"the incidence of ADHD, ASD, and DD significantly increased after TBI events in early childhood"

TBI mentioned in the title of this post refers to traumatic brain injury, and represents the 'target variable' examined by Hsuan-Kan Chang and colleagues [1] in the context of rates of "attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and developmental delay (DD)."

Consistent with various other research published by this authorship group, the fantastic but sadly now defunct National Health Insurance Research Database (NHIRD) in Taiwan was the resource used by Chang et al in pursuit of their research goal. And the participant numbers under study reflected the use of the NHIRD: "A total of 7,801 and 31,204 children were enrolled in the TBI and control cohorts, respectively."

As well as instances of TBI being listed in the NHIRD "from 1998-2008", researchers also had access to "the incidence of subsequent ADHD, ASD, or DD (according to ICD-9 criteria)." They observed that: "The TBI cohort exhibited a higher incidence of subsequent ADHD, ASD, or DD than the controls" and that said developmental diagnoses tended to be made "at a younger age compared with the controls" (non-TBI controls). They concluded that TBI seemed to increase the risk of each developmental diagnosis and that "severe TBI, repeated TBI events, and TBI at a younger age" were all (variably) potentially important factors for the labels.

This is interesting and thought-provoking research. It does require some 'treading carefully' sentiments; not least with the idea that within the huge heterogeneity and variability of labels such as ADHD and autism (ASD), TBI *might* be a route or part of a possible route towards a diagnosis. Whilst not discounting the idea that sub-clinical signs and symptoms of developmental disorders could actually put someone at greater risk for TBI (see here for example), the possibility that TBI 'might lead to' a developmental diagnosis should not be shied away from. Indeed, other independent findings might also be important (see here). I say that mentioning that TBI is a general term that says nothing about the reason for the injury, the type of injury or what specific part of the brain may be affected. If one however takes autism as an example, it's not beyond the realms of possibility that certain TBIs could 'mimic' effects seen in other examples of 'acquired autism' where brain injury is part-and-parcel of the clinical picture (see here and see here). Indeed, similar sentiments have been expressed in relation to ADHD too (see here).

Whatever the relationship and mechanisms involved, the Chang findings imply that further investigations are needed in this area. Also, far greater efforts need to go into first preventing and then managing TBI...

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[1] Chang HK. et al. Traumatic Brain Injury in Early Childhood and Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder: A Nationwide Longitudinal Study. J Clin Psychiatry. 2018 Oct 16;79(6). pii: 17m11857.

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Establishing environmental exposures as risk factors for bipolar disorder: Difficult.

The findings reported by Ciro Marangoni and colleagues [1] made for some interesting reading recently and their systematic review of longitudinal studies looking at the various environmental exposures put forward as possible risk factors pertinent to the development of bipolar disorder (BD).

Trawling through the peer-reviewed material on this topic, the authors were able to 'clump' the various proposed risk factors into one of three categories: "neurodevelopment (maternal influenza during pregnancy; indicators of fetal development), substances (cannabis, cocaine, other drugs - opioids, tranquilizers, stimulants, sedatives), physical/psychological stress (parental loss, adversities, abuses, brain injury)."

They did not however, report the presence of any specific 'smoking gun' on the basis of their investigations, concluding that: "Only preliminary evidence exists that exposure to viral infection, substances or trauma increase the likelihood of BD." That also the various risk categories seemed to be 'correlated' with various other psychiatric and/or behavioural labels is also an important point to make in these days of overlap and RDoC.

I personally am not surprised by these results. Appreciating that diagnostic labels do not equal homogeneous groups, and that just as when defining the genetics of something like BD, so defining the non-genetic correlates is an equally difficult task, studies of this type remind us just how complicated and individual the paths are bringing someone to such a clinically-relevant label. I say this with the understanding that just because an specific environmental (or non-environmental) risk factor might not be generalisable to all BD does not mean it can't exert a more pronounced effect in smaller groups or individuals. Lessons from other labels teach us this (see here).

Whilst important to understand whether there may be specific environmental exposures that might be more generally linked to an enhanced risk of developing BD, I do believe that the [research] future lies in a couple of other areas looking at: (a) how many different types of BD are there and what are the 'other' conditions/labels potentially related? (b) what does the biology of BD look like and does it include some common targets with other labels? and (c) outside of the array of interventions put forward for managing symptoms (see here), are there other intervention strategies that might fit with the findings of (a) and (b)?

To close, LEGO do it best...

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[1] Marangoni C. et al. The role of environmental exposures as risk factors for bipolar disorder: A systematic review of longitudinal studies. J Affect Disord. 2016 Jan 1;193:165-174.

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Marangoni C, Hernandez M, & Faedda GL (2016). The role of environmental exposures as risk factors for bipolar disorder: A systematic review of longitudinal studies. Journal of affective disorders, 193, 165-174 PMID: 26773919

Autism secondary to enterovirus encephalitis

"We describe a 32-month-old patient with enteroviral encephalitis confirmed by polymerase chain reaction in cerebrospinal fluid, with unfavorable clinical course with marked developmental regression, autistic features, persistent stereotypes and aphasia". So said the report by Filipa Marques and colleagues [1] describing the course and investigations of a previously healthy girl who initially presented at an emergency department with "fever (39°C) and vomiting" and who subsequently deteriorated and over the course of some some months improved although still meeting "criteria for an autistic spectrum disorder".

Unfortunately the paper is not open-access so I can't link to the complete manuscript. I would however like to pick out a few choice details with some discussion to follow. So:

• Enterovirus encephalitis... as the authors note is "diverse and incompletely understood". Enteroviruses cover quite a bit of area with poliovirus being perhaps the most infamous. The watchwords when it comes to enterovirus encephalitis (which I'll now refer to as EE) are: immune response, cytokine production, "hyperinflammatory syndrome" and onwards the possibility of long-term "neurologic sequelae" including "neurodevelopmental delay, reduced cognitive functioning and learning and behavioral problems".
• The child described in this report seemed to plunge into a state of developmental arrest and regression over the course of a relatively short period of time incurring a "loss of speech, eye contact and sphincter control" during the first few days of her admission to a hospital in Portugal. Even at discharge on day 31 "she maintained developmental regression with autistic features, self-mutilation and persistent stereotypes". 
• The medical work-up for this young girl whilst comprehensively was generally unimpressive in terms of results obtained. "Enterovirus PCR was positive" although "No enterovirus serotype was identified on cerebrospinal fluid and stool specimen cultures". The authors speculate that the serotype may have been one that "usually does not circulate in Europe and therefore could not be identified in available kits". Interestingly, authors were also able to rule out anti-NMDAR (see here) and anti-ganglioside antibodies (see here) as being present.
• Magnetic Resonance Imaging (MRI) and Single-Photon Emission Computed Tomography (SPECT) findings did detect something of a typical pattern of brain findings seen in other cases of EE [2]. I'm not a brain man in respect of being able to expertly describe what the various findings mean but will draw your attention to one sentence: "The progression and distribution of lesions on the MRI scans in our patient seemed to correlate well with clinical severity in the acute phase of the disease".
• There is a better ending to the story of this girl, as the authors note: "she had a favorable outcome with improvement in all skills and developmental quotient enhancement" 17 months after her hospital discharge.
• The authors conclude that their report "provides further evidence that autistic symptoms as well as loss of other developmental skills can emerge following an external event such as infection". 

There is quite a bit to discuss from this report bearing in mind that this was a single case study and as things currently stand at the time of writing, the first occasion that EE has been linked to the presentation of autism in the peer-reviewed literature. I suppose I should start with the concept of regression, that is a loss of previously acquired skills, which has appeared more than once on this blog (see here and see here) and will likely appear a few more times still. It happens. And the Marques paper is pretty good evidence of how dramatically it can appear in some cases of autism.

That also regression, including being linked to the emergence of "autistic features", can come about as a consequence of a viral illness is also important. I'm gonna be talking about congenital cytomegalovirus in relation to autism [3] in a future post so providing another example of a possible link between viruses and autism on top of other more classical correlations [4]. Another angle to this potential connection is that of a 'recovery' of sorts when it comes to behavioural presentation (something Chess also noted in the various studies on congenital rubella and autism). One wonders for example, whether some of those optimal outcomers (see here) for example, might also fall into this virus-related autism onset category?

I'll reiterate that this was a case study and hence I'm not implying that every case of autism which follows a period of regression is going to be due to EE or other viral infection. Remember autisms and the N=1. That being said, there is enough detail in papers such as the one from Marques and other peer-reviewed data to suggest that where children do undergo some sort of regression, quite a bit more clinical inspection might be indicated to rule out a viral or bacterial 'cause' to the onset of any physical or behavioural symptoms. Indeed, whether any clinical findings related to viral / bacterial infection in such cases might guide autism research towards further elucidating underlying physiology...

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[1] Marques F. et al. Autism Spectrum Disorder Secondary to Enterovirus Encephalitis. J Child Neurology. 2014; 29: 708-714.

[2] Shen WC. et al. MR imaging findings of enteroviral encephaloymelitis: an outbreak in Taiwan. AJNR Am J Neuroradiol. 1999 Nov-Dec;20(10):1889-95.

[3] Sakamoto A. et al. Retrospective diagnosis of congenital cytomegalovirus infection in children with autism spectrum disorder but no other major neurologic deficit. Brain Dev. 2014 Apr 22. pii: S0387-7604(14)00094-1.

[4] Chess S. Follow-up report on autism in congenital rubella. J Autism Child Schizophr. 1977 Mar;7(1):69-81.

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Marques F, Brito MJ, Conde M, Pinto M, & Moreira A (2014). Autism Spectrum Disorder Secondary to Enterovirus Encephalitis. Journal of child neurology, 29 (5), 708-714 PMID: 24782421

Sensitizing to gluten?

Actually the title to this post should really read 'sensitising' rather than 'sensitizing' as a function of my Limey status. No mind, today I'd like to introduce you to two pretty unusual papers which I stumbled across in recent times which have the common denominators of (a) both being about gluten and the possible induction of problems with gluten, and (b) both carrying Marios Hadjivassiliou as part of the authorship team. They're both open-access too.

The first paper is by Currie and colleagues* who concluded that: "Alcohol related cerebellar degeneration may, in genetically susceptible individuals, induce sensitization to gluten". The second paper by Ludvigsson & Hadjivassiliou** in a similar vein suggested that there was a: "very small excess risk for future CD [coeliac disease] in individuals with an earlier head trauma".

Why am I talking about these papers you might ask? Well, outside of any autism-gluten research obsession I might have, I was interested to read about how an issue with gluten might come about as a function of an environmental insult; in these cases, alcohol abuse and head injury. Just however before I stray away from the autism-gluten science, the keen reader might have already spotted the name Ludvigsson, Jonas Ludvigsson, as being one and the same lead author on that 'not coeliac disease but something gluten related' paper in relation to cases of autism (see here for some discussion).

I'm not going too heavily into these papers but it strikes me that there are a few possible connections to be made from the cumulative data. Autoimmunity is the source of some speculation in both papers. The Currie paper speculates that: "autoimmunity may have a role to play in the development of ataxia in patients that drink excessively". Ataxia by the way, refers to a group of conditions which affect motor skills. Similarly, L & H (because they both have particularly long surnames) talk about "an autoimmune response against transglutaminases triggered by the brain injury". The transglutaminases (plural) or at least one of them (tTG) have already been talked about on this blog with reference to the process of coeliac (celiac) disease (see here).

That 'development of autoimmunity' suggestion also leads into another potential commonality across these papers: the cerebellum. Part of the brain long thought to be involved in motor control (as well as other cognitive functions), the suggestion is that "antigliadin antibodies may arise after a cerebellar insult rather than being the cause of it per se" in the alcohol study. The head injury paper provides an equally interesting commentary, if a little less 'proven' by results: "head trauma resulting in cerebral and cerebellar insults may trigger autoimmunity against TG6 which in turn may lead in some genetically susceptible individuals, to the development of CD".

If I've got all my factoids correct, there is a rather interesting hypothesis to test from these collected results. Take an immune system which genetically looks a little like that seen in coeliac disease with regards to those HLA-DQ2 and DQ8 heterodimers. Add an environmental insult which in particular, targets the cerebellum or indeed some other part of the brain. For whatever reason, the exposure to that insult starts to do odd things to "normally shielded" self epitopes such as TG6 which "may result in the immune system reacting to self-antigens in the central nervous system ultimately leading to autoimmunity". Gluten just happens to be one of the external agents to which antibodies also start being produced against as self and other start to become mixed up, and hey presto, you're gluten sensitive.

OK, I know there is still much to do in this area of research and by no means should anyone take such a hypothesis as fact at this point in time. Marios Hadjivassiliou has done a lot of work in the area of extra-intestinal presentation of gluten issues (see here for example***) but we're not yet in a position to start definitively linking all the pieces together just yet. That and the differences between the two papers discussed in this post in terms of what was looked at (antigliadin antibodies vs. patient register details for head injury and/or small intestinal biopsy reports) and how participants were examined, means I am to a large extent comparing apples and oranges.

Still, I do find this line of inquiry to be quite fascinating. I'm also thinking back to the paper by Emily Severance and colleagues**** on how infection with the gondii (that's Toxoplasma gondii) in a mouse model might also be able to invoke an immune reaction to gluten (see here for my take of the study). There's more to come on this blog from Dr Severance, but again, speculations on immune activation through the slightly different environmental process of infection translating into a immunological effect against gluten.

But still the possibility of an acquired sensitivity to dietary gluten...

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* Currie S. et al. Alcohol induces sensitization to gluten in genetically susceptible individuals: a case control study. PLoS One. 2013 Oct 15;8(10):e77638.

** Ludvigsson JF. & Hadjivassiliou M. Can head trauma trigger celiac disease? Nation-wide case-control study. BMC Neurol. 2013 Aug 9;13:105.

*** Hadjivassiliou M. et al. Gluten sensitivity as a neurological illness. J Neurol Neurosurg Psychiatry 2002;72:560-563.

**** Severance EG. et al. Anti-gluten immune response following Toxoplasma gondii infection in mice. PLoS One. 2012;7(11):e50991.

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Currie S, Hoggard N, Clark MJ, Sanders DS, Wilkinson ID, Griffiths PD, & Hadjivassiliou M (2013). Alcohol induces sensitization to gluten in genetically susceptible individuals: a case control study. PloS one, 8 (10) PMID: 24204900




Ludvigsson JF, & Hadjivassiliou M (2013). Can head trauma trigger celiac disease? Nation-wide case-control study. BMC neurology, 13 PMID: 23927742