“Schizophrenia” does not exist. Discuss.

With a title like "“Schizophrenia” does not exist", the opinion piece by Jim van Os [1] (open-access) was bound to attract some attention and comment (indeed, several). As per other examples where diagnostic labels have been questioned (see here) the response to such viewpoints typically falls into one of two categories: (a) the person or persons making the suggestion just want to make a name for themselves (and how better than to stir up a bit of controversy) or (b) the person or persons making the claim have a valid point.

In the case of the viewpoint posited by van Os, and without trying to offend too many people, I'm tending towards the latter option because I think he has a point. Read onwards and I'll try and explain why.

The crux of the suggestion is that in these days of increasing pluralisation of diagnostic labels (see here for another example) and realisation that individual behavioural or psychiatric labels rarely occur unaccompanied (see here) the idea that there is a discrete condition called schizophrenia is fast losing 'evidence-based' backing. His descriptions of how DSM-5 classifies schizophrenia and the various diagnostic classifications that patients may 'move in and out of', harks back to some of the reasons why the RDoC (Research Domain Criteria) initiative was first suggested and continues to gather momentum.

As per other entries on this blog acknowledging the idea of the more plural 'schizophrenias' (see here) and even a 'bipolar - schizoaffective - schizophrenia spectrum' (see here), van Os suggests a more wide-ranging term to supplant schizophrenia: psychosis spectrum syndrome. This label, it is suggested, takes account of the "extreme heterogeneity, both between and within people, in psychopathology, treatment response, and outcome." van Os also suggests that the creation of such a spectrum is a way to "forget about “devastating” schizophrenia as the only category that matters and start doing justice to the broad and heterogeneous psychosis spectrum syndrome that really exists."

I don't believe we're going to see a dramatic migration towards psychosis spectrum syndrome as a replacement for the singular schizophrenia term very quickly. Much like what goes on behind other conditions/labels, change is often a slow process in medicine and convincing people who might have their own reasons for sticking with the label schizophrenia (e.g. identity, management options, etc.) will prove difficult. That we already have a similarly worded term, [unspecified] schizophrenia spectrum disorder in the current manifestation of DSM is an additional point of complication to make.

Still, I can see the benefits of taking a wider approach to the categorisation of symptoms in this area of psychiatry. Indeed, if one considers the data on schizophrenia spectrum disorder appearing alongside 22q11.2 deletion syndrome for example (see here) you get a flavour for how many routes there may be taking someone towards clinically significant symptoms. That 'treatment response' may also guide the appreciation of a wider spectrum definition encompassing schizophrenia (see here for example), one could foresee a time when a specific place on the psychosis spectrum is given to patients and the trial-and-error of symptom management potentially becomes a thing of the past with the right patient work-up. That is also assuming some accuracy in [some of] the management options put forward [2]...

That all being said, in agreement with this article by Allen Frances on a related topic, I think we also have to be a little careful not to be too broad in our brush strokes on spectrum generalisations.

Music: War and Low Rider.

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[1] Os van J. "Schizophrenia" does not exist. BMJ. 2016 Feb 2;352:i375.

[2] Jauhar S. et al. Cognitive-behavioural therapy for the symptoms of schizophrenia: systematic review and meta-analysis with examination of potential bias. Br J Psychiatry. 2014 Jan;204(1):20-9.

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Os, J. (2016). “Schizophrenia” does not exist BMJ DOI: 10.1136/bmj.i375

C-section and the microbial transplant

I'm pretty sure that the paper by Maria Dominguez-Bello and colleagues [1] speaks for itself when describing the results of "a pilot study in which infants delivered by C-section [Caesarean section] were exposed to maternal vaginal fluids at birth." If you need a graphic, some coverage of the research in the New York Times helpfully provides a visual aid (see here).

The long-and-short of it is that following some concerns that infants delivered via C-section might be missing out on some valuable exposure to their mother's microbial passengers [2] as a function of their by-passing the birth canal and beyond, the use of a "vaginal microbial transfer" might be an option. Detailing results based on a small number of births - 11 born by C-section (planned or elective) and 7 via the more traditional route - researchers report what happened when 4 of the C-section infants were swabbed with previously collected gauze containing mum's bacterial passengers. Swabbing by the way, was done on various parts of the infant's body.

The authors concluded that: "Similarly to vaginally delivered babies, the gut, oral and skin bacterial communities of these newborns [swabbed C-section infants] during the first 30 d[ays] of life was enriched in vaginal bacteria—which were underrepresented in unexposed C-section–delivered infants." That being said, the results appeared to show that whilst swabbing was good at delivering a microbial transplant for C-section infants, it was no substitute for the real thing (a vaginal birth) bacterially-speaking. I might also add that important variables such as breastfeeding (or not) can also influence the constitution of our gut bacteria (see here).

There is some media chatter about this study and onwards what the longer-term effects might be in terms of health and well-being in the context of how our bacterial masters may show various health/disease links [3]. I'd be interested to see how this cohort and other larger ones fare as a result. I do however, have a word of caution to add to proceedings alongside others it seems (see here).

Accepting that a vaginal microbial transfer is not the same as the more 'popular' talking point that is a faecal microbiota transplant, and that the bacteria that colonise the gut may not necessarily be the same as that colonising other parts of the body, I'm minded to direct readers to a post not-so-long-ago covering weight gain following poo(p) transplant (see here). I don't think the specific 'obesogenic' bacteria were isolated in the case report by by Neha Alang and Colleen Kelly [3] or indeed, whether other elements such as the gut virome may have exerted some effect on patient weight gain following "receiving stool from a healthy but overweight donor." But one question might be to ask whether a similar 'process' could potentially be pertinent to the swabbing of C-section infants?

OK, I appreciate that there has been some research discussion about how C-section babies *might* be slightly more prone to obesity in later life (see here). But if one assumes that outside of the typical risk factors linked to obesity, there may be a microbial link too, is it not inconceivable that an early-days microbial transplant from a mum who is herself overweight or obese at the time of birth might potentially 'transmit' the basis of such weight problems to offspring too? Indeed, with all the chatter about microbes and mood these days (see here for example) one could potentially stretch the 'bacterial association' even further...

I'll leave you with those thoughts and some (new) music from the Leppard (hopefully really not a "nuclear waste of time").

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[1] Dominguez-Bello MG. et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nature Medicine. 2016. Feb 2.

[2] Biasucci G. et al. Cesarean delivery may affect the early biodiversity of intestinal bacteria. J Nutr. 2008 Sep;138(9):1796S-1800S.

[3] Alang N. & Kelly CR. Weight Gain After Fecal Microbiota Transplantation. Open Forum Infect Dis. 2015; 2: 1.

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Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, Cox LM, Amir A, Gonzalez A, Bokulich NA, Song SJ, Hoashi M, Rivera-Vinas JI, Mendez K, Knight R, & Clemente JC (2016). Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nature medicine PMID: 26828196

Wandering and autism continued

I probably don't need to provide most readers with too much background information on the topic of wandering/elopement and autism given the multitude of news reports that have been, and continue to be, generated on this worrying behaviour. The article titled: 'The Life and Death of Avonte Oquendo' pretty much sums up the very saddest outcome of wandering, and how in some respects, autism can potentially be a life-limiting condition.

I do however think it is important to discuss the findings reported by Bridget Kiely and colleagues [1] (open-access) and how science continues to contribute to questions such as "the prevalence and correlates of wandering in a nationally representative sample of school-age children in the United States with developmental conditions." I might add that I've seen very little in the peer-reviewed domain about wandering behaviour and autism here in Blighty (UK) or indeed, in other countries outside of the USA. Another important research inequality methinks...

The Kiely paper, which has itself received some press attention (see here), starts with the idea that as a result of the increasing numbers of people being diagnosed with an autism spectrum disorder (ASD) (see here) the likelihood that issues such as wandering or elopement will happen is going to increase. You can um-and-ah about the reasons for the increase in cases (bearing in mind findings such as the one by Russell and colleagues [2] talked about recently) but by mass action, increasing numbers of people with autism = increasing numbers of wandering/elopement episodes.

"Data were obtained from the 2011 Survey of Pathways to Diagnosis and Services (“Pathways”), a cross sectional, nationally representative survey of the parents and guardians of children with special health care needs (CSHCN) ages 6–17 with a current or past parent-reported diagnosis of ASD, ID [intellectual disability], and/or DD [developmental delay]." In all some 4000 parents and guardians of children with ASD, ID and/or DD were surveyed from a total population of some 7500. A proportion of those 4000 parents/guardians provided some data on their children incorporating elements from "the Children’s Social Behavior Questionnaire (CSBQ)." The issue of wandering/elopement "was assessed based on four questions about the child’s history of wandering from various locations within the previous twelve months" and data was divided according to diagnosis.

Results: "Among all children with a current developmental condition (ASD, ID, and/or DD), the overall rate of elopement within the previous 12 months was 26.7%." Readers should bear in mind the emphasis on elopement within 'the previous 12 months'. Further: "Compared to the ID/DD-only group, the odds of elopement were higher for the ASD-only group... and the ASD+ID/DD-group." This is based on participant groupings including: "492 had ASD-only; 924 had ASD plus ID and/or DD; and 2,085 had ID and/or DD without ASD."

The authors also observed that "children who were between the ages of 6 and 11 were more likely to have eloped than those that were 12–17 at the time of the Pathways interview" but there was little to see when it came to factors such as "household income, sex, or race/ethnicity." Elopement behaviour, it appears, crosses socio-economic differences. They did however report some associations between wandering behaviour and some of the clinical data reported using the CSBQ among other things. So; "wanderers were more likely than non-wanderers to show sudden mood changes...; to over-react to everything and everyone...; to get angry quickly...; not to realize when there is danger...; to have difficulty distinguishing between strangers and familiar people...; to be disobedient...; to panic in new situations or if change occurs...; to remain clammed up in new situations or if change occurs...; and to get lost easily." At this point I'm also going to introduce a new measure that also covers the topic of 'disappearing behaviour' [3] that might figure in future work in this area.

There is little more for me to say on this topic outside of the presented results. As I've indicated in previous posts (see here), in amongst all the 'differences' that divide people when it comes to the label of autism, moves to reduce the potentially devastating consequences of elopement/wandering when it occurs alongside autism seemingly unites everyone. Statistics that point to accidental death potentially including wandering as being contributory to early mortality in autism (see here) provide a stark message that investment in technology in particular, is an important area to minimise the potential adverse effects of wandering. Teaching skills such as those related to pedestrian safety [4] could also be a good idea. I might liekwise add that the involvement of water in several cases of death following wandering in relation to autism should also persuade policy-makers to provide something like free swimming classes to those on the autism spectrum?

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[1] Kiely B. et al. Prevalence and Correlates of Elopement in a Nationally Representative Sample of Children with Developmental Disabilities in the United States. PLoS ONE. 2016; 11(2): e0148337.

[2] Russell G. et al. Changes in diagnosis rates and behavioural traits of autism spectrum disorder over time. British Journal of Psychiatry Open. 2015; 1: 110-115.

[3] Tyrer P. et al. The Problem Behaviour Checklist: short scale to assess challenging behaviours. British Journal of Psychiatry Open. 2016; 2: 45-49.

[4] Harriage B. et al. An Evaluation of a Parent Implemented In Situ Pedestrian Safety Skills Intervention for Individuals with Autism. J Autism Dev Disord. 2016 Feb 10.

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Kiely, B., Migdal, T., Vettam, S., & Adesman, A. (2016). Prevalence and Correlates of Elopement in a Nationally Representative Sample of Children with Developmental Disabilities in the United States PLOS ONE, 11 (2) DOI: 10.1371/journal.pone.0148337

Does rubella (german measles) cause autism?

Rubella rash @ NHS Choices

"Rubella might still cause autism, even in vaccinated populations."

That was one of the points raised in the '2015 reappraisal' document published by Jill Hutton [1] (open-access) covering a topic that has quite a long history with autism in mind (see here).

Rubella, also called german measles, a previously common childhood disease characterised by a rash, high temperature and cold-like symptoms, has in many parts of the world almost been entirely eradicated as a consequence of vaccination and other health measures. Here in Blighty (UK), our public health agency has even recently announced that it will soon halt screening for rubella in pregnant women as a result of the decline of the disease (see here). That screening was carried out following some potentially pretty serious complications to the unborn child known to be associated with maternal contraction of the disease. Sounds familiar doesn't it?

Anyhow, Hutton takes readers through the main points of the research linking rubella or rather congenital rubella syndrome (CRS) and autism down the years. Stella Chess, the first person to talk about rubella (CRS) and autism [2] (at least in the peer-reviewed domain) gets a pretty big shout-out throughout the article, alongside the overlap between CRS and autism from various different perspectives (behavioural, physiological, genetic). Drawing also on literature around the topic of vaccination and autism (see here), discussions also turn to the quite important group of children with autism who do not seem to display the appropriate immunological response to rubella infection/vaccination as per that discussed by Libbey and colleagues [3] for example. The idea being that antibody titers normally showing whether a vaccination has 'worked' in terms of conferring protection against a disease, were lower or none existent in some children on the autism spectrum and potentially indicates some type of immune dysfunction. Similar things have been talked about in other research papers (see here).

Hutton also discusses an important feature of the literature intersecting with migration and autism (see here) and how some: "Foreign born mothers (from the developing world, without vaccinations) are less likely to be immune or again more likely to be susceptible to rubella" and what potential effect this might have on cases of CRS and autism. During the times I've discussed the topic of autism and migration, I've tended to labour the point about how different foods, different exposures and in particular, different levels of vitamin D *might* be part and parcel of the effect noted in cases (see here). The Hutton discussions have been food for thought for me particularly in light of other findings [4].

"The thought that vaccination has wiped out rubella is falsely reassuring and has managed to wipe out most rubella research, but unfortunately rubella lingers." I was also interested in this statement and how, on the back of those previous findings about how a certain kind of immune system might react, or rather not react, to vaccination (assuming complete vaccine coverage), there may be quite a bit more scope for further research with at least some autism in mind. I know this has the potential to take us back into some quite heated discussions but if we are learning anything about the plural autisms (see here) it is that exposure to viral infection in particular, seems to have some important links to at least some types of autism (see here and see here).

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[1] Hutton J. Does Rubella Cause Autism: A 2015 Reappraisal? Front. Hum. Neurosci. 2016. 1 Feb.

[2] Chess S. Autism in children with congenital rubella. J Autism Child Schizophr. 1971 Jan-Mar;1(1):33-47.

[3] Libbey JE. et al. Are there altered antibody responses to measles, mumps, or rubella viruses in autism? J Neurovirol. 2007 Jun;13(3):252-9.

[4] Bahta L. & Ashkir A. Addressing MMR Vaccine Resistance in Minnesota's Somali Community. Minn Med. 2015 Oct;98(10):33-6.

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Hutton, J. (2016). Does Rubella Cause Autism: A 2015 Reappraisal? Frontiers in Human Neuroscience, 10 DOI: 10.3389/fnhum.2016.00025

Parents lived experience of an offspring autism diagnosis

I recently happened upon the paper by Emilia Carlsson and colleagues [1] talking about parental experiences of the diagnostic processes for their children (with autism in mind) and thought it worthy to mention on this blog.

Detailing the results of a qualitative study where "parents were interviewed about their experiences of the neuropsychiatric diagnostic process, i.e. the time before the screening, the time during the neuropsychiatric multidisciplinary evaluation and the time after diagnosis" some potentially valuable snippets of information emerged.

Three themes are reported on based on parental interviews: "seeking knowledge, trusting and challenging experts, and empowered but alone." The authors suggest that some modifications could be made to the current system (based in Sweden where the research took place) including: "developing a checklist outlining relevant contacts and agencies, establishing a coordinator responsible for each child, dividing the summary meeting at the clinic into two parts, making more than one visit to the preschool, and providing a parental training programme."

Outside of the continuing focus on how long the whole assessment/diagnosis procedure related to autism can sometimes take (see here) and the idea that parents/caregivers generally know their children better than strangers (see here), I'd like to think the Carlsson recommendations might stretch further than just applicability to Sweden. Indeed, the findings reported by Laura Crane and colleagues [2] on the UK parent experience of offspring autism diagnosis paint an unequally 'unsatisfactory' picture for many families.

Personally I think there are other ways that the diagnostic procedure can be improved allowing for the current state of research on autism assessment/diagnosis and particularly the notion that an in-depth analysis of a child (or adult) trumps pop psychology quizzes (see here). First and foremost is money and resources. We need lots more of both and a move away from the idea that 'more can be done with less'. Autism assessment and diagnosis is currently time- and resource-consuming because it has to be. Not least because autism rarely appears in some sort of diagnostic vacuum (see here) and each person tends to present differently. If you want an accurate picture of someone's strengths and difficulties, you need to put time into assessing them. Second, I think there is a compelling case for the setting up of regional centres of excellence focused specifically on the assessment and diagnosis of autism spectrum disorders (ASDs). I appreciate that here in Blighty there are centres already in place but these need to be rolled out further across the country and where concerns are raised about a child (or adult) appropriate referral to such centres is made in a timely fashion. The idea that in parts of the UK we might have already started national screening for autism (see here) is complementary to that referral model. This model also pools money and resources together. I might add that the increasing moves to incorporate telemedicine and technology into autism assessments should also be accelerated (see here for example).

Insofar as the support and information provided to parents of newly diagnosed children or indeed, adults finding themselves with an autism diagnosis, I'd like to think that there are already some good measures in place to answer the question: where next? Here in the UK, most people will probably be referred to the National Autistic Society (NAS) as a start. They have some very detailed information about many aspects of autism and have been a mainstay for many, many years. That being said, they are not the only provider of information. I've always been under the impression that for many parents at least, seeking out other parent-based groups perhaps on a more local level has also been important to them. Putting any politics aside, it is not beyond current capability that a list of various agencies and groups could be provided to the parents of newly diagnosed children or newly diagnosed adults at those regional centres carrying further information. This could cover many topics including what educational and financial benefits people are entitled to.

Insofar as the idea of 'empowered but alone' mentioned by Carlsson et al there are some suggestions that can be made here. Not least is a strengthening of the idea that local-level support is a key area requiring more investment. As an example of a resource near where I am, we have services such as this. With a little more investment, I'd like to think that such resources could again be rolled out on a more national scale. Combined also with further training and investment in more on-line resources (including that covering social media [3]) and I'd like to think some small changes could make some big differences to families. The idea also of asking families and their children what they need and how it might be best delivered might also be a rather good idea.

And such support shouldn't just stop as and when the assessment/diagnostic procedure is completed...

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[1] Carlsson E. et al. Negotiating knowledge: parents' experience of the neuropsychiatric diagnostic process for children with autism. Int J Lang Commun Disord. 2016 Feb 1.

[2] Crane L. et al. Experiences of autism diagnosis: A survey of over 1000 parents in the United Kingdom. Autism. 2016 Feb;20(2):153-62.

[3] Mohd Roffeei SH. et al. Seeking social support on Facebook for children with Autism Spectrum Disorders (ASDs). Int J Med Inform. 2015 May;84(5):375-85.

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Carlsson E, Miniscalco C, Kadesjö B, & Laakso K (2016). Negotiating knowledge: parents' experience of the neuropsychiatric diagnostic process for children with autism. International journal of language & communication disorders / Royal College of Speech & Language Therapists PMID: 26833425

On the question of a 'real' increase in cases of autism

A quote to begin: "Increased ASD [autism spectrum disorder] diagnosis may partially reflect [an] increase in rates of behaviour associated with ASD and/or greater parent/teacher recognition of associated behaviours."

That was a primary finding reported by Ginny Russell and colleagues [1] (open-access) who set about to "confirm an increase in parent-reported ASD diagnosis at age 7 in the UK between two time points (two population-based cohorts from 1998/1999 and 2007/2008)" among other things. Their findings were based on the examination of 2 UK birth cohorts: the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Millennium Cohort Study (MCS). As per other entries on ALSPAC (see here) and the MCS (see here) respectively, these two initiatives continue to give as a function of their large participant numbers and longitudinal status.

Russell et al threw their research hat into one of the more important autism debates in recent times on whether the quite extraordinary increase in cases of autism being reported (see here) is representative of a real increase or solely down to variables such as changing diagnostic criteria or diagnostic substitution or just better awareness of autism or some combination of these and other factors. My view, if you want it, is that the increase is likely due to many different factors operating in different parts of the world, but at least some of the rise is probably going to be real (see here). Why else would we have headlines such as this one - see here - and reports that autism spectrum assessment facilities "anticipating 1,500 children coming each year forward to autism services" are faced with double that amount? Did we miss so many children in years gone by? The associated issue of waiting times of up to nearly 2 years to be seen and assessed (even 6 YEARS in some cases) is nothing short of a modern day tragedy given what's coming out on the [peer-reviewed] topic of early diagnosis and the value of early intervention (see here). We might do well to listen more to parents on the topic of their own children I might add (see here).

Anyhow, Russell and colleagues set about looking at "parent-reported ASD diagnosis" in the ALSPAC and MCS groups, using a line of questioning not a million miles away from that used in the latest 1 in 45 [estimated] prevalence on autism in the United States (see here). Further: "To validate parent-reported diagnosis of ASD, parent report of an autism diagnosis was checked against the medical report of clinical ASD diagnosis" in at least one of the cohorts (ALSPAC). And: " The sensitivity of parent report in identifying medical diagnosis was 95% and the specificity was 99%, indicating it was a good but not perfect indicator of clinical diagnosis."

Behavioural traits associated with autism were also assessed by teacher and parent report. Indeed, we are told that derived from the various measures employed across the study, a "composite autism-type trait score (CATS)" was built up that "resulted in 4530 children with CATS scores in ALSPAC (56% of the age 7 sample) and 11 210 in MCS (81% of the age 7 sample)."

Results: almost 1.1% of the 1998 ALSPAC cohort had an ASD diagnosis. This contrasted with approaching 1.7% of the 2008 MCS participants; a not-insignificant step-up. Likewise those CATS scores also seemed to suggest a disparity between the different years covered by the different cohorts: 4.2% of the ALSPAC cohort "fell in the high CATS category" defined as having "poor communication, was less able to sustain peer relationships, and/or was afraid of new situations and/or did not share easily or empathise well." For the later MCS cohort, 6.8% were similarly coded into that high CATS category; again something potentially significant to see.

One might quibble about the use of a composite score (CATS) to describe the behaviours of autism when so many instruments can make claim to this purpose but as the authors comment "no such measures are presently available across UK population cohorts" at the times of sampling. I might add that this is likely to change as new measures are (knowingly or unknowingly) rolled out across parts of the United Kingdom (see here). The authors are also relaxed on CATS "representing autism" instead choosing to suggest that CATS 'characterises' facets of autism but "is not a validated ASD measure." Bear these details in mind by all means.

But still I find these results to be really quite important and crying out for further investgation. As per other discussions on the topic of diagnosis vs. "the autism symptom phenotype" (see here) the peer-reviewed literature in this area is not totally one-way. But for anyone shouting about all the increase in cases of autism purely being down to administrative factors, I'd suggest that you might need to look again at the collected data. And that's not also to say that children presenting with autism/autistic traits are correctly identified all the time [2]...

Now, if one does accept that there is at least a partial 'real' increase in the number of cases of autism, how about edging closer to the idea that genes and environment might [variably] work together [3] to bring someone to a diagnosis of autism?

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[1] Russell G. et al. Changes in diagnosis rates and behavioural traits of autism spectrum disorder over time. BJPysch Open. 2015; 1: 110-115.

[2] Russell G. et al. Identification of children with the same level of impairment as children on the autistic spectrum, and analysis of their service use. J Child Psychol Psychiatry. 2010 Jun;51(6):643-51.

[3] Charman T. & Chakrabarti B. Commentary: Not just genes - reclaiming a role for environmental influences on aetiology and outcome in autism. A commentary on Mandy and Lai (2016). J Child Psychol Psychiatry. 2016 Mar;57(3):293-295.

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Russell, G., Collishaw, S., Golding, J., Kelly, S., & Ford, T. (2015). Changes in diagnosis rates and behavioural traits of autism spectrum disorder over time British Journal of Psychiatry Open, 1 (2), 110-115 DOI: 10.1192/bjpo.bp.115.000976

C-reactive protein and late onset bipolar disorder

Prospective study, roughly defined as the study of a cohort free of any 'outcomes of interest' at the time of enrolment are an important part of the scientific landscape. Granted, they are typically expensive to do and often mean that researchers have to wait literally years for a particular outcome to occur, but when the data does start to roll in, they can be goldmines of information.

With that in mind, I'd like to [briefly] bring the findings reported by Marie Kim Wium-Andersen and colleagues [1] to your attention and the suggestion that under a prospective study design: "Elevated CRP [C-reactive protein] is associated with increased risk of late-onset bipolar disorder in the general population." This research group, who have some research form [2] when it comes to the examination of the pentraxin that is CRP - a chemical produced by the liver that increases in response to systemic inflammation - looked at data from almost 80,000 people living in Denmark on this occasion. They concluded that: "Elevated levels of CRP were associated both cross-sectionally and prospectively with late-onset bipolar disorder."

Although this is important data, I draw back from the universal suggestion that CRP is a primary 'cause' of bipolar disorder on the basis of this study and previous notes from other work by this group [3]. Indeed on that other occasion looking at CRP in relation to depression (based on the same cohort), the bottom line was that: "Elevated CRP was associated with increased risk of depression in individuals in the general population, but genetically elevated CRP was not. This indicates that CRP per se is not a causal risk factor for depression." That time as this, the examination of genotypes that may genetically predispose to elevated levels of CRP [4] was an additional important part of the analysis.

I have talked previously on this blog about immune alterations being potentially important to [some] bipolar disorder (see here). This seems to fit with a wider appreciation of the role of inflammation or response to inflammation in psychiatric circles (see here). Setting the Wium-Andersen results in that context reiterates that inflammation is probably important to cases of bipolar disorder if not the only 'causal' factor. That specific sites of inflammation may also be pertinent (see here) is worth noting, as is the idea that treating inflammation (whatever that might involve) could be a consideration for at least some (see here) based on more general research on depression. Indeed, I'm minded to suggest that the use of physical activity strategies (see here) should perhaps be given more prominence as a first-line intervention than it already is bearing in mind my blogging caveat about not giving medical or clincal advice. And this might stand just as well when bipolar disorder is comorbid to other diagnoses too (see here)...

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[1] Wium-Andersen MK. et al. Elevated C-reactive protein and late-onset bipolar disorder in 78 809 individuals from the general population. Br J Psychiatry. 2015 Aug 6. pii: bjp.bp.114.150870.

[2] Wium-Andersen MK. et al. Elevated C-reactive protein levels, psychological distress, and depression in 73, 131 individuals. JAMA Psychiatry. 2013 Feb;70(2):176-84.

[3] Wium-Andersen MK. et al. Elevated C-reactive protein, depression, somatic diseases, and all-cause mortality: a mendelian randomization study. Biol Psychiatry. 2014 Aug 1;76(3):249-57.

[4] Ancelin ML. et al. C-reactive protein gene variants: independent association with late-life depression and circulating protein levels. Transl Psychiatry. 2015 Jan 20;5:e499.

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Wium-Andersen MK, Ørsted DD, & Nordestgaard BG (2015). Elevated C-reactive protein and late-onset bipolar disorder in 78 809 individuals from the general population. The British journal of psychiatry : the journal of mental science PMID: 26250741

Lower autism rate under DSM-5

"[The] Rate of autism spectrum disorder diagnosis was significantly lower under the recently implemented DSM-5 criteria."

The results reported by Michelle Hartley-McAndrew and colleagues [1] won't be a surprise to many of those who've been following the literature on transitioning from DSM-IV to DSM-5 criteria with autism diagnosis in mind. Indeed, I've covered the topic a few times on this blog (see here) and specifically the idea that "between 50 and 75% of individuals will maintain diagnoses" but that "the greatest decreases [were] among high-functioning populations with IQs over 70 and/or previous diagnoses of PDD-NOS or Asperger's disorder" as reported by Smith and colleagues [2] (their words not mine).

Hartley-McAndrew et al report results based on a chart review of participants attending an autism spectrum disorder (ASD) clinic. Looking at participants diagnosed with an ASD between 2010 - May 2013 using DSM-IV criteria and those diagnosed between June 2013 - June 2015 using DSM-5 criteria the authors report that "the 2013 to 2015 rate of autism spectrum disorder diagnosis (39%) was significantly lower (p<0.01) than the 2010- May 2013 sample years rate (50%)." So, unless something really dramatic has happened to the presentation of autism over those years, the stricter DSM-5 criteria employed is indeed impacting on the autism (prevalence) rate.

Following on from data (with appropriate caveats) suggesting that the rate of autism in parts of the world might be nearing 1 in 45 children (see here), the full extent of any effects from the DSM-5 change-over are not likely to be seen for some time as word continues to spread about DSM-5 (and bearing in mind that DSM is not the only diagnostic schedule around). With the cold dispassionate science spectacles on, one might see an interesting experiment emerging from the DSM transition as to the extent that the expanded diagnostic criteria of DSM-IV is represented in the autism rate as DSM-5 continues to become mainstream. I might also add that analysis of diagnostic movement to the category social communication disorder (SCD) - the unspoken 'catch-all' diagnostic category also included in DSM-5 - is likely to aid studies into how at least part of the quite massive increase in cases of autism was due to the way the condition was defined.

But then there are the questions: what if the autism prevalence rate more generally continues to rise? And what also will happen to rates of conditions such as attention-deficit hyperactivity disorder (ADHD) under DSM-5 (see here) in light of the increasing appreciation of such comorbidity quite frequently appearing when it comes to autism (see here)? I have a few hunches but let's see how this plays out.

And since we're on the topic of DSM-5 and autism, I'll point you in the direction of the 'Concise history of Asperger syndrome' review by Barahona-Corrêa & Filipe [3] (open-access) for some additional reading.

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[1] Hartley-McAndrew M. et al. Rates of Autism Spectrum Disorder Diagnosis under the DSM-5 criteria compared to DSM-IV-TR criteria in a Hospital Based Clinic. Pediatric Neurology. 2016. Jan 18.

[2] Smith IC. et al. The Effects of DSM-5 Criteria on Number of Individuals Diagnosed with Autism Spectrum Disorder: A Systematic Review. J Autism Dev Disord. 2015 Aug;45(8):2541-52.

[3] Barahona-Corrêa JB. & Filipe CN. A Concise History of Asperger Syndrome: The Short Reign of a Troublesome Diagnosis. Front Psychol. 2016 Jan 25;6:2024.

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Hartley-McAndrew, M., Mertz, J., Hoffman, M., & Crawford, D. (2016). Rates of Autism Spectrum Disorder Diagnosis under the DSM-5 criteria compared to DSM-IV-TR criteria in a Hospital Based Clinic Pediatric Neurology DOI: 10.1016/j.pediatrneurol.2016.01.012

Behavioural outcomes in autism following exercise

It's our birthday today (this blog I mean). We've reached the ripe old age of 5. Many happy returns Questioning Answers. According to some people (one person anyway) "Those who can, publish. Those who can't, blog". Personally, I enjoy doing a bit of both and when it comes to peer-reviewed science, quantity does not always trump quality. That's my excuse anyway.

And onwards...

Today I'm talking about the paper by Emily Bremer and colleagues [1] who set out to "systematically search and critically analyse the literature pertaining to behavioural outcomes of exercise interventions for individuals with autism spectrum disorder aged ⩽16 years."

Researchers concluded that pretty consistently, various exercise interventions "can result in improvements to numerous behavioural outcomes including stereotypic behaviours, social-emotional functioning, cognition and attention." At the very least, adverse side-effects and harms were minimal and it goes without saying that any sort of physical activity is normally quite a good thing anyway. The sorts of activity included in the review ranged from swimming to yoga/dance and quite a bit in-between. Further: "Horseback riding and martial arts interventions may produce the greatest results with moderate to large effect sizes, respectively."

Martial arts in particular cutting the scientific mustard? Well, I'm impressed. Indeed I've said as much about the use of martial arts such as karate for autism before (see here and see here) realising that certain aspects of the discipline such as kumite might not initially be to everyone's taste. That being said, karate and other martial arts might tend to instil a degree of confidence in their practitioners [2], so even those who might not be natural-born 'fighters' might eventually develop a liking (and talent) for this side of the activity. A sprinkling of competition can also sometimes be a good thing (head to 2m36s to see how kata can translate into action)...

Of course the authors are correct in their assertion that further: "well-controlled designs, standardized assessments, larger sample sizes and longitudinal follow-ups is necessary". I might add that a focus on the biology associated with using particular exercise regimes as well as the behavioural effects might also be a good idea so as to potentially ascertain what it is about particular sports/pastimes that seem to produce the behavioural outcomes noted.

I think more people are cottoning on to the idea that sports and physical activity might hold lots of different promises for many people with autism. Most people on the autism spectrum do not lack the capacity to engage in sports and exercise (see here) but again, it tends to be about the provision of opportunities and putting forward a good case as to why taking up a physical activity might be a good thing (see here). I say this keeping in mind individual tastes.

Finally, with again the martial arts in mind, at least one of the governing bodies here in Blighty is starting to open doors. The question is: what's stopping you? Kiai!

Music to close, and given some enthusiasm from some of my brood for Ferris Bueller's Day Off, Yello and Oh Yeah...

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[1] Bremer E. et al. A systematic review of the behavioural outcomes following exercise interventions for children and youth with autism spectrum disorder. Autism. 2016. Jan 28.

[2] Chen MA. & Cheesman DJ. Mental toughness of mixed martial arts athletes at different levels of competition. Percept Mot Skills. 2013 Jun;116(3):905-17.

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Bremer, E., Crozier, M., & Lloyd, M. (2016). A systematic review of the behavioural outcomes following exercise interventions for children and youth with autism spectrum disorder Autism DOI: 10.1177/1362361315616002

Long-term outcome and autism continued

"The long-term outcome of almost half of all individuals with autistic disorders is poor."

I know that opening sentence doesn't make great reading, but when reported as part of the "systematic review and meta-analysis of studies reporting on the overall outcome in terms of a global measure of adjustment in children with autistic disorders followed up in adolescence and adulthood" by Steinhausen and colleagues [1], there are potential lessons to be learned. That some 20% of those participants included in the various studies by Steinhausen et al were said to have a "good outcome" offers a template for further investigation as to how science and practice might increase such an outcome status among the wider autism spectrum.

Outcome is a bit of a fuzzy term but is something that has been discussed before on this blog (see here). In that instance as in this, the idea that there is (a) "strong evidence for heterogeneity" when it comes to long-term outcome in autism and (b) "little is known about the pathways and predictors" of outcome, are important points. I might also add that overall outcome as gauged by factors such as living arrangements, degree of independence and/or education/employment status does not automatically mean that a person leads a 'happy' or 'unhappy' life. Even those who gain employment for example, might not necessarily have a great quality of life (see here). Likewise a dependency on others for day-to-day support is to expected for some people on the autism spectrum, particularly for those where routine tasks cannot be accomplished alone or where core and/or comorbid issues can be sometimes utterly disabling [2]. This does not mean a person is necessarily unhappy. I'm adverse to the idea that there is one-size-fits-all instruction manual for 'good' long-term outcome for everyone on the autism spectrum just as there isn't for those not on the autism spectrum.

With all that in mind, the area of outcome and autism and specifically the idea that we know little about the 'pathways and predictors' of it is perhaps a slight misnomer. If we happen to look at that group of people who have been headed under the label of 'optimal outcome' we can see important signals emerging (see here) including the idea that early communicative behaviours and general cognitive ability might be important behavioural variables for later outcome with autism in mind. I say this in the context of newer research also [3]. The suggestion that such cases of optimal outcome might have implications for psychiatric comorbidity outside of the presentation of core autism (see here) will no doubt also impact on perceptions/experiences of long-term outcome.

Although I don't want to get too bogged down in this area, I'd like to think that there are a few, quite simple, accommodations that could be made to improve overall long-term outcome for people on the autism spectrum. From a clinical perspective, some of the first things I'd like to see are moves to addressing the numerous health inequalities that seem to be popping up quite frequently with autism in mind and some rather distressing news on the extreme that is early mortality for example (see here and see here). Preferential screening for potentially 'over-represented' comorbidity might be a good start (see here and see here) and importantly, treating/managing what can be treated as and when it is identified (see here). The days of saying that every ailment experienced by a person on the autism spectrum is 'just down to their autism' are passing by very, very quickly.

Enabling individuals on the autism spectrum to further participate in society is perhaps another route towards better long-term outcome. I've talked before about research suggesting that greater societal inclusion is quite a big desire for quite a few people on the autism spectrum (see here) and what it might mean to them in terms of outcome. Of course this includes aspects such as getting a job (and not necessarily a job in the technology industry! [4]) and participating in activities such as sports or hobbies relevant to a person. More than that however are the opportunities to make and have friends and perhaps even meeting that special someone. If we've learned anything generally about favourable long-term outcome, it is that social and familial support are also paramount.

I'd finally like to add in the findings reported by Gotham and colleagues [5] and the notion that "understanding and acceptance of adults with ASD [autism spectrum disorder]" might also be something pretty important to outcome. As per the suggestion from Gotham on "calls for survey and qualitative research to ascertain what “understanding and acceptance” mean to individuals with ASD and their families" I do think more needs to be known about what expectations and requirements are included under such fuzzy terminology. In these days when autism awareness has its own day many people will know something about autism even if it is just sweeping generalisations (see here). Of course more needs to be done to inform the masses about how 'if you've met one person with autism, you've met one person with autism' and the like, but over and above that issue is a question to put out there: what more can be done to improve elements related to long-term outcome in autism?

And (once again) as if to prove a point...

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[1] Steinhausen HC. et al. A systematic review and meta-analysis of the long-term overall outcome of autism spectrum disorders in adolescence and adulthood. Acta Psychiatr Scand. 2016 Jan 13.

[2] Posserud M. et al. Autism traits: The importance of “co-morbid” problems for impairment and contact with services. Data from the Bergen Child Study. Research in Developmental Disabilities. 2016. Jan 27.

[3] Eigsti IM. et al. Language comprehension and brain function in individuals with an optimal outcome from autism. Neuroimage Clin. 2015 Dec 2;10:182-91.

[4] Lorenz T. & Heinitz K. Aspergers – Different, Not Less: Occupational Strengths and Job Interests of Individuals with Asperger’s Syndrome. Dichter GS, ed. PLoS ONE. 2014;9(6):e100358.

[5] Gotham K. et al. Characterizing the daily life, needs, and priorities of adults with autism spectrum disorder from Interactive Autism Network data. Autism. 2015 Oct;19(7):794-804.

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Steinhausen HC, Mohr Jensen C, & Lauritsen MB (2016). A systematic review and meta-analysis of the long-term overall outcome of autism spectrum disorders in adolescence and adulthood. Acta psychiatrica Scandinavica PMID: 26763353

Toxicant exposures and Gulf War Syndrome

Of the various directions away from autism research that I tend to take on this blog, discussions based on the collected [peer-reviewed] research literature on Gulf War Syndrome will always retain a special interest (see here). Not least because here we have a group of some of our bravest men and women who went out to liberate Kuwait in the early 1990s and who came back home in an often quite appalling state and thereafter basically left to rot.

I know that might all sound a little dramatic but after having met one or two veterans down the years and seen first hand how their health and well-being has been affected following their deployment to the Persian Gulf all those years ago I'm just telling it like it is. As much due to political reasons as scientific ones, the plight of these veterans - who really only want to know what happened to them and some acknowledgement that something 'did' happen to them outside of it being wholly 'psychosomatic' - has been the source of much controversy and debate down the years. Now at last it appears that a consensus based on the available science might have been reached [1]: "the research to date supports the conclusion that veterans are suffering from a "persistent pathology due to chemical intoxication.""

The paper by Roberta White and colleagues (someone not unfamiliar to Gulf War research) carries that conclusion and is open-access for all to read. Following a lengthy review of the various exposures that faced veterans and the likelihood of them (adversely) affecting their health, the authors detailed a few 'bottom lines'.

To quote:

"Between one-fourth and one-third of deployed GW [Gulf War] veterans are affected by a disorder characterized by chronic symptoms involving multiple body systems; this condition is best identified by the term GWI [Gulf War Illness]."

Further:

"This disorder was caused by toxicant exposures, individually or in combination, that occurred in the GW theater. At present, research most clearly and consistently links pesticide and PB [pyridostigmine bromide] exposures to GWI, while exposures to low-level nerve gas agents, contaminants from oil well fires, multiple vaccinations, and combinations of these exposures cannot be ruled out."

And also:

"Further research into the mechanisms and etiology of the health problems of GW veterans is critical to developing biomarkers of exposure and illness and preventing similar problems for military personnel in future deployments; this information is also critical for developing new treatments for GWI and related neurological dysfunction."

I'm sure you'll agree that these are pretty important conclusions. That also the authors talk about the potential overlap between GWI and other states specifically related to exposure to organophosphate (pesticides) such as during pesticide application (see here) or during sheep dipping (those with so-called dippers flu) is another important element. I say this not to somehow come down too hard on organophosphate (OP) pesticides, which serve an important purpose in modern agriculture and the like, but merely to reiterate that (a) caution is needed in their handling and use, and (b) they are chemically-speaking, not a million miles away from some of the most toxic nerve agents the world has ever seen. Indeed, with all the talk about Zika virus these past weeks (see here) I'm minded to suggest that one might need some additional controls in place to ensure the safe use of OPs when controlling the insect carrier (see here).

Bundled alongside the various chemical exposures - and other events [2] such as exposure to depleted uranium - that might be linked to symptoms is the added suggestion that "multiple vaccinations" may have also played a role in the presentation of the condition for some [3]. When I say vaccinations, the data suggests that these weren't just routine vaccinations against your typical childhood diseases, but rather included those aimed at a slightly more unusual disease set such as anthrax and plague (see here). The jury is still out on the extent to which these agents (singularly or combined) might have contributed to symptoms but I'm minded also to bring in the concept of ASIA (‘autoimmune (auto-inflammatory) syndrome induced by adjuvants’) that has been mentioned with GWI in mind (see here) as potentially being relevant.

Of course, more research is indicated on many aspects identified by White et al including the idea of some overlap between GWI and the presentation of chronic fatigue syndrome (CFS) [4] being careful with how wide we cast the CFS diagnostic net [5]. Alongside, perhaps one might think that an apology or two to some of our brave veterans wouldn't also go amiss from Government and others following various comments made down the years about the nature of their illness.

And for those who still might scoff at the idea of the 'toxic' effects of war, the chemical legacy of another campaign still continues to haunt some to this day...

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[1] White RF. et al. Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment. Cortex. 2016; 74: 449-475.

[2] McDiarmid MA. et al. Health effects of depleted uranium on exposed Gulf War veterans. Environ Res. 2000 Feb;82(2):168-80.

[3] Unwin C. et al. Health of UK servicemen who served in Persian Gulf War. Lancet. 1999 Jan 16;353(9148):169-78.

[4] Ismail K. et al. Chronic fatigue syndrome and related disorders in UK veterans of the Gulf War 1990-1991: results from a two-phase cohort study. Psychol Med. 2008 Jul;38(7):953-61.

[5] Jason LA. et al. Unintended Consequences of not Specifying Exclusionary Illnesses for Systemic Exertion Intolerance Disease. Diagnostics (Basel). 2015 Jun 23;5(2):272-86.

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White RF, Steele L, O'Callaghan JP, Sullivan K, Binns JH, Golomb BA, Bloom FE, Bunker JA, Crawford F, Graves JC, Hardie A, Klimas N, Knox M, Meggs WJ, Melling J, Philbert MA, & Grashow R (2016). Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment. Cortex; a journal devoted to the study of the nervous system and behavior, 74, 449-75 PMID: 26493934

9-12% of those with autism also have a tic disorder

The title of this brief post reflects the findings reported by Efrosini Kalyva and colleagues [1] who undertook a review looking at the co-occurrence of autism spectrum disorder (ASD) and Tourette syndrome (TS) including the presence of tic disorder (part and parcel of the diagnosis of TS). The authors concluded that although the overlap rates might, to some degree, be tied into the "level of ASD severity" there may be quite a bit more to do research-wise to look at the hows and whys of the overlap.

I was not surprised to read such results. As per musings on this topic before on this blog (see here) tics - vocal or physical that can be both simple and complex - have been reported in about one in ten children and young adults diagnosed with ASD. Further: "Tic awareness is limited in ASD." [2] I might add that as and when autism appears with certain other comorbidities, the likelihood of tic disorder appearing jumps even further (see here).

Kalyva et al also suggested that anywhere between 4-20% of those with autism may also present with TS (reiterating the issue of 'level of ASD severity' as being a mediating factor). Again, one can only assume that such reporting should have implications for preferential screening where autism is diagnosed and onwards an appropriate assessment of the necessity of intervention (and not just of the pharmacological kind). I might also add that to talk about autism and TS appearing together does not necessarily mean that this reflects a homogeneous phenotype [3]. The concept of 'autism plus' [4] marches on...

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[1] Kalyva E. et al. A review of co-occurrence of autism spectrum disorder and Tourette syndrome. Research in Autism Spectrum Disorders. 2016; 24: 39-51.

[2] Kahl U. et al. Tic Phenomenology and Tic Awareness in Adults With Autism. Movement Disorders Clinical Practice. 2015. March 30.

[3] Zappella M. Early-onset Tourette syndrome with reversible autistic behaviour: a dysmaturational disorder. Eur Child Adolesc Psychiatry. 2002 Feb;11(1):18-23.

[4] Posserud M. et al. Autism traits: The importance of "co-morbid" problems for impairment and contact with services. Data from the Bergen Child Study. Res Dev Disabil. 2016 Jan 27. pii: S0891-4222(16)30002-6.

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Kalyva, E., Kyriazi, M., Vargiami, E., & Zafeiriou, D. (2016). A review of co-occurrence of autism spectrum disorder and Tourette syndrome Research in Autism Spectrum Disorders, 24, 39-51 DOI: 10.1016/j.rasd.2016.01.007

A familiar message... maternal immune disease and offspring ADHD risk

"Several maternal somatic diseases with immune components were found to increase the risk of ADHD [attention-deficit hyperactivity disorder] in offspring."

That was the research bottom line reported by Johanne Instanes and colleagues [1] following their analysis of some 48,000 people with ADHD (well, "receiving ADHD medication during the years 2004-2012") compared against over 2.2 million control individuals (er, not receiving ADHD medication). Indeed, once again those very useful Scandinavian registries (see here for example) keep on giving in research terms, this time based on "data from longitudinal Norwegian registers."

The sorts of diagnosis included under the heading of "chronic somatic diseases with immune components" that were found to be related to offspring ADHD ranged from multiple sclerosis to type 1 diabetes. Even taking into account potentially important variables such as parental ADHD and gestational age did little to alter the odds ratios reported; although analyses by gender did seem to produce some potentially interesting results when it came to maternal asthma for example, and boy vs. girl offspring risk of ADHD. The authors conclude that: "insight into the mechanisms behind these relationships could enhance our understanding of the etiology of ADHD."

I titled this post 'a familiar message' because the data reported by Instanes et al seems to follow a trend of large population-based inquiry reporting offspring developmental outcomes when certain maternal immune-related diagnoses/pathology are present. Y'know things like a potentially slightly increased risk of offspring autism in the presence of maternal thyroid autoantibodies (see here) or how the appearance of psoriasis in one or other parents might also play a role (see here). Yes, correlation is not the same as causation but let's face it, the involvement of the immune system in at least some cases of autism is hardly a new thing (see here for example). Indeed, let us not forget 'MAR autism' (see here) (as many people seem to have).

That ADHD is also one of the most common overlapping diagnoses associated with autism (see here) further extends the idea that maternal immune related features (potentially present during some critical period during pregnancy/gestation) might extend to a number of diagnoses. Nature also tends to blur diagnostic boundaries (see here).

What's more to say? Well, having specifically mentioned asthma already, I was quite interested in the data suggesting that maternal asthma might be something to look further at with offspring outcomes in mind on the back of other data (see here). More and more science is also realising that asthma and ADHD are not uncommon bedfellows (see here and see here) and given the suggestion of heredity strongly governing the onset of asthma (see here) one can perhaps see how this data might strengthen the possibility of a wider association. Remember, genes suggested to play a role in specific conditions are generally not confined to one diagnosis (see here) as we've seen in recent times [2]. Dare I also mention how the use of certain medicines during pregnancy might also have a bearing on both the presentation of asthma [3] (see here also) and perhaps even more behavioural indicators (see here) too?

Further research is of course indicated.

Music: Viola Beach - Swings and Waterslides. RIP.

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[1] Instanes JT. et al. Attention-Deficit/Hyperactivity Disorder in Offspring of Mothers With Inflammatory and Immune System Diseases. Biol Psychiatry. 2015 Dec 9. pii: S0006-3223(15)01034-3.

[2] Hagenaars SP. et al. Shared genetic aetiology between cognitive functions and physical and mental health in UK Biobank (N=112 151) and 24 GWAS consortia. Mol Psychiatry. 2016 Jan 26.

[3] Magnus MC. et al. Prenatal and infant paracetamol exposure and development of asthma: the Norwegian Mother and Child Cohort Study. Int J Epidemiol. 2016 Feb 9. pii: dyv366.

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Instanes JT, Halmøy A, Engeland A, Haavik J, Furu K, & Klungsøyr K (2015). Attention-Deficit/Hyperactivity Disorder in Offspring of Mothers With Inflammatory and Immune System Diseases. Biological psychiatry PMID: 26809250