another important issue: "post-exertional malaise in myalgic encephalomyelitis/ chronic fatigue syndrome."

On this most recent publishing occasion, Chu et al set out to: "Describe ME/CFS onset and course in one United States-based cohort." They did this via the use of "a detailed survey" that asked various questions about the first stages of participants' illness and what this eventually led to. The results obtained weren't exactly unexpected, but yet again stress how lots of things 'assumed' about ME/CFS really need to be properly verbalised in the peer-reviewed science literature (see here and see here for other examples). Of particular note in the Chu findings pertinent to inquiry on the 'course' of ME/CFS is this important snippet of information: "Based on available data, the median age of illness onset was 36.6 ± 12.3 years and median duration of illness was 12.5 ± 10.1 years." That's 'median duration of illness was 12.5± 10.1 years'.

Results: "The most common peri-onset events reported by subjects were infection-related episodes (64%), stressful incidents (39%), and exposure to environmental toxins (20%)." Infection or rather 'infection-related episodes' came out top of the pops with regards to possible onset events. I've said 'possible onset events' in that last sentence not to be belittle the first-hand reports obtained, but rather to emphasise how we're still in a bit of a 'not knowing' state when it comes to definite causative infective agents and ME/CFS onset. Yes, there is some quite strong evidence that infections caused as a result of Epstein–Barr virus (EBV) seem to be involved in some cases of ME/CFS (see here) but more often that not, people aren't screened for every possible viral or bacterial agent. At this point, I'd also hark back to the viral 'hit-and-run' hypothesis that has been talked about in some ME/CFS circles recently (see here and see here) and what this also means.

Onward: "For the overwhelming majority of patients (96%, n = 141), their illness did not improve with time although different patterns of illness were seen." That last sentence really speaks for itself in terms of what ME/CFS means in the long-term. That's not to say that symptoms did not 'fluctuate' - "59%, fluctuating (symptoms could change in severity but were always present)" - but participants on the whole did not 'shake off' their disability. And when it came to some details about how symptoms ebbed and flowed over the course of time, Chu et al have some data on that too: "Over time, flu-like symptoms, fatigue, unrefreshing sleep, and exertion-related items decreased the most, by between 12 and 25%... Cognitive symptoms present at the beginning of the illness tended to persist, declining by only 4–10%." Further focus on 'cognitive symptoms' is perhaps important [3].

Further: "Ninety-seven percent suffered from at least one other illness: anxiety (48%), depression (43%), fibromyalgia (39%), irritable bowel syndrome (38%), and migraine headaches (37%) were the most diagnosed conditions." The authors phrase this in the context that "patients with co-morbid medical or psychiatric conditions are the rule rather than the exception" when it comes to ME/CFS. But just before anyone starts making noises that anxiety and depression are so significantly present in this cohort and probably beyond, such findings does not open the door to any psychobabble 'biopsychosocial' (BPS) explanations about the cause/perpetuation of ME/CFS. I think many patients (and researchers) have had quite enough of all that (see here).

The Chu paper is a comprehensive one and adds to our knowledge about ME/CFS. It has its limitations - "reliance on subject self-report, recall bias, and relative superficiality of some survey items" - but no more or less than lots of other ME/CFS research. It hopefully will open the door to a lot more similar study; perhaps also including the odd biological measure also.

And just before you go, I'll draw your attention to the findings reported by Katherine Rowe [4] who also asked a cohort of participants with ME/CFS about their illness experiences. There's a few important matching details included in the paper - "Eighty percent reported a defined onset following an infection" - but also some other noteworthy information. One such observation was that: "Many indicated the need to be sensitive about when psychological assistance is offered... They were sensitive as to whether this was implying that psychological issues were the “cause.”." It's not difficult to see why patients with ME/CFS would think such [BPS] things.

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[1] Chu L. et al. Onset patterns and course of myalgic encephalomyelitis/ chronic fatigue syndrome. Front. Pediatr. 2019. Jan 16.

[2] Chu L. et al. Deconstructing post-exertional malaise in myalgic encephalomyelitis/ chronic fatigue syndrome: A patient-centered, cross-sectional survey. PLoS One. 2018;13(6):e0197811.

[3] Robinson LJ. et al. Impairments in cognitive performance in chronic fatigue syndrome are common, not related to co-morbid depression but do associate with autonomic dysfunction. PLoS One. 2019 Feb 5;14(2):e0210394.

[4] Rowe KS. Long Term Follow up of Young People With Chronic Fatigue Syndrome Attending a Pediatric Outpatient Service. Front Pediatr. 2019 Feb 21;7:21.

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"by the time ongoing fatigue was established, the immune activation was no longer present"

The quote heading this post - "by the time ongoing fatigue was established, the immune activation was no longer present" - comes from some media coverage of the paper published by Alice Russell and colleagues [1]. Said paper observed some interesting results in relation to the use of interferon-alpha (IFN-α) "used in the treatment of chronic Hepatitis C Virus (HCV) infection" and what this *could* mean in relation to a "proxy model of chronic fatigue syndrome."

The long-and-short of the Russell results and their possible application to chronic fatigue syndrome (CFS) is that for quite a few years now there have been rumblings that at least some cases of CFS (also known as myalgic encephalomyelitis, ME) might be *associated* with a viral hit-and-run encounter. By saying 'hit-and'run' I mean that an initial viral or bacterial infection is experienced which induces the symptoms of CFS. Said infection then eventually disappears for whatever reason(s) but leaves persisting symptoms such as long-term fatigue and more. Further explanation of this hypothesis can be seen in another of my posts on CFS (see here).

So: "Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6–12 months of IFN-α treatment, and at six-months post-treatment." The use of IFN-α is clinically indicated for HCV infection as part of an antiviral therapeutic regime ("IFN-α and ribavirin"). Various biological parameters were assessed in the 55 participants as well as in separate groups of those diagnosed with CFS and so-called "healthy volunteers."

Treatment with IFN-α induced fatigue in quite a few of those being treated for HCV infection. Most cases of fatigue resolved at 6-months post-treatment but for some, fatigue remained and for about 30%, levels of fatigue were "higher six-months post-treatment than at baseline." The authors looked at the biological results obtained for those with 'persistent fatigue' (PF) and compared them with those with 'resolved fatigue' (RF) to see if they could discern some differences.

They came up with a few important group observations: "Subjects who later develop PF have higher fatigue in response to IFN-α", "Subjects who later develop PF have higher IL-10 levels before treatment, and IL-6 and IL-10 levels in response to IFN-α", and "Psychosocial and clinical risk factors do not distinguish PF from RF subjects." What this all amounts to is that within quite a small participant group: "findings from this study support the hypothesis that abnormal immune mechanisms are important in CFS, but only early in the course of the illness, around the time of the trigger, rather than when the syndrome is established." Further the study: "confirms the importance of the acute fatigue response to the trigger, rather than of the recovery period preceding the illness."

There is more to do in this area bearing in mind that CFS is a pretty heterogeneous condition both in terms of symptom onset and the course of the illness. Researchers also admit that they "can only speculate at this stage on whether or not the mechanisms underlying the persistence of fatigue in CFS and IFN-α induced PF are related" and their suggestion of a proxy model. Others who have covered this study have said similar things (see here). This is also important given other results reported by the authors on those diagnosed with CFS compared with those 'healthy' controls/volunteers.

Still, there are some interesting observations made by Russell et al and once again, such results hopefully move CFS further away from the biopsychosocial (BPS) model of old that has seemingly done considerable damage to those diagnosed (see here and see here). Indeed, such post-infective thinking kinda brings CFS back full circle...

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[1] Russell A. et al. Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome. Psychoneuroendocrinology. 2018 Dec 17.

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"Has Daniel always been autistic?"

"Has Daniel always been autistic?"

That was the question that led to Twitter uproar and newspaper headlines calling a TV presenter an 'idiot' and "embarrassing" and "ignorant" these past few days. Some have even called for veteran daytime TV presenter Richard Madeley to be sacked, as one of the premier national autism charities here in Blighty authoritatively announced "autism is a lifelong condition, people are born autistic, it’s not something a child grows out of" following the reporting of an interview between Madeley and Daniel Wakeford, one of the stars of the not particularly well titled TV series called The Undateables. Personally, I would have liked to have seen said charity comment on how the term 'undateable' really shouldn't be used in this day and age with any diagnosis/label in mind...

Emotions ran high following the interview, as many parents of children with autism and autistic people voiced their opinions about their own personal experiences of autism. These are all valid opinions. The problem however, is that within the wide - very wide - heterogeneity that is autism, some of the peer-reviewed science on the topic of autism actually supports the line of questioning from Madeley. Some of the peer-reviewed science highlights the sweeping error in saying that autism is (a) lifelong for everyone and (b) that everyone, past, present and future is 'born autistic'.

OK, first things first, autism is a label ripe for sweeping generalisations. We've seen it numerous times as psychological theories for example, have swept through proclaiming that everyone with autism is lacking a theory of mind or empathy or some other related construct. Likewise, I've seen people quite vehemently opine that autism is the product of this or that 'environmental factor' insinuating that simple changes to drink, food or medicines use for example, will 'stop autism'. The reality however is that autism is a label used to describe vast heterogeneity. It's also a label that says nothing about how a person came to be autistic and nothing about the prognosis of their presentation or their life in general.

So what is the cold, objective peer-reviewed scientific evidence to say that autism is not present from birth for everyone? Well, it's multi-fold. It comes from a number of studies that have followed children from early infancy into later childhood to see whether autism *always* manifest from the very earliest days. Take the recent findings from Sally Ozonoff and colleagues [1] (see here for my take) that concluded among late diagnosed children in their cohort: "Seven showed very little evidence of ASD [autism spectrum disorder] in preschool, whereas 7 demonstrated subtle, subthreshold symptomatology." Add it to other independent data [2] that "validate parents' reports that ASD may appear after a period of nonautistic development" (also that "such reports should not be attributed to recall bias") and then throw in the idea that 'regression', as in a regression of previously acquired skills, is perhaps no stranger to many instances of autism (see here). Then to top it all add in other data highlighting specific cases of 'acquired autism' following exposure to particular post-natal infections for example (see here), and the old 'autistic from birth' mantra does not universally hold for everyone diagnosed as being on the autism spectrum. The evidence against the sweeping 'autism is a lifelong condition' statement made following the interview? I'll direct you to some of the numerous occasions that I've talked about such an idea on this blog (see here and see here and see here) based again on the available peer-reviewed science. Cold. Objective. Science.

Minus making any sweeping generalisations of my own, there is scientific evidence out there that 'born autistic' is not something that can be universally applied to everyone on the autism spectrum no matter how many people would like it to be so. In that respect, the question from Richard Madeley was not ignorant nor disrespectful but rather quite sensible and easily discernible from the available science. The fact also that Daniel's mother Carol talked about a 'loss of his language abilities' in her reply to the question (something I'm sure must have been mentioned before the interview took place and was aired) kinda adds to the sound reasoning for Madeley to ask. It also implies that science should keep studying such an important phenomenon.

It seems that when Carol Wakeford responded with the words 'yes, well there's controversy about that' as the first part of her answer to Madeley's question about Daniel, she certainly wasn't wrong...

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[1] Ozonoff S. et al. Diagnosis of Autism Spectrum Disorder After Age 5 in Children Evaluated Longitudinally Since Infancy. J Am Acad Child Adolesc Psychiatry. 2018 Nov;57(11):849-857.e2.

[2] Landa RJ. et al. Social and communication development in toddlers with early and later diagnosis of autism spectrum disorders. Arch Gen Psychiatry. 2007 Jul;64(7):853-64.

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Regressive vs. non-regressive autism: limited chemical differences noted

The paper published by Antonio Gomez-Fernandez and colleagues [1] examining whether or not there may be some potentially important biological differences as a function of reported regression vs. no regression in autism provides the blogging fodder today. Not for the first time has the immune system and 'regressive autism' been mentioned in the peer-reviewed science literature (see here and see here), but the current work focuses on the examination of various immune system and other related compounds: in a seemingly well-defined cohort: "Analyses of plasma molecules, such as cathepsin, IL1β, IL6, IL8, MPO, RANTES, MCP, BDNF, PAI NCAM, sICAM, sVCAM and NGF."

"Fifty-four children (45 males and nine females) aged 2-6, who were diagnosed with ASD [autism spectrum disorder], and a control group of 54 typically-developing children of similar ages were selected." Authors relied on quite an extensive battery of assessments looking at behaviour, alongside their use of the DSM-5 diagnostic criteria for autism (see here). Also accompanying physical examination "with a special emphasis on neurological and nutritional status", authors garnered blood samples from participants (overnight fasting) for their immune system and related functioning evaluations.

"The group of ASD children was further divided into two subgroups based on the presence or absence of neurodevelopmental regression during the first two years of life, which was assessed using a five-item questionnaire following the guidelines used by the Autism Diagnostic Interview-Revised (ADI-R) for the evaluation of this process." The ADI-R has been previously discussed on this blog in relation to regression in autism (see here). And just in case you might not be totally convinced that regression can be part of a pathway to autism, here's some more evidence for you (see here)...

Results: "there were 20 children included in the AMR [neurodevelopmental regression] subgroup and 32 in the ANMR [without neurodevelopmental regression] subgroup; two children could not be classified in these subgroups because they were adoptees, allocated by a national adoption agency." Bearing in mind that we cannot rule out any recruitment bias that might have leaned towards including those with regressive autism on the Gomez-Fernandez study, the figure of approaching 40% of their cohort showing such a regressive profile is notable. I'd also draw your attention to the finding that the behavioural profile for the regressive group (AMR) was also significantly different from the non-regressive group (ANMR) insofar as perhaps painting a picture of greater [group] autism severity...

Interestingly, the study did not show too many immune system and other compound differences between those diagnosed with autism and the asymptomatic (for autism) control group. So: "No differences were found between the two groups in terms of the cytokine and adhesion molecule levels studied, except for NGF [nerve growth factor], in which the group of ASD children was found to have twice the plasma levels compared to the control group." NGF is no stranger to autism research, and other studies have come to a similar conclusion [2].

When it came to examining results based on comparing the regressive (AMR) and non-regressive (ANMR) groupings, things got slightly more interesting but again no complicated pattern of difference was noted. So, for the ANMR (non regression) grouping: "lower plasma levels of the NCAM adhesion molecule were detected compared to the levels in the AMR subgroup and the control group. This ANMR group also exhibited higher NGF levels than the typically-developing children, which could indicate an alteration in neuronal development." Again, adhesion molecules have been mentioned in other autism research (see here).

"In conclusion, the results of this study show that there is not a typical profile for the expression of relevant plasma cytokines, adhesion molecules or growth factors in children with ASD compared with that in typically-developing children." OK, there are caveats to the phrasing used by the authors; not least that the participant numbers were quite small in the Gomez-Fernandez study and the idea that within the very heterogeneous autism spectrum, there may be smaller groupings (phenotypes) that perhaps show a tendency to greater immune system and related 'issues' (see here). But there are also some strengths attached to the Gomez-Fernandez study; not least the study "benefits from a careful selection of children of similar ages, as well as the complete diagnosis of ASD with multiple tests, clinical follow-up and associated complementary tests."

Questions still remain. Perhaps an important one is the question around why some children show a regressive pattern of behaviour as part of their path to a diagnosis of autism? Yes, issues such as infection do seem to be part-and-parcel of the clinical profile for some (see here and see here for examples) and perhaps more detailed focus is required in such areas. But much like a group showing the opposite of regressive autism - those who seemed to 'grow out' of autism - currently thought to include as many as one in ten (see here), a wider range of biological as well as psychometric measures are required to help pick out potentially important mechanisms pertinent to the idea that autism is not necessarily 'hard-wired' for all...

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[1] Gomez-Fernandez A. et al. Children With Autism Spectrum Disorder With Regression Exhibit a Different Profile in Plasma Cytokines and Adhesion Molecules Compared to Children Without Such Regression. Front. Pediatr. 2018. September 26.

[2] Dinçel N. et al. Serum nerve growth factor levels in autistic children in Turkish population: a preliminary study. Indian J Med Res. 2013 Dec;138(6):900-3.

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Borna disease virus antibodies and autism: baseline data setting the scene

The findings reported by Tomoyuki Honda and colleagues [1] setting out a baseline prevalence rate of antibodies against bornavirus in children diagnosed with an autism spectrum disorder (ASD) provides the blogging fodder today. Whilst the Honda findings might not exactly sound like 'exciting science' I would perhaps beg to differ...

Although no expert on Borna disease or Borna disease virus (BDV), I am an interested amateur. Borna disease was named after the town of Borna in Germany, where a fatal neurological (encephalitic) disease affected certain livestock including sheep, cattle and horses. The causative agent was found to be BDV. As well as being characterised by a "meningoencephalomyelitis" state, the symptoms of Borna disease also stretch to certain behaviours. This includes stereotypical behaviours (animals travelling in circular movements or standing in peculiar positions and poses) as well as ataxia affecting coordination and balance. Presentation in some animals has led to the name 'Staggering disease' being used.

Although predominantly seen as a disease affecting animals and livestock, there has been a gradual shift towards the idea that Borna disease virus can also infect humans too. Quite a lot of scientific resources have, for example, concluded that BDV might show an important connection to human psychiatric diagnoses/conditions such as schizophrenia [2]. This, on the basis of serological evidence for recent or continued viral exposure. Following on from a previous case report from Honda and colleagues [3] describing antibodies against BDV in a child with autism and her mother, the authors seem to have developed an interest in all-things BDV and autism. There has also been discussion about a BDV rodent model of autism from other research groups [4] including from the now [sadly] non-functioning research tag-team that was Hornig and Lipkin [5].

On this latest research occasion, Honda et al observed a few things. First: "The prevalence of antibodies against bornavirus-specific speckles, N, and P proteins were 22%, 48%, and 33%, respectively, in the ASD children." For discussions on 'Bornavirus-specific speckles, N, and P proteins' I'll refer you to some other work including Honda on the authorship title [6] on the viral nitty-gritty details. Second: "According to our criteria, the prevalence of antibodies against bornaviruses was 7.4% in the ASD children." Bearing in mind a dearth of investigations on the estimated prevalence of Borna virus more generally, particularly in children, and the various ways and means that immunological contact with the virus can be assayed by, that percentage did seem quite high. Other work [6] for example, has talked about a figure of 2% 'exposure' rate in non-clinical populations. I suppose the 'baseline data' from Honda is trying to make in-roads into this prevalence issue.

Obviously, there's a way to go yet on this topic before any sweeping generalisations are made. The impact of viral infection/illness in relation to [some] autism has quite a long peer-reviewed research history; be that the effect of congenital cytomegalovirus (CMV) (see here) or the work looking at rubella and autism (see here) for examples. The more contemporary research base examining various encephalitis conditions also presenting as autism or autistic-like disorder(s) (see here and see here) is also important. With regards to any specific possible connection between Borna disease virus and autism, future work needs to establish lots of things (infection route, exposure characteristics, etc.). We also need to know whether behavioural symptoms/traits are actually 'caused' by such viral exposure or perhaps more generally linked to immune responses as per the whole 'immune system does more than just fight infection' bit. If a link is shown beyond reasonable doubt, there could be some real scientific advances possibilities on the back of what is already emerging [7]. But at the moment, it's still 'a big if'...

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[1] Honda T. et al. Prevalence of antibodies against Borna disease virus proteins in Japanese children with autism spectrum disorder. Microbiol Immunol. 2018 May 22.

[2] Azami M. et al. The association between Borna Disease Virus and schizophrenia: A systematic review and meta-analysis. Asian J Psychiatr. 2018 Apr;34:67-73.

[3] Honda T. et al. Detection of Antibodies against Borna Disease Virus Proteins in an Autistic Child and Her Mother. Jpn J Infect Dis. 2017;70(5):599.

[4] Pletnikov MV. et al. Developmental brain injury associated with abnormal play behavior in neonatally Borna disease virus-infected Lewis rats: a model of autism. Behav Brain Res. 1999 Apr;100(1-2):43-50.

[5] Hornig M. et al. An infection-based model of neurodevelopmental damage. Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12102-7.

[6] Matsumoto Y. et al. Bornavirus Closely Associates and Segregates with Host Chromosomes to Ensure Persistent Intranuclear Infection. Cell Host & Microbe. 2012; 11: 492-503.

[7] Honda T. et al. Neuropathogenesis of persistent infection with Borna disease virus. Uirusu. 2015;65(1):145-54.

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Regression in autism: the rule rather than the exception?

"Declining trajectories of development, consistent with a regressive onset pattern, are common in children with ASD [autism spectrum disorder] and may be more the rule than the exception."

So said the findings reported by Sally Ozonoff and colleagues [1] who reported results based on a study of developmental / behavioural regression in autism, and specifically: "how rates of regression differed by measurement method."

Regression in relation to autism is a topic I've covered a few times on this blog (see here and see here for examples). I've followed the [peer-reviewed] story from where behavioural and/or developmental regression was initially thought to be a figment of the [parental] imagination, right up to these days where regression is pretty much accepted as being part and parcel of quite a few cases of autism. The road has not been a smooth one; but the question of whether autism is universally something inborn and hereditary for everyone is slowly starting to be answered: no, it is probably not. The reason(s) for regression still remain fertile grounds for discussion / debate / argument, but there are some important clues in the science literature (see here and see here for examples) with the caveats that autism is a very heterogeneous condition and onset patterns are likely to be influenced by all-manner of different variables. Think different phenotypes in the context of autism (see here) for example; and that's outside of the label previously known as Heller's syndrome.

Anyhow, Ozonoff et al report results for infants "with (n = 147) and without a family history of ASD (n = 83)" who were "seen prospectively for up to 7 visits in the first three years of life." Various different ways and means of assessing reports of symptom onset were collected, "that systematically varied the informant (examiner vs. parent), the decision type (categorical [regression absent or present] vs. dimensional [frequency of social behaviors]), and the timing of the assessment (retrospective vs. prospective)."

Depending on who said what and how they said it, patterns of regression in skills were noted in quite a large proportion of the Ozonoff cohort. So: "A majority of the sample was classified as having a regressive onset using either examiner (88%) or parent (69%) prospective dimensional ratings." The authors suggest that their observations highlight how quite a few more resources (and cautions) need to go into looking at symptom onset patterns in relation to autism.

For quite a few people, the findings reported by Ozonoff et al are 'catch-up' rather than something novel. I can think of quite a few instances where parents / guardians have had their important observations - very important observations - described as being 'talked down' when it came to reporting a regression in previously acquired skills in the context of autism. This should no longer be the case; particularly when also set in the context of the increasing pluralisation of the label of autism (see here) and perhaps even, the changing face of autism (see here) compared with yesteryear.

Then to the next important questions: how and why? I've already alluded to a role for infection in relation to the onset of regressive autism for some, but much more data is required on the specific details and mechanisms. There is also the issue of what *might* potentially be done to minimise factors linked to regression in autism too. Minus any sweeping generalisations, I'd also direct your attention to other mentions of regressive autism in the peer-reviewed science literature [2] and where, minus any hype, there could be some important clues for some. The important point once again, is that the diagnosis of autism should be the start of further investigations, not the finishing line.

To close, don't ask me how or why but one of my brood has started watching and enjoying an old staple part of the weekend TV quiz scene in 1980s Blighty... BFH by the way, is most classically referred to as your 'bus fare home'.

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[1] Ozonoff S. et al. Onset patterns in autism: Variation across informants, methods, and timing. Autism Res. 2018 Mar 10.

[2] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.

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"findings suggest a protective effect of CRP" on schizophrenia risk?

Science is often a puzzling endeavour. Sometimes, just when you think that you've got something nailed down, scientific results appear that 'trash' long held, cherished beliefs. So it was with the publication of the results by Fernando Pires Hartwig and colleagues [1] who presented findings looking at "the effect of inflammatory markers on schizophrenia risk" based on the use of "a mendelian randomization (MR) design."

MR, by the way, is a interesting technique based on the principle that "genetic variants that either alter the level of, or mirror the biological effects of, a modifiable environmental exposure that itself alters disease risk should be related to disease risk to the extent predicted by their influence on exposure to the environmental risk factor." It's a technique that has already been applied to inflammatory markers in the context of schizophrenia on more than one occasion (see here and see here). Those inflammatory markers studied have included ones which were covered by the Hartwig paper. Specifically: "Genetically elevated circulating levels of C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra), and soluble interleukin-6 receptor (sIL-6R)." I should also point out that Hartwig and colleagues have some research form in the area of applying MR to various aspects of medical science (see here).

As per an accompanying editorial on the Hartwig paper [2], the long-and-short of it was that researchers "used 2-sample MR to test for a potentially causal relationship between inflammation and schizophrenia and to improve inference for the association between genes, inflammatory biomarkers, and risk of developing schizophrenia." I can't claim any specific expertise in the use of MR (see here for a good overview [3]) but it appears that data on single-nucleotide polymorphisms (SNPs) in relation to those inflammatory markers was used to test whether said markers might be linked 'causally' to risk of schizophrenia. Their results were interesting: "we did not find strong evidence that lifelong exposure to increased action of these proinflammatory cytokines increases schizophrenia risk, as previously hypothesized" and indeed that: "blockade of IL-6 effects and low CRP levels might instead increase schizophrenia risk." This is contrary to quite a lot of other research in this area (see here for example).

There are a few words of caution to attach to the Hartwig results that need mentioning not least the primary tenet on which analyses are based: genetic variants (SNPs) affecting something like CRP are of primary importance to schizophrenia. I don't for example, see anything in the data looking at gene function/expression being affected as a result of non-structural changes to the genome via something like epigenetic 'alterations' for example (and there is such a thing as epigenetic Mendelian randomization y'know). I say this on the basis that other genes involved potentially involved in processes linked to DNA methylation have also been *associated* with cases of schizophrenia (see here). The authors also caution that their analyses are based on "lifelong exposure to elevated cytokine and CRP levels" and that exposure during 'critical windows' might be the important issue when it comes to any change in schizophrenia risk. Similarly they note that "it is possible that IL-6 and CRP effects on schizophrenia risk are related to a maternal effect (eg, maternal susceptibility to infections during pregnancy), so that our findings are explained by the correlation between maternal and offspring genotypes." This final point is based on the idea that maternal infection during pregnancy (or the biological consequences of) seems to be quite a big risk factor for at least some presentations of schizophrenia (see here) as well as [cautiously] other labels (see here). Here, the importance of a reprogrammed immune system during pregnancy might also come into play alongside any maternal 'susceptibility'.

Personally I'm not yet ready to totally trash the idea that the immune system, and specifically elevations in inflammatory markers such as CRP and other pentraxins, might not be important to some schizophrenia risk in a more detrimental way. I appreciate that one has to be careful when talking about immune system markers and their inflammatory direction (see here for some chatter on IL-6 and its pro- and anti-inflammatory natures) but the existing data is too evident to just discard on the basis of one new study, despite it's scientific prowess. I don't however doubt that there may be several confounding variables linked to increases in CRP in schizophrenia; not least the impact of something like increased body mass index (BMI) that seems to follow some cases of schizophrenia [4]. These variables need to be further explored, particularly in the context of what side-effects pharmacological management of schizophrenia might have (see here). And I also hat-tip the paper by Manu and colleagues [5] applying the Bradford Hill's guidelines on 'causation' to this area and concluding that (upto 2014) "there is insufficient evidence that the replicated, strong association between schizophrenia and elevated inflammatory markers has etiopathological relevance"...

For now however, the Hartwig findings reiterate that science is an ever-changing, ever-evolving process...

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[1] Hartwig FP. et al. Inflammatory Biomarkers and Risk of Schizophrenia: A 2-Sample Mendelian Randomization Study. JAMA Psychiatry. 2017. Nov 1.

[2] Byrne E. et al. Inference in Psychiatry via 2-Sample Mendelian Randomization—From Association to Causal Pathway? JAMA Psychiatry. 2017. Nov 1.

[3] Sheehan N. et al. Mendelian Randomisation and Causal Inference in Observational Epidemiology. PLoS Med. 2008; 5(8): e177.

[4] Fernandes BS. et al. C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications. Mol Psychiatry. 2016 Apr;21(4):554-64.

[5] Manu P. et al. Markers of inflammation in schizophrenia: association vs. causation. World Psychiatry. 2014 Jun; 13(2): 189–192.

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On preventing the deleterious effects of CMV: implications for some autism?

"Anxiety drug may prevent common virus that causes birth defects" went one of the headlines covering the study results published by Sara Ornaghi and colleagues [1].

Continuing a research theme from this group (see here) on how use of some mood stabilising medicines at critical periods might have some important impact on the deleterious effects of cytomegalovirus (CMV) infection, there is quiet optimism that this new research could have big implications for a range of different labels including some autism (see here).

So: "Valnoctamide (VCD), a neuroactive mood stabilizer with no known teratogenic activity, was recently demonstrated to have anti-CMV potential" was the starting premise for the Ornaghi study. Using mouse models - that's MOUSE models - of CMV infection and whether the anti-CMV potential of VCD could be "translated into an efficacious therapeutic effect to improve CMV-induced adverse neurological outcomes", researchers first looked at survival rates when injected 'low-dose' VCD was used. They reported that compared with those receiving a control substance (not VCD), the mice in receipt of VCD were more likely to survive. As per the media chatter about this study: "They lived longer, their body weight was greater – everything about them looked better" on the basis that congenital CMV infection can, in some cases, prove fatal.

Researchers also assessed whether various 'adverse neurological outcomes' associated with congenital CMV infection might be potentially offset by the use of VCD. They observed that: "VCD during the first 3 weeks of life restored timely acquisition of neurological milestones in neonatal male and female mice and rescued long-term motor and behavioral outcomes in juvenile male mice."

Then to the possible mechanism of effect, and based on the use of "CMV-infected human fetal astrocytes" they observed that "VCD reduced both viral infectivity and replication by blocking viral particle attachment to the cell." In other words, VCD, a medicine typically indicated as a sedative, seemed to possess some quite potent activity in relation to how CMV takes hold in important cells in the brain.

I've already mentioned about how at least some cases of autism might benefit from this work. I say this on the basis that there is a robust evidence base suggesting that congenital CMV infection could very well result in autism (see here). There is a need for quite a bit more investigation in this area in terms of translating mouse findings into human findings (see here) but the promises of this area of work are not to be under-estimated...

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[1] Ornaghi S. et al. Valnoctamide inhibits cytomegalovirus infection in developing brain and attenuates neurobehavioral dysfunctions and brain abnormalities. J Neurosci. 2017. June 19.

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MoBa does prenatal fever and autism risk

'MoBa does..' is fast becoming a common title on this blog (see here and see here). Referring to the Norwegian Mother and Child Cohort Study (MoBa), this initiative based on the examination of 100,000 pregnancies in Norway is yielding some useful observations for all-manner of different condition/labels.

When MoBa is applied to autism, a few names seem to quite consistently crop up - Mady Hornig and Ian 'virus hunter' Lipkin - as is the same for today's blogging material from Hornig and colleagues [1] (open-access). Their findings supporting "a role for gestational maternal infection and innate immune responses to infection in the pathogenesis of at least some cases of ASD [autism spectrum disorder]" make for interesting reading.

Authors set about determining whether maternal fever episodes during pregnancy might show some connection with risk of offspring autism. To do this they relied on questionnaire data from pregnant mums completed at specific times of their pregnancy pertinent to "fever, along with their timing, as well as the names of medications used for fever, and the timing of that medication use" as a function of a subsequent diagnosis of offspring autism or not. That 'medication use' side of things adds to a further stream of research suggesting that some medicines used as fever-reducers/eliminators (antipyretics) during pregnancy might also have some bearing on offspring behavioural/developmental outcomes (see here and see here for examples). Alongside such information, authors also took into account various potentially confounding variables that might have also affected offspring autism risk.

Results: based on data covering nearly 100,000 children, with nearly 600 subsequently being diagnosed with an ASD, researchers concluded that: "Prenatal fever was associated with increased ASD risk among offspring." Exposure to reported pregnancy fever at any time during pregnancy seemed to be more common in those children who were eventually diagnosed with ASD but notably during the second trimester of pregnancy. They also noted a possible dose-response effect from pregnancy fever exposure: "Risks increased markedly and dose dependently with fever frequency, with particularly strong effects after 12 weeks’ gestation." As to the use of antipyretics and any additional risk or mitigation of risk, I'm inclined to suggest that on this research occasion, there wasn't very much to see either way.

Added to the idea that infection exposure during the nine months that makes us might also affect the risk of subsequent offspring autism (see here), this latest data sit well with the idea that infection and/or response to infection during pregnancy might very well be able to influence offspring outcomes. Pregnancy is a time of reprogrammed maternal immune function (to stop mum's immune system attacking the developing foetus) so already science has a basis for looking at something like enhanced maternal immune activation (MIA) during pregnancy as being potentially pertinent to offspring outcomes particularly autism.

Of course one has to note that the strengths of the MoBa study - "a large, prospective, population-based birth cohort with exposure data collected in 4-week intervals and linkage to a patient registry for case ascertainment" - need to be balanced against the weakness, i.e. maternal self-report. The authors have however promised more detailed study in this area: "we are testing the possibility that risk is associated with specific infectious agents through sequence-based and serological assays of samples collected mid-pregnancy and at birth from cases and controls" so there may be more to add in future times [2] in addition to some already published inklings from authors (see here).

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[1] Hornig M. et al. Prenatal fever and autism risk. Molecular Psychiatry. 2017. June 13.

[2] Mahic M. et al. Epidemiological and Serological Investigation into the Role of Gestational Maternal Influenza Virus Infection and Autism Spectrum Disorders. mSphere. 2017. June 21.

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The PANDAS hypothesis is supported

PANDAS - pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection - is, as the name suggests, a condition / group of conditions? characterised by bacterial infection, or response to bacteria infection, leading to behavioural / psychiatric presentation(s).

Although fairly widely accepted (at least in the United States) there are some that still question this diagnosis and the idea that infection or response to infection can affect functioning in many more ways than just the somatic. There are, I might add, other examples of this in the clinical literature (see here).

The paper by Sonja Orlovska and colleagues [1] should put a few minds at rest with their 'large-scale' findings that "individuals with a streptococcal throat infection had elevated risks of mental disorders, particularly OCD [obsessive compulsive disorder] and tic disorders"; both key facets of a diagnosis of PANDAS. The additional finding that "nonstreptococcal throat infection was also associated with increased risks, although less than streptococcal infections for OCD and any mental disorder" adds something further to this area.

So, examining one of those oh-so important Scandinavian population registries - this time in Denmark - individuals with "registration of a streptococcal test" were followed up for "a diagnosis of any mental disorder, OCD, or tic disorders." The numbers of participants eventually included were in the hundreds of thousands (+600K) about half of whom at evidence of at least one positive strep test. The authors found that: "Individuals with a positive streptococcal test result had an increased risk of any mental disorder..., particularly of OCD... and tic disorders..., compared with individuals without a streptococcal test."

These are important results. Reiterating the title of this post, the concept of PANDAS is supported by the Orlovska findings. Noting the name Michael Benros on the authorship group of this current paper - someone who has previously explored the possibility that immune function/dysfunction can impact on psychiatry - I daresay that the previous ideas on how infection can affect cognitive abilities for example, (see here) are further extended by this work. Not least that possible identification of bacterial infections as one *cause* of issues such as OCD or tics gets a boost; as does the idea that treating said infections might lead to some rather interesting outcomes. There could also be tie-ups with specific diagnostic labels too (see here)...

To close, there is an election here in Blighty today, so here is party political broadcast for the largest party in the country: The ‘Can’t Be Arsed’ Party. Please exercise your democratic right.

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[1] Orlovska S. et al. Association of Streptococcal Throat Infection With Mental Disorders. JAMA Psychiatry. 2017. May 24.

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Orlovska, S., Vestergaard, C., Bech, B., Nordentoft, M., Vestergaard, M., & Benros, M. (2017). Association of Streptococcal Throat Infection With Mental Disorders JAMA Psychiatry DOI: 10.1001/jamapsychiatry.2017.0995

Congenital cytomegalovirus (CMV) infection and autism continued

I wanted to briefly talk about the paper by Francesca Garofoli and colleagues [1] on congenital cytomegalovirus (CMV) infection and autism not because it contains any novel data (see here), but because it reminds us that the potential 'pathways' to a diagnosis of autism are multiple and not necessarily 'pre-programmed' as per the 'it's all genetic' arguments that frequently figure in various domains.

Congenital CMV infection refers to the transmission of CMV - "a common virus that belongs to the herpes family of viruses" - from mother to foetus during pregnancy. The details are still under investigation as to how and why CMV affects a foetus (bearing in mind this is quite a common virus) but autism as a consequence of [some] congenital CMV infection has growing evidence-based support [2].

Garofoli et al included 70 'proven' cases of CMV "congenitally-infected infants" in their study; specifically looking "to correlate congenital cytomegalovirus (CMV) infection with autism spectrum disorder (ASD) and to define its prevalence." They determined that 2 of their 70 strong cohort met criteria for an ASD at the age of 3 years. Two of 70 translated as 2.8% of their cohort and contrasts with [estimated] autism prevalence "in general Italian population (0.66-1.36%)." The figure of 2.8% is also not a million miles away from other estimates of autism suggested via congenital CMV infection [3].

Although 2.8% of the cohort (2/70) might not sound like a lot I'm inclined to suggest that it does prompt quite a lot more additional investigation. Not least is the question: 'why was autism/ASD not diagnosed in the other 68 children?' and onward whether other factors (genetics(!), biology, infection timing, immunologic response, etc) might come into play [4] in relation to the congenital CMV infection - autism association? Taking also into account the estimated prevalence of ASD in Italy, these figures (estimates) do seem to be a little lower than that described in other geographical locations (see here and see here for examples). Indeed, bearing in mind the research evidence already looking at estimated ASD prevalence in Italy [5] it's not unfair to say that 'under-estimation' might be a familiar theme...

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[1] Garofoli F. et al. An Italian Prospective Experience on the Association Between Congenital Cytomegalovirus Infection and Autistic Spectrum Disorder. J Autism Dev Disord. 2017 Mar 3.

[2] Ornoy A. et al. Prenatal factors associated with autism spectrum disorder (ASD). Reprod Toxicol. 2015 Aug 15;56:155-69.

[3] Engman ML. et al. Prenatal acquired cytomegalovirus infection should be considered in children with autism. Acta Paediatr. 2015 Aug;104(8):792-5.

[4] Lombardo MV. et al. Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder. Mol. Psychiatr. 2017. March 21.

[5] Ferrante M. et al. Prevalence and age at diagnosis of Autism Spectrum Disorder in south Italy, 2004–2014. Eur J Public Health. 2015; 25 (suppl_3).

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Garofoli F, Lombardi G, Orcesi S, Pisoni C, Mazzucchelli I, Angelini M, Balottin U, & Stronati M (2017). An Italian Prospective Experience on the Association Between Congenital Cytomegalovirus Infection and Autistic Spectrum Disorder. Journal of autism and developmental disorders PMID: 28258350

Premature mortality in intellectual disability in Australia (and England)

"Adults with ID [intellectual disability] experience premature mortality and over-representation of potentially avoidable deaths."

The paper by Julian Trollor and colleagues [1] (open-access available here) provides some sombre reading today, as once again the topic of early mortality is raised on this blog. Looking at several measures - the "Age Standardised Mortality Rate (ASMR), Comparative Mortality Figure (CMF), years of productive life lost (YPLL) and proportion of deaths with potentially avoidable causes" - authors paint a depressing picture of a 'mortality gap' between those diagnosed with a learning (intellectual) disability and the wider, general population.

I don't want to trawl through the Trollor paper in great detail given that it is open-access for all to see, but a few points are worthwhile raising. So, based on data from some 20,000 adults (aged 20 or over) registered with an intellectual disability (ID) in New South Wales (NSW) in Oz, there were 732 deaths reported (4%) "equivalent to a crude death rate of 5.9 deaths per 1000 people per year." The median age at death was 54 years and about 60% of deaths were in men. A control cohort consisting of adults from NSW was used as a comparator where "a crude death rate of 9.1 deaths per 1000 person years" was calculated. The median age at death however, for the control group, was 81 years. When looking at death rates between the groups according to age banding (20-44 years, 45-64 years, 65+ years) authors noted that: "People with ID in the 20–44 years age category had four times the death rate of the comparison group."

Looking at the causes of death between the ID and control groups, authors noted some potentially important trends. So: "Cause of death in [the] ID cohort was dominated by respiratory, circulatory, neoplasm and nervous system." This bearing in mind that cause of death was not available for everyone diagnosed with an ID (only 87%). Such causes were not wildly different from those noted in the control population but when it came to 'potentially avoidable deaths' the ID group were placed at some quite notable disadvantage, with 31% of deaths falling into this category (revised up to 38% depending on the 'death classification' used) compared with 17% in the general population. Readers should also note that: "Potentially avoidable deaths are deaths from conditions that are preventable through individualised care and/or treatable through existing primary or hospital care for persons aged under 75 years and which are avoidable in the context of the present health system."

As you can see, there are some quite shocking details noted in the Trollor paper. The emerging picture that some of the most vulnerable people in society (certainly in Australia) are (a) at risk of dying earlier than the general population and (b) at greater risk of suffering a 'potentially avoidable death' is one that no-one should be proud of. And just in case you though the results might not be generalisable to other parts of the world... you're wrong [2] (open-access here) as data from England reveals that: "Mortality rates for people with ID were significantly higher than for those without. Their all-cause standardised mortality ratio was 3.18. Their life expectancy at birth was 19.7 years lower than for people without ID." Truly shocking.

What can society do about such a state of affairs? Well, potentially lots (and it doesn't take monumental shifts to achieve better outcomes either). "Particularly stark is the large proportion of
potentially avoidable deaths due to infections. Such deaths suggest that people with ID experience delays, difficulties or differences in accessing specific and effective interventions for infections. Medical assistance must be sought assertively in individuals who manifest symptoms, but this is made difficult as patients with ID may not readily report symptoms, and some providing direct care
lack skills in early identification of relevant physical signs. Primary care providers should consider careful assessment, proactive treatment and close monitoring of progress if there are infections in this population." Sorry for the large chunk of replication text there but several important themes are laid out by Trollor, some of which overlap with other work in relation to autism for example (see here). Not least is the need for 'proactivity' on the part of clinicians and other professionals, potentially dealing with a group who may not be able to readily communicate their physical state for example and so shifting the responsibility on medical care being inspective and proactive. This means regular health screening and, at the basic level, understanding that a diagnosis of ID (or autism or schizophrenia [3]) does not seemingly provide any protection against the development of life-threatening illness or other conditions becoming evident.

I close with an article discussing another part of the reason why people with ID are being placed at an unacceptably high risk of early death: when those who are supposed to provide care, fail.

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[1] Trollor J. et al. Cause of death and potentially avoidable deaths in Australian adults with intellectual disability using retrospective linked data. BMJ Open. 2017. Feb 7.

[2] Glover G. et al. Mortality in people with intellectual disabilities in England. J Intellect Disabil Res. 2017 Jan;61(1):62-74.

[3] Hjorthøj C. et al. Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. Lancet Psychiatry. 2017 Feb 22. pii: S2215-0366(17)30078-0.

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Trollor J, Srasuebkul P, Xu H, & Howlett S (2017). Cause of death and potentially avoidable deaths in Australian adults with intellectual disability using retrospective linked data. BMJ open, 7 (2) PMID: 28179413